针对宫颈癌的图像引导强度调制放射治疗肠道副作用更少 (12/27/2020)
Image-guided IMRT reduces GI toxicity in cervical cancer
图像引导强度调制放射治疗（intensity-modulated radiation therapy, IMRT）与三维共形放射治疗（3D-CRT）相比，在子宫切除术后接受放射治疗的女性中，导致更少的胃肠道副作用, 仍有相似的疾病控制。
印度的PARCER III期随机试验（NCT01279135）结果提供了第一个这样的证据，在这项研究中，将283例年龄在18至65岁之间，接受过宫颈癌子宫切除术的患者按1：1比例随机分配接受图像引导的IMRT（n = 142）或3D-CRT（n = 141）。 CRT包括在5周内分送的25个组分中的50 Gy，有或没有每周顺铂（40 毫克/平方米）。随后是2份6 Gy的高剂量率近距离放射治疗。 总体上，在图像引导的IMRT臂中有117名患者（占76.5％），在3D-CRT臂中的114名患者（占77％）同时接受了化疗。接受影像引导IMRT的患者中有35（23.5％）接受了常规放疗，接受3D-CRT的患者中有34（23％）接受了常规放疗。 主要终点为≥2级的晚期肠毒性。PARCER使用医生报告的数据。
经过4年的治疗后随访，IMRT组中的19.2％的患者和3D-CRT组中36.2％的患者出现了≥2级的晚期肠毒性（危险比0.53，95％置信区间0.33– 0.83； P <0.01）。在IMRT组中，四年中≥3级晚期肠毒性的发生率为2.0％，在3D-CRT组中为8.7％（危险比0.23，95％置信区间0.06-0.81，P <.01）。治疗组之间的恶心和呕吐发作次数无明显差异。但是，随着时间的推移，其他症状也存在明显差异，IMRT明显优于3D-CRT。这些包括≥2级的急性腹泻（17.2％相比于 27.2％； P = .004），晚期腹胀（14％相比于 28％），肠梗阻（1％相比于7％）以及食欲不振（1％相比于7％）。 与接受3D-CRT的患者相比，接受影像引导IMRT的患者显示2级无毒生存率（78％相比于57％； P = .0009）和3级无毒生存率（97.6％相比于81.6％）显著更高，P = 0.001）。无病生存率相似: 影像引导IMRT的73％相比于3D-CRT的68％； P = .30）。 这是第一项针对宫癌症的研究，显示出新的技术在改善癌症妇女生活质量的作用。
Compared with three-dimensional conformal radiation therapy (3D-CRT), image-guided intensity-modulated radiation therapy (IMRT) results in fewer gastrointestinal side effects while achieving similar disease control in women receiving radiation therapy after hysterectomy. The results of India’s PARCER Phase III randomized trial (NCT01279135) provided the first such evidence. In this study, 283 patients between the ages of 18 and 65 who had undergone hysterectomy for cervical cancer were randomly assigned in 1: 1 ratio to receive image-guided IMRT (n = 142) or 3D-CRT (n = 141). CRT includes 50 Gy of the 25 fractions distributed in 5 weeks, with or without cisplatin (40 mg/m²) per week. This was followed by 2 high-dose brachytherapy of 6 Gy. In total, 117 patients (76.5%) in the image-guided IMRT arm and 114 patients (77%) in the 3D-CRT arm received chemotherapy at the same time. 35 (23.5%) of patients receiving image-guided IMRT received conventional radiotherapy, and 34 (23%) of patients receiving 3D-CRT received conventional radiotherapy. The primary endpoint is late intestional toxicity ≥ grade 2. PARCER study used data reported by doctors.
After 4 years of follow-up, 19.2% of the patients in the IMRT group and 36.2% in the 3D-CRT group had enterotoxicity ≥grade 2 (hazard ratio 0.53, 95% confidence interval 0.33-0.83; P < 0.01). In the IMRT group, the incidence of ≥ grade 3 late enterotoxicity in four years was 2.0%, and in the 3D-CRT group it was 8.7% (hazard ratio 0.23, 95% confidence interval 0.06-0.81, P <.01). There was no significant difference in the number of nausea and vomiting episodes between the treatment groups. However, as time went by, other symptoms were also significantly different, and IMRT is significantly better than 3D-CRT. These included acute diarrhea ≥ grade 2 (17.2% vs. 27.2%; P = .004), late abdominal distension (14% vs. 28%), bowel obstruction (1% vs. 7%), and loss of appetite (1% vs. 7%). Compared with patients who received 3D-CRT, patients who received image-guided IMRT showed a grade 2 non-toxic survival rate (78% vs. 57%; P = .0009) and a grade 3 non-toxic survival rate (97.6% vs. 81.6%; P = 0.001). Disease-free survival rate was similar: 73% for image-guided IMRT compared to 68% for 3D-CRT; P = .30). This is the first study on cervical cancer, demonstrating the role of advanced technology in improving the quality of life of women.
参考文献 Reference Chopra S e al. ASTRO Annual Virtual Meeting 2020, abstr 2
双特异性分子MGD019在经过多线治疗的实体瘤中有潜在的用途 (12/26/2020)
Dual specific agent has potential activity against solid tumors after multiple-lines of therapy
MGD019是一种四价双特异性DART（dual affinity re-targeting）分子，对PD-1和CTLA-4具有双价。PD-1和CTLA-4作为单克隆组合的双重阻断可提高多种肿瘤类型的疗效。 与抑制PD-1和CTLA-4的单一疗法药物和联合用药相比，MGD019保持了同样的受体阻滞作用。 在表达PD-1和CTLA-4的细胞中（如在肿瘤微环境中发现的细胞），与抗CTLA-4单一疗法和抗CTLA-4/PD-1联合用药相比，MGD019表现出增强的CTLA-4阻滞作用（2个数量级）。 CTLA-4 / PD-1抑制剂组合的一个缺点是毒性高，所有剂量水平的MGD019均优于CTLA-4/PD-1联合用药（nivolumab加ipilimumab）。即使在最低剂量下，DART分子也会诱导T细胞扩增。
这是一项1期剂量递增临床试验（NCT03761017）, 参加试验的患者（n = 43）具有多种肿瘤类型，包括胃肠道，泌尿生殖道，妇科和肺部恶性肿瘤。患者的中位年龄为62岁（范围为30-85）。先前治疗的中位数为3，但大多数患者没有检查点抑制剂阻滞的经验（60.5％）。 可评估患者（n = 30）的中位治疗时间为12.0周（范围1.3 – 60.4）。 在最初的24周中，每3周对患者进行一次全身性治疗，其后每6周进行一次治疗; 研究了七个剂量组，范围从0.3 毫克/公斤到10 毫克/公斤 MGD019。在试验中观察到线性药代动力学， 6 毫克/公斤及以上的剂量可达到稳定的血清谷浓度，超过PD-1抑制剂pembrolizumab公布的数据。在3 毫克/公斤或更高的剂量下，MGD019会增加患者外周血单核细胞中Ki67 + T细胞的比例（T细胞增殖的标志物）。
关于MGD109的安全性，患者通常对剂量小于10 毫克/公斤的药物耐受良好。在任何剂量水平上均未观察到剂量限制性毒性，但在10 毫克/公斤 的队列中观察到较高的3级副作用发生率，包括心肌炎，小肠结肠炎，肝炎，大疱性皮炎和斑丘疹。免疫抑制+/-中断免疫抑制可解决大多数免疫相关副作用的发生。等级3或更高的不良事件发生在32.6％的患者中。
在使用MGD019治疗的多种肿瘤类型中观察到初步的抗肿瘤活性。以3毫克/公斤或更高的剂量水平治疗的四名患者具有客观反应，其中1例转移性结直肠癌已确认完全响应。其他3例患者（微卫星稳定结直肠癌，转移性胸腺瘤和浆液性输卵管癌）有部分反应。 这些类型的肿瘤通常对检查点抑制无反应，在4例响应患者中，有3例基线PD-L1表达低，阳性总分不超过1分。剂量水平低于3 毫克/公斤的患者均无客观反应。总的来说，十名患者的疾病稳定，是他们最好的响应。总队列的客观响应率为13.3％，疾病控制率为43.3％。仅评估接受3 毫克/公斤治疗的患者时，总客观响应率率为22.2％，疾病控制率为50.0％。
正在进行以推荐的2期推荐剂量6 毫克/公斤进行的单药治疗扩展队列研究， 这些肿瘤类型包括非小细胞肺癌，头颈部鳞状细胞癌，宫颈癌，肾细胞癌，微卫星稳定结直肠癌和软组织肉瘤。
MGD019 is a tetravalent dual affinity re-targeting (DART) molecule with bivalency for both PD-1 and CTLA-4. The dual blockade of PD-1 and CTLA-4 as a monoclonal combination can improve the efficacy of multiple tumor types. Compared with monotherapy and combination therapy that inhibit PD-1 and CTLA-4, MGD019 maintains the same receptor blocking effect. In cells expressing PD-1 and CTLA-4 (such as those found in the tumor microenvironment), MGD019 showed enhanced CTLA-4 blocking effect (2 orders of magnitude) compared with anti-CTLA-4 monotherapy and anti-CTLA-4/PD-1 combination therapy. One disadvantage of the anti-CTLA-4/PD-1 combination is its high toxicity. MGD019 at all dose levels is better than the CTLA-4/PD-1 combination (nivolumab plus ipilimumab). Even at the lowest dose, DART molecules can induce T cell expansion.
This is a phase 1 dose-escalation clinical trial (NCT03761017). The participants (n = 43) in the trial had multiple tumor types, including gastrointestinal, genitourinary, gynecological and lung cancers. The median age of patients was 62 years (range 30-85). The median of previous treatments was 3, but most patients had no exposure to checkpoint inhibitor block (60.5%). The median treatment time for evaluable patients (n = 30) was 12.0 weeks (range 1.3-60.4). During the first 24 weeks, patients were given systemic treatment every 3 weeks and then every 6 weeks; seven dose cohorts were studied, ranging from 0.3 mg/kg to 10 mg/kg MGD019. Linear pharmacokinetics was observed across all dose ranges in the trial. A dose of 6 mg/kg and above reached a stable trough serum concentration, which exceeded the data published by the PD-1 inhibitor pembrolizumab. At doses of 3 mg/kg or higher, MGD019 increased the proportion of Ki67 + T cells in patients’ peripheral blood mononuclear cells (a marker of T cell proliferation).
Regarding the safety of MGD109, patients usually tolerated well at doses less than 10 mg/kg. No dose-limiting toxicity was observed at any dose level, but a higher incidence of grade 3 side effects was observed in the 10 mg/kg cohort, including myocarditis, enterocolitis, hepatitis, bullous dermatitis, and maculopapular rash. Immune suppression with or without treatment interruption resolved most immune-related side effects. Adverse events of grade 3 or higher occurred in 32.6% of patients.
Preliminary anti-tumor activity was observed in multiple tumor types treated with MGD019. Four patients treated at a dose level of 3 mg/kg or higher had objective responses, of which one case of metastatic colorectal cancer had confirmed complete response. The other 3 patients (microsatellite stable colorectal cancer, metastatic thymoma and serous fallopian tube cancer) had partial reactions. These types of tumors usually do not respond to checkpoint inhibition. Of the 4 responding patients, 3 had low baseline PD-L1 expression, and the combined positive score did not exceed 1. Patients with dose levels below 3 mg/kg had no objective response. In general, the disease of ten patients was stable, which is their best response. The objective response rate of the total cohort was 13.3%, and the disease control rate was 43.3%. When only evaluating patients receiving 3 mg/kg treatment, the overall objective response rate was 22.2%, and the disease control rate was 50.0%. An extended cohort study of monotherapy at the recommended phase 2 recommended dose of 6 mg/kg is ongoing. These tumor types include non-small cell lung cancer, head and neck squamous cell carcinoma, cervical cancer, renal cell carcinoma, and microsatellite stable colorectal cancer and soft tissue sarcoma.
参考文献 Reference Shama M. e al. 2020 ESMO Virtual Congress Virtual abstr 1020O Selby MJ et al. PloS One 2016: 11: e0161779
晚期癌症异常良好治疗响应者的可能关键 (12/20/2020)
Study on exceptional responders in advanced cancer reveals possible key elements
晚期癌症患者中, 异常良好的治疗响应者，其寿命较可比性的其他肿瘤癌症患者长得多。为了找出其原因，Baylor医学院与美国国家癌症研究所进行了为期六年的研究，克服了仅提供少量肿瘤活检样本的挑战, 分析了异常良好响应者的肿瘤基因组和微环境，以确定存活是否可以由遗传机制解释。结果显示, 肿瘤中的某些遗传缺陷使癌症治疗更加有效。这项研究检查了111名不同癌症类型并接受了不同疗法的患者，所有患者均表现出异常良好的治疗响应。通过对活检肿瘤的基因组测序分析，研究人员能够找到约25％的患者对治疗药物异常响应的遗传学解释。促成治疗反应的机制分为四类: DNA损伤反应，细胞内信号转导，免疫参与和有利于预后的基因改变。
例如，这项研究有一个关于抗癌药物temozolomide的发现。该药破坏肿瘤DNA, 通常用于治疗胶质母细胞瘤，这是一种侵袭性脑癌，一般寿命约12个月。在典型的胶质母细胞瘤病例中，肿瘤会不断修复由temozolomide引起的DNA损伤，并很快变得耐药。但是，一位异常良好的治疗反应者在诊断后10年仍无肿瘤。 研究人员发现该患者肿瘤的关键DNA修复途径已被基因灭活，因此肿瘤无法自我修复，使temozolomide对肿瘤具有致命性。研究人员还发现，temozolomide-DNA损伤途径在结肠腺癌的异常良好响应中很重要。
在一名膀胱癌患者中，研究人员发现肿瘤的免疫微环境促进了患者的异常良好响应。这个病人的肿瘤产生高水平的一种蛋白质，它通常是免疫系统的T细胞产生的, 含这种蛋白质高的患者通常对免疫检查点抑制剂治疗反应良好。肿瘤中的这种微小的基因突变结果使其很容易对免疫治疗产生响应，结果，这名患者产生完全响应，并且在四年后还活着，没有发现有肿瘤。 每个癌症患者都是独一无二的，无法预先知道谁将是杰出的响应者，但是基因组学方法可能会起到关键作用。
Among patients with advanced cancer, those who respond well to treatment have a much longer life span than other comparable cancer patients. In order to find out the reason, Baylor College of Medicine and the National Cancer Institute conducted a six-year study. They overcame the challenge of only a small number of tumor biopsy samples available, and analyzed the tumor genome and microenvironment of exceptional responders to determine survival if this can be explained by genetic mechanisms.
The results show that certain genetic defects in tumors make cancer treatments more effective. This study examined 111 patients with different cancer types and received different therapies, and all patients showed exceptional responses. Through the genome sequencing analysis of the biopsy tumor, the researchers were able to find the genetic explanation for the exceptional response in about 25% of patients. The mechanisms that contribute to the therapeutic response are divided into four categories: DNA-damage response, intracellular signaling, immune engagement and genetic alterations characteristic of favorable prognosis.
This study has found something new about the anti-cancer drug temozolomide. The drug destroys tumor DNA and is usually used to treat glioblastoma, an aggressive brain cancer with a life expectancy of about 12 months. In a typical case of glioblastoma, the tumor will continue to repair the DNA-damage caused by temozolomide and quickly becomes resistant. However, an exceptional responder remained tumor-free 10 years after diagnosis. The researchers found that the key DNA repair pathway of the patient’s tumor has been genetically inactivated, so the tumor cannot repair itself, making temozolomide lethal to the tumor. The researchers also found that the temozolomide-DNA damage pathway is important in exceptional responders of colon adenocarcinoma.
In a patient with bladder cancer, researchers found that the tumor’s immune microenvironment contributed to the patient’s exceptional response. This patient’s tumor produces high levels of a protein, which is usually produced by T-cells of the immune system. Patients with high levels of this protein usually respond well to immune checkpoint inhibitor. The result of this tiny gene mutation in the tumor made it easy to respond to immunotherapy. As a result, this patient had a complete response and was alive four years later with no detectable tumors. Every cancer patient is unique, and it is impossible to know in advance who will be an exceptional responder. However, genomics analyses may provide insight.
参考文献 Reference https://blogs.bcm.edu/2020/12/15/from-the-labs-exceptional-responders-reveal-cancers-achilles-heel/
Amcenestrant对绝经后雌激素受体阳性的乳腺癌妇女显示抗肿瘤活性 (12/19/2020)
Amcenestrant shows activity in post-menopausal breast cancer patients
Amcenestrant为一种口服雌激素受体降解剂， 这是一项I期临床试验（AMEERA-1）, 患者的中位年龄为63岁（范围37-88），先前治疗的中位数为2（范围1-8）。 48.4％的患者接受过3次或更早的治疗；这些方案包括雌激素受体降解剂（46.8％），选择性雌激素受体调节剂（29.0％），芳香化酶抑制剂（95.2％），mTOR抑制剂（33.9％），CDK4 / 6抑制剂（62.9％）和化学疗法（41.9％）。此外，93.5％的患者发生内脏转移。 汇总的人群（n = 62）包括13名每天接受剂量为150 毫克或更高的amcenestrant和49位每天接受400 毫克。截至2020年5月30日，中位治疗时间为13.9周（范围1-90）。
结果表明，amcenestrant的客观响应率为8.5％，临床受益率为33.9％。此外，在未接受过先前CDK4 / 6抑制剂，mTOR抑制剂或氟维司群的患者的亚组中，使用amcenestrant观察到较高的疗效，客观响应率为21.4％，临床受益率为64.3％。在接受过3种或更多先前疗法的患者中，客观响应率为15.2％，临床受益率为42.4％。
在基线时具有ESR1（雌激素受体1）cfDNA突变患者（n = 30）中，用amcenestrant治疗的患者获得了临床益处，包括具有难治性D538G（62.5％）和Y537S（37.5％）的肿瘤。 在基线和第2周期的第28天（ddPCR，n = 31）有数据可用的患者中，有93％的ESR1突变的患者在治疗期间至少出现1个突变的等位基因频率降低。 对于获得临床益处的患者和未获得临床益处的患者，可以在第2周期的第28天减少大多数ESR1突变（包括已知的等位基因D538G和Y537S）; 一些突变被完全清除。
Amcenestrant具有良好的安全性，有62.9％的患者发生与治疗相关的不良事件，均不超过3级。在每天接受150mg或更高剂量的患者中，最常见的不良事件（≥5％）包括潮热（16.1％），便秘（9.7％），关节痛（9.7％），减少食欲（8.1％），呕吐（8.1％），腹泻（8.1％），恶心（8.1％）和疲劳（6.5％）。 尽管其他口服雌激素受体降解剂与心脏毒性或视力障碍有关，但尚未报道这些不良事件与amcenestrant的关系。患者中均未由于不良事件不良事件而停用。
Amcenestrant is an oral estrogen receptor degrader. This is a phase I clinical trial (AMEERA-1). The median age of participants was 63 years (range 37-88) and the median lines of previous treatment was 2 ( Range 1-8). A total of 48.4% of patients received 3 or more treatments, including estrogen receptor degraders (46.8%), selective estrogen receptor modulators (29.0%), aromatase inhibitors (95.2%) , MTOR inhibitors (33.9%), CDK4/6 inhibitors (62.9%) and chemotherapy (41.9%). In addition, 93.5% of patients had visceral metastases. The pooled population (n = 62) included 13 patients receiving amcenestrant at a daily dose of 150 mg or higher and 49 patients receiving 400 mg daily. As of May 30, 2020, the median duration of treatment was 13.9 weeks (range 1-90). The results showed that the objective response rate of amcenestrant was 8.5%, and the clinical benefit rate was 33.9%. In addition, in the subgroup of patients who had not received previous CDK4/6 inhibitors, mTOR inhibitors or fulvestrant, higher efficacy was observed with amcenestrant: an objective response rate of 21.4% and a clinical benefit rate of 64.3% . Among patients who had received 3 or more previous therapies, the objective response rate was 15.2%, and the clinical benefit rate was 42.4%.
In those with an ESR1 (estrogen receptor 1) mutation in cfDNA (n = 30), those treated with amcenestrant received clinical benefits, including resilient D538G (62.5%) and Y537S (37.5%). In patients with available data at baseline and at day 28 of cycle 2 (ddPCR, n = 31), 93% of patients with ESR1 mutations showed a decrease in allele frequency in at least one mutation during treatment. Amcenestrant reduced most ESR1 mutations on day 28 of cycle 2 for patients who received clinical benefit and those who did not, including alleles D538G and Y537S; some mutations were completely eliminated.
Amcenestrant has a favorable safety profile. A total of 62.9% of patients had treatment-related adverse events, none of which exceeded Grade 3. Among patients receiving 150 mg or higher doses per day, the most common adverse events (≥5%) included hot flashes (16.1%), constipation (9.7%), arthralgia (9.7%), decreased appetite (8.1%), vomiting (8.1%), diarrhea (8.1%), nausea (8.1%) and fatigue (6.5%). Although other oral estrogen receptor degraders are associated with cardiotoxicity or visual impairment, this relationship between these adverse events and amcenestrant has not been reported. Amcenestrant was discontinued in any patient due to adverse events.
参考文献 Reference Linden HM et al. 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD8-08. Campone MC et al. J Clin Oncol. 2020;38(suppl 15):1070. doi:10.1200/JCO.2020.38.15_suppl.1070.
Enfortumab Vedotin在膀胱癌中具有生存益处 (12/13/2020)
Enfortumab Vedotin showed survival benefit in bladder cancer
在一项3期试验中, 抗体-药物偶联物enfortumab vedotin与化疗相比显着提高了膀胱癌总生存期; 在另一项试验中，它显示了有希望的长期总体生存率。与先前接受铂类化学疗法和PD-1 / PD-L1抑制剂治疗的局部晚期或转移性尿路上皮癌患者相比, enfortumab vedotin与化疗相比将死亡风险降低了30％ （HR，0.70; P = .001）; 它还使疾病进展或死亡的风险降低了39％（HR，0.61; P <.00001）。
在2020年ESMO大会上提交的单臂2期EV-201试验的第1组数据显示，enfortumab vedotin在局部晚期或转移性尿路上皮患者（先前已接受铂类化疗和免疫检查点抑制剂治疗）中的总生存率在12个月时为50.4％，在18个月时为34.2％。该试验组包括125名患者，中位年龄为69岁，中位为3次先前的全身治疗。 Enfortumab vedotin的中位治疗时间为4.6个月，最长治疗时间为27.3个月（至数据截止）。 2020年ESMO大会期间提供的数据显示，在22.3个月的中位随访中，中位总生存期为12.4个月。FDA已批准了在这种情况下使用enfortumab vedotin。
基于先前报告的EV-201数据, Enfortumab vedotin的客观响应率为44％，包括12％的完全缓解率。中位响应时间为7.6个月。 最常见的治疗相关不良事件包括脱发（49.6％），疲劳（49.6％）和食欲下降（44％）。 3级或更高级别的最常见的与治疗相关的治疗相关不良事件包括中性粒细胞减少（8.0％），贫血（7.2％）和疲劳（6.4％）。 12％的患者因治疗相关不良事件停药，最常见的是由于周围感觉神经病（6％）。有1例因间质性肺疾病导致的与治疗相关的死亡。
In a phase 3 trial, an antibody-drug conjugate enfortumab vedotin significantly improved the overall survival of bladder cancer compared with chemotherapy; in another trial, it showed promising long-term overall survival. Compared with patients with locally advanced or metastatic urothelial cancer who had previously received platinum chemotherapy and PD-1/PD-L1 inhibitors, enfortumab vedotin reduced the risk of death by 30% compared with chemotherapy (HR, 0.70; P = .001); it also reduced the risk of disease progression or death by 39% (HR, 0.61; P <.00001).
The first set of data from the single-arm phase 2 EV-201 trial presented at the 2020 ESMO World Congress showed that enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer (previously received platinum-based chemotherapy and immune checkpoint inhibitor treatment), the overall survival rate was 50.4% at 12 months and 34.2% at 18 months. The trial included 125 patients with a median age of 69 years and a median of 3 previous systemic treatments. The median treatment time of Enfortumab vedotin was 4.6 months, and the longest treatment time was 27.3 months (until data cut-off). The data provided during the 2020 ESMO showed that in a median follow-up of 22.3 months, the median overall survival was 12.4 months. The FDA has previously approved enfortumab vedotin for use in this situation. Based on previously reported EV-201 data, the objective response rate of Enfortumab vedotin was 44%, including 12% complete remission rate. The median response time was 7.6 months.
The most common treatment-related adverse events included hair loss (49.6%), fatigue (49.6%) and decreased appetite (44%). The most common treatment-related adverse events of grade 3 or higher included neutropenia (8.0%), anemia (7.2%), and fatigue (6.4%). Twelve % of patients discontinued the drug due to treatment-related adverse events, most commonly due to peripheral sensory neuropathy (6%). There was one treatment-related death due to interstitial lung disease.
O”Donnell MD et al. ESMO World Cong 2020 abstr 746p Rosenberg J et al. J Clin Onc 2020; 38: 1041 Seattle Genetics and Astellas Announcement https://bwnews.pr/3343rxD
针对CD-47的ALX148开始临床II期头颈癌临床试验(12/2/2020)
Phase II clinical research to study ALX148 targeting CD-47 in advanced head-and neck cancer
将有这两项II期研究针对晚期头颈部鳞状细胞癌患者。入组上限为50名转移性或不可切除的复发性头颈部鳞状细胞癌。一项研究将评估ALX148联合派姆单抗（pembrolizumab）用于第一线治疗PD-L1阳性（combined positive score, CPS, > 1）的患者。第二项研究将评估ALX148结合派姆单抗和标准化疗的第一线治疗。在Ib期扩展队列（ASPEN-01）中, 用于转移性或无法切除的复发性头颈部鳞状细胞癌患者的一线治疗, ALX148与派姆单抗，5-氟嘧啶和铂联合使用，达到了75％（n = 4）的总体响应率（包括一例完全响应）; ALX148与派姆单抗结合在从未接受过检查点抑制剂的晚期疾病患者中达到了40％总体响应率（n = 10）。 在大于 二线 HER2阳性胃/胃食管连接癌患者（n = 14）中, 在先前的曲妥珠单抗治疗后其肿瘤已经进展, ALX148与曲妥珠单抗加Ramucirumab和紫杉醇联合使用 , 观察到的总体响应率为64％。
初步数据表明，ALX148可以安全地与研究的多药物化疗方案联合使用，而没有达到最大耐受剂量。组合使用ALX148的最大剂量为每周一次15 毫克/公斤。 这些数据代表了第一个通过CD47靶向药物治疗对某些实体肿瘤有活性。
There will be two phase II studies for patients with advanced head and neck squamous cell carcinoma. The upper limit of enrollment is 50 patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma. A study will evaluate ALX148 in combination with pembrolizumab for the first-line treatment of patients with PD-L1 positivity (combined positive score, CPS,> 1). The second study will evaluate ALX148 combined with pembrolizumab and standard chemotherapy as the first-line treatment. In the Phase Ib extended cohort (ASPEN-01), for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma, ALX148 in combination with pembrolizumab, 5-fluoropyrimidine and platinum, achieved a 75% (n = 4) overall response rate (including one complete response); ALX148 combined with pembrolizumab achieved a 40% overall response rate in patients with advanced disease who had never received checkpoint inhibitors (n = 10). In patients with more than two lines of HER2-positive gastric/gastroesophageal junction cancer (n = 14), where the tumors have progressed after previous trastuzumab treatment, ALX148 was used in combination with trastuzumab plus Ramucirumab and paclitaxel. It was observed that the overall response rate was 64%. Preliminary data indicate that ALX148 can be safely used in combination with mult-chemotherapy regimen without reaching the maximum tolerated dose. The maximum dose of ALX148 in combined use is 15 mg/kg once a week. These data represent the first to use CD47-targeted drugs in treatment that was active against certain solid tumors.
参考文献 Reference Chow L et al. J Clin Onc 2020; 38:15_suppl, 3056 https://www.globenewswire.com/news-release/2020/12/07/2140425/0/en/ALX-Oncology-Announces-Updates-on-Planned-ALX148-Phase-2-Head-and-Neck-Cancer-Studies.html
Amivantamab-lazertinib组合可安全治疗EGFR突变的非小细胞肺癌 (12/6/2020)
Amivantamab-lazertinib combination can be safely used in EGFR-mutated NCSLC
研究人员报告说，在第三代不可逆的EGFR（epidermal growth factor receptor）酪氨酸激酶抑制剂（TKI）奥西替尼（osimertinib）治疗后复发的非小细胞肺癌（NSCLC）患者中, Amivantamab-lazertinib联合使用具有令人鼓舞的初步活性。
Amivantamab是靶向EGFR和MET突变的完全人类双特异性抗体，具有免疫细胞定向活性，并且以前在多种EGFR突变的非小细胞肺癌中均表现出临床活性。临床前研究表明，amivantamab和第三代EGFR酪氨酸激酶抑制剂lazertinib的组合可协同抑制肿瘤生长。
这是一项I期临床试验（CHRYSALIS）, 包括71例NSCLC和EGFR外显子19缺失或L858R突变的患者（中位年龄61岁；范围36-79）。 在研究的第1部分中，开始28天内, 患者从每星期一次静脉700 毫克amivantamab增至1,050 毫克，然后每两周给予相同剂量，并与口服lazertinib联合（每日标准剂量为240 毫克）。 试验方案对先前曾接受过的治疗没有限制（先前的中位线，1；范围，0-9）。 研究人员将最大评估剂量1,050 毫克（体重80公斤者则为1,400 毫克）阿米万单抗和240 毫克lazertinib作为推荐的2期联合用药剂量。 中期安全性数据显示不良事件包括皮疹（78％），输液相关反应（61％），甲沟炎（42％），口腔炎（31％），瘙痒（24％）和腹泻（14％）。 只有7％不良事件为3级或更高。
在研究的第1部分中，有23位患者患有可测量的疾病，其总响应率为43.5％（95％CI，23.2-65.5）。 10名患者获得了部分响应，9名患者病情稳定。 中位治疗时间为8.2个月（范围0.5-10.7），有13例患者在数据截止时仍在接受治疗。 研究人员还报告了在剂量扩展队列中接受过奥西替尼治疗的20名可评估的患者中有14名显示抗肿瘤活性。包括一个完全缓解，7个部分缓解和6名病情稳定的患者。
这只是一个早期研究。研究者认为, Amivantamab可以安全地与Lazertinib联合使用，在剂量递增期间未发现剂量限制性毒性。这种组合对晚期EGFR突变的NSCLC有效。
Researchers reported that in NSCLC patients who failed third-generation irreversible EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor (TKI) osimertinib (osimertinib) , the combination of Amivantamab and Lazertinib demonstrated encouraging activity. Amivantamab is a fully human bispecific antibody targeting EGFR and MET mutations. It has immune cell-directing activity and has previously shown clinical activity in a variety of EGFR-mutated non-small cell lung cancers. Preclinical studies have shown that the combination of Amivantamab and the third-generation EGFR tyrosine kinase inhibitor Lazertinib can synergistically inhibit tumor growth.
This is a phase I clinical trial (CHRYSALIS), including 71 patients with NSCLC and EGFR exon 19 deletion or L858R mutation (median age 61; range 36-79). In the first part of the study, patients received at increased dsoe from 700 mg amivantamab intravenously once a week to 1,050 mg once a week for the first 28 days, and then they were given the same dose every two weeks in combination with oral lazertinib (standard daily dose of 240 mg). The trial protocol had no restrictions on prior treatments (previous median line, 1; range, 0-9). The researchers set the maximum estimated dose of 1,050 mg (1,400 mg for a body weight of 80 kg) of amivumab and 240 mg of lazertinib as the recommended phase 2 combination dose. Interim safety data showed that adverse events included skin rash (78%), infusion-related reactions (61%), paronychia (42%), stomatitis (31%), itching (24%) and diarrhea (14%). Only 7% of adverse events were grade 3 or higher. In the first part of the study, 23 patients with measurable diseases, had an overall response rate of 43.5% (95% CI, 23.2-65.5). Ten patients received partial responses, and 9 patients were in stable condition. The median treatment duration was 8.2 months (range 0.5-10.7), and 13 patients were still receiving treatment at the time of the data cutoff. Researchers also reported anti-tumor activity in 14 of the 20 evaluable patients previously treated with osimertinib in the dose expansion cohort, including one complete remission, 7 partial remissions and 6 stable patients.
This is just an early study. Researchers believe that Amivantamab can be safely used in combination with lazertinib, with no dose-limiting toxicity during dose escalation. This combination is effective for NSCLC with advanced EGFR mutations.
参考文献 Reference Cho BC et al. Ann Oncol 2020; 31 (suppl_4): S754Tisotumab vedotin治疗复发或转移性宫颈癌有临床活性 (125/2020)
Tisotumab vedotin demonstrated clinical activity against recurrent/refractory cervical cancer
Tisotumab vedotin是一种人类抗体（抗组织因子）-药物（微管破坏剂, monomethyl auristatin E）偶联物。组织因子 是一种跨膜糖蛋白，发现在许多血管外细胞的表面，构成了血管壁的组成部分; 它还是凝血途径的一部分。它可促进肿瘤生长，血管生成和转移。 基于发现其在许多实体瘤（包括宫颈癌）中的高表达及其快速内在化，组织因子被选作抗体–药物偶联物方法的靶标。
这是一项多中心的II期单臂临床试验（innovaTV 204）, 有101位在美国和欧洲的多个中心局部晚期或己转移的宫颈癌病人参加。患者先前曾接受过双重化疗，或作为一线治疗使用贝伐单抗。 此外，如果患者在复发和/或转移性环境中接受了最多两次以前的治疗，也符合条件。 试验的主要终点是缓解评估标准（RECIST）v1.1确定的客观缓解率。次要终点包括反应持续时间，无进展生存期，总体生存期，安全性和耐受性。 该试验的结果显示，客观缓解率为24％（95％可信区间：15.9％-33.3％），其中7例（7％）完全缓解，17例（ 17％）有部分回应。中位随访10个月后，中位缓解时间为8.3个月（95％CI：4.2 – 未达到）。中位反应时间为1.4个月（范围1.1-5.1），通常在前两个治疗周期内（每3星期为一个周期）观察到活性。亚组分析表明，无论肿瘤组织学，既往治疗方案如何，反应基本一致。中位无进展生存期为4.2个月（95％CI：3.0 – 4.4），六个月无进展生存率为30％（95％CI：20.8 – 40.1），而中位总生存期为12.1个月（95％CI：9.6 – 13.9）和六个月的总生存率为79％（95％CI：69.3 – 85.6）。
大多数与治疗相关的不良事件为1级或2级，并且未报告新的安全性信号。Tisotumab vedotin治疗可能引起的预先指定的不良事件包括眼部事件，出血和周围神经病变。被认为与患者治疗相关的眼部不良事件多为轻度至中度（1级为25％，2级为27％，3级为2％），其中大多数事件得以缓解（86％）。由于败血性休克而导致的一名死亡与治疗有关。
Tisotumab vedotin is a human antibody (anti-tissue factor)-drug (microtubule disruptor, monomethyl auristatin E) interaction. It is a transmembrane protein. It promotes tumor growth, angiogenesis and metastasis. Based on the discovery of its high expression and rapid internalization in many solid tumors (including cervical cancer), tissue factor was selected as the target of the antibody-drug conjugate.
This is a multi-center phase II single-arm clinical trial (innovaTV 204), involving 101 patients with locally advanced or metastatic cervical cancer in multiple centers in the United States and Europe. Theos patients had previously received dual chemotherapy or bevacizumab as a first-line treatment. In addition, if patients received up to two previous treatments in a recurrent and/or metastatic setting, they were also eligible. The primary endpoint of the trial is objective response rate determined by the results of the trial determined by the Remission Evaluation Criteria (RECIST) v1.1. Secondary endpoints include response duration, progression-free survival, overall survival, safety and tolerability. The results demonstrated an objective response rate of 24% (95% confidence interval: 15.9%-33.3%). Among them, 7 cases (7%) had a complete remission, and 17 cases (17%) had a partial response. After a median follow-up of 10 months, the median time to remission was 8.3 months (95% CI: 4.2-not reached). The median response time was 1.4 months (range 1.1-5.1), and activity was usually observed during the first two treatment cycles (every 3 weeks as a cycle). Subgroup analysis showed that regardless of tumor histology and previous treatment history, the response was essentially the same. The median progression-free survival was 4.2 months (95% CI: 3.0-4.4), Six-month progression-free survival period was 30% (95% CI: 20.8-40.1), and the median overall survival was 12 months. The overall survival rate was 79% (95% CI: 69.3-85.6) at 6 months (95% CI: 9.6-13.9) . Most of the treatment-related adverse events were grade 1 or 2, and no new safety signals were reported. Pre-specified adverse events that may be caused by Tisotumab vedotin include ocular events, bleeding, and peripheral nerve damage. Treatment-related ocular adverse events were mostly mild to moderate (25% for grade 1, 27% for grade 2, and 2% for grade 3), and most of them can be relieved (86%). The death of a person due to septic shock was thought to be related to the treatment.
参考文献 Reference Coleman Rl et al. ESMO Virtual Congress abstr #LBA32/#3435
LUM成像系统用于乳腺癌手术 (11/28/2020)
LUM imaging system used in breast cancer surgery
最初的乳腺癌外科手术可能无法识别并去除所有癌组织，导致20–40％的患者需要第二次手术以去除残留癌组织。 FDA授予LUM成像系统快速通道的认证。 它的开发旨在使外科医生能够实时查看和清除残留的癌症，从而显着降低了二次手术和癌症复发的风险。
该系统包括三个不同的组件。一种是研究用的荧光成像剂，称为LUM015，专门设计用于在接近肿瘤边缘的癌细胞时发出荧光信号，第2种是可以放置在手术伤口腔内的轻巧的手持成像设备。在肿瘤边缘寻找癌性残留组织。第3个是专有软件，能够提供外科医生的实时图像，指示剩余癌症组织的位置。目前已经完成了三项临床试验：I期（NCT01626066）和两项II期 （NCT02438358; NCT03321929），评估了LUM癌症成像系统在乳腺癌患者中的安全性和可行性。这些试验的数据表明LUM015具有良好的安全性和药理学特性，并显示LUM成像系统使外科医生能够在癌症切除手术中快速识别残留肿瘤的一小部分。 目前正在进行另一项II期试验（NCT04440982），以评估LUM 成像系统在作为术前疗法进行保乳手术的乳腺癌患者中检测残留癌症的能力。此外，一项重要的III期试验（NCT03686215）正在进行中，以评估LUM成像系统在乳腺癌女性中的安全性和有效性。招聘活动正在美国各地的多个地点进行，该试验预计将招募约170名女性, 预计将于2021年3月结束。
Initial breast cancer surgery may fail to identify and remove all cancerous tissue, resulting in 20-40% of patients requiring a second surgery to remove residual cancer. FDA granted the LUM imaging system fast track designation. The system was developed to enable surgeons to view and remove residual cancer in real time, thereby significantly reduce the risk of secondary operations and cancer recurrence. The system consists of three different components. One is a research fluorescent imaging agent called LUM015, which is specifically designed to emit a fluorescent signal when it approaches cancer cells at the tumor margins. The second is a lightweight handheld imaging device that can be placed in the cavity of a surgical wound to look for residual cancerous tissue at the tumor margins. The third is a proprietary software that can provide a real-time image to surgeon, indicating the location of the remaining cancer tissue.
Three clinical trials have been completed: s phase I (NCT01626066) and two Phase II studies (NCT02438358; NCT03321929), evaluating the safety and feasibility of the LUM cancer imaging system in breast cancer patients. The data from these trials showed that LUM015 has good safety and pharmacological properties, and demonstrated that the LUM imaging system enabled surgeons to quickly identify a small portion of the residual tumor during cancer resection. Another phase II trial (NCT04440982) is currently underway to evaluate the ability of the LUM imaging system to detect residual cancer in breast cancer patients undergoing breast-conserving surgery after neoadjuvant therapy. In addition, an pivotal phase III trial (NCT03686215) is underway to evaluate the safety and effectiveness of the LUM imaging system in women with breast cancer. Recruitment is being conducted at several sites across the United States. The trial is expected to enroll approximately 170 women and is expected to end in March 2021.
参考文献 Reference http://mdsource.com/fda-grants-fast-track-status-rolling-review-to-lumicells-lum-imaging-system
FDA授予SRF388快速通道称号用于治疗肝细胞癌 (11/22/2020)
FDA granted fast track designation to SRF338 to treat refractory hepatocellular carcinoma
FDA授予SRF388快速通道称号，用于治疗先前已接受过标准疗法（例如血管内皮生长因子靶向药物和PD-L1抑制剂）治疗的肝细胞癌患者。 SRF388是一种完全人类抗IL-27抗体，旨在抑制这种免疫抑制细胞因子的活性。肝癌和肾癌已被确定为潜在治疗对像，其中IL-27在免疫抑制性肿瘤微环境中起着重要作用，并可能有助于抵抗检查点抑制剂的治疗。 研究表明IL-27在肾癌和肝癌中均被上调并且具有功能。表明高水平的IL-27与患肝癌的风险密切相关。SRF388靶向IL-27的限速亚基p28，临床前研究表明，用SRF388进行治疗可阻断IL-27的免疫抑制作用，与其他癌症疗法联合使用可导致免疫细胞活化; 它作为单一疗法具有强大的抗肿瘤作用。此外，已鉴定出与IL-27相关的潜在生物标志物，可帮助选择最可能对SRF388产生反应的患者。
SRF388的开放标签1期临床试验于2020年4月开始，正在招募患有各种晚期实体瘤的患者。来自9个患者的汇总结果包括以下五个剂量水平（每4周静脉内0.003、0.03、0.1、0.3和1 毫克/公斤）, 具有良好的耐受性, 尚未观察到剂量限制性毒性，剂量的增加将继续。 试验中从患者的血中测得的SRF388在0.3毫克/公斤剂量时已实现了IL-27信号通路的最大抑制。有一名在先前在抗PD-1治疗后病情进展的肾癌患者，在该试验中病情长期稳定（> 6个月）。 迄今为止，尚无肝癌患者参与该试验的剂量递增部分。该药公司计划在2021年上半年开始在肝癌和肾癌中进行单一疗法的2期扩展队列，招募患者。
FDA has granted SRF388 fast track designation for the treatment of hepatocellular carcinoma patients who have previously received standard therapies (such as vascular endothelial growth factor targeted drugs and PD-L1 inhibitors). SRF388 is a fully human anti-IL-27 antibody designed to inhibit the activity of this immunosuppressive cytokine. Hepatocellular carcinoma and kidney cancer have been identified as potential therapeutic targets, in which IL-27 plays an important role in the immunosuppressive tumor microenvironment and may help resist checkpoint inhibitor treatment. Studies have shown that IL-27 is up-regulated and functional in both kidney cancer and liver cancer. It shows that high levels of IL-27 are closely related to the risk of liver cancer. SRF388 targets the rate-limiting subunit p28 of IL-27. Preclinical studies have shown that treatment with SRF388 can block the immunosuppressive effect of IL-27, and its combined use with other cancer therapies can lead to immune cell activation; it has potent anti-tumor effect as a monotherapy. In addition, potential biomarkers related to IL-27 have been identified, They can help select patients who will most likely respond to SRF388.
The open-label phase 1 clinical trial of SRF388 started in April 2020 and is recruiting patients with various advanced solid tumors. The aggregate results from 9 patients included the following five dose levels (0.003, 0.03, 0.1, 0.3, and 1 mg/kg intravenously every 4 weeks), The drug was well tolerated, and dose-limiting toxicity has not been observed. The dose will continue to increase. SRF388 level measured in the participants’ blood has indicated that maximum inhibition of IL-27 signaling pathway was achieved at a dose of 0.3 mg/kg. In this trial, a kidney cancer patient who had progressed through previous anti-PD-1 treatment is achieving a long-term stable condition (> 6 months). To date, no patients with liver cancer have participated in the dose escalation portion of the trial. The drug company plans to start a phase 2 expansion cohort of monotherapy in liver cancer and kidney cancer in the first half of 2021 to recruit patients.
参考文献 Reference https://ascopost.com/news/november-2020/fda-pipeline-fast-track-designations-in-liver-and-pancreatic-cancers/ https://www.biospace.com/article/releases/surface-oncology-announces-srf617-and-srf388-will-advance-to-combination-and-expansion-stages-of-ongoing-phase-1-clinical-trials/
新的DNA修复抑制剂可增加脑转移对放射的敏感性 (11/21/2020)
A new DNA repair inhibitor may sensitize brain metastases to radiation
当乳腺癌转移到大脑时，主要的治疗方式是放射。但是其疗效受到可以安全使用剂量的限制。因为大多数细胞的内在机制使它们一旦受到辐射就会开始修复过程。因此，需要足够高的辐射剂量以完全破坏癌细胞并阻止其自身修复，研究者发现一种新的DNA修复抑制剂, 能使转移灶对辐射敏感, 因而可增加辐射剂量而杀死更多癌细胞。
通过全基因组CRISPR筛选而确定的富含亮氨酸的重复序列蛋白31（LRRC31），它与DNA损伤修复反应蛋白形成复合物, 阻遏修复结合物聚集到DNA双链的断裂处，并且抑制催化亚基的募集和激活。同时，LRRC31还通过另一个重要途径（ATR, 起监视DNA损伤作用）抑制DNA修复。LRRC31与DNA损伤修复分子的这种竞争性结合削弱了修复反应，促进了细胞对放射的敏感性。但是,如何将新的DNA抑制剂输送到大脑存在一个问题。血脑屏障可以防止潜在的危险物质（包括化疗药物等）从血液流到大脑。在动物模型中, 研究者利用靶向递送专门设计的纳米粒子, 来包裹LRRC31基因, 对人乳腺癌脑转移的小鼠进行治疗，证实LRRC31具有显著的放疗增敏效果。这为将来的治疗提供了指导。
When breast cancer spreads to the brain, the main treatment modality is radiation. However, its efficacy is limited by the safe dose that can be administered. There exists an internal cellular mechanism whereby cells can start repair process once they are exposed to radiation. Therefore, a sufficiently high radiation dose is required to completely destroy cancer cells and prevent their own repair. Researchers have discovered a new DNA repair inhibitor that can make cancer cells sensitive to radiation, so that more cancer cells can be killed by increasing radiation dose. The leucine-rich repetitive sequence protein 31 (LRRC31), identified through genome-wide CRISPR screening, forms a complex with the DNA damage repair response protein to prevent the repair conjugate from gathering at the DNA double-strand break and inhibit the recruitment and activation of catalytic subunit. At the same time, LRRC31 also inhibits DNA repair through another important pathway (ATR, which monitors DNA damage). This competitive binding of LRRC31 and DNA damage repair molecules weakens the repair response and promotes the sensitivity of cells to radiation. However, there is an important issue about how to deliver the new DNA inhibitor to the brain. The blood-brain barrier can prevent potentially dangerous substances (including chemotherapy drugs, etc.) from entering the brain from the blood. In animal models, the researchers used targeted delivery of specially designed nanoparticles to encapsulate the LRRC31 gene to enable to enter the brain in a mouse model that has brain metastases from human breast cacner, and confirmed that LRRC31 has a significant radiosensitization effect. This provides guidance to future treatment.
参考文献 Reference Chen Y et al. Nature Cell Biol 2020; 22:1276
腰以下的诊断性放射可能会增加睾丸癌的风险 (11/15/2020)
Diagnostic radiation below the waist may increase the risk of testicular cancer
睾丸生殖细胞肿瘤是15至44岁白人男性中常见的癌症之一。据报导,1975年以来，发病率翻了一番，从100,000名男性中的三名增加到100,000名男性中的六名。
研究者对1,246名18至55岁的男性进行了观察性研究, 315名有和931名没有睾丸生殖细胞肿瘤的参与者, 完成了一份有关其一生中睾丸生殖细胞肿瘤已知的和推测的风险因素问卷，以及一生中诊断成像和扫描位置（腰部以下的X射线或CT，以及较低的胃肠系列或钡灌肠）。还收集了肿瘤样品。
研究人员使用逻辑回归（logistic regression ）根据放射线暴露的次数（0、1-2或3）和首次放射线暴露的年龄来计算患睾丸生殖细胞肿瘤的风险。然后，他们针对年龄，出生年份，地区, 种族，诊断时的BMI，疾病的家族史和个人隐睾症史进行了调整。
结果表明，与没有放射线暴露的男性相比，报告至少接受过3次X射线或CT暴露的男性患睾丸生殖细胞肿瘤的风险显著提高（OR = 1.78； 95％CI，1.15-2.76）。暴露于三个或三个以上胃肠系列或钡灌肠（OR = 4.58; 95％CI，2.39-8.76）或暴露于三个或三个以上合并变量（OR = 1.59; 95％CI，1.05-2.42）。 那些10岁以下暴露于诊断性放射线的人比18岁或18岁以上初次暴露的人表现出更高的睾丸生殖细胞肿瘤风险，尽管这种关联在统计学上不显著（OR = 2； 95％CI，0.91-4.42 ）。
研究者认为,虽然样本人群相对较小，但很难就这个问题进行前瞻性研究。回顾性匹配病例对照研究是唯一的选择。
Testicular germ cell tumors are one of the common cancers in white men aged 15 to 44. According to reports, the incidence has doubled since 1975, from three out of 100,000 men to six out of 100,000.
The researchers conducted observational studies on 1,246 men between the ages of 18 and 55, 315 participants with and 931 without testicular germ cell tumors They all completed a questionnaire regarding known and presumptive risk factors for testicular germ cell tumor during their lifetime, and diagnostic imaging during their life including body location of the scans (X-ray or CT below the waist, and lower gastrointestinal series or barium enema) and number of exposures. Tumor samples were also collected.
Researchers used logistic regression to calculate the risk of testicular germ cell tumors based on the number of radiation exposures (0, 1-2, or 3) and the age of the first radiation exposure. Then, they adjusted for age, year of birth, countyn, race, BMI at diagnosis, family history of the disease, and personal history of cryptorchidism.
The results showed that compared with men who were not exposed to radiation, men who reported at least 3 X-ray or CT exposures had a significantly higher risk of testicular germ cell tumors (OR = 1.78; 95% CI, 1.15-2.76). Exposure to three or more GI series or barium enema (OR = 4.58; 95% CI, 2.39-8.76) or exposure to three or more combined variables (OR = 1.59; 95% CI, 1.05-2.42 ). Those under 10 years of age who were exposed to diagnostic radiation showed a higher risk of testicular germ cell tumors than those 18 years of age or older who were initially exposed, although this association was not statistically significant (OR = 2; 95% CI, 0.91-4.42).
Researchers thought that although the sample size is relatively small, it is difficult to conduct prospective studies on this issue. A retrospective matched case-control study is the only option.
参考文献 Reference Need KT et al. PLOS ONE 2020; November 11. https://doi.org/10.1371/journal.pone.0239321
Nivolumab/化疗联合治疗可延长胃/食管/胃食管连接癌的生存期 (11/14/2020)
Nivolumab plus chemotherapy may prolong survival in gastric/esophageal/GE-junctional carcinoma
这是一项III期国际多中心临床试验（CheckMate649）, 参加者包括无法通过手术切除的晚期或转移性胃癌患，还包括患有食道癌，以及胃食管连接癌的患者。该试验排除了已知肿瘤为HER2阳性的患者。他们从未接过受治疗。患者随机接受1) nivolumab（每3星期360 毫克 或每2星期240 毫克）加上化疗（每3星期XELOX 或每2星期FOLFOX），2) nivolumab 加上 ipilimumab, 或3) 单独化疗。通过盲法独立的中央评价，nivolumab加上化疗相对于单独化疗的双重主要试验终点是总生存期和无进展生存期。
在这1,581位患者中，其中955 位（60％）的PD-L1 CPS≥5。随访最少12个月，相对于单独化疗,nivolumab/化疗联合显著改善了PD-L1 CPS≥5患者的总生存期（预先指定的中期分析）和无进展生存期（最后分析）。 中位无进展生存期为7.7个月（联合组）（7.0-9.2）相对于6.1个月（化疗组）（5.6-6.9）（HR 0.68 , 98％CI 0.56-0.81; P <.0001 ）。中位总生存期为14.4个月（联合组）（13.1-16.2）相对于11.1个月（化疗组）（HR 0.71, 98.4％CI 0.59-0.86; P <.0001）。在PD-L1 CPS≥1的患者和所有参加人群中，HR分别为0.77 (0.64–0.92; P = .0001) 和0.80 (0.68-0.94, P=.0002) 。
治疗相关的3/4级副作用为59％（联合组）相对于44％（化疗组）。由于副作用而导致停药的为38%（联合组）相对25%（化疗组）。在试验中死亡率为2％相对于<1％。
研究者认为, nivolumab加上化疗可能成为无法手术切除的胃/食管/胃食管连接癌患者新的一线标准治疗方案。
This is a phase III international multi-center clinical trial (CheckMate649). Participants include patients with unresectable advanced or metastatic gastric cancer, esophageal cancer and gastroesophageal junction cancer. The trial excluded patients whose tumors were known to be HER2-positive. They have never received prior treatment. Patients were randomized to receive 1) nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (XELOX every 3 weeks or FOLFOX every 2 weeks), 2) nivolumab plus ipilimumab, or 3) chemotherapy alone. Through blinded independent central evaluation, the dual primary endpoints of nivolumab plus chemotherapy versus chemotherapy alone are overall survival and progression-free survival.
Among the 1,581 patients, 955 (60%) had PD-L1 CPS ≥5. The follow-up was at least 12 months. Compared with chemotherapy alone, the combination of nivolumab plus chemotherapy significantly improved overall survival (pre-determined interim analysis) and progression-free survival (final analysis) of patients with PD-L1 CPS≥5. The median progression-free survival was 7.7 months (combination group) (7.0-9.2) compared to 6.1 months (chemotherapy group) (5.6-6.9) (HR 0.68, 98% CI 0.56-0.81; P <.0001). The median overall survival was 14.4 months (combination group) (13.1-16.2) compared to 11.1 months (chemotherapy group) (HR 0.71, 98.4%CI 0.59-0.86; P <.0001). In patients with PD-L1 CPS≥1 and all participants, HR was 0.77 (0.64–0.92; P = .0001) and 0.80 (0.68-0.94, P=.0002), respectively.
Treatment-related grade 3/4 side effects were 59% (combination group) compared to 44% (chemotherapy group). The rate of discontinuation due to side effects was 38% (combination group) versus 25% (chemotherapy group). The mortality rate in the trial was 2% versus <1%.
Researchers believed that nivolumab plus chemotherapy may become a new standard first-line treatment for patients with unresectable advanced or metastatic gastric/esophageal/gastroesophageal junction cancer.
参考文献 Reference Moehler M et al. ESMO Virtual Congress 2020; abstr LBA6_PR
Ixazomib作为多发性骨髓瘤未进行自体干细胞移植的维持治疗延长了无进展生存期 (11/8/2020)
Ixazomib as maintenance therapy prolonged progression-free survival in newly-diagnosed multiple myeloma not undergoing autologous stem cell transplantation
这是一项III期双盲，安慰剂对照的临床试验（TOURMALINE-MM4）, 有706位新诊断的多发性骨髓瘤病人参加, 未接受自体干细胞移植。在接受标准诱导疗法取得好于或等于部分响应（6-12个月）后, 患者被随机分配接受口服蛋白酶体抑制剂ixazomib（n = 425）或安慰剂（n = 281）（3:2）, 在28天周期的第1、8和15天使用ixazomib或安慰剂维持24个月。试验主要终点为无进展生存期。
中位随访时间为21.1个月, 临床试验达到了主要终点指标， ixazomib与安慰剂相比，其疾病进展或死亡风险降低了34.1％（随机分组后中位无进展生存期为17.4 v相对于9.4个月；危险比[HR]为0.659； 95％CI为0.542-0.801； P <.001）。诱导后完全或非常好的部分响应的患者显著受益于 ixazomib（中位无进展生存期，25.6 相对于 12.9个月； HR，0.586； P <.001）。
Ixazomib与安慰剂比较，分别有36.6％和23.2％的患者出现≥3级治疗紧急事件；由于治疗紧急事件中断治疗的比例为12.9％和8.0％。常见的任何级别的治疗紧急事件包括恶心（26.8％相对于 8.0％），呕吐（24.2％相对于 4.3％）和腹泻（23.2％相对于12.3％）。新发生的原发性恶性肿瘤没有增加（5.2％相对于6.2％）；在试验中死亡率为2.6％相对于2.2％。
结论: 在未接受自体干细胞移植的的新诊断的多发性骨髓瘤患者中，Ixazomib维持治疗可延长无进展生存期且无意外毒性。作者认为，这是在一项随机临床试验中首次证明蛋白酶体抑制剂具有单药维持疗效，并且是该患者人群中可选择的首个口服蛋白酶体抑制剂。
This is a phase III double-blind, placebo-controlled clinical trial (TOURMALINE-MM4). A total of 706 newly diagnosed multiple myeloma patients participated in the trial, who did not receive autologous stem cell transplantation. After receiving standard induction therapy with better or equal to partial response (6-12 months), patients were randomly assigned to receive oral proteasome inhibitor, ixazomib (n = 425) or placebo (n = 281) (3:2) , Patients were given ixazomib or placebo for 24 months on days 1, 8 and 15 of the 28-day cycle. The primary endpoint of the trial is progression-free survival.
The median follow-up time was 21.1 months. The clinical trial reached the primary endpoint. Compared with placebo, the risk of disease progression or death was reduced by 34.1% for ixazomib (median progression-free survival after randomization was 17.4 v vs. 9.4 months; hazard ratio [HR] is 0.659; 95% CI is 0.542-0.801; P <.001). Patients with complete or very good partial responses after induction significantly benefited from ixazomib (median progression-free survival, 25.6 vs 12.9 months; HR, 0.586; P <.001).
Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 36.6%（ixazomib）and 23.2% （placebo）respectively. Treatment interruption due to due to TEAEs was 12.9% and 8.0%. Common TEAEs of any grade include nausea (26.8% vs. 8.0%), vomiting (24.2% vs. 4.3%), and diarrhea (23.2%v vs. 12.3%). There was no increase in new primary malignancies (5.2%v vs. 6.2%). The rates of on-study death was 2.6% vs. 2.2%.
Conclusion: In newly diagnosed multiple myeloma patients not undergoing autologous stem cell transplantation, iIxazomib maintenance therapy prolongs progression-free survival with no unexpected toxicity. The authors believe that this is the first proteasome inhibitor that demonstrated single-agent maintenance effect in a randomized clinical trial, and it is the first oral proteasome inhibitor option in this patient population.
参考文献 Reference Dimopoulos MA et al. J Clin Onc 2020; Oct. 6,. https://creativecommons.org/licenses/by-nc-nd/4.0/
ASCO 关于PARP抑制剂对卵巢癌的治疗指南 (11/7/2020)
ASCO guideline about management of ovarian cancer using PARP Inhibitors
I. 新诊断的卵巢癌（上皮性卵巢癌，输卵管癌或原发性腹膜癌）
- 不推荐在EOC的女性中重复PARPi治疗。 不建议将PARPis用于I-II期患者的初期治疗
- 对于刚诊断为III-IV期的女性, 对一线铂类化学疗法有完全或部分响应的，，应使用olaparib进行PARPi维持治疗（适用于具有BRCA1或BRCA2基因的种系变异, 或体细胞致病性或可能致病性变异的患者） 或niraparib用于患有高度浆液性或子宫内膜样卵巢癌（适用于所有女性）。
PARPi维持疗法应包括olaparib（口服，每12小时300毫克，持续2年）或niraparib（每日200-300毫克，持续3年）。 在选定的个别患者中可以考虑更长的持续时间。 - 对于患有III-IV期高度浆液性或子宫内膜样卵巢癌，BRCA1或BRCA2基因的种系或体细胞变异, 或具有可能致病的BRCA1/BRCA2基因变异或/和/基因组不稳定患者（通过Myriad myChoice CDx确定）, 对化疗加贝伐单抗联合治疗有部分或完全响应, 将olaparib添加至贝伐单抗维持治疗中。
- 目前不建议将PARPi veliparib与联合化疗并用veliparib维持治疗。
II.复发性卵巢癌, 第二线或更晚的维持和治疗
- 对尚未接受PARPi且对铂类疗法有响应的卵巢癌患者（无论BRCA突变状态如何）提供PARPi单药治疗（二线以上）。 治疗仍持续到疾病进展或尽管减少剂量和提供最佳支持治疗，毒性仍然存在。
可以选择：olaparib每12小时300毫克； 或rucaparib每12小时600毫克； 或niraparib 200-300毫克每天一次 - 对于尚未接受PARPi且在BRCA1或BRCA2基因中具有种系或体细胞致病性或可能致病性变异的复发性卵巢癌患者，应提供PARPi治疗。
选项包括：奥拉帕尼每12小时300毫克； 或rucaparib每12小时600毫克； 或niraparib 200-300毫克每天一次 - 对于尚未接受PARPi且肿瘤表现出基因组不稳定性（根据Myriad myChoice CDx而确定），且在铂类治疗后6个月内未复发的卵巢癌患者，应提供PARPi单药治疗。
- 不建议将PARPis用于治疗BRCA野生型或耐铂类复发性的卵巢癌。
- 不建议在复发的患者中, 在临床试验范围以外,，将PARPi与化疗，其他靶向药物或免疫肿瘤药物联合使用
- III不良事件的管理
- 贫血: 需要输血以缓解症状和/或血红蛋白水平<8 克/分升的患者, 应当减少PARPi剂量，以避免多次输血。
- 中性粒细胞减少症：未表明它是接受PARPi患者使用生长因子的适应症。
但当发生4级中性粒细胞减少持续, 至少5-7天或伴有发烧, 应停药直至感染恢复和中性粒细胞计数恢复，然后减少剂量。在这种情况下，可以使用生长因子来支持患者的安全。 - 血小板：最常见于niraparib。应根据体重和血小板计数，使用Niraparib剂量指南降低起始剂量（200 毫克）。
对尽管剂量减少，但血小板仍持续性减少或明显出血者, 应中断PARPi。 - 恶心和心动过速: 在治疗的第一个周期中，许多患者会出现这些症状。
持续的恶心需要每天服用止吐药; 若工作状态降低，和/或体重减轻> 5％，应减少剂量。
I. Newly diagnosed epithelial ovarian cancer (EOC) (ovarian, fallopian tube, or primary peritoneal cancer)
• It is not recommended to repeat PARPi treatment in the treatment of women with EOC. It is not recommended to use PARPis for the initial treatment of patients with stage I-II
• For women who have just been diagnosed with stage III-IV, who have a complete or partial response to first-line platinum chemotherapy, olaparib should be used for PARPi maintenance therapy (for those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes) or niraparib (all women) for patients with high-grade serous or endometrioid ovarian cancer .
PARPi maintenance therapy should include olaparib (orally, 300 mg every 12 hours for 2 years) or niraparib (200-300 mg daily for 3 years). A longer duration can be considered in selected individual patients.
• The addition of olaparib to bevacizumab maintenance may be offered to patients who have stage III-IV high grade sersous or endometrioid ovarian cancer and germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, as determined by Myriad myChoice CDx, and who have had a partial or complete response to chemotherapy plus bevacizumab combination
• It is not currently recommended to use PARPi veliparib and combination chemotherapy with veliparib for maintenance therapy.
II. Recurrent ovarian cancer, second-line or later maintenance and treatment
• PARPi monotherapy (second-line or more) to ovarian cancer patients who have not yet received PARPi and who have responded to platinum therapy (regardless of BRCA mutation status). Treatment continues until disease progresses or toxicity despite dose reductions and best supportive care.
Options include: olaparib 300 mg every 12 hours; or rucaparib 600 mg every 12 hours; or niraparib 200-300 mg once a day
• For patients with recurrent ovarian cancer who have not received PARPi and have germline or somatic pathogenic or possibly pathogenic variants in the BRCA1 or BRCA2 gene, PARPi treatment should be provided.
Options include: olaparib 300 mg every 12 hours; or rucaparib 600 mg every 12 hours; or niraparib 200-300 mg once a day
• For patients with ovarian cancer who have not received PARPi and whose tumor demonstrates genomic instability, as determined by Myriad myChoice CDx, and has not recurred within 6 months of platinum-based therapy
- It is not recommended to use PARPis to treat BRCA wild-type or platinum-resistant recurrent EOC.
- It is not recommended to use PARPi in combination with chemotherapy, other targeted drugs or immuno-oncology drugs in patients
who have relapsed outside the context of clinical trials.
III. Management of Adverse Events:
a) Anemia: Patients requiring a blood transfusion for symptom relief and/or hemoglobin level < 8 g/dL should be monitored. PARPi dose should be reduced with evidence of repeated anemia to avoid multiple transfusions.b) Neutropenia: Growth factor is not indicated for use in patients receiving daily PARPi.
b) Neutropenia (grade 4 lasting at least 5-7 days or associated with fever) should result in dose hold until recovery of infection and granulocyte count, followed by dose reduction. Growth factor support may be used in this setting to support patient safety during the drug hold.
c) Platelets: Thrombocytopenia is most common with niraparib. Niraparib dosing guidelines should be used to lower starting dose (200 mg) based on weight and platelet count.
Discontinue PARPi for persistent thrombocytopenia or significant bleeding despite dose reduction.
d) Nausea and tachycardia: Many patients will have tachyphylaxis of nausea symptoms over the first cycle of therapy.
Persistent nausea requiring daily antiemetic intervention, causing a reduction in performance status, and/or resulting in > 5% weight loss should result in dose reduction.
针对CD19 的同种异体CTX11在复发/难治性恶性B细胞恶性肿瘤的1期临床试验结果 (11/1/2020)
Results of phase I clinical trial using allogeneic CTX11 in recurrent/relapsed CD19-positive B-cell malignancy
CTX110是CRISPR编辑的针对CD19 + B细胞恶性肿瘤的同种异体CAR-T细胞。以下是基于该制药公司的新闻报道。
这是一项I期开放性，多中心临床试验（CARBON），评估CTX110在复发或难治性非霍奇金淋巴瘤成年患者中的安全性和有效性，这些患者已接受了至少两次先前的治疗。截至2020年9月28日数据截止，已有12例患者参加并接受了CTX110。报告了截至数据截止日期至少完成一个月治疗和评估的11名患者的数据。
患者先接受了三天fludarabine（30毫克/平方米 /天）和环磷酰胺（500毫克/平方米/天）的清除淋巴细胞，然后为接受了CTX110。主要终点包括剂量限制毒性, 安全性和总响应率。次要终点包括响应持续时间，无进展生存期和总体生存期。
安全性: 在剂量水平1-3的10名患者中没有观察到剂量限制毒性。尽管同种异体CAR-T供体和患者之间的HLA高度不匹配，但没有发生移植物抗宿主病（GvHD）。没有观察到对CTX110的输注反应。细胞因子释放综合征（CRS）发生在三名患者中（30％），每种情况均为2级或以下，并通过使用tocilizumab治愈。一名患者（10％）患有2级免 疫效应细胞相关的神经毒性综合症，通过标准干预措施在24小时内改善。 CTX110输注后又发生了另外两个严重不良事件（周周蜂窝织炎和发热性中性粒细胞减少症），但均已解决，并且确定与疾病进展或CTX110无关。在剂量水平4的一名患者接受了CTX110的第5天，患者经历了2级细胞因子释放综合征，并在5天内消失。第25天的PET/CT评估显示患者已完全缓解。第26天，该患者因发热性中性粒细胞减少而住院，并出现了短期记忆丧失和意识模糊的症状。最终发展为需要气管插管。最初，他曾接受类固醇，anakinra和鞘内化疗治疗免疫效应细胞相关的神经毒性综合症，但无改善。后来发现他患有重新激活的HHV-6和HHV-6脑炎，并接受了抗病毒治疗。最后决定撤回支持治疗，患者在CTX110输注后52天死亡。
临床活性（n = 11）: 发现有剂量依赖性抗肿瘤活性的早期证据。疾病评估是根据2014年卢加诺（Lugano）响应标准通。
剂量水平1 (30×106 CAR + T细胞, n=3): 无临床响应;
剂量水平2 (100×106 CAR + T细胞, n=3): 总临床响应: n=1 （33%）, 完全响应, n=1 （33%）;
剂量水平3 (300×106 CAR + T细胞, n=4): 总临床响应: n=2 （50%）, 完全响应, n=2 （50%）;
剂量水平4 (600×106 CAR + T细胞, n=1): 总临床响应: n=1 （100%）, 完全响应, n=1 （100%）。
在剂量水平3时，2/4的患者完全响应。这两名患者仍处于完全响应中。四名完全响应者具有较深的反应，包括淋巴结外疾病完全消退，所有淋巴结疾病均正常化至1.5公分或更小, 以及Deauville评分为2或更低。另外，有一位患者的骨髓中有30％淋巴母细胞的, 在CTX110输注后获得了完全清除。 无论是弥漫性大B细胞淋巴瘤, 转化的滤泡性淋巴瘤，或者原发性难治性和自体干细胞移植后复发的患者均达到完全响应。在剂量水平2及以上级别，所有患者均在多个时间点检测到CTX110，在1-2周出现峰扩展，最晚的在输注后180天才检测到细胞。
CTX110 is a CRISPR-edited allogeneic CAR-T cell targeting CD19 + B cell malignancies. The following is based on the news release from the drug company.
This is a phase I open label, multi-center clinical trial (CARBON) that evaluates the safety and efficacy of CTX110 in adult patients with relapsed or refractory non-Hodgkin’s lymphoma who had received at least two previous lines of treatment. As of the data cutoff deadline of September 28, 2020, 12 patients had participated and received CTX110. Data was reported on 11 patients who had completed at least one month of treatment and evaluation was completed as of the data cutoff date.
Patients first received three days of fludarabine (30 mg/m2/day) and cyclophosphamide (500 mg/m2/day) to achieve lymphopenia and then received CTX110. Primary endpoints include dose limiting toxicity, safety and overall response rate. Secondary endpoints include response duration, progression-free survival and overall survival.
Safety: No dose limiting toxicity was observed in 10 patients at dose levels 1-3. Despite the high degree of HLA mismatch between the allogeneic CAR-T donor and the patient, graft versus host disease (GvHD) did not occur. No infusion reaction to CTX110 was observed. Cytokine release syndrome (CRS) occurred in three patients (30%), each of which was grade 2 or below, and was cured by the use of tocilizumab. One patient (10%) had grade 2 immune effector cell-related neurotoxicity syndrome, which was improved within 24 hours by standard interventions. Two other serious adverse events (cellulitis and febrile neutropenia) occurred after CTX110 infusion, but they were resolved and were determined not to be related to disease progression or CTX110. At dose level 4, one patient on the 5th day patient experienced a grade 2 cytokine release syndrome, which disappeared within 5 days. The PET/CT assessment on day 25 showed that the patient had completed remission. On the 26th day, the patient was hospitalized with febrile neutropenia and developed short-term memory loss and confusion. Eventually he developed pbstructin and required tracheal intubation. He had received steroids, anakinra and intrathecal chemotherapy to treat immune effector cell-related neurotoxicity syndrome, but there was no improvement. It was later discovered that he was suffering from reactivation of HHV-6 and HHV-6 encephalitis and received antiviral treatment. Finally, it was decided to withdraw supportive treatment, and the patient died 52 days after CTX110 infusion.
Clinical activity (n = 11): Early evidence of dose-dependent anti-tumor activity was found. The disease assessment was based on the Lugano response criteria in 2014.
Dose level 1 (30×106 CAR + T cells, n=3): no clinical response;
Dose level 2 (100×106 CAR + T cells, n=3): overall response: n=1 (33%), complete response, n=1 (33%);
Dose level 3 (300×106 CAR + T cells, n=4): overall response: n=2 (50%), complete response, n=2 (50%);
Dose level 4 (600×106 CAR + T cells, n=1): overall response: n=1 (100%), complete response, n=1 (100%).
At dose level 3, 2/4 of the patients had CR. These two patients are still in CR. Four complete responders had deeper responses, including complete regression of extranodal disease, all lymph node diseases normalized to 1.5 cm or less, and Deauville score of 2 or lower. In addition, a patient with 30% lymphoblasts in the bone marrow was completely cleared after CTX110 infusion. Whether patients had diffuse large B-cell lymphoma, transformed follicular lymphoma, or primary refractory or patients who relapsed after autologous stem cell transplantation have achieved a complete response. At dose level 2 and above, CTX110 was detected in all patients at multiple time points, with peak expansion occurring in 1-2 weeks, and cells were detected as late as 180 days after infusion.
手术前内分泌治疗对保乳手术率的影响 (10/31/2020)
Neoadjuvant endocrine therapy on the rates of breast-conversing surgery
在最近的SSO国际会议上，MD安德森癌症中心的Hunt博士谈到了手术前内分泌治疗对保乳手术率的数据。ACOSOG Z1031试验招募了临床II至III期, 绝经后乳腺癌女性, 大多数患者患有T2肿瘤，临床为淋巴结阴性。 雌激素受体为强阳性（Allred 评分 =6-8），中位年龄为66岁（范围：43-90岁），中位肿瘤大小为4.0厘米（范围：2-13厘米）。在基线时，参与者要么是保乳手术边缘患者（MBCS），或是仅能接受乳房切除术（MO），或是无法手术的患者（IO）。她们随机分配给三种芳香化酶抑制剂之一（阿那曲唑，来曲唑，依西美坦）。她们接受了16-18周的芳香化酶抑制剂治疗，随后进行了手术。队列B包括245位在2至4周进行活检的患者。如果发现Ki67指数大于10％，则建议患者进行手术前化疗或手术。
17名患者没有接受手术: 由于拒绝（12人），病情进展（3人）或其他健康状况（2人）。 MBCS组的保乳手术率为78％（163/207）； MO组的保乳手术率为42％（77/163）； 以及IO的保乳手术率为（3/4）的75％。一共有67％的妇女能够进行保乳手术（有五名患者的乳房没有残留疾病），而这些女性中在初次就诊时50％以上被认为需要进行乳房切除术。在进行了淋巴结手术的患者中，有47％的患者在手术时没有淋巴结转移。局部或区域复发是12例患者中的首次事件，估计5年累积发生率为1.6％。在这些患者中，有9例接受了部分乳房切除术，而3例进行了全乳房切除术。三种芳香化酶抑制剂基本上是等效的，并且在临床上是有效的。
研究者认为, 对绝经后雌激素受体为强阳性的乳腺癌, 手术前内分泌疗法的保乳手术率略高于术前化疗, 手术后局部复发事件很少见。
At the recent SSO International Conference, Dr. Hunt from MD Anderson Cancer Center talked about the data about preoperative endocrine therapy on breast-conserving surgery rates. The ACOSOG Z1031 trial recruited clinical stage II to III postmenopausal women with breast cancer. Most of the patients had T2 tumors and clinically negative lymph nodes. The estrogen receptor was strongly positive (Allred score = 6-8), the median age was 66 years (range: 43-90 years), and the median tumor size was 4.0 cm (range: 2-13 cm). At baseline, participants were either marginal for breast-conserving surgery (MBCS), candidates for mastectomy only (MO), or inoperable (IO). They were randomly assigned to one of three aromatase inhibitors (anastrozole, letrozole, and exemestane). Patients received aromatase inhibitor therapy for 16-18 weeks, followed by surgery. Cohort B included 245 patients who underwent biopsy in 2 to 4 weeks. If the Ki67 index is found to be greater than 10%, the patient is advised to undergo chemotherapy or surgery before surgery.
Seventeen patients did not undergo surgery: due to refusal (12 people), disease progression (3 people) or other medical comorbidities (2 people). The breast-conserving surgery rate in the MBCS group was 78% (163/207); the breast-conserving surgery rate in the MO group was 42% (77/163); and the breast-conserving surgery rate in the IO group was 75% (3/4). A total of 67% of women were able to undergo breast-conserving surgery (five patients had no residual disease in the breast), and more than 50% of these women were considered to need mastectomy at the first visit. Among patients who underwent lymph node surgery, 47% had no lymph node metastasis at the time of surgery. Local or regional recurrence is the first event in 12 patients, with an estimated 5-year cumulative incidence of 1.6%. Of these patients, 9 patients underwent partial mastectomy and 3 underwent total mastectomy. The three aromatase inhibitors were basically equivalent and clinically effective.
Researchers believe that for postmenopausal breast cancer that is strongly positive for estrogen receptors, the preoperative endocrine therapy has a slightly higher breast-conserving operation rate than preoperative chemotherapy as per Dr. Hunt, and local recurrences after surgery are rare.
参考文献 Reference Hunt K. et al: 2020 SSO International Conference on Surgical Cancer Care 2020; Sept 25, Abstract 5.
第一线单药派姆单抗改善了转移性结直肠癌患者的无进展生存期和生活质量 (10/25/2020)
First line pembrolizumab improvise life quality compared with standard chemotherapy in metastatic colorectal cancer
在2020年5月的一份中期报告中已有报道, 在未经治疗的微卫星不稳定性高（MSI-H）和/或错配修复缺乏（dMMR）的转移性结直肠癌患者中，第一线单药派姆单抗（pembrolizumab）与标准治疗化疗相比，单药派姆单抗改善了无进展生存期 [16.5个月，相对于化疗的8.2个月（危险比[HR] = 0.60; P = .0002）]。最近的ESMO会议上还报告了生活质量的改善。
这是一项III期临床试验（KEYNOTE-177）, 参加者为转移性结直肠癌癌病人, 确诊为MSI-H / dMMR, 且从未接受过对转移性疾病的全身治疗，随机分配1:1，每3周接受200 mg派姆单抗，最长两年，或者治疗者选择的mFOLFOX6或FOLFIRI化疗, 每两周一次，有或没有贝伐单抗或西妥昔单抗。 生活质量问题问卷是在基线以及在长达一年或治疗结束的各个时间点（包括停药后30天）进行的。该分析包含来自272例（141位接受派姆单抗治疗和131位接受化疗）接受至少1个剂量治疗并完成至少1 次健康相关的生活质量评估的数据。从基线到预定的第18周，计算出95％的置信区间和标称的两面p值。恶化时间（TTD）被定义为从基线下降≥10点，并通过Kaplan-Meier方法和Cox回归模型进行了评估。
接受派姆单抗的患者表现出改善的整体健康状况和自我报告的健康状况，以及几个TTD参数的延长。整体健康状况/ 生活质量的最小二乘均值（LSM ）差异为9（95％CI，4.2-13.7; p = 0.0002）。身体功能, 社交功能和疲劳都以派姆单抗组为优。
It has been reported in an interim report in May 2020 that in untreated patients with metastatic colorectal cancer with high microsatellite instability (MSI-H) and/or deficient mismatch repair (dMMR), Compared with standard chemotherapy, single-agent pembrolizumab improved the progression-free survival [16.5 months, compared with 8.2 months of chemotherapy (hazard ratio [HR] = 0.60; P = .0002)]. The recent ESMO meeting also reported improvement quality of life.
This is a phase III clinical trial (KEYNOTE-177). The participants are patients with metastatic colorectal cancer, who are diagnosed with MSI-H / dMMR and have never received systemic treatment for metastatic disease. They were randomly assigned 1: 1 to receive 200 mg pembrolizumab every 3 weeks for a maximum of two years, or mFOLFOX6 or FOLFIRI chemotherapy of physicians’ choice, once every two weeks, with or without bevacizumab or cetuximab. The quality of life questionnaire was conducted at baseline and at various time points up to one year or the end of treatment (including 30 days after drug withdrawal, whichever comes first). The analysis included data from 272 patients (141 received pembrolizumab and 131 received chemotherapy) who received at least one dose and completed at least one health-related quality of life assessment. From baseline to the scheduled 18th week, the 95% confidence interval and the nominal two-sided p-value were calculated. Time to deterioration (TTD) was defined as a decrease of ≥10 points from the baseline, and was evaluated by the Kaplan-Meier method and Cox regression model.
Patients receiving pembrolizumab showed improved overall health and self-reported health status, as well as prolonged TTD in several parameters. The least squares mean (LSM) difference in overall health status/quality of life was 9 (95% CI, 4.2-13.7; p = 0.0002) in favor of the pembrolizumab group. There was also improvement in physical functioning, social functioning and fatigue.
参考文献 Reference André T et al. ESMO Virtual Congress 2020; Sept 19 André T et al. ASCO Virtual Scientific Program 2020; abstr LBA4
Sacituzumab govitecan对激素受体阳性/HER-2阴性的乳腺癌有效 (10/24/2020)
Sacituzumab govitecan appears to be active for advanced stage of ER-positive/HER-2-negative breast cancer
Sacituzumab govitecan是由SN-38（化疗药伊立替康的活性代谢产物）组成的新型人源化单克隆抗体-药物偶联物，抗体靶向滋养层抗原2（Trop2, 在大约80％至90％的乳腺癌中都存在）。
这是一项I/II期临床试验, 有54位局部晚期或己转移的雌激素受体阳性/HER-2阴性的乳腺癌病人参加, 中位年龄为54岁 （范围33-79）。她们接受过一种或多种先前治疗; 67％的患者接受了3种或以上激素治疗。每21天的第1天和第8天以10 毫克/公斤的剂量接受sacituzumab govitecan，并每8周进行一次重新扫描, 直至疾病进展或出现不可接受的毒性。
所有患者均接受至少1个剂量的sacituzumab govitecan。中位剂量数为11（范围为1-74），中位治疗时间为4个月（范围为0.2-26个月）。在数据报导时，有23名患者死亡。根据研究结果，在5.3个月时失去了1例患者的随访，而缺少了1例患者。在长期随访的29例患者中，有10例仍在接受治疗。这10例患者中有7例获得部分缓解，其他3例疾病稳定。
在中位随访11.5个月后，, 中位响应持续时间为7.4个月（95％CI，4.4-18.3个月）。中位无进展生存期为6.8个月（95％CI，4.6-8.9个月）。中位总生存期为12个月（95％CI 9.0-18.2）。客观响应率为31％（n = 17）。 17名患者达到了部分响应（没有完全响应）。部分/完全响应以及疾病稳定持续大于或等于6个月的临床获益率为48％（n = 26）。
观察到的不良事件是可以忍受的，与早期报道中观察到的不良事件相似。没有发生与治疗有关的死亡。不良事件可以通过其它药物或调节剂量来控制, 28％的患者接受了生长因子。
Sacituzumab govitecan已于今年四月获得FDA批准用于三阴性乳腺癌, 最近有报道可延长三阴性乳腺癌总生存期（危险比为0.48 [95％CI，0.38-0.59; p < 0.0001], ASCENT试验）。 对雌激素受体阳性/HER-2阴性的转移性乳腺癌病人, 一项III期随机试验（TROPiCS-02）正在进行中（NCT03901339, https://clinicaltrials.gov/ct2/show/NCT01631552）。
Sacituzumab govitecan is a new humanized monoclonal antibody-drug conjugate composed of SN-38 (the active metabolite of the chemotherapeutic drug irinotecan). The antibody targets trophoblast antigen 2 (Trop2, found in approximately 80% to 90% of breast cancer patients).This is a phase I/II clinical trial involving 54 locally advanced or metastatic estrogen receptor positive/HER-2 negative breast cancer patients, with a median age of 54 (range 33-79) . They had received one or more previous treatments; 67% of patients had received 3 or more hormone treatments. Sacituzumab govitecan was given at 10 mg/kg every 21 days on the 1st and 8th days, and repeat scans were performed every 8 weeks until disease progresses or unacceptable toxicity.All patients received at least one dose of sacituzumab govitecan. The median number of dose was 11 (range 1-74), and the median treatment time was 4 months (range 0.2-26 months). At the time of data report, 23 patients had died. According to the results of the study, 1 patient was lost for follow-up at 5.3 months, and 1 patient was missing. Of the 29 patients followed up for a long time, 10 were still receiving treatment. Seven of these 10 patients achieved partial remission, and the other three had stable disease.After a median follow-up of 11.5 months, the median duration of response was 7.4 months (95% CI, 4.4-18.3 months). The median progression-free survival was 6.8 months (95% CI, 4.6-8.9 months). The median overall survival was 12 months (95% CI 9.0-18.2). The objective response rate was 31% (n = 17). Seventeen patients achieved a partial response (no complete response). The clinical benefit rate of partial/complete response and stable disease for greater than or equal to 6 months was 48% (n = 26).The adverse events were similar to those observed in earlier reports. There were no treatment-related deaths. Adverse events could be controlled by other drugs or dose adjustment. Twenty-eight percent patients received growth factor support.Sacituzumab govitecan has been approved by the FDA in April this year for triple-negative breast cancer. Most recently, it has been reported that it can prolong the overall survival in triple-negative breast cancer (hazard ratio 0.48 [95% CI, 0.38-0.59; p <0.0001], ASCENT trial ). For patients with estrogen receptor positive/HER-2 negative metastatic breast cancer, a phase III randomized trial (TROPiCS-02) is underway (NCT03901339, https://clinicaltrials.gov/ct2/show/NCT01631552).参考文献 ReferenceBardia A et al. ASCO, 2018 abstr 1004
Bardia A et al. ESMO 2020; Sept 20抗CD47抗体Magrolimab有望用于骨髓增生异常综合征和急性粒细胞性白血病的治疗 (10/18/2020)
Anit-CD47 monoclonal antibody Magrolimab is hopeful in MDS and AML
Magrolimab加阿扎胞苷（azacitidine, AZA）改善了急性粒细胞性白血病（AML）和骨髓增生异常综合征（MDS）患者的预后。该组合对于具有TP53突变的患者特别有希望。
CD47使癌细胞逃避巨噬细胞吞噬, 其表达增加预示患者的转归会恶化。Magrolimab是首个抗CD47单克隆抗体，可通过巨噬细胞吞噬作用促进肿瘤细胞的消除。这是一项Ib期临床试验（NCT03248479）, 有39例未经治疗的MDS和29例未经治疗的AML病人参加, 该研究检查了Magrolimab/AZA结合是否会产生协同作用。该研究的主要目的是检查单用Magrolimab或与AZA联合使用的安全性，以及疗效。 MDS和AML患者具有较差的细胞遗传风险，分别为72％和64％。p53突变分别存在于13％和45％的患者中。
在参加的MDS或AML患者中，研究的前60天中没有发生死亡; 仅在接受少数Magrolimab/AZA联合治疗的患者中（1.5％）观察到因药物相关不良事件而终止治疗。治疗没有引起明显的中性粒细胞减少或血小板减少，并且大多数患者在治疗期间改善了中性粒细胞和血小板计数。 大多数患者的血红蛋白显著改善。
在MDS患者中，Magrolimab/AZA组合使用产生91％的总响应率，以及42％的完全响应（在6个月时增加至56％）。 AML患者经历了64％的总响应率（56％的完全响应/不完全血液学缓解）。这些结果比AZA单药疗法（完全响应率6％-17％）更有优势。 在58％的MDS患者和64％的AML患者中实现了红细胞输血的独立性，而且分别在35％和50％的患者中看到了细胞遗传学完全响答。 联合治疗对p53突变的患者特别有效，MDS和AML的总响率均为75％，完全缓解率分别为42％和50％。在报告的研究时间内，未达到中位生存期。再次，这些是持久的。基于这些数据，扩展队列在继续进行中。
Combination treatment with Magrolimab and azacitidine (AZA) improves the prognosis of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). This combination holds particular promise for patients with TP53 mutations.
CD47 allows cancer cells to escape macrophage phagocytosis, and its increased expression is associated with worse outcome. Magrolimab is the first anti-CD47 monoclonal antibody that can promote elimination of tumor cells through macrophage phagocytosis. This is a phase Ib clinical trial (NCT03248479), with 39 untreated MDS and 29 untreated AML patients. The study examined whether the Magrolimab/AZA combination can produce synergistic effects. The main purpose of the study is to examine afety and efficacy of Magrolimab alone or in combination with AZA. The participating MDS and AML patients had poorer cytogenetic risk of 72% and 64%, respectively. The p53 mutations are present in 13% and 45% of patients, respectively.
Among the participating MDS and AML patients, no deaths occurred in the first 60 days of the study; only a small number of patients (1.5%) who received the Magrolimab/AZA combination discontinued treatment due to drug-related adverse events. The treatment did not cause significant neutropenia or thrombocytopenia, and most patients improved their neutrophil and platelet counts during treatment. The level of hemoglobin in most patients improved significantly.
In MDS patients, the Magrolimab/AZA combination resulted in an overall response rate of 91% and a complete response of 42% (increased to 56% at 6 months). AML patients experienced a 64% overall response rate (56% complete response/incomplete hematological remission). These results are more favorable compared with AZA monotherapy (complete response rate of 6%-17%). The independence of RBC transfusion was achieved in 58% of MDS and 64% of AML patients, and a complete cytogenetic response was seen in 35% and 50% of patients, respectively. Combination therapy is particularly effective for patients with p53 mutations. The overall response rate of MDS and AML was both 75%, and the complete remission rate was 42% and 50%, respectively. During the reported study time, the median survival was not reached and the response was durable. Based on these data, the expansion cohort is still recruiting.
参考文献 Reference Sallman DA et al. ASCO Virtual Meeting 2020; abstr 7507
延迟手术前化疗会对乳腺癌患者生存产生影响 (10/17/2020)
Delayed neoadjuvant chemotherapy could impact overall survival in breast cancer patients
接受手术前全身化疗的乳腺癌患者其肿瘤通常表现出高风险特征。研究者检查了从乳腺癌诊断到化疗开始时间间隔与生存结果之间的关系。研究者回顾性分析了1995年1月至2015年12月之间诊断为I–III期浸润性原发性乳腺癌患者，总共包括5,137名患者, 她们在美国MDAnderson癌症中心接受了手术前全身化疗。根据从乳腺癌诊断到化疗的时间, 将患者分为三个亚组：0-30天，31-60天和≥61天。主要终点是总生存期。
中位随访时间为6.5年。在诊断后0-30、31-60和≥61天之内接受手术前全身化疗的患者，估计的5总生存率分别为87％，85％和83％（p = .006）。在多变量分析中，与化疗间隔0-30天相比，延迟化疗≥61天与死亡风险增加相关（31-60天：危险比[HR] = 1.05 [95％置信区间（CI）0.92 –1.19]；≥61天，HR = 1.28 [95％CI 1.06-1.54]）。在分层分析中，对于I和II期患者，化疗启动延迟与死亡风险增加之间的相关性具有统计学意义（31-60天：HR = 1.22 [95％CI 1.02-1.47]；≥61天，HR = 1.41 [95％CI 1.07–1.86]）; 对于HER2阳性肿瘤患者（≥61天，HR = 1.86 [95％CI 1.21-2.86]）。 临床医生应避免在这些人群中延误治疗。
Breast cancer patients undergoing neoadjuvnt systemic chemotherapy (NSC) before surgery often exhibit high-risk features in their tumors. The researchers from MD Anderson Cancer Center examined the relationship between the time interval from breast cancer diagnosis to the start of NSC and survival outcomes. Patients with stage I–III invasive primary breast cancer diagnosed between January 1995 and December 2015 were analyzed, and a total of 5,137 patients received NSC before surgery in the cancer enter. According to the time from breast cancer diagnosis to NSC, patients were divided into three subgroups: 0-30 days, 31-60 days and ≥61 days. The primary endpoint is overall survival.
The median follow-up time was 6.5 years. For patients who received NSC within 0-30, 31-60, and ≥ 61 days after diagnosis, the estimated 5-year overall survival rates were 87%, 85%, and 83%, respectively (p = .006). In a multivariable analysis, compared with the interval of 0-30 days, delayed chemotherapy for ≥ 61 days was associated with an increased risk of death (31-60 days: hazard ratio [HR] = 1.05 [95% confidence interval (CI) 0.92 –1.19 ]; ≥ 61 days, HR = 1.28 [95% CI 1.06-1.54]). In stratified analyses, for patients with stage I and II breast cancer, the correlation between delayed chemotherapy initiation and increased risk of death was statistically significant (31-60 days: HR = 1.22 [95%CI 1.02-1.47]; ≥ 61 days , HR = 1.41 [95%CI 1.07–1.86]); for patients with HER2-positive tumors (≥ 61 days, HR = 1.86 [95%CI 1.21-2.86]). Clinicians should avoid delaying treatment in these groups of patients
参考文献 Reference Sanford RA et al. The oncologist 2020; 25:749
靶向ILT4的MK-4830抗体有希望的I期临床试验结果 (10/11/2020)
MK-4830 monoclonal antibody targeting ILT4 shows promising results in phase I clinical trial
MK-4830是新型人IgG4单克隆抗体, 它针对抑制性免疫检查点受体 ”髓样特异性抗免疫球蛋白样转录物4（ILT4）”，后者是一种跨膜蛋白, 属于ILT4家族。ILT4在肿瘤免疫逃逸中起关键作用。 ILT4主要由髓样细胞表达，包括巨噬细胞等以及某些肿瘤细胞。抗ILT4单克隆抗体MK-4830靶向结合ILT4，从而防止ILT4配体与其受体结合, 并阻止ILT4介导的信号传导。这消除了肿瘤微环境中ILT4的免疫抑制活性，激活了包括肿瘤坏死因子-α（TNFalpha）在内的促炎性细胞因子的表达，并增强了细胞毒性T淋巴细胞介导的抗肿瘤免疫反应。
这是一项I期临床试验（NCT03564691）, 有84位局部晚期实体瘤病人参加, 参与研究的大多数患者（51％）已经接受了三个或三个以上先前的疗法。患者的中位年龄为62岁。共有50例患者接受了MK-4830单一疗法的治疗，另有34例患者接受了MK-4830加上派姆单抗（pembrolizumab）的治疗。无论是单独使用MK-4830还是与派姆单抗联合给药，所有患者每三周均接受递增剂量的静脉MK-4830。研究的主要终点为安全性和耐受性，而药代动力学为次要终点，探索性目标包括客观响应率，评估受体占有率（receptor occupancy）以及血液和肿瘤中治疗缓解的免疫相关性。
该药耐受性良好, 任何级别的与治疗有关的不良事件都与报告的派姆单抗一致。总体而言， 52％患者报告的大多数与治疗有关的不良事件为1级和2级。关于剂量递增数据，未达到最大耐受剂量，也没有发生剂量限制性毒性。
药代动力学分析表明，在最高剂量水平下，MK-4830达到稳态血清药代动力学。在这些高剂量水平下，几乎所有患者的血液受体占有率≥95％。15名患者提供了治疗前和治疗中的活检，这使得能够在治疗之前和期间初步评估受体占有率和免疫细胞亚群之间的关联。
在这些患者中，观察到客观反应，包括三名先前未对抗PD-1治疗产生响应的患者，以及两名在先前抗PD-1治疗中进展的患者。功效数据的初步分析显示11项客观响应，其中2例达到完全响应，9例显示部分响应。一位接受单药MK-4830治疗的患者出现了响应。这些反应是持久的，有些患者继续接受治疗超过一年。
结论: 基于这些初步结果，靶向ILT4的MK-4830抗体安全性良好, 既可作为单一疗法，也可与派姆单抗联合使用。
MK-4830 is a new type of human IgG4 monoclonal antibody, which targets the inhibitory immune checkpoint receptor “myeloid specific anti-immunoglobulin-like transcript 4 (ILT4)”, which is a transmembrane protein belonging to the ILT4 family . ILT4 plays a key role in tumor immune escape. It is mainly expressed by myeloid cells, including macrophages etc and some tumor cells. The anti-ILT4 monoclonal antibody MK-4830 targets ILT4, thereby preventing ILT4 ligand from binding to its receptor and preventing ILT4-mediated signal transduction. This eliminates the immunosuppressive activity of ILT4 in the tumor microenvironment, activates the expression of pro-inflammatory cytokines including tumor necrosis factor-α (TNFalpha), and enhances the anti-tumor immune response mediated by cytotoxic T lymphocytes.
This is a phase I clinical trial (NCT03564691), with 84 participants with locally advanced solid tumors. Most of the patients (51%) who participated in the study have received three or more lines of previous therapies. The median age of the patients was 62. A total of 50 patients received MK-4830 monotherapy, and another 34 patients received MK-4830 plus pembrolizumab. Whether using MK-4830 alone or in combination with pembrolizumab, all patients received escalating doses of intravenous MK-4830 every three weeks. The primary endpoint of the study is safety and tolerability, while pharmacokinetics is the secondary endpoint. The exploratory goals include objective response rate, assessment of receptor occupancy, and immune correlates of response in blood and tumor. .
The drug is well tolerated, and any level of treatment-related adverse events are consistent with that of eported pembrolizumab. Overall, the majority of treatment-related adverse events reported by 52% of patients were grade 1 and 2. Regarding the dose escalation data, the maximum tolerated dose was not reached and no dose limiting toxicity occurred.
Pharmacokinetic analysis showed that at the highest dose level, MK-4830 reached steady-state serum pharmacokinetics. At these high dose levels, almost all patients have blood receptor occupancy ≥ 95%. Biopsies of 15 patients were obtained before and during treatment, which allowed preliminary assessment of the association between receptor occupancy and immune cell subpopulations before and during treatment.
Among the participants, objective response was observed, including three patients who had not previously responded to anti-PD-1 therapy, and two patients who had progressed on previous anti-PD-1 therapy. Preliminary analysis of efficacy data showed 11 objective responses, of which 2 cases achieved complete response and 9 cases showed partial response. A patient who was treated with a single-agent MK-4830 responded. These responses were long-lasting, and some patients continued to receive treatment for more than a year.
Conclusion: Based on these preliminary results, the MK-4830 antibody targeting ILT4 can be used safely as a monotherapy or in combination with pembrolizumab.
参考文献 Reference Siu LL et al. ESMO Virtual Congress 2020辅助性Abemaciclib加内分泌用于治疗高复发率的早期乳腺癌 (10/10/2020)
Adjuvant abemaciclib plus standard endocrine therapy in early breast cancer patients at high risk of recurrence
这是一项开放标签临床试验（monarchE）, 从2017年7月至2019年8月，一共随机分配了来自38个国家/地区的5,637名乳腺癌患者（雌激素受体阳性，HER2阴性，淋巴结阳性），2,808人接受标准的内分泌治疗, 加上每天两次150 毫克的abemaciclib（连续2年），2,829人接受标准的内分泌治疗。大多数患者已接受过放疗/化疗。 患者必须有4个或更多的阳性淋巴结，或1-3个阳性淋巴结, 并且或者肿瘤大小≥5 厘米，或者组织学等级3, 或者中心测试Ki-67≥20％。主要终点是意图治疗人群的无浸润性癌症生存期。
在第二次预先计划的疗效中期分析中（2020年3月数据截止），每组的中位随访时间约为15.5个月。共有323名患者具有无浸润性癌症生存事件，其中abemaciclib组为136名（4.8％），对照组为187名（6.6％）。abemaciclib组与对照组的危险比（HR）为0.75（95％CI = 0.60-0.93，P = 0.01, ）, 2年无浸润性癌症生存率分别为92.2％和88.7％。
大多数浸润性癌症事件都是远处复发, 包括abemaciclib组的87例和对照组的138例患者。 Abemaciclib组显著改善了无远处转移的生存率（HR = 0.72，95％CI = 0.56-0.92，P = 0.01），两年发生率分别为93.6％和90.3％。在分析时，总体生存数据尚不成熟，死亡发生率分别为1.4％相对于1.3％。
Abemaciclib组任何级别的最常见不良事件是腹泻，中性粒细胞减少和疲劳; 对照组为关节痛，潮热和疲劳。发生≥3级不良事件的机率为45.9％相对于12.9％。严重不良事件发生率分别为12.3％相比于7.2％，最常见的是肺炎（0.8％相比于0.5％）。 静脉血栓栓塞发生率分别为2.3％和0.5％，其中肺栓塞发生率为0.9％相比于0.1％。间质性肺疾病发生率为2.7％相比于1.2％。不良事件导致abemaciclib组的11例患者死亡（其中2例为腹泻和肺炎, 可能与治疗有关）相比于对照组的7例。
研究人员的结论是：Abemaciclib与内分泌治疗联合使用, 是首个CDK4/6抑制剂，用于雌激素受体阳性，HER2阴性，淋巴结阳性的早期乳腺癌高危复发者, 显著其改善无浸润性癌症生存。
This is an open-label clinical trial (monarchE). From July 2017 to August 2019, a total of 5,637 breast cancer patients (estrogen receptor positive, HER2 negative, lymph node positive) from 38 countries/regions were randomly assigned, 2,808 people received standard endocrine therapy plus 150 mg of abemaciclib twice a day (for 2 consecutive years), 2,829 people received standard endocrine therapy. Most patients had received radiotherapy/chemotherapy. The patients must have 4 or more positive lymph nodes, or 1-3 positive lymph nodes, and either tumor size ≥ 5 cm, or histological grade 3, or central Ki-67 ≥ 20%. The primary endpoint is the invasive disease-free survival in the intent-to-treat population.
In the second pre-planned interim efficacy analysis (data cutoff in March 2020), the median follow-up time for each group was approximately 15.5 months. A total of 323 patients had invasive disease-free survival events, including 136 (4.8%) in the abemaciclib group and 187 (6.6%) in the control group. The hazard ratio (HR) of the abemaciclib group vs. the control group was 0.75 (95% CI = 0.60-0.93, P = 0.01), and the 2-year rates were 92.2% and 88.7%, respectively.
Most invasive disease-free survival events were distant recurrences, observed in 87 patients in the abemaciclib group and 138 patients in the control group, The Abemaciclib group significantly improved metastases-free survival rate (HR = 0.72, 95% CI = 0.56-0.92, P = 0.01), and the two-year rates were 93.6% and 90.3%, respectively. At the time of analysis, the overall survival data was not mature, and the mortality rate was 1.4% versus 1.3%.
The most commonly adverse events of any grade in the Abemaciclib group were diarrhea, neutropenia and fatigue; in the control group they were arthralgia, hot flashes and fatigue. Adverse events ≥ grade 3 were 45.9% versus 12.9%. The incidence of serious adverse events was 12.3% vs. 7.2%, and the most common was pneumonia (0.8% vs. 0.5%). The incidence of venous thromboembolism was 2.3% vs. 0.5%, and the incidence of pulmonary embolism was 0.9% compared to 0.1%. The incidence of interstitial lung disease was 2.7% compared to 1.2%. Adverse events led to death of 11 patients in the abemaciclib group (2 of which were diarrhea and pneumonia, which may be related to treatment) compared to 7 patients in the control group.
The researchers concluded that: Abemaciclib combined with endocrine therapy is the first CDK4/6 inhibitor for estrogen receptor-positive, HER2-negative, and lymph node-positive early breast cancer patients at high risk of recurrence. It significantly improves invasive disease-free survival.
参考文献 Reference Johnson S RD et al. J Clin Onc 2020; Sept 20. DOI: 10.1200/JCO.20.02514
Ivosidenib可延长胆管癌和IDH1突变患者无进展生存时间 (10/6/2020)
Ivosidenib provided prolonged progression-free survival in cholangiocarcinoma with IDH1 mutation
这是一项全球随机3期临床试验（ClarIDHy），用于先前治疗过的IDH1突变型胆管癌患者，这些患者已接受过一或两次全身治疗后疾病进展。患者按照2:1的比例, 随机接受每日一次单剂500 毫克Ivosidenib或安慰剂，并允许在放射学进展时交叉使用Ivosidenib。至2020年5月30日的数据截止时，已有185例患者被随机分组，其中Ivosidenib组为124例患者，安慰剂组为61例患者。在放射影像学进展时，安慰剂的43例患者（70％）交叉而使用开放标签的Ivosidenib。ClarIDHy试验的主要终点是放射影像学的无进展生存期。
试验结果表明，与安慰剂患者相比，Ivosidenib组的无进展生存期有统计学意义的改善（危险比[HR] 0.37； 95％CI 0.25-0.54，p < 0.0001），中位无进展生存期为2.7个月, 相比对于安慰剂组的1.4个月。截至数据截止，Ivosidenib组患者的估计无进展生存率在六个月时为32％，在12个月时为22％，而在数据截止后的六个月内，没有随机分配给安慰剂的患者没有进展或死亡。次要终点包括安全性和耐受性，总缓解率，总生存期，缓解持续时间，药代动力学，药效动力学和生活质量评估。
基于这些数据，美国国家综合癌症网络 （NCCN）推荐Ivosidenib作为治疗IDH1突变的胆管癌晚期患者。
This is a global randomized phase 3 clinical trial (ClarIDHy) for previously treated patients with IDH1 mutant cholangiocarcinoma who had already received one or two systemic treatments and their disease progressed. Patients were randomized to receive a single dose of 500 mg Ivosidenib or placebo once a day in a 2:1 ratio, and cross-over was allowed to receive Ivosidenib when progressed radiographically. As of the data cutoff on May 30, 2020, 185 patients were randomized, including 124 patients in the Ivosidenib group and 61 patients in the placebo group. When progressed radiographically, 43 patients (70%) on placebo crossed over to receive open-label Ivosidenib. The primary endpoint of the ClarIDHy trial is progression-free survival determined radiographically.
The results of the trial showed that compared with placebo, the progression-free survival of the Ivosidenib group was significantly improved (hazard ratio [HR] 0.37; 95% CI 0.25-0.54, p <0.0001), and the median progression-free survival was 2.7 months, compared to 1.4 months for the placebo group. As of the data cutoff, the estimated progression-free survival rate for patients in the Ivosidenib group was 32% at six months and 22% at 12 months. Within six months after the data cutoff, there were no death of patients who were not randomized to placebo. Secondary endpoints include safety and tolerability, overall response rate, overall survival, duration of response, pharmacokinetics, pharmacodynamics, and quality of life assessment.
Based on these data, the National Comprehensive Cancer Network (NCCN) recommends Ivosidenib as a treatment for patients with advanced cholangiocarcinoma with IDH1 mutation.
参考文献 Reference Abou-Alfa GK et al. 2020 ESMO Virtual Congress LBA10_PR
溶瘤痘苗病毒（Olvi-Vec）为主的免疫化疗治疗铂类耐药/治性卵巢癌病人 (10/3/2020)
Olvi-Vec-primed immunochemotherapy treating platinum-resistant/refractory ovarian cancer
溶瘤痘苗病毒OLVImulecogene nanivacirepvec（Olvi-Vec）为主的免疫化学疗法显示，在先前接受过多重治疗的卵巢癌患者中，可能有望延长总体生存率。病毒诱导的肿瘤微环境变化可能逆转对铂的耐药性。
这是一项II期临床试验（VIRO-15 , NCT02759588）, 有27位铂类耐药/难治性卵巢癌病人参加, 她们接受了中位数为4线的治疗, 铂类难治性为52％，耐药性为48％。患者连续2天接受腹膜内输注Olvi-Vec治疗，然后静脉输注卡铂双联±贝伐单抗, 然后维持单一药物±贝伐单抗。患者进行病毒治疗前后的活检和血液检查以进行分析。主要目标是总体缓解率和无进展生存期。次要目标包括总体生存期，CA-125反应，安全性和临床研究。
所有患者的中位总生存期为15.7 个月（95％CI：12.3-23.5）。 9/27（33.3％）的患者存活时间 > 18个月，其中4例存活时间超过3-4年。在患有铂金难治性疾病的患者中，中位总生存期为15.2个月（95％CI：10.8-33.6）。
Olvi-Vec治疗的安全性与先前的1b期研究一致。
Oncolytic vaccinia virus OLVImulecogene nanivacirepvec (Olvi-Vec) primed immunochemotherapy has been promising to increase overall survival in patients heavily treated ovarian cancer patients. Virus-induced changes in the tumor microenvironment may play a role in reversing resistance to platinum.
This is a phase II clinical trial (VIRO-15, NCT02759588), with 27 platinum-resistant/refractory ovarian cancer patients. They received a median of 4-lines of prior therapy, with 52% being platinum-refractory, and 48% platinum-resistant. All the patients received intraperitoneal infusion of Olvi-Vec for 2 consecutive days, followed by intravenous infusion of carboplatin combo ± bevacizumab, and then maintained with the single drug ± bevacizumab. Patients underwent biopsy and blood tests before and after virus treatment for analysis. The primary goals were overall response rate and progression-free survival. Secondary goals included overall survival, CA-125 response, safety and translational research.
The median overall survival of all patients was 15.7 months (95% CI: 12.3-23.5). 9/27 (33.3%) patients survived longer than 18 months, 4 of them survived more than 3-4 years. Among patients with platinum refractory diseases, the median overall survival was 15.2 months (95% CI: 10.8-33.6).
The safety of Olvi-Vec treatment was consistent with the previous phase 1b study.
Sotorasib治疗具有KRASG12C基因突变的肿癌 (9/27/2020)
Sotorasib targeting cancers harboring KRASG12C mutation
目前为止，还没有针对具有KRAS突变癌症的疗法,。 Sotorasib是一个选择性且不可逆地靶向KRASG12C的小分子（这种突变发生在13％的非小细胞肺癌和1-3％的大肠癌和其他癌症中）。
这是一项I期临床试验, 在剂量递增和扩展队列中, 总共129例患者参加（59例非小细胞肺癌，42例大肠癌，28例其他肿瘤）。患者以前接受过中位数为3种的转移性抗癌治疗（0到11）。患者每天口服一次Sotorasib。主要终点是安全性。关键的次要终点是药代动力学和客观响应。治疗中没有观察到剂量限制的毒性作用或与治疗有关的死亡。共有73例患者（56.6％）发生治疗相关的不良事件； 15名患者（11.6％）为3或4级事件。
在患有非小细胞肺癌的亚组中，32.2％（19例患者）有确诊的客观响应（完全或部分响应），88.1％（52例患者）疾病得到控制（客观响应或疾病稳定）；中位无进展生存期为6.3个月（范围从0.0+到14.9 [+表示该值包括在数据截止时患者的数据]）。在患有大肠癌的亚组中，有7.1％（3例患者）有确诊的客观响应和73.8％（31例患者）疾病得到控制。中位无进展生存期为4.0个月（范围从0.0+到11.1+）。在胰腺癌，子宫内膜癌，阑尾癌和黑色素瘤患者中也观察到了响应。
So far, there is no target therapy for cancers harboring KRAS mutations. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C, which occurs in 13% of non-small cell lung cancer and 1-3% of colorectal cancer and other cancers.
So far, there is no target therapy for cancers harboring KRAS mutations. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C, which occurs in 13% of non-small cell lung cancer and 1-3% of colorectal cancer and other cancers.
This is a phase I clinical trial. In the dose escalation and expansion cohort, a total of 129 patients participated (59 cases of non-small cell lung cancer, 42 cases of colorectal cancer, 28 cases of other tumors). Patients have previously received a median of 3 anticancer treatments in the metastatic setting (0 to 11). Patient took Sotorasib orally once a day. The primary endpoint is safety. The key secondary endpoints are pharmacokinetics and objective response. No dose-limiting toxic effects or treatment-related deaths were observed during treatment. A total of 73 patients (56.6%) had treatment-related adverse events; grade 3 or 4 events were seen in 15 patients (11.6%).
In the subgroup with non-small cell lung cancer, 32.2% (19 patients) had a confirmed objective response (complete or partial response), and 88.1% (52 patients) had disease under control (objective response or stable disease); The median progression-free survival was 6.3 months (range from 0.0+ to 14.9 [with + indicating that the value includes patient’s data at the time of data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed objective response and 73.8% (31 patients) had disease under control. The median progression-free survival was 4.0 months (range from 0.0+ to 11.1+). Responses have also been observed in patients with pancreatic cancer, endometrial cancer, appendix cancer and melanoma.
参考文献 Reference Hong DS et al. NEJM 2020; 383:1207
曲妥珠单抗在早期乳腺癌中治疗持续时间: 荟萃分析 (9/26/2020)
Meta-analysis of duration of transtuzumab in early breast cancer
在一项荟萃分析中，对于早期乳腺癌患者，给予曲妥珠单抗不到1年的无病生存期不低于曲妥珠单抗治疗1年。另外，较短的治疗时间与降低充血性心力衰竭风险有关。
该研究包括来自六个随机临床试验的数据，该试验比较了2005年1月至2019年6月间早期乳腺癌患者接受1年曲妥珠单抗的辅助治疗和不到1年的治疗的情况。其中有5个试验个体参与者数据可提取用于荟萃分析。主要结果指标是无病生存期。所有六个临床试验均采用非劣效性而设计。与结束1年曲妥珠单抗的治疗持续时间相比，若缩短治疗时间的无病生存期P值 <.025则认为是具有非劣效性。如果较短治疗时间与1年曲妥珠单抗的治疗持续时间的危险比（HR）的95％置信区间（CI）上限小于1.3（随机分组的非劣效性中位边界），则较短的治疗时间被认为是具有非劣效性。
参与者数据分析包括11,376名患者。较短时间组的5年无病生存率为85.42％，而1年组为87.12％，估计的危险比为1.14（95％CI = 1.03-1.25；非劣效性P = .004）。 5年总生存率为92.39％相对于93.46％（HR = 1.17，95％CI = 1.02-1.33）。
试验水平分析包括11,603名患者。短于1年曲妥珠单抗的病程对于1年组，无病生存的危险比是1.15（95％CI = 1.04-1.26；非劣效性P = .002）。总体生存的危险比为1.17（95％CI = 1.03-1.33）。
治疗时间较短的患者充血性心力衰竭的风险较低（3.9％vs 6.9％，相对风险[RR] = 0.53，95％CI = 0.38-0.74； P <.001）出现无症状的左心室射血分数下降（5％vs 7％，RR = 0.71，95％CI = 0.50–1.00； P = .049）。
研究人员认为, 这项荟萃分析的结果表明，就无病生存期而言，曲妥珠单抗的持续治疗时间短于1年并且不劣于持续1年给药，但心脏毒性作用却较小。两组之间的绝对生存率差异很小，在资源有限的情况下，尤其对临床上低危疾病患者，较短的治疗时间也是合适的。
参考文献 Reference Gupta S et al.JAMA Network Open, 2020 doi:10.1001/jamanetworkopen.2020.11777
亲脂性他汀类降脂药可减少卵巢癌患者的死亡率 (9/20/2020)
Use of lipophilic statins associated with reduced ovarian cancer mortality
亲脂性他汀类药物*（用于降低胆固醇）与降低卵巢癌患者的死亡率有关。
以往几项较小的研究评估了他汀类药物和卵巢癌患者的死亡率，但结果不一。有一项针对10,000多名卵巢癌女性进行的大规模研究使研究人员能够评估不同的他汀类药物类型及其对不同亚型卵巢癌的影响。
研究人员将芬兰国家癌症登记系统的数据与1995年至2015年间诊断为卵巢癌的10,062名妇女的处方药相关联，以研究诊断前后他汀类药物的使用与卵巢癌死亡率之间的关系。在10,062名患者中，有2,621名使用他汀类药物，其中80％使用了亲脂性他汀类药物。诊断时的中位年龄总体为62岁，而他汀类药物使用者的平均年龄为67岁。
与从未使用他汀类药物的患者相比，使用任何他汀类药物可使卵巢癌死亡率降低40％ （HR，0.60； 95％CI，0.54-0.66）。 在5年时，HR为0.63（95％CI，0.56-0.70）。而亲脂性他汀类药物与卵巢癌死亡率降低43％有关。
所有卵巢癌亚型的女性死亡率都有所降低，但是降低的幅度却有所不同。死亡率最大的降低发生在高度浆液性癌（降低40％, 95% CI, 32-47)）和子宫内膜样卵巢癌（降低50％）的患者中。一些妇女在卵巢癌诊断后开始使用亲脂性他汀类药物，她们的死亡率也降低了。降低的幅度与治疗意图也有关, 接受治愈性意图治疗的女性（HR，0.19； 95％CI，0.18-0.20）相比于使用姑息意图治疗的女性（HR，0.41； 0.39-0.40）使用他汀类药物的获益更大。亲脂性atorvastatin (Lipitor) 或 simvastatin (Zocor) 与死亡率降低特别相关（HR为0.35, 95％CI，0.22-0.50, 和0.25, 95％CI，0.22-0.34）, 它们与未使用他汀类药物相比，患者生存率均有提高。
在成为标准做法之前，一般需要在随机临床试验中确认结果并在其他人群中进行研究。但由于长期生存率低，很难在长期研究中检查卵巢癌。以上研究得益于高质量的数据和多年来的收集。
*亲脂性他汀类药物: atorvastatin, cerivastatin , fluvastatin, lovastatin, pitavastatin, 和simvastatin,
亲水性他汀类药物: pravastatin 和rosuvastatin
Lipophilic statins* (used to lower cholesterol) have been linked to reduced mortality in patients with ovarian cancer.
Several small studies in the past have evaluated the association between statins and ovarian cancer mortality, but the results have been mixed. Recently, a large study of more than 10,000 women with ovarian cancer allowed researchers to evaluate different types of statins and their effects on different subtypes of ovarian cancer.
The researchers correlated data from the Finnish National Cancer Registry with the prescription drugs of 10,062 women diagnosed with ovarian cancer between 1995 and 2015. They studied the relationship between statin use before and after diagnosis and mortality from ovarian cancer. Of the 10,062 patients, 2,621 used statins, and 80% of them used lipophilic statins. The median age at diagnosis was 62 years, and the median age of statin users was 67 years.
Compared with patients who never used statins, the use of any statin reduced the mortality of ovarian cancer by 40% (HR, 0.60; 95% CI, 0.54-0.66). At 5 years, the HR was 0.63 (95% CI, 0.56-0.70). The lipophilic statins were associated with a 43% reduction in ovarian cancer mortality.
The mortality rate of women with all ovarian cancer subtypes was decreased, but the magnitude of the decrease was different. The greatest reduction in mortality occurred in patients with high-grade serous cancer (40% reduction, 95% CI, 32-47)) and endometrioid ovarian cancer (50% reduction). Some women started using lipophilic statins after the diagnosis of ovarian cancer, and their mortality rate was also reduced. The magnitude of the reduction was also related to treatment intent. In women receiving treatment of curative intent, the benefits of using statins were greater. (HR, 0.19; 95% CI, 0.18-0.20) versus women on palliative treatment (HR, 0.41; 0.39-0.40). The lipophilic atorvastatin (Lipitor) or simvastatin (Zocor) was particularly associated with reduced mortality (HR 0.35, 95% CI, 0.22-0.50, and 0.25, 95% CI, 0.22-0.34 respectively), with improved survival rate compared with non-statin users.
Before becoming a standard practice, it is generally necessary to confirm the results in randomized clinical trials and then conduct research in other populations. However, due to the low long-term survival rate, it is difficult to detect ovarian cancer in long-term studies. The above observation benefited from high-quality data and years of collection.
*Lipophilic statins: atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin,
Hydrophilic statins: pravastatin and rosuvastatin
抑制SHP2可望克服肺癌的多种耐药机制 (9/19/2020)
SHP2 inhibitor overcomes resistance mechanisms towards osimertinib
新型SHP2抑制剂IACS-13909能够克服非小细胞肺癌的多种治疗耐药机制，提示了一种可能的新方法来治疗已对靶向EGFR抑制剂奥西替尼（osimetinib）产生抗药性的癌症。
含Src同源2域的磷酸酶（SHP2）是一种磷酸酶，可介导多个受体酪氨酸激酶下游的信号传导，是MAPK通路完全激活所必需的。在临床前研究中，SHP2抑制作用已在受体酪氨酸激酶激活的癌症中证明了肿瘤生长抑制作用。奥西替尼是一种靶向EGFR抑制剂，为治疗具有特定EGFR突变的非小细胞肺癌患者第一线药物。但是，肺癌细胞会发展出奥西替尼耐药性，这可能是通过阻止药物活性的EGFR突变引起的，或者是通过激活了补偿性信号通路。 SHP2是一种在这些途径下游发挥作用的蛋白质，并且它是MAPK信号传导途径所必需的。IACS-13909是SHP2的一种特异且有效的变构（allosteric）抑制剂，可抑制通过MAPK途径的信号传导。研究者报导了 IACS-13909有效地阻止了具有广谱活化作为致癌驱动因子的肿瘤的增殖。在具有EGFR依赖性和非EGFR依赖性耐药机制的 ”EGFRmut” 奥西替尼耐药的非小细胞肺癌模型中，以单药IACS-13909或与奥西替尼联合给药, 在体外有效抑制肿瘤细胞增殖, 联合给药还导致动物模型体内肿瘤消退更持久。这些数据表明，靶向SHP2可以为克服通过多种机制发生的奥西替尼耐药性而提供新的治疗策略。
研究者期待着今年晚些时候将SHP2抑制剂推入临床。
The new SHP2 inhibitor IACS-13909 can overcome multiple resistance mechanisms of non-small cell lung cancer, suggesting a possible new method to treat cancers that have developed resistance to the targeted EGFR inhibitor osimetinib.
Src homology 2 domain (SHP2) phosphatase is an enzyme that can mediate the signaling downstream of multiple receptor tyrosine kinases and is necessary for the complete activation of the MAPK pathway. In preclinical studies, SHP2 inhibition has demonstrated tumor growth inhibition in cancers activated by receptor tyrosine kinases. Osimertinib is a targeted EGFR inhibitor and is the first-line drug for the treatment of non-small cell lung cancer patients harboring a specific EGFR mutation. However, lung cancer cells eventually develop resistance to osimetinib, which may be caused by EGFR mutations that prevent drug activity, or by activating compensatory signaling pathways. SHP2 is a protein that functions downstream of these pathways, and it is necessary for the MAPK signaling pathway. IACS-13909 is a specific and effective allosteric inhibitor of SHP2, which can inhibit signal transduction through the MAPK pathway. Researchers reported that IACS-13909 effectively prevented the proliferation of tumors with broad-spectrum activation as a oncogenic driver. In a non-small cell lung cancer model with EGFR-dependent and EGFR-independent drug resistance mechanisms of EGFRmut osimertinib, single-drug IACS-13909 or in combination with osimertinib can effectively inhibit tumors in vitro cell proliferation and co-administration also led to longer-lasting tumor regression in animal models. These data indicate that targeting SHP2 can provide a new therapeutic strategy for overcoming osimertinib resistance that occurs through multiple mechanisms.
Researchers expect to bring SHP2 inhibitors into clinic use later this year.
参考文献 Reference Sun Y et al. Cancer Res 2020; Sept 14, doi: 10.1158/0008-5472.CAN-20-1634
下一代ALK抑制剂Ensartinib提高ALK阳性的非小细胞肺癌的无进展生存期 (9/13/2020)
Next-generation ALK-inhibitor Ensartinib benefited ALK-positive non-small cell lung cancer in PFS
Ensartinib在以往酶促测定中已显示出比crizotinib强10倍的功效，并且在I / II期试验中, 对crizotinib难治性晚期ALK阳性非小细胞肺癌患者（包括脑转移）显示出抗肿瘤活性。
在一项III期临床试验（eXalt3）中, 有89位IIIB / IV期ALK阳性非小细胞肺癌患者参加, 患者没有事先接受过ALK抑制剂治疗，最多可以接受过一种先前的化疗方案。患者被随机分配使用Ensartinib（每天225 毫克, 64例）或crizotinib（每天两次250 毫克, 25例），不允许交叉试验。研究的主要终点是无进展生存期。主要的次要终点包括总体生存率，响应率，响应时间和大脑治疗失败的时间。
预先设定的中期（2020年7月1日）分析显示，在当地确定的ALK阳性患者的意向治疗人群中，使用ensartinib的中位无进展生存期为25.8个月，而使用crizotinib的患者的为12.7个月（HR = 0.51； P = .0001）。但在中央确诊的ALK阳性的患者中，ensartinib尚未达到中位无进展生存期（HR = 0.45； P <.0001）。
Ensartinib治疗的患者的客观响应率为75％，而crizotinib患者为67％。完全响应率分别为14％和6％。接受crizotinib患者的中位响应持续时间为27.3个月, 而接受ensartinib治疗的患者尚未达到中位响应持续时间。在36个月时仍有58.7％的患者继续使用ensartinib, 但crizotinib组中只有26.7％仍在接受治疗。在基线时可测量的脑转移患者中，ensartinib的客观缓解率也优于crizotinib（64％vs 21％）。在基线时没有脑转移的患者中，接受ensartinib的患者的12个月复发率为4.2％，而接受crizotinib的患者为23％（HR = 0.32； P = .0001）。任一治疗组均未达到中位总生存期。
Ensartinib显示出良好的安全性。低度皮疹和转氨酶升高是最常见不良事件。Ensartinib代表ALK阳性非小细胞肺癌患者的第一线治疗新选择。
Ensartinib was shown in the past enzymatic assays 10 times stronger efficacy than crizotinib. In the phase I/II trial, it demonstrated anti-tumor activity for patients with advanced ALK-positive NSCLC patients (including brain metastases) refractory to crizotinib.
In a phase III clinical trial (eXalt3), 89 patients with stage IIIB/IV ALK-positive NSCLC patients participated. They did not receive prior ALK inhibitors, and could not receive more than one previous chemotherapy regimen. Patients were randomly assigned to receive ensartinib (225 mg per day, 64 patients) or crizotinib (250 mg twice a day, 25 patients), and no crossover was allowed. The primary endpoint of the study is progression-free survival. The primary secondary endpoints include overall survival, response rate, response duration, and time to brain treatment failure.
A pre-determined mid-term (July 1, 2020) analysis showed that among the locally-determined ALK-positive patients (intention-to-treat), the median progression-free survival of ensartinib was 25.8 months, while that of crizotinib group was 12.7 months (HR = 0.51; P = .0001). However, among the centrally-determined ALK-positive patients, ensartinib has not yet reached the median progression-free survival (HR = 0.45; P <.0001).
The objective response rate of patients treated with ensartinib was 75%, while that of patients treated with crizotinib was 67%. The complete response rates were 14% vs. 6%, respectively. The median response duration of patients receiving crizotinib was 27.3 months, while patients receiving ensartinib have not yet reached the median response duration. At 36 months, 58.7% of patients continued to use ensartinib, while only 26.7% of the crizotinib group were still receiving treatment. Among patients with measurable brain metastases at baseline, the objective response rate of ensartinib was also better than that of crizotinib (64% vs 21%). Among patients without brain metastases at baseline, the 12-month recurrence rate for patients who received ensartinib was 4.2%, compared with 23% for patients who received crizotinib (HR = 0.32; P = .0001). None of the treatment groups reached the median overall survival.
Ensartinib showed good safety. Low-grade skin rash and elevated transaminases were the most common adverse events. Ensartinib represents a new first-line treatment option for ALK-positive NSCLC patients
参考文献 Reference
Horn L et al. 2020 World Conference on Lung Cancer. Presidential Symposium. Abstract 2 Horn L et al. Clin Cancer Res 2018; 24:2771-2779 Yang Y et al. Lancet Respir Med 2020; 8:45-53
免疫检查点抑制剂增加结核病感染的罕见风险 (9/12/2020)
Check-point inhibitors may rarely increase infections of mycobacteria infections
研究人员使用FDA不良事件报告系统（FAERS），报告了在2015年1月1日至2020年3月31日期间, 所有接受抗PD-1或PD-L1患者的结核病和非典型分枝杆菌感染病例。
FAERS 报告系统中, 所有药物引起的的不良事件为10,146,481起, 其中, PD-L1抑制剂引起的不良事件为73,886起, PD-1抑制剂引起的为62,823起。FAERS报告系统中结核病为5,560起, PD-1 / PD-L1抑制剂引起的为 72起, 。FAERS 中非典型分枝杆菌感染为336起, PD-1 / PD-L1抑制剂导致的为 13起。
在PD-1 / PD-L1抑制剂引起的72例结核病例中，45例（62.5％）归因于nivolumab，18例（25％）归因于pembrolizumab。其余病例归因于atezolizumab（6.94％）或durvalumab（5.55％）。此外，确定了13例非典型分枝杆菌感染病例，其中9例（69.23％）归因于nivolumab，2例（15.38％）归因于pembrolizumab。其余病例归因于atezolizumab（7.69％）或durvalumab（7.69％）。
根据FAERS数据的分析，PD-1 / PD-L1抑制剂导致的结核病的报告整体风险（ROR）为1.79（95％CI，1.42至2.26）（p < 0.0001），而非典型分枝杆菌感染为5.49（95％CI，3.15至 9.55）（p < 0.0001）。在72例结核病例中，有13例（18.05％）报告死亡。 报告结核病最常见的起源地区是亚洲（70.83％）。
研究作者认为, 尽管这种并发症很少见，但使用免疫检查点抑制剂的医生应意识到这种可能性。
Researchers used the FDA Adverse Event Reporting System (FAERS) to analyze total cases of tuberculosis and atypical mycobacterial infections in all patients receiving anti-PD-1 or PD-L1 inhibitors between January 1, 2015 and March 31, 2020.
In FAERS, there were 10,146,481 adverse events caused by all drugs. Among them, there were 73,886 adverse events associated with PD-L1 inhibitors and 62,823 associated with PD-1 inhibitors. There were 5,560 cases of tuberculosis in FAERS, and 72 cases associated with PD-1/PD-L1 inhibitors. In FAERS, there were 336 cases of atypical mycobacterial infections and 13 cases associated with PD-1/PD-L1 inhibitors.
Of the 72 tuberculosis cases related to PD-1/PD-L1 inhibitors, 45 (62.5%) were attributed to nivolumab and 18 (25%) were attributed to pembrolizumab. The remaining cases were attributed to atezolizumab (6.94%) or durvalumab (5.55%). In addition, 13 cases of atypical mycobacterial infection were identified, of which 9 (69.23%) were attributable to nivolumab and 2 (15.38%) were attributable to pembrolizumab. The remaining cases were attributed to atezolizumab (7.69%) or durvalumab (7.69%).
According to the analysis of FAERS data, the reported overall risk (ROR) of tuberculosis caused by PD-1/PD-L1 inhibitors is 1.79 (95% CI, 1.42 to 2.26) (p <0.0001), while atypical mycobacterial infection is 5.49 (95% CI, 3.15 to 9.55) (p <0.0001). Among 72 tuberculosis cases, 13 (18.05%) reported deaths. The most common origin area reported for tuberculosis is Asia (70.83%).
The study authors believe that although this complication is rare, doctors who use immune checkpoint inhibitors should be aware of this possibility.
参考文献 Reference Anand K et al. ESMO Open. 2020; 5:866
无驱动程序改变的IV期非小细胞肺癌治疗: ASCO和OH（Ontario Health）联合指南 (9/6/2020)
Therapy for stage IV non-small cell lung cancer without driver alterations: Joint guideline from ASCO and OH
请参阅: 实体肿瘤->肺->非小细胞->无法切除或转移
Please see Solid Tumor–>Lung–>Non-small Cell –> Unresectable or metastatic
Berzosertib加上吉西他滨治疗耐铂类高度浆液性卵巢癌 (9/5/2020)
Berzosertib plus gemcitabine effective in treating platinum-resistant high-grade serous ovarian cancer
由于TP53突变，高度浆液性卵巢癌几乎全部丢失G1 / S检查点过早进入S期, 使细胞易于受到ATR抑制。选择性ATR抑制剂Berzoserti和吉西他滨组合, 在高度浆液性卵巢癌中显示出比单独的吉西他滨可接受的毒性和更好的疗效。
在一项多中心，开放标签，随机2期研究中，美国11个不同中心招募了复发性耐铂的浆液性卵巢癌的女性, 符合条件的患者被随机分配（1：1）在第1天和第8天接受静脉吉西他滨（1000 毫克/平方米）或在第2天和第9天接受吉西他滨加静脉berzosertib（210 毫克/平方米）的治疗。直至疾病进展或无法忍受的毒性。主要终点是研究者评估的无进展生存期。
在2017年2月14日至2018年9月7日之间，对88例患者进行了评估，其中70例被随机分配到单独接受吉西他滨治疗（36例）或吉西他滨联合berzosertib的治疗（34例）。在数据截止日期（2020年2月21日），吉西他滨联合berzosertib组的中位随访时间为53.2周（25.6–81.8）和43.0周（吉西他滨单独治疗组, 23.2–69.1）。联合组的中位无进展生存期为22.9周（17.9–72.0），单药治疗组的中位无进展生存期为14.7周（90％CI 9.7–36.7）（危险比0.57， 90％CI 0.33-0.98；p = 0·044）。与治疗相关的最常见的3或4级不良事件是嗜中性粒细胞计数降低（单药组36例患者中的14例[39％]，联合组34例患者中16例[47％]）和血小板计数降低（2个[6％]对8个[24％]）。单独组中有10名（28％）患者出现了严重的不良事件，而联合组中的9名（26％）患者发生了严重不良事件。单独组因败血症发生了1例与治疗有关的死亡，而联合组因肺炎引起了1例与治疗有关的死亡。
这是ATR抑制剂对任何肿瘤类型的的首次随机研究。在耐铂类的高级浆液性卵巢癌中向吉西他滨添加berzosertib具有益处, 值得进一步的研究。
Due to TP53 mutation, almost all of the high-serous ovarian cancer loses the G1/S checkpoint and enters the S phase prematurely, making the cells vulnerable to ATR inhibition. The combination of the selective ATR inhibitor Berzoserti and gemcitabine shows acceptable toxicity and better curative effect than gemcitabine alone in highly serous ovarian cancer.
In a multicenter, open-label, randomized phase 2 study, 11 different centers in the United States recruited women with recurrent platinum-resistant serous ovarian cancer, and eligible patients were randomly assigned (1:1) on day 1. And on the 8th day received intravenous gemcitabine (1000 mg/m²) or received gemcitabine plus intravenous berzosertib (210 mg/m²) on the 2nd and 9th days. Until the disease progresses or intolerable toxicity. The primary endpoint is the progression-free survival as assessed by the investigator.
Between February 14, 2017 and September 7, 2018, 88 patients were evaluated, of which 70 were randomly assigned to receive gemcitabine therapy alone (36 patients) or gemcitabine combined with berzosertib therapy (34 patients) . At the data cutoff date (February 21, 2020), the median follow-up time for the gemcitabine combined with berzosertib group was 53.2 weeks (25.6-81.8) and 43.0 weeks (gemcitabine alone treatment group, 23.2-69.1). The median progression-free survival in the combination group was 22.9 weeks (17.9-72.0), and the median progression-free survival in the monotherapy group was 14.7 weeks (90% CI 9.7-36.7) (hazard ratio 0.57, 90% CI 0.33- 0.98; p = 0·044). The most common treatment-related grade 3 or 4 adverse event was a decrease in neutrophil count (14 out of 36 patients in the monotherapy group [39%], 16 out of 34 patients in the combination group [47%]) And a decrease in platelet count (2 [6%] vs. 8 [24%]). Serious adverse events occurred in 10 (28%) patients in the single group, while 9 (26%) patients in the combined group experienced serious adverse events. There was 1 treatment-related death in the single group due to sepsis, and 1 treatment-related death in the combined group due to pneumonia.
This is the first randomized study of an ATR inhibitor for any tumor type. The addition of berzosertib to gemcitabine in platinum-resistant advanced serous ovarian cancer has benefits and is worthy of further research.
参考文献 Reference Konstantinopoulos PA et al. Lancet Oncol. 2020; 21: 957–68
RET抑制剂selpercatinib在RET基因融合的肺癌患者中的效果 (8/30/2020)
Efficacy of RET inhibitor selpercatinib in RET fusion-positive lung cancer patients
RET融合约占非小细胞肺癌的1至2％, 是致癌驱动因素。 在所有RET融合阳性癌症中，多达一半转移到大脑。
在一项I-II期临床试验（LIBRETTO-001）中, 有105名RET融合阳性非小细胞肺癌患者参加, 他们曾接受过铂类化疗但未接受过selpercatinib单独治疗; 39名先前未接受治疗。主要终点客观响应。次要终点包括响应持续时间，无进展生存期和安全性。
在105名连续入组患者中，客观响应的百分比为64％（95％[CI]，54-73）。中位响应时间为17.5个月（95％CI，12-无法评估），在中位随访时间12.1个月中, 63％的响应持续进行。在39名先前未接受治疗的患者中，客观响应的百分比为85％（95％CI，70-94），并且90％的响应在6个月时仍在进行。在入组时中枢神经系统转移的11例患者中，具有客观颅内响应的百分比为91％（95％CI，59-100）。
最常见的3级或更高级别不良事件是高血压（14％的患者），丙氨酸转氨酶水平升高（12％），天冬氨酸转氨酶水平升高（10％），低钠血症（6％），和淋巴细胞减少症（6％）。 531名患者中有12名（2％）因药物相关不良事件而停用了selpercatinib。
Selpercatinib对RET融合阳性非小细胞肺癌患者具有持久的功效，包括颅内活性，而且毒性低。Selpercatinib也显示了对RET改变的甲状腺癌的活性，它已于2020年5月被FDA批准用于RET阳性肺癌和甲状腺癌。
根据2020 Virtual ASCO的报道，另一个RET抑制剂BLU-667（pralsetinib）对RET变更的非小细胞肺癌有活性。在II期研究中，35名可评估的患者中，先前接受治疗的患者中有60％肿瘤显著缩小，该治疗消除了一名患者的癌症，直到报告时为止, 阻止了全部35名患者的癌症生长。
RET fusion accounts for about 1 to 2% of non-small cell lung cancer and is a cancer driving factor. As many as half of all RET fusion-positive cancers will develop brain metastasis.
In a phase I-II clinical trial (LIBRETTO-001), 105 patients with RET fusion-positive non-small cell lung cancer participated. They had received platinum chemotherapy but had not received selpercatinib alone; another 39 had not previously received treatment . Objective response was the primary endpoint. Secondary endpoints include response duration, progression-free survival, and safety.
Among 105 consecutive patients, the percentage of objective responses was 64% (95% [CI], 54-73). The median response duration was 17.5 months (95% CI, 12-not reached), and 63% of the responses continued during the median 12.1 months of follow-up. Among 39 patients who had not previously received treatment, the percentage of objective responses was 85% (95% CI, 70-94), and 90% of responses were still ongoing at 6 months. Among the 11 patients with measurable central nervous system metastases at the time of enrollment, the percentage of objective intracranial responses was 91% (95% CI, 59-100).
The most common adverse events of grade 3 or higher were hypertension (14% of patients), elevated alanine aminotransferase levels (12%), elevated aspartate aminotransferase levels (10%), hyponatremia (6%), and lymphopenia (6%). Twelve (2%) of 531 patients discontinued selpercatinib due to drug-related adverse events.
Selpercatinib has durable effects on patients with RET fusion-positive non-small cell lung cancer, including intracranial activity, with a low toxicity profile. Selpercatinib has also been shown to be active against RET-altered thyroid cancer, and it has been approved by the FDA for RET-positive lung cancer and thyroid cancer in May 2020.
According to 2020 Virtual ASCO, another RET inhibitor BLU-667 (pralsetinib) is also active against RET-altered non-small cell lung cancer. In the phase II study, among the 35 evaluable patients, 60% of previously treated patients had tumors significantly reduced. The treatment eliminated one patient’s cancer and, at the time of report, prevented cancer growth in all 35 patients.
参考文献 Reference Drilon A et al. NEJM 2020; 383:813 Boral A et al. 2020 Virtual ASCO Meeting
口服Tesetaxel用于转移性乳腺癌患者 (8/29/2020)
Oral Tesetaxel in metastatic breast cancer
Tesetaxel（口服紫杉烷）在转移性乳腺癌患者中进行的第3期研究的结果为阳性。
CONTESSA是一项正在北美，欧洲和亚洲18个国家/地区的180个研究地点进行的随机，3期试验, 研究Tesetaxel在转移性乳腺癌患者中的活性。 有685位病人参加, 她们为HER2）阴性，激素受体阳性的转移性乳腺癌患者, 先前用过在术前或辅助剂中用过紫杉烷。根据疾病需要，患者必须接受过内分泌治疗（无论是否接受CDK4/6抑制剂）。她们按1：1比例随机分配，每21天周期的第一天口服Tesetaxel27 毫克/平方米加上减少剂量的卡培他滨（capecitabine）（每21天周期14天口服1,650毫克/平方米/天）比较于单独使用卡培他滨（每21天周期的14天口服2,500 毫克/平方米 /天），主要终点是无进展生存期。次要功效终点是总体生存率，客观响解率和疾病控制率。
试验组的中位无进展生存期为9.8个月，而单剂卡培他滨为6.9个月。疾病发展或死亡的风险降低了28.4％（HR = 0.716; 95％CI：0.573-0.895; p = 0.003）。
Tesetaxel加卡培他滨的不良反应与以前的临床研究结果一致。 ≥5％的患者发生的≥3级治疗紧急不良事件为：中性粒细胞减少（试验组为71.2％，而卡培他滨为8.3％）；腹泻（13.4％相对于8.9％）；手足综合症（6.8％相对于12.2％）;发热性中性粒细胞减少症（12.8％相对于1.2％）；疲劳（8.6％相对于4.5％）；低血钾症（8.6％相对于2.7％）; 和贫血（8.0％相对于2.1％）。
导致≥1％患者中止治疗的不良事件为：中性粒细胞减少或发热性中性粒细胞减少（4.2％相对于1.5％）；神经疾病（3.6％相对于0.3％）；腹泻（0.9％相对于1.5％）；和手足综合症（0.6％相对于2.1％）。Tesetaxel加卡培他滨治疗的患者中有23.1％的患者因任何不良事件而终止治疗，而卡培他滨单独治疗的患者为11.9％。
根据制造Tesetaxel公司发布的新闻 。
A phase 3 study of Tesetaxel (oral taxane) in patients with metastatic breast cancer was positive.
CONTESSA is a randomized, phase 3 trial being conducted at 180 research sites in 18 countries/regions in North America, Europe and Asia to study the activity of Tesetaxel in patients with metastatic breast cancer. There were 685 patients participating. They were HER2 negative and hormone receptor positive metastatic breast cancer patients who had previously been treated with neoadjuvant or adjuvant taxanes. As indicated, the patient must have received endocrine therapy (regardless of whether or not received CDK4/6 inhibitors). They were randomly assigned at 1:1, receiving oral Tesetaxel 27 mg/m² on the first day of every 21-day cycle plus reduced dose of capecitabine (1,650 mg/m²/day orally every 14 days in a 21-day cycle ) , compared with capecitabine alone (2,500 mg/m2/day orally every 14 days of a 21-day cycle). The primary endpoint is progression-free survival. The secondary endpoints are overall survival, objective response rate and disease control rate.
The median progression-free survival of the experimental group was 9.8 months, while the single-dose capecitabine was 6.9 months. The risk of disease progression or death was reduced by 28.4% (HR = 0.716; 95% CI: 0.573-0.895; p = 0.003).
The adverse reactions of Tesetaxel plus capecitabine are consistent with the results of previous clinical studies. Treatment-emergency adverse events ≥ grade 3 that occurred in ≥ 5% of patients were: neutropenia (71.2% in the experimental arm vs. 8.3% in capecitabine alone arm); diarrhea (13.4% vs. 8.9%); hand-foot Symptoms (6.8% vs. 12.2%); febrile neutropenia (12.8% vs. 1.2%); fatigue (8.6% vs. 4.5%); hypokalemia (8.6% vs. 2.7%); anemia (8.0% vs. 2.1%).
Adverse events leading to discontinuation of treatment in ≥1% of patients were: neutropenia or febrile neutropenia (4.2% vs. 1.5%); neuropathy (3.6% vs. 0.3%); diarrhea (0.9% vs. 1.5%); and hand-foot syndrome (0.6% vs. 2.1%). A total of 23.1% of patients treated with Tesetaxel plus capecitabine discontinued treatment due to any adverse events, compared with 11.9% of patients treated with capecitabine alone.
The above is based on the news release by the manufacturing company.
参考文献 Reference https://investor.onconova.com/news-releases/news-release-details/onconova-therapeutics-announces-topline-results-pivotal-phase-3Capmatinib用于MET-阳性的非小细胞肺癌 (8/23/2020)
Capmatinib used in MET-positive NSCLC
Capmatinib的功效在一项多中心，非随机，开放标签, 多队列II期临床试验（GEOMETRY mono-1, NCT02414139）中得到了证实， 97例转移性非小细胞肺癌患者（包括脑转移）纳入试验，他们都证实有MET外显子14突变。患者每天两次口服Capmatinib 400 毫克，直至疾病进展或出现不可接受的毒性。 主要疗效结局指标总响应率。
在28名从未接受过治疗的患者中，总响应率为68％（95％CI：28.9-53.1），缓解期为12.6个月（95％CI：5.5-25.3）。在之前接受2-3线治疗的69位患者中，总响应率为41％（95％CI：29-53），响应持续时间为9.7个月（95％CI：5.5-13.0）。中位无进展生存期为个9.69月（95％CI：5.52-13.9）相对于5.42个月（95％CI：4.17-6.97）。
在这两个队列中，有13名患者在基线脑转移评估时发现有脑转移, 每位患者中位转移数为3.3（1-8）。 RECIST评估显示13名患者中有7名（54％）对治疗产生了颅内响应，其中4名患者所有脑转移病灶完全响应。除一名患者外，所有患者颅内病灶都得到控制。
最常见的不良反应（≥20％的患者）是周围水肿，恶心，疲劳，呕吐，呼吸困难和食欲下降。Capmatinib还可引起间质性肺疾病，肝毒性，和胚胎胎儿毒性。患者可能对日光更为敏感，建议服用Capmatinib时应采取预防措施。
该药已由FDA加快批准。
The efficacy of Capmatinib was confirmed in a multi-center, non-random, open-label, multi-cohort phase II clinical trial (GEOMETRY mono-1, NCT02414139), and 97 patients with metastatic non-small cell lung cancer (including brain metastases) were included in the trial , They all had confirmed MET exon 14 skipping mutation. The patients were given 400 mg of Capmatinib orally twice a day until disease progression or unacceptable toxicity. The primary end-point of the trial was total objective response rate.
In 28 patients who had never received treatment, the overall response rate was 68% (95% CI: 28.9-53.1), and the response duration was 12.6 months (95% CI: 5.5-25.3). Among 69 patients who received 2-3 lines of prior treatment, the overall response rate was 41% (95% CI: 29-53), and the response duration was 9.7 months (95% CI: 5.5-13.0). The median progression-free survival was 9.69 months (95% CI: 5.52-13.9) compared to 5.42 months (95% CI: 4.17-6.97).
In these two cohorts, 13 patients were found to have brain metastases at baseline brain metastasis assessment, and the median number of metastases per patient was 3.3 (1-8). RECIST assessment showed that 7 of 13 patients (54%) had an intracranial response to the treatment, and 4 patients had a complete response in all brain metastases. Except for one patient, all patients with intracranial lesions had disease control.
The most common adverse reactions (≥20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea and loss of appetite. Capmatinib can also cause interstitial lung disease, liver toxicity, and embryofetal toxicity. Patients may be more sensitive to sunlight, and it is recommended to take precautions when taking Capmatinib.
It has received fast-track approval from FDA.
参考文献 Reference Garon EB et al. 2020 Am Asso Cancer Res Virtual Ann Meeting 2020; Abstr CT082 https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-capmatinib-metastatic-non-small-cell-lung-cancer.
一种使胰腺癌对免疫疗法有效应的药物 (8/22/2020)
Devement of a drug that makes pancreatic cancer responsive to immunotherapy
BL-8040是一种CXCR4拮抗剂, 它使肿瘤微环境更易于接受免疫治疗的药物。当它与pembrolizumab联合使用时，能够缩小转移性胰腺癌的肿瘤体积。先前的研究表明胰腺肿瘤是“冷的”，这意味着像pembrolizumab这样的免疫疗法无法对胰腺癌起作用。
COMBAT试验（NCT02826486）是一项前瞻性，开放标签，IIa期临床试验， 这项研究是在美国以及全球其他30个地点（包括西班牙，以色列和韩国）进行的。临床试验分为两部分，于2016年9月开始。治疗的终了目标为客观响应率。
队列1，该组的37名患者的癌症已经接受过一线化疗后进展，他们接受了pembrolizumab和BL-8040的治疗。这种联合疗法似乎使胰腺癌更容易与人体自身的免疫系统协同工作。
文章报导了队列2的22例患者的初步结果（该队列中预计总共40例患者），他们都接受过第一线化疗, 在这项临床试验中，他们接受了BL-8040与pembrolizumab, 以及5-氟尿嘧啶和纳米脂质体伊立替康。客观响应率为32％，是传统化疗治疗的两倍。疾病控制率和中位反应持续时间分别为77％和7.8个月。该临床试验目前处于研究的后续阶段, 这项研究的下一步是将COMBAT组合疗法与其他治疗方案进行比较，例如5-氟尿嘧啶和纳米脂质体伊立替康。
BL-8040 is a CXCR4 antagonist, which makes the tumor microenvironment more susceptible to immunotherapy drugs. When it is used in combination with pembrolizumab, it can reduce the tumor size of metastatic pancreatic cancer. Previous studies have shown that pancreatic tumors are “cold”, which means that immunotherapies like pembrolizumab cannot work against pancreatic cancer.
The COMBAT trial (NCT02826486) is a prospective, open-label, phase IIa clinical trial. This study was conducted in the United States and 30 other locations around the world (including Spain, Israel, and South Korea). The clinical trial is divided into two parts and started in September 2016. The primary goal of treatment is objective response rate.
In cohort 1, 37 patients in this group had cancer that had progressed after receiving first-line chemotherapy. They were treated with pembrolizumab and BL-8040. This combination seemed to make it easier for body’s own immune system to work with pancreatic cancer.
The article reported the preliminary results of 22 patients in cohort 2 (a total of 40 patients are expected in the cohort). All of them received first-line chemotherapy. In this clinical trial, they received BL-8040/pembrolizumab, and 5-Fluorouracil and nanoliposome irinotecan. The objective response rate was 32%, twice that of traditional chemotherapy. The disease control rate and median response duration were 77% and 7.8 months, respectively. The clinical trial is currently in the follow-up phase of the research. The next step in this research is to compare the COMBAT combination therapy with other treatment options, such as 5-fluorouracil and nanoliposome irinotecan.
参考文献 Reference Bockorny B et al. Nature Med 2020; 26: 878
XMT-1536治疗高度浆液性卵巢癌和非小细胞肺腺癌 (8/16/2020)
XMT-1536 for high-grade serous ovarian cancer and NSCLC
FDA授予了XMT-1536用于耐铂类的高度（high-grade）浆液性卵巢癌和非小细胞肺腺癌的快速通道（fast track）名称。她们接受了多达三个之前的全身疗法（包括铂类），或者已经接受了总共四个先前的全身疗法。
XMT-1536是一种抗体-药物偶联物（antibody-drug conjugate, ADC），靶向钠依赖性磷酸转运蛋白（sodium-dependent phosphate transport protein） NaPi2b，后者是在卵巢癌和非小细胞肺腺癌中表达的抗原。该药物正在1期临床试验中进行评估，该临床试验的对象是表达NaPi2b的肿瘤患者，包括卵巢癌和非小细胞肺腺癌。
在I期研究的剂量递增部分（NCT03319628）中，XMT-1536在>20毫克/平方米的剂量下表现出临床活性，在接受过多个全身疗法的卵巢癌和非小细胞肺癌患者中，即使没有预先选择NaPi2b表达, 已证实有客观响应, 并延长了疾病的稳定时间。 XMT-1536具有良好的耐受性，没有其他ADC观察到的严重毒性（如中性粒细胞减少症，周围神经病或眼毒性）。
正在进行的I期研究中的扩展队列（包括先前治疗路线较少的患者）, 有两个队列（1）高度浆液性卵巢癌，输卵管或原发性腹膜癌（最多接受过4个以前的治疗方案）, 评估每4周静脉内给药36和43 毫克/平方米; （2）非小细胞肺腺癌 （接受过铂类，免疫检查点抑制剂和TKI治疗）。患者需要有回顾性评估档案肿瘤组织或新肿瘤活检组织的NaPi2b表达。截至2020年2月10日, 扩展队列纳入了23名患者（19例卵巢癌和4例非小细胞肺癌）：16例以36 毫克/平方米的剂量给药，7例以43 毫克/平方米的剂量给药。不良事件与先前报道的事件相似，包括短暂的AST升高，疲劳，恶心和发热。已经观察到临床客观响应和疾病稳定。卵巢癌的抗肿瘤活性，包括2/20（10％）达到确定的完全响应, 5/20（25％）达到部分响应, 8/20（40％）达到疾病稳定。
FDA granted XMT-1536 fast track for platinum-resistant high-grade serous ovarian cancer and NSCLC adenocarcinoma. The patients could have received up to three previous systemic therapies (including platinum) or have received a total of four previous systemic therapies.
XMT-1536 is an antibody-drug conjugate (ADC) that targets sodium-dependent phosphate transport protein NaPi2b, which is an antigen expressed in ovarian cancer and non-small cell lung adenocarcinoma. The drug is being evaluated in a phase 1 clinical trial that targets patients with tumors expressing NaPi2b, including ovarian cancer and non-small cell lung adenocarcinoma.
In the dose escalation part of the phase I study (NCT03319628), XMT-1536 showed clinical activity at a dose of >20 mg/m2. In patients with ovarian cancer and non-small cell lung cancer who have received multiple systemic therapies, without pre-selection of NaPi2b expression, the drug has proved to have an objective response and prolong the duration of disease stability. XMT-1536 is well tolerated and does not have the severe toxicity observed with other ADC platform (such as neutropenia, peripheral neuropathy or ocular toxicity).
In the ongoing phase I study, the dose-expansion cohort (including patients with fewer lines of previous treatment) has two cohorts (1) high-grade serous ovarian cancer, fallopian tube or primary peritoneal cancer (who received up to 4 previous treatments), evaluating intravenous administration of 36 and 43 mg/m² every 4 weeks; (2) Non-small cell lung adenocarcinoma (who received platinum, immune checkpoint inhibitor and TKI treatment). Patients need to have a retrospective assessment of NaPi2b expression in archived tumor tissue or fresh tumor biopsy tissue. As of February 10, 2020, the expansion cohort included 23 patients (19 cases of ovarian cancer and 4 cases of non-small cell lung cancer): 16 cases were administered at a dose of 36 mg/m² and 7 cases were administered at a dose of 43 mg/m². Adverse events were similar to what was previously reported, including transient AST elevation, fatigue, nausea, and fever. Clinical objective response and stable disease have been observed. Anti-tumor activity in ovarian cancer includes complete response in 2/20 (10%), partial response in 5/20 (25%) , and stable disease in 8/20 (40%).
参考文献 Reference Ricardson DL et al. J Clin Onc 2020; 38:suppl 3549 https://www.globenewswire.com/news-release/2020/05/27/2039179/0/en/Mersana-Therapeutics-Reports-Positive-Interim-Data-from-the-Expansion-Portion-of-the-XMT-1536-Phase-1-Study.html
Pevonedistat加上azacitidine可能会增加骨髓增生异常综合症（MDS）/急性粒细胞白血病（AML）的存活率 (8/15/2020)
Pevonedistat plus azacytidine may have survival benefit in MDS and AML patients
Pevonedistat是一种NEDD8-激活酶的抑制剂，在细胞机制上阻止癌细胞的生长。与单独使用阿扎胞苷（azacidine）相比，在高风险的MDS和低原始细胞（low-blast）AML中，Pevonedistat加阿扎胞苷可提高整体生存率，无事件生存率和缓解率。
在一项随机2期临床试验（NCT02610777）中, 120例患者以1：1随机分配为1)在第1、3和5天接受静脉注射20 毫克/平方米pevonedistat，和在第1、5、8、9天静脉或皮下注射75 毫克/平方米阿扎胞苷（n = 58）; 2) 阿扎胞苷单药治疗（n = 62），28天为一周期，直到出现不可接受的毒性，复发，转化为AML或死亡。主要终点是无事件生存率。 在参加者中, 67例为高风险MDS，另外36例低原始细胞AML和17例CMML。
研究显示，接受联合用药的患者的中位无事件生存期为21个月，相对于单药阿扎胞苷组的16.6个月（HR = 0.65； 95％CI，0.41-1.02） 。高风险MDS患者的立即无事件生存期为20个月，而接受阿扎胞苷的患者则为15个月（HR = 0.54； 95％CI，0.29–1）。
尽管这项研究无法显示总体生存率的差异，但总生存率也有改善的趋势。在高危MDS患者中，接受联合用药的患者的中位总生存率为23.9个月，相对于19.1个月（HR = 0.7； 95％CI，0.39–1.27）。在低原始细胞AML患者中，接受联合治疗的中位总生存率为23.6个月，相对于16个月（HR 0.49； 95％CI，0.22-1.11）。
联合用药的患者的总缓解率为71％，而阿扎胞苷单药治疗的总缓解率为60％。在高风险MDS中，联合治疗与单药治疗的完全缓解率分别为52％和27％（P = .05）。
接受阿扎胞苷单药治疗的患者与接受联合治疗的患者的常见和严重不良事件的发生率相似。接受联合治疗的患者中3级或更高级别不良事件的发生率为90％，接受单一疗法的患者为87％。最常见的事件包括中性粒细胞减少症（31％对27％），发热性中性粒细胞减少症（26％对29％），贫血（19％对27％）和血小板减少症（19％对23％）。在研究期间，有9％的联合治疗患者和16％的单药治疗患者死亡。
这些发现代表了当前进行中的第3期随机研究的基础。
In a randomized phase 2 clinical trial (NCT02610777), 120 patients were randomly assigned 1:1 to 1) receiving intravenous injection of 20 mg/m2 pevonedistat on days 1, 3 and 5, plus intravenous or subcutaneous injection of 75 mg/m² azacitidine (n = 58) on days 1, 5, 8 and 9; 2) azacitidine monotherapy (n = 62), for 28 days as a cycle, until unacceptable toxicity , recurrence, conversion to AML or death. The primary endpoint is event-free survival. Among the participants, 67 had high-risk MDS, another 36 had low-blast AML and 17 had CMML.
The data has shown that the median event-free survival of patients receiving the combination therapy was 21 months, compared to 16.6 months in the single-agent azacitidine group (HR = 0.65; 95% CI, 0.41-1.02). The immediate event-free survival of patients with high-risk MDS was 20 months, compared with 15 months in patients receiving azacitidine (HR = 0.54; 95% CI, 0.29–1). Although this study was unable to show differences in overall survival, overall survival rates did demonstrate a trend of improvement. Among high-risk MDS patients, the median overall survival among patients receiving combination therapy was 23.9 months, compared to 19.1 months (HR = 0.7; 95% CI, 0.39–1.27). In patients with low-blast AML, the median overall survival for combination therapy was 23.6 months, compared to 16 months (HR 0.49; 95% CI, 0.22-1.11).
The overall response rate of patients with combination therapy was 71%, while that of azacitidine monotherapy was 60%. In high-risk MDS, a complete remission rates of combination therapy and monotherapy were 52% and 27%, respectively (P = .05).
The incidence of common and serious adverse events was similar between the two groups . The incidence of grade 3 or higher adverse events was 90% in patients receiving combination therapy, and 87% in patients receiving monotherapy. The most common events included neutropenia (31% vs. 27%), febrile neutropenia (26% vs. 29%), anemia (19% vs. 27%), and thrombocytopenia (19% vs.23%). During the study period, 9% of combination therapy patients and 16% of monotherapy patients died.
These findings provided the basis of the current phase 3 randomized study.
参考文献 Reference Sekeres M. et al 2020 Virtual ASCO.Belantamab mafodotin治疗复发/难治性多发性骨髓瘤 (8/9/2020)
Belantamab mafodotin for relapsed or refractory myeloma
2020年8月5日，FDA批准了Belantamab mafodotin用于复发性或难治性多发性骨髓瘤的成年患者，这些患者至少接受了4种先前疗法，包括抗CD38单克隆抗体，蛋白酶体抑制剂和免疫调节剂
Belantamab mafodotin在开放式多中心试验（DREAMM-2, NCT 03525678）中进行了评估。患者每3周一次静脉接受2.5 毫克/公斤或3.4 毫克/公斤belantamab mafodotin ，直至疾病进展或出现不可接受的毒性。
疗效评估是基于独立委员会使用国际骨髓瘤工作组统一响应标准评估的总体响应率和响应持续时间。 总体响应率为31％（97.5％CI：21％，43％）。 73％的响应者的反应持续时间≥6个月。在接受2.5毫克/公斤（推荐剂量）的患者中观察到了这些结果。
接受belantamab mafodotin治疗的≥20％患者的不良反应为角膜病变，视力下降，恶心，视物模糊，发热，输液相关反应和疲劳。严重不良反应（药物警告）: Belantamab mafodotin可能引起角膜上皮的变化，导致视力改变，严重的视力丧失和角膜溃疡，以及其它症状，如视力模糊和眼干。应在基线时和每次给药之前，进行眼科检查，并在症状恶化时迅速检查。由于存在眼毒性风险，因此只能通过风险评估和缓解策略的受限计划才能获得belantamab mafodotin。
On August 5, 2020, FDA approved Belantamab mafodotin for adult patients with relapsed or refractory multiple myeloma. These patients received at least 4 lines of previous therapies, including anti-CD38 monoclonal antibodies, proteasome inhibitors and Immunomodulator
Belantamab mafodotin was evaluated in an open multicenter trial (DREAMM-2, NCT 03525678). Patients received 2.5 mg/kg or 3.4 mg/kg belantamab mafodotin intravenously every 3 weeks until disease progression or unacceptable toxicity.
Efficacy evaluation is based on the overall response rate and response duration evaluated by the independent committee using the uniform response criteria of the International Myeloma Working Group. The overall response rate was 31% (97.5% CI: 21%, 43%). 73% of the responders had response duration ≥ 6 months. These results were observed in patients who received 2.5 mg/kg (recommended dose).
Adverse reactions in ≥20% of patients treated with belantamab mafodotin were corneal disease, decreased vision, nausea, blurred vision, fever, infusion-related reactions, and fatigue. Serious adverse reactions (boxed warning): Belantamab mafodotin may cause changes in the corneal epithelium, leading to vision changes, severe vision loss and corneal ulcers, as well as other symptoms such as blurred vision and dry eyes. Eye examinations should be performed at baseline and before each administration, and promptly on worsening symptoms. Due to the risk of ocular toxicity, belantamab mafodotin can only be available through a restricted program of Risk Evaluation and Mitigation Strategy.
参考文献 Reference https://www.fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myelomaDarolutamide提高非转移性去势抵抗性前列腺癌的总生存率 (8/8/2020)
Darolutamide improves overall survival in non-metastatic castration-resistant prostate cancer
Darolutamide是一种独特的雄激素受体抑制剂，于2019年7月被FDA批准用于治疗非转移性去势抵抗性前列腺癌（nmCRPC）。 该批准基于ARAMIS, 该研究达到了改善无转移生存期的主要终点（40.4个月对18.4个月，HR 0.41），并且安全性良好。 在2020 ASCO虚拟会议上，报道了有关1509名患者的总生存结果。在研究中观察到254例死亡后，进行了总体生存分析。 该研究允许交叉使用，接受抗雄激素治疗加上安慰剂的170例患者交叉使用了darolutamide。 就总生存而言，与单独使用安慰剂相比，darolutamide的死亡风险降低了31％。 3年时，darolutamide组活着的患者为93％，而安慰剂组为77％。 尽管安慰剂组中有一半的患者随后接受了darolutamide或主动疗法，但仍能看到总生存的益处。darolutamide还显著改善了疼痛进展时间（40.3个月vs 25.4个月，HR 0.65，p <0.001），首次化疗的时间（HR, 0.58）和首次症状性骨骼事件的时间（HR 0.48）。
延长随访期未发现新的安全信号，安全性与初步分析一致。 在疲劳方面，只有0.4％的患者接受了darolutamide有3/4级疲劳，而使用安慰剂的患者为0.9％。 相对于其他雄激素受体抑制剂，darolutamide的主要优点之一是不会穿越血脑屏障。 与安慰剂相比，这不会导致跌倒或中枢神经系统事件的差异。 癫痫发作患者被允许参加本研究，两组之间癫痫发作的发生率没有差异。 达洛鲁胺组的心脏心律失常比安慰剂要多, 但是，患者的基线特征显示， darolutamide组的心脏合并症患者比安慰剂组相更多，这可能有助于解释这两组差的异。
鉴于这些结果，darolutamide是所有非转移性去势抵抗性前列腺癌患者的理想选择。
Darolutamide is a unique androgen receptor inhibitor, approved by FDA in July 2019 for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). The approval was based on ARAMIS trail, which reached the primary endpoint of improving metastasis-free survival (40.4 months vs. 18.4 months, HR 0.41), and was safe. At the 2020 ASCO virtual meeting, the data of overall survival results of 1509 patients were reported. After 254 deaths were observed in the study, overall survival analysis was performed. The study allowed cross-over. 170 patients who received anti-androgen therapy plus placebo crossed over and received darolutamide. In terms of overall survival, darolutamide reduced risk of death was by 31% compared with placebo. At 3 years, 93% of patients in the darolutamide group were still alive, compared with 77% in the placebo group. Although half of the patients in the placebo group subsequently received darolutamide or active therapy, the overall survival benefit was still seen. Darolutamide also significantly improved the time to pain progression (40.3 months vs 25.4 months, HR 0.65, p <0.001), time to first chemotherapy (HR, 0.58), and time to first symptomatic skeletal event (HR 0.48).
No new safety signals were found during the extended follow-up period, and the safety was consistent with the initial analysis. In terms of fatigue, only 0.4% of patients who received darolutamide had grade 3/4 fatigue, compared with 0.9% of patients who received placebo. Compared to other androgen receptor inhibitors, one of the main advantages of darolutamide is that it does not cross the blood-brain barrier. Compared with placebo, this did not lead to differences in falls or central nervous system events. Patients with seizures were allowed to participate in the study, and there was no difference in the incidence of seizures between the two groups. There were more cardiac arrhythmias in the darolutamide group than in the placebo group. However, the baseline characteristics of the patients showed that the darolutamide group had more cardiac comorbidities than the placebo group, which may help explain the difference between the two groups .
In view of these results, darolutamide is an ideal choice for all patients with non-metastatic castration-resistant prostate cancer.
参考文献 Reference Fizazi K et al. New Engl J of Med 2019;380:1235-46. Fizazi K et al. 2020 ASCO Virtual Meeting
第一线Pembrolizumab加标准化疗可改善广泛期小细胞肺癌的无进展生存率 (8/2/2020)
First line pembrolizumab plus standard chemotherapy improves progression-free survival in small cell lung cancer
SCLC约占所有肺癌的15％，5年总生存率约为6％至7％。用于广泛期小细胞肺癌的标准一线治疗在过去30年中一直是铂类/依托泊苷, 但该方案的中位总生存期不到1年。
KEYNOTE-604临床试验在18个国家/地区的133个地点进行了研究，并以1:1的比例将453例先前未接受过治疗的广泛期小细胞肺癌患者随机分配给pembrolizumab/铂类/依托泊苷或安慰剂/铂类/依托泊苷。每3周一次给予pembrolizumab 200 毫克（一个周期），最多35个周期，外加4个周期的铂类/依托泊苷。在对照组中，以相同的化疗方案给予生理盐水安慰剂。研究者选择铂类为顺铂或卡铂。入组时允许治疗和病情稳定的脑转移瘤。
基线特征在两个治疗组之间达到了很好的平衡，但在pembrolizumab组中有更多的脑转移（14.5％比9.8％）。研究患者的中位年龄为65岁。大约40％的患者肝转移。41％的人检测PD-L1阳性（综合阳性评分≥1％）。
Pembrolizumab组的客观响应率为70.6％，而安慰剂/依托泊苷/铂的客观响应率为61.8％。在12个月时，观察到的持续响应分别为19％和3％。
在第二次中期分析中，pembrolizumab组的无进展生存期显着延长（HR= 0.75； P = .0023）。 12个月无进展生存率分别为13.6％和3.1％。最终分析时，pembrolizumab组有169例患者死亡，对照组为188例。总体生存的危险比为0.80（95％置信区间= 0.64-0.98； P = .0164）。估计的24个月总生存率分别为22.5％和11.2％。对于无进展生存期和总生存期的亚组分析，无论PD-L1阳性如何，结果都是相似的。至今为止，pembrolizumab组有20例患者接受治疗，而安慰剂组有3例正在接受治疗。疾病进展是停药的最常见原因。
两组中约75％的患者经历了3或4级不良事件。 Pembrolizumab组中有14.8％的患者因不良事件而终止治疗，而对照组中则有6.3％。 两组的不良事件很相似。 导致死亡的不良事件发生率分别为6.3％和5.4％。 两组由于治疗引起的死亡率相同（2.7％）。与先前的研究一致，pembrolizumab组中约25％的患者有免疫治疗相关的不良事件。 但是，没有患者死于免疫相关事件, 而且大多数事件是1/2级。
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers, and the 5-year overall survival rate is about 6% to 7%. The standard first-line treatment for extensive-stage SCLC has been platinum/etoposide for the past 30 years, but the median overall survival of this regimen is less than 1 year.
The KEYNOTE-604 clinical trial was conducted in 133 sites in 18 countries/regions, and 453 patients with previously untreated extensive-stage SCLC were randomly assigned at a ratio of 1:1 to pembrolizumab/platinum/etoposide or placebo/platinum/etoposide. Patients were given pembrolizumab 200 mg (one cycle) every 3 weeks for a maximum of 35 cycles, plus 4 cycles of platinum/etoposide at front. In the control group, normal saline placebo was given with the same chemotherapy regimen. The researchers chose either cisplatin or carboplatin as platinum. At the time of enrollment, previously treated and stable brain metastases were allowed.
The baseline characteristics were well-balanced between the two treatment groups, but there were more brain metastases in the pembrolizumab group (14.5% vs. 9.8%). The median age of the study patients was 65 years. About 40% of patients had liver metastases. 41% tested positive for PD-L1 (combined positive score ≥ 1%).
The objective response rate of the pembrolizumab group was 70.6%, while that of placebo/etoposide/platinum was 61.8%. At 12 months, the observed sustained response was 19% and 3%, respectively.
In the second interim analysis, the progression-free survival of the pembrolizumab group was significantly prolonged (HR = 0.75; P = .0023). The 12-month progression-free survival rates were 13.6% and 3.1%, respectively. In the final analysis, 169 patients died in the pembrolizumab group and 188 patients in the control group. The hazard ratio for overall survival was 0.80 (95% confidence interval = 0.64-0.98; P = .0164). The estimated 24-month overall survival rates were 22.5% and 11.2%, respectively. For subgroup analysis of progression-free survival and overall survival, the results were similar regardless of PD-L1 positive. So far, 20 patients in the pembrolizumab group are receiving treatment, while 3 patients in the placebo group are receiving treatment. Disease progression is the most common reason for discontinuation.
Approximately 75% of patients in both groups experienced grade 3 or 4 adverse events. A total of 14.8% of patients in the pembrolizumab group discontinued treatment due to adverse events, compared with 6.3% in the control group. The adverse events of the two groups were very similar. The incidence of adverse events leading to death was 6.3% and 5.4%, respectively. The two groups had the same mortality due to treatment (2.7%). Consistent with previous studies, approximately 25% of patients in the pembrolizumab group had immunotherapy-related adverse events. However, no patient died from immune-related events, and most events were grade 1 or 2.
参考文献 Reference Rudin CM et al. ASCO20 Virtual Scientific Program. Abstract 9001 Rudin CM et al. J Clin Oncol. May 29, 2020
AKT抑制剂ipatasertib治疗晚期三阴性乳腺癌的生存益处 (8/1/2020)
Survival benefit of an AKT inhibitor in triple-negative breast cancer
在紫杉醇一线治疗晚期三阴性乳腺癌时,添加AKT抑制剂ipatasertib产生生存益处。
LOTUS是一项全球性，双盲，随机II期试验，包括124例先前未接受治疗，局部晚期或转移性三阴性乳腺癌的患者。四分之三的妇女发生内脏转移。患者被随机分配至紫杉醇加安慰剂（n = 62）或ipatasertib，每日400 毫克（n = 62）。主要终点是意向治疗和PTEN低的人群的无进展生存期, 次要终点是意向性治疗人群的总体生存率。
意向治疗人群的中位无进展生存期单独使用紫杉醇的生存期为4.9个月，而添加AKT抑制剂则为6.2个月（HR = 0.60； 95％ CI = 0.37-0.98）。 PI3K / AKT / PTEN改变在亚组中显示出更大的益处，其中位总生存期分别为4.9个月和9.0个月（HR = 0.44； 95％CI = 0.20-0.99）。
中位随访时间分别为16个月（对照组）和19个月（ipatasertib组）。单独使用紫杉醇的中位总生存期为16.9个月，使用紫杉醇加ipatasertib的中位总生存期为25.8个月（HR = 0.80； 95％CI = 0.50-1.28）。这被认为具有临床意义，但未达到统计学意义，可能是因为患者人数过少。对于年龄小于50岁的患者，加入ipatasertib可使疾病进展的风险降低59％，存活时间增加20个月。 可能反映出某一个年龄组可能特别容易受到AKT抑制作用。通过IHC决定PTEN的状态，PTEN正常和PTEN低的患者均显示出总体生存率的数字改善。可是，样本量太小，无法得出明确的结论。这将在一项III期试验中进行进一步评估。
OTUS is a global, double-blind, randomized phase II trial involving 124 patients with previously untreated, locally advanced or metastatic triple-negative breast cancer. Three-quarters of women have visceral metastases. Patients were randomly assigned to paclitaxel plus placebo (n = 62) or plus ipatasertib, 400 mg daily (n = 62). The primary endpoint is progression-free survival in the intent-to-treat and low PTEN population. The secondary endpoint is overall survival of in the intent-to-treat population.
The median progression-free survival of the intent-to-treat population was 4.9 months with paclitaxel alone and 6.2 months with AKT inhibitor (HR = 0.60; 95% CI = 0.37-0.98). PI3K/AKT/PTEN changes showed greater benefits in the subgroups, with median overall survival times of 4.9 months and 9.0 months, respectively (HR = 0.44; 95% CI = 0.20-0.99).
The median follow-up was 16 months (control group) and 19 months (ipatasertib group). The median overall survival of paclitaxel alone was 16.9 months, and the median overall survival of paclitaxel plus ipatasertib was 25.8 months (HR = 0.80; 95% CI = 0.50-1.28). This was considered clinically significant, but it did not reach statistical significance, possibly because the number of patients was too small. For patients younger than 50 years old, adding ipatasertib can reduce the risk of disease progression by 59% and increase survival time by 20 months. It may reflect that a certain age group may be particularly vulnerable to AKT inhibition. When the status of PTEN was determined by IHC, patients with normal and low PTEN both showed a numerical improvement in overall survival. However, the sample size is too small to draw a clear conclusion. This will be further evaluated in a phase III trial.
参考文献 Reference Dent R et al. 2020 ESMO Breast Cancer Virtual Meeting Abstr139O.
口服选择性雌激素受体降解剂的活性 (7/26/2020)
Oral selective estrogen receptor degrader has activity
口服选择性雌激素受体降解剂（SERD）LSZ102与CDK4 / 6抑制剂ribociclib或α特异性PIK3CA抑制剂alpelisib结合显示活性，这是这种联合使用的第一份临床报告。
大多数乳腺癌患者最终会通过耐药途径对内分泌治疗产生耐药性，包括对细胞周期蛋白CDK4 / 6 /视网膜母细胞瘤蛋白和PI3K / AKT / mTOR的耐药途径。其他抗性机制涉及雌激素受体1中的突变，该突变可在没有雌激素的情况下仍然驱动雌激素受体依赖性转录和增殖。氟维司群（Fulvestrant）是目前唯一批准的选择性雌激素受体降解剂，与ribociclib和alpelisib联合使用已显示出生存的益处。新一代口服雌激素受体降解剂可以代替氟维司群，并且具有更高的全身暴露率，从而提高功效和对雌激素受体1突变的潜在活性。
这是一项I/Ib期开放标签，剂量递增临床试验, 评估了193例内分泌治疗后疾病进展患者，LSZ102雌激素受体降解剂作为单一药物或与ribociclib/alpelisib联合进行广泛剂量的研究：A组（n = 78）：LSZ102作为单一药物（允许以往使用过氟维司群，CDK4 / 6抑制剂和化疗）; B组（n = 76）：LSZ102加上ribociclib（允许已使用氟维司群，CDK4 / 6抑制剂和化疗）; C组（n = 39）：LSZ102加alpelisib（允许使用氟维司群，CDK4 / 6抑制剂和化疗，但不允许先用PI3K，mTOR或AKT抑制剂）。 在所有3组研究中，超过50％的患者曾接受过氟维司群，而70％的患者曾接受过化疗。在60％的A组，70％的C组和40％的B组中先前使用过CDK4 / 6抑制剂。
最常见的不良反应是胃肠道毒性。在所有研究组中，观察到恶心（所有级别）的患者占50％至60％，腹泻发生在B组的患者中占35％，C组的患者中占60％。B组中3级毒性包括中性粒细胞减少症（13.2％）和天冬氨酸转氨酶升高（3.9％）可能是由于ribociclib。而C组中的3级毒性高血糖（10.0％）和皮疹（15.4％）可能是由于alpelisib。目前使用的300毫克剂量的alpelisib与300毫克的LSZ102不能很好地耐受。在此水平上有12位患者发生了5种剂量限制性毒性。推荐剂量为300 毫克 LSZ102和250 毫克alpelisib。
总客观响应率为1.3%（A组）, 15.9%（B组）和5.4% （C组）。临床受益率（完全响应，部分响应和疾病稳定 > 24个月）为9.1%（A组）, 35.5%（B组）和18.9% （C组）。中位无进展生存期为1.8个月（A组）,6.2个月（B组）和3.5个月（C组）。
在任何组中均未观察到剂量依赖性活性，并且临床响应与雌激素受体1和PIK3CA突变状态没有关系。另外, C组的结论受到样本量的限制。
Oral selective estrogen receptor degrader (SERD) LSZ102 combined with CDK4/6 inhibitor ribociclib or α-specific PIK3CA inhibitor alpelisib showed activity. This is the first clinical report of such combinations.
Most breast cancer patients will eventually develop resistance to endocrine therapy through drug-resistant pathways, including cyclin CDK4/6/retinoblastoma protein and PI3K/AKT/mTOR. Other resistance mechanisms involve mutations in estrogen receptor 1 (ER1), which can drive estrogen receptor-dependent transcription and proliferation in the absence of estrogen. Fulvestrant is currently the only approved SERD, and its combination with ribociclib and alpelisib has shown survival benefits. A new generation of oral ESRD can replace fulvestrant, and has a higher systemic exposure rate, thereby improving the efficacy and potential activity of ER 1 mutations.
This is a phase I/Ib open-label, dose-escalation clinical trial that evaluated 193 patients with disease progression after endocrine therapy. The LSZ102 ESRD was used as a single drug or in combination with ribociclib/alpelisib for a wide-range dose study: Group A (n = 78): LSZ102 as a single drug (allowing previous use of fulvestrant, CDK4/6 inhibitors and chemotherapy); group B (n = 76): LSZ102 plus ribociclib (allowing previous use of fulvestrant , CDK4/6 inhibitors and chemotherapy); Group C (n = 39): LSZ102 plus alpelisib (fulvestrant, CDK4/6 inhibitors and chemotherapy are allowed, but PI3K, mTOR or AKT inhibitors are not allowed) . In all three groups, more than 50% of patients had received fulvestrant, and 70% of patients had received chemotherapy. CDK4/6 inhibitors were previously used in 60% of group A, 70% of group C and 40% of group B.
The most common adverse reaction is gastrointestinal toxicity. In all study groups, patients with nausea (all grades) were observed in 50% to 60%, diarrhea occurred in 35% of patients in group B, and 60% of patients in group C. Grade 3 toxicities in group B included neutropenia (13.2%) and elevated aspartate aminotransferase (3.9%) that may be due to ribociclib. The grade 3 toxic hyperglycemia (10.0%) and rash (15.4%) in group C may be due to alpelisib. The reported 300 mg of alpelisib and 300 mg of LSZ102 were not well tolerated. At this level, 12 patients experienced 5 dose-limiting toxicities. The recommended doses are 300 mg of LSZ102 and 250 mg of alpelisib.
The overall objective response rate was 1.3% (group A), 15.9% (group B) and 5.4% (group C). The clinical benefit rate (complete response, partial response and stable disease > 24 months) was 9.1% (group A), 35.5% (group B), and 18.9% (group C). The median progression-free survival was 1.8 months (group A), 6.2 months (group B), and 3.5 months (group C).
No dose-dependent activity was observed in any group, and the clinical response was not related to ER 1 and PIK3CA mutation status. In addition, the outcome of group C was limited by the sample size.
RAF/MEK和FAK抑制剂组合显示对KRAS突变型肿瘤有活性 (7/19/2020)
RAF/MEK and FAK inhibitor demonstrated clinical activity in KRAS-mutated tumor
一项研究结果表明，RAF-MEK加FAK抑制剂的新型治疗间歇方案在KRAS突变的低度浆液性卵巢癌（LGSOC）患者（包括以前接受过MEK抑制剂治疗）中观察到具有临床活性。KRAS突变型肿瘤具有高度侵袭性，难以治疗，在非小细胞肺癌, 胰腺癌, 结直肠癌和LGSOC的晚期实体瘤中非常普遍。
这是一项I期开放标签临床试验，评估KRAS突变的LGSOC和非小细胞肺癌患者中VRAF-MEK抑制剂VS-6766和FAK抑制剂defactinib的组合。研究人员以高度间歇性，每周两次的时间表给予VS-6766, 每天两次给予defactinib。两种药物的给药周期均为连续3周，休息1周。联合使用MEK抑制剂，一直存在很大毒性问题，因此第一阶段的研究，以间歇性的时间表向患者提供足够的药物，以能够在一段时间内抑制目标，而避免导致高毒性。探索的剂量水平包括队列1（VS-6766 3.2 毫克， defactinib200 毫克），队列2a（VS-6766 4 毫克，defactinib 200 毫克）和队列2b（VS-6766 3.2 毫克，defactinib 400 毫克）。研究人员在同时使用两种药物的第1周期第15天收集了药代动力学数据。在同意进行多次活检的患者亚组中，进行了三次活检（基线，单剂量VS-6766输注后以及联合治疗8-15天后）。
在数据报导时，该试验已治疗42例患者。队列1的前三名患者没有剂量限制性毒性，因此将患者招募至队列2a和2b。但是, 队列2b剂量水平是无法忍受的，因为2/3的患者正在经历2级皮疹的剂量限制性毒性，不允许按计划剂量的75％给药。 按2a计划治疗的前六名患者未见剂量限制性毒性。但是，考虑到治疗> 6个月的患者具有慢性2级毒性，推荐的II期推荐剂量被视为队列1。
最常见的副作用是皮疹，肌酸激酶升高，AST升高，高胆红素血症和恶心，其中大多数为1-2级。所有变化都是可逆的。
使用RAF-MEK抑制剂后p-FAK升高，而与FAK抑制剂联合使用后p-FAK降低。该组合还可减少FOXP3细胞的数量。早期初步功效发现该组合有临床活性。
早期功效发现这种联合方法的临床活性: 在LGSOC患者（n = 8）中，缓解率为50％（n = 4）。对于那些拥有KRAS突变LGSOC（n = 6）的人，这一比例为67％（n = 4）。在有反应的四名患者中，三名曾接受过MEK抑制剂治疗。中位治疗时间为20.5个月。一些患有KRAS突变的非小细胞肺癌患者显示出肿瘤消退。在这一队列（n = 10）中，一名患者获得了部分缓解, 一名患有KRASG12D突变的患者实现了22％的肿瘤减少，并且截至2019年11月仍在接受治疗。70％的患者接受了至少12周的治疗，而30％的患者接受了至少24周的治疗。该队列的中位治疗时间约为18周。
一旦达到建议的II期剂量，计划将扩大到20例LGSOC，20例KRAS突变的非小细胞肺癌和10例KRAS突变的结直肠癌患者。
A phase I study showed that the new intermittent treatment regimen with RAF-MEK plus FAK inhibitors has demonstrated clinical activity in patients with low-grade serous ovarian cancer (LGSOC) that harbors KRAS mutations, including those previously treated with MEK inhibitors.
KRAS mutant tumors are highly invasive and difficult to treat. They are very common in advanced solid tumors of non-small cell lung cancer, pancreatic cancer, colorectal cancer, and LGSOC.
This is a phase I open-label clinical trial evaluating the combination of RAF-MEK inhibitor, VS-6766 and FAK inhibitor, defactinib in patients with KRAS-mutated LGSOC and non-small cell lung cancer patients. The researchers gave VS-6766 on a highly intermittent, twice-weekly schedule, and defactinib twice a day. The administration period of the two drugs is 3 weeks on, 1 week off. The combinatin use of MEK inhibitors has always had great toxicities, so the first phase of the study provided patients with sufficient drugs on an intermittent schedule to be able to suppress the target for a period of time and avoid causing high toxicity. The dose levels explored included cohort 1 (VS-6766 3.2 mg, defactinib 200 mg), cohort 2a (VS-6766 4 mg, defactinib 200 mg) and cohort 2b (VS-6766 3.2 mg, defactinib 400 mg). The researchers collected pharmacokinetic data on the 15th day of the first cycle of the two drugs. In the subgroup of patients who agreed to perform multiple biopsies, three biopsies were performed (baseline, after single-dose VS-6766 infusion and 8-15 days after combination therapy).
At the time of data reporting, the trial had treated 42 patients. The first three patients in cohort 1 had no dose-limiting toxicity, so patients were recruited to cohorts 2a and 2b. However, the cohort 2b dose level was intolerable because 2/3 of patients are experiencing dose-limiting toxicity of grade 2 rashes and do not allow 75% dose reduction of the planned dose. The first six patients treated according to plan 2a did not see dose-limiting toxicity. However, considering that patients with treatment> 6 months have chronic grade 2 toxicity, the recommended phase II recommended dose is considered cohort 1.
The most common side effects are rash, elevated CK, elevated AST, hyperbilirubinemia and nausea, most of which were grade 1-2. All abnormalities were reversible.
P-FAK increased after using RAF-MEK inhibitor, but decreased when combined with FAK inhibitor. This combination can also reduce the number of FOXP3 cells. Early preliminary efficacy found that the combination has clinical activity.
Early efficacy found the clinical activity of this combined approach: In LGSOC patients (n = 8), the remission rate was 50% (n = 4). For those with KRAS mutation LGSOC (n = 6), the proportion was 67% (n = 4). Of the four patients who responded, three had been treated with MEK inhibitors. The median treatment time was 20.5 months. Some patients with non-small cell lung cancer with KRAS mutations showed tumor regression. In this cohort (n = 10), one patient achieved partial remission, one patient with the KRASG12D mutation achieved a 22% tumor reduction, and was still receiving treatment as of November 2019. 70% of patients received at least 12 weeks of treatment, while 30% of patients received treatment for at least 24 weeks. The median treatment time for this cohort was approximately 18 weeks.
Once the recommended phase II dose is reached, the plan will be expanded to 20 patients with LGSOC, 20 patients with KRAS-mutated non-small cell lung cancer and 10 patients with KRAS-mutated colorectal cancer.
参考文献 Reference Barneji, U. et al AACR 2020 Virtual Annual Meeting 2020; Abstr CT143
预测三阴性乳腺癌复发的血液生物标志物 (7/18/20)
Blood biomarkers in predicting recurrence after neoadjuvant therapy for triple-negative breast cancer
手术治疗早期三阴性乳腺癌后, 血浆中存在循环肿瘤DNA（ctDNA）和循环肿瘤细胞（CTC）, 是预测疾病复发和无病生存的关键指标。
在一项II期随机临床试验（BRE12-158）中, 对196名女性患者的数据进行了预先计划的二次分析（从2014年3月26日至2018年12月18日），该试验将早期三阴性乳腺癌患者在术前化疗后尚有残留疾病者进行了随机分组, 她们或接受基因学指导的治疗或医师选择治疗。在分配治疗时，采集了患者的血液样本用于分析ctDNA和CTC。对142例患者进行了ctDNA和生存关系分析，对123例患者进行了CTC和生存关系分析。中位临床随访时间为17.2个月（范围为0.3-58.3个月）。
在196名女性患者（平均年龄为49.6 [岁）中，ctDNA的检测与低度远处无病生存率著相关（中位远处无病生存为32.5个月相对于未达到；HR，2.99； 95％CI，1.38 -6.48； P = .006）。在24个月时，ctDNA阳性患者的远处无病生存概率为56％，而ctDNA阴性患者为81％。 ctDNA的检测与低无病生存（HR，2.67; 95％CI，1.28-5.57; P = 0.009）和低总生存（HR，4.16; 95％CI，1.66-10.42; P = 0.002）相关。 ctDNA和CTC的结合为提高敏感性和区分能力提供了更多信息。与ctDNA阴性和CTC阴性的患者相比，ctDNA阳性和CTC阳性的患者的远处无病生存明显较差（中位远处无病生存为32.5个月相对于未达到； HR，5.29； 95％CI，1.50-18.62； P = 0.009）。在24个月时，ctDNA阳性和CTC阳性的患者的远处无病生存概率为52％，而ctDNA阴性和CTC阴性的患者的远处无病生存概率为89％。 同样, 无病生存（HR，3.15; 95％CI，1.07-9.27; P = .04）和总生存（HR，8.60; 95％CI，1.78-41.47; P = .007）观察到类似的趋势。
手术和化疗后，部分三阴性乳腺癌会残留疾病，她们有可能复发。这项研究旨在帮助发现针对高风险复发者发现个性化疗法。
After surgery of early triple-negative breast cancer, the presence of circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) in plasma is a key indicator for predicting disease recurrence and disease-free survival.
In a phase II randomized clinical trial (BRE12-158), a pre-planned secondary analysis of data from 196 female patients (from March 26, 2014 to December 18, 2018). The trial included patients with early-stage triple-negative breast cancer who had residual disease after preoperative chemotherapy were randomized. They either received genetically directed post-surgery treatment or treatment of physician’s choice. Blood samples of patients were collected for analysis of ctDNA and CTC. The relationship between ctDNA and survival was analyzed in 142 patients, and the relationship between CTC and survival was analyzed in 123 patients. The median follow-up time was 17.2 months (range 0.3-58.3 months).
Among 196 female patients (mean age 49.6 years), the detection of ctDNA was associated with a inferior distant disease-free survival (DDFS) (median DDFS was 32.5 months vs. unreached; HR, 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, the probability of DDFS in ctDNA-positive patients was 56%, compared with 81% in ctDNA-negative patients. The detection of ctDNA was associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = 0.009) and low overall survival (HR, 4.16; 95% CI, 1.66-10.42; P = 0.002). The combination of ctDNA and CTC provides more information for improving sensitivity and discrimination. Compared with ctDNA-negative and CTC-negative patients, ctDNA-positive and CTC-positive patients had significantly poorer DFS (median DDFS was 32.5 months vs. unreached; HR, 5.29; 95% CI, 1.50-18.62; P = 0.009). At 24 months, the ctDNA-positive and CTC-positive patients had a DDFS probability of 52%, while the ctDNA-negative and CTC-negative patients had a DDFS probability of 89%. Similarly, similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and overall survival (HR, 8.60; 95% CI, 1.78-41.47; P = .007).
After surgery and chemotherapy, some triple-negative breast cancers will have residual disease, and they may relapse. This aim of this study is to help find personalized therapies for those at high-risk for relapses.
参考文献 Reference Radovich M et al. JAMA Onc 2020; July 9. doi:10.1001/jamaoncol.2020.2295
Cedazuridine 被FDA批准与地西他滨合用于成年骨髓增生异常综合症（MDS） (7/12/2020)
FDA has approved cedazuridine and decitabine in adult MDS patients
在两项开放标签，随机，交叉试验中对cedazuridine进行了研究。 ASTX727-01-B试验包括80名MDS或慢性粒单核细胞白血病成年患者，而ASTX727-02试验包括133名成年患者MDS或慢性粒单核细胞白血病，其IPSS （ International Prognostic Scoring System）Intermediate-1，Intermediate-2或高风险预后评分。
在这两项试验中，患者均按1:1的比例随机分配，在第1周期口服cedazuridine（35 毫克地西他滨和100 毫克cedazuridine），在第2周期或相反顺序中静脉内接受地西他滨20 毫克/平方米。在28天周期的第1至第5天，每天一次给予cedazuridine和静脉内地西他滨。从第3周期开始，所有患者在每个28天周期的第1至5天每天口服一次cedazuridine，直到疾病进展或出现不可接受的毒性。两项试验均比较了口服cedazuridine和静脉内地西他滨前两个周期的暴露和安全性。无法比较cedazuridine和静脉内地西他滨的疾病反应，因为所有患者均从第3周期开始接受cedazuridine。
01-B试验显示完全缓解率为18％（95％CI：10-28），完全缓解的中位持续时间为8.7个月（范围：1.1-18.2）。在基线时依赖红细胞和/或血小板输注的41例患者中，有20例（49％）在基线后任何连续56天内不依赖红细胞和血小板输注。在基线时不依赖红细胞和血小板输注的39例患者中，有25例（64％）在基线后任何连续56天期间仍保持不依赖输血。
02试验表明，连续5次每天一次cedazuridine给药后5天累积地西他滨AUC的几何平均比率为99％（90％CI：93，106）。疗效结果表明，有21％的患者获得了完全缓解（95％CI：15-29），中位完全缓解率持续时间为7.5个月（范围：1.6-17.5）。在基线时依赖红细胞和/或血小板输注的57例患者中，有30例（53％）在基线后任何56天期间不依赖红细胞和血小板输注。在基线时不依赖RBC和血小板输注的76例患者中，基线后任何56天期 间，仍有63％的患者不依赖输血。
对cedazuridine最常见的不良反应（发生率≥20％）是疲劳，便秘，出血，肌痛，粘膜炎，关节痛，恶心，呼吸困难，腹泻，皮疹，头晕，发热性中性粒细胞减少，水肿，头痛，咳嗽，食欲下降，上呼吸道感染，肺炎和转氨酶升高。最常见的3级或4级实验室异常（≥50％）是白细胞减少，血小板计数减少，中性粒细胞计数减少和血红蛋白减少。口服cedazuridine的总体安全性与静脉内地西他滨相似。
Cedazuridine was studied in two open-label, randomized, crossover trials. The ASTX727-01-B trial included 80 adult patients with MDS or chronic myelomonocytic leukemia, while the ASTX727-02 trial included 133 adult patients with MDS or chronic myelomonocytic leukemia. Its IPSS (International Prognostic Scoring System) was Intermediate-1 , Intermediate-2 or high-risk prognostic score.
In both trials, patients were randomly assigned at a 1:1 ratio, taking cedazuridine (35 mg decitabine and 100 mg cedazuridine) orally in the first cycle, and receiving decitabine intravenously in the second cycle or the reverse order decitabine 20 mg/m2. On days 1 to 5 of the 28-day cycle, cedazuridine and intravenous decitabine were given once a day. Starting from cycle 3, all patients took cedazuridine orally once a day on days 1 to 5 of each 28-day cycle until disease progression or unacceptable toxicity. Both trials compared the exposure and safety of the first two cycles of oral cedazuridine and intravenous decitabine. The disease response of cedazuridine and intravenous decitabine could not be compared because all patients received cedazuridine from cycle 3.
The 01-B trial showed a complete response rate of 18% (95% CI: 10-28), and the median duration of complete response was 8.7 months (range: 1.1-18.2). Of the 41 patients who were dependent on red blood cell and/or platelet transfusion at baseline, 20 (49%) were free from red blood cell and platelet transfusion for any consecutive 56 days after baseline. Of the 39 patients who were independent of red blood cell and platelet transfusion at baseline, 25 (64%) remained independent of blood transfusion during any consecutive 56 days after baseline.
The 02 test showed that the geometric mean ratio of cumulative decitabine AUC 5 days after 5 consecutive days of cedazuridine administration was 99% (90% CI: 93, 106). Efficacy results showed that 21% of patients achieved complete remission (95% CI: 15-29), and the median duration of complete remission was 7.5 months (range: 1.6-17.5). Of the 57 patients who were dependent on red blood cell and/or platelet transfusion at baseline, 30 (53%) were independent on red blood cell and platelet transfusion during any 56 days after baseline. Of the 76 patients who were not dependent on RBC and platelet transfusion at baseline, 63% of patients remained independent of blood transfusion during any 56 days after baseline.
The most common adverse reactions to cedazuridine (incidence ≥20%) were fatigue, constipation, bleeding, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infections, pneumonia and increased transaminases. The most common grade 3 or 4 laboratory abnormalities (≥50%) were leukopenia, decreased platelet count, decreased neutrophil count and decreased hemoglobin. The overall safety of oral cedazuridine is similar to intravenous decitabine.
参考文献 Reference https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-oral-combination-decitabine-and-cedazuridine-myelodysplastic-syndromes
改良的蒽环类药物可保持抑制肿瘤的能力而减少心脏损害 (7/11/2020)
Modified anthracycline retains ability to damage DNA while reducing cardiotoxicity
蒽环类药物（anthracycline）阿霉素（Doxorubicin）及其类似物柔红霉素（Daunorubicin），表柔比星（Epirubicin）和伊达柔比星（Idarubicin）已成为抗癌治疗的基石。然而，它们的临床应用受到剂量依赖性不可逆的心脏毒性。蒽环类药物执行两种细胞活性：DNA损伤（拓扑异构酶II [Topo II] 中毒后引起双链断裂），以及染色质损伤（通过组蛋白驱逐在基因组的选定位点介导）。
蒽环类药物引起的心脏毒性需要这两种细胞活性的结性。具有对Topo II毒性的aclarubicin和依托泊苷均无法在小鼠和人的心脏微组织中诱发心脏毒性。研究还显示阿霉素可以通过化学方法分离这两种活性而被解毒。在不引起双链断裂的情况下, 诱导染色质破坏的蒽环类药物在细胞系，小鼠和人类急性髓性白血病患者中维持相似的抗癌效力，这些结果表明破坏染色质是蒽环类药物的主要细胞毒性机制。主要通过破坏染色质起杀死肿瘤细胞作用的蒽环类药物变体, 可以延长癌症患者的治疗时间，并改善癌症幸存者的生活质量。
研究者测试了两种蒽环类药物变体，它们能在不破坏DNA的情况下去除组蛋白：一种批准的抗癌药Aclarubicin和一种经过调整的阿霉素（称为diMe-Doxo）。这些化合物在杀死培养的癌细胞方面，即使不是更好，也和原始药物一样有效，并且在减缓小鼠肿瘤生长方面几乎一样有效。然而，易患肿瘤的小鼠服用Aclarubicin后并未表现出心脏受损的迹象，这提示人心脏也可能不受这种药物影响。研究者表示Aclarubicin似乎对血癌最有效，而diMe-Doxo对实体瘤似乎更有效。
The anthracycline Doxorubicin and its analogs Daunorubicin, Epirubicin and Idarubicin have become the cornerstones of anti-cancer treatment. However, their clinical application suffers from dose-dependent, irreversible cardiotoxicity. Anthracyclines exert two types of cellular activity: DNA damage (poisoning of topoisomerase II [Topo II] causes double-strand breaks), and chromatin damage (mediated by histone eviction at selected sites in the genome).
Cardiotoxicity caused by anthracyclines requires the combination of these two cellular activities. Neither aclarubicin nor etoposide, which is toxic to Topo II, can induce cardiotoxicity in the cardiac micro-tissues of mice and humans. Studies have also shown that doxorubicin can be detoxified by chemically separating these two activities. Without causing double-strand breaks, anthracycline drugs that induce chromatin destruction maintain similar anticancer efficacy in cell lines, mice, and human patients with acute myeloid leukemia. These results indicate that chromatin destruction is the main cytotoxic mechanism of anthracycline drugs. Variants of anthracycline drugs that mainly kill tumor cells by destroying chromatin can prolong the treatment time of cancer patients and improve the quality of life of cancer survivors.
The researchers tested two variants of anthracycline that can remove histones without destroying DNA: an approved anticancer drug Aclarubicin and an adjusted doxorubicin (called diMe-Doxo) . These compounds are as effective as the original drug in killing cultured cancer cells, if not better, and are almost as effective in slowing tumor growth in mice. However, the mice susceptible to tumors showed no signs of heart damage after taking Aclarubicin, suggesting that the human heart may also not be affected by this drug. The researchers said that Aclarubicin seems to be the most effective for blood cancer, while diMe-Doxo seems to be more effective for solid tumors.
参考文献 Reference Qiao X et al. PNAS 2020;117: 15182
手术治疗乳腺癌对转移性患者并不提高总生存率 (7/5/2020)
Surgery did not increase overall survival for de novo metastatic breast cancer patient
一项随机临床试验（ECOG-ACRIN E2108）的结果显示，对于一开始就发现转移的乳腺癌患者，原发肿瘤的局部治疗并不能改善其生存率。
迄今为止，仅有两项完成的局部疗法随机试验却产生了矛盾的数据。来自印度的一项研究显示，早期局部区域治疗没有生存优势，而土耳其的一项研究则显示，对原发肿瘤的治疗具有更好的5年总生存率。
ECOG-ACRIN E2108试验于2011年开始招募患者，于2015年结束。最初计划招募368名患者，但缓慢的入组导致设计修改，并将招募人数减少到258名患者。该试验仍具有统计能力，可检测出3年生存率19％的改善（即全身治疗为30％，局部治疗为49.3％）。
随机分组患者的中位年龄为55-56岁，超过80％是白人，大多数患者有单个器官转移，57-59％患者的激素受体阳性/HER2阴性乳腺癌，其次是HER2阳性乳腺癌（33％）。 在转移乳腺癌诊断后，所有患者均接受了最佳全身治疗。那些在4到8个月的全身治疗后疾病没有进展的患者被随机分配继续进行全身治疗或完成原发肿瘤的手术切除以取得清晰切缘，并按标准护理接受或不接受放射治疗。
在随机接受手术的125例患者中，有109人实际接受了手术，其中87例手术边缘清晰，有74例接受了局部放疗。在131名随机接受全身治疗的妇女中，有25名随后接受了手术。
在中位随访53个月后，所有256名随机分组患者的中位生存期为54个月，持续的全身疗法相对于局部疗法（手术+/-放疗）的危险比为1.09（90％CI 0.80-1.49）。同样，无进展生存期曲线重叠（P = 0.40）。总生存率和无进展生存期均没有差异。
仅接受全身治疗的患者乳腺癌局部进展（症状的发展导致局部治疗）更为频繁。随访期间，两臂之间与健康相关的生活质量相似，但18个月数据分析时，当时被分配全身治疗的患者的综合评分明显更高（P = 0.001）。
但是，研究者认为不排除某些初发IV期疾病患者局部疗法受益的可能性。 当全身疾病通过全身治疗得到良好控制但原发部位仍在进展时，局部治疗可以考虑。目前正在日本进行的一项规模更大，设计相似的研究，预计生存分析的结果将于2022年完成。
也请参考: 切除原发病灶改善HER2阳性IV期乳腺癌的生存 (6/2/2019)
The results of a randomized clinical trial (ECOG-ACRIN E2108) showed that local treatment of the primary tumor did not improve overall survival of breast cancer patients with de novo metastases.
To date, only two randomized trials of local therapy have produced conflicting data. A study from India showed that early local regional treatment did not have a survival advantage, while a study conducted in Turkey showed the opposite with a better 5-year overall survival rate.
The ECOG-ACRIN E2108 trial started enrolling patients in 2011 and ended in 2015. Initially, 368 patients were planned to be recruited. However, slow enrollment led to design modifications and the number of recruits was reduced to 258 patients. The trial was still capable of detecting a 19% improvement in 3-year survival (ie, 30% for systemic therapy only and 49.3% for local therapy).
The median age of the trial patients was 55-56 years. More than 80% were white, and most patients had a single organ metastasis. Between 57-59% of patients had hormone receptor positive/HER2 negative breast cancer, followed by HER2 positive breast cancer ( 33%). After the diagnosis of de novo metastatic breast cancer, all patients received optima; systemic treatment. Those patients whose disease did not progress after 4 to 8 months of systemic treatment were randomly assigned to continue systemic treatment or complete surgical resection of the primary tumor to obtain a clear margin, and to receive or not to receive radiotherapy as per standard care criteria.
Of the 125 patients randomized to surgery, 109 actually received surgery, of which 87 had clear surgical margins and 74 received local radiotherapy. Of the 131 women who were randomized to receive systemic treatment, 25 subsequently underwent surgery.
After a median follow-up of 53 months, the median overall survival of all 256 randomized patients was 54 months, and the hazard ratio of continuous systemic therapy relative to local therapy (surgical +/- radiotherapy) was 1.09 (90% CI 0.80 -1.49). Similarly, progression-free survival curves overlap (P = 0.40). There was no difference in overall survival and progression-free survival.
Patients who received systemic treatment only had local breast cancer progression (development of symptoms leading to local treatment) more frequently. During follow-up, health-related quality of life was similar between the two arms, although at 18 months of data analysis, the overall score of patients assigned to systemic therapy at that time was significantly higher (P = 0.001).
The researchers believe that the possibility of local therapy benefiting some patients with initial stage IV disease cannot be ruled out. When systemic disease is well controlled by systemic treatment but the primary site is still progressing, local treatment can be considered. A larger study of similar design is currently underway in Japan, and the results of the survival date are expected to be completed in 2022.
Please aslo see: Surgery improves survival in HER2-positive metastatic breast cancer women (6/2/2019)
参考文献 Reference Khan S. et al ASCO 2020; Abstract LBA2.
血液检查诊断脑肿瘤 (7/4/2020)
Blood test to diagnose and classify brain cancer
一种简单但高灵敏的血液测试可以诊断和分类不同类型的脑肿瘤，从而避免侵入性诊断手段。
DNA甲基化的表观遗传修饰，在调节细胞中的基因表达（打开或关闭基因）中起着重要作用。在癌细胞中，DNA甲基化模式被破坏，导致癌症生长不受控制。研究者利用这种机制开发基于DNA甲基化的液体活检方法，以分析循环血液中的DNA分子内成千上万的这些表观遗传学变化。这些片段称为循环肿瘤DNA或ctDNA。将这项新技术与机器学习相结合，从而开发出一种高灵敏，准确的测试方法，以检测和分类多种脑实体瘤。
临床医生和科学家通过比较患者脑癌病理学样本, 来分析221位患者血浆中循环的无细胞DNA来追踪癌症的起源和类型。 使用这种方法，他们能够使循环血浆ctDNA与肿瘤DNA匹配，从而证实了他们识别这些患者血液中循环的脑肿瘤DNA的能力。然后，他们使用机器学习方法，开发了一种计算机程序，仅根据循环的肿瘤DNA对脑肿瘤类型进行分类。
A simple but highly sensitive blood test can diagnose and classify different types of brain tumors, thereby avoiding invasive diagnostic procedures.
Epigenetic modification of DNA methylation plays an important role in regulating gene expression (turning genes on or off) in cells. In cancer cells, the DNA methylation pattern is disrupted, leading to uncontrolled cancer growth. Researchers used this mechanism to develop liquid biopsy methods based on DNA methylation to analyze thousands of these epigenetic changes in DNA molecules in circulating blood. These fragments are called circulating tumor DNA or ctDNA. This new technology is combined with machine learning to develop a highly sensitive and accurate test to detect and classify a variety of solid brain tumors.
Clinicians and scientists analyze the cell-free DNA circulating in the plasma of 221 patients to compare the origin and type of cancer using the pathology samples of their brain cancer. Using this method, they were able to match circulating plasma ctDNA with their tumor DNA, confirming validity to recognize brain tumor DNA circulating in these patients’ blood. Then, using machine learning methods, they developed a computer program to classify brain tumor types based only on circulating tumor DNA.
参考文献 Reference Nassari F. et al. Nature Med 2020; June 22,
FDA批准Selinexor用于复发性或难治性弥漫性大B细胞淋巴瘤 (6/28/2020)
FDA has approved Selinexor for relapsed or refractory diffuse large B-cell lymphoma
6月22日，FDA）批准了口服selinexor用于治疗复发或难治性 弥漫性大B细胞淋巴瘤。它也被批准用于由滤泡性淋巴瘤引起的弥漫性大B细胞淋巴瘤。
FDA对selinexor的加速批准基于多中心，单臂IIb SADAL研究的结果，该研究评估了134例复发或难治性弥漫性大B细胞淋巴瘤患者，包括了具有生发中心B细胞或非生发中心B细胞亚型的患者, 这些患者曾接受过中位为2种先前的全身治疗（范围= 1-5 ）。每周两次给患者口服固定剂量的60毫克selinexor。
SADAL研究达到了主要终点，总体缓解率为29％，其中包括18例（13％）完全缓解，21例（16％）部分缓解。次要终点包括有响应的患者的中位响应持续时间； 56％的患者在3个月时保持缓解，6个月时为38％，在12个月时为15％。
所有134例患者均纳入安全性分析。最常见的与治疗相关的不良事件是血细胞减少症以及胃肠道和体质症状，通常是可逆的，可以通过调整剂量和/或标准支持治疗来控制。最常见的非血液学不良事件为疲劳（63％），恶心（57％），食欲下降（37％）和腹泻（37％），主要为1级和2级事件。不小于15％的患者的3级和4级实验室异常包括血小板减少症，淋巴细胞减少症，中性粒细胞减少症，贫血和低钠血症。 不小于5％的患者的4级实验室异常是血小板减少症（18％），淋巴细胞减少症（5％）和中性粒细胞减少症（9％）。
On June 22, FDA approved oral selinexor for the treatment of relapsed or refractory diffuse large B-cell lymphoma. It is also approved for diffuse large B-cell lymphoma caused by follicular lymphoma.
FDA’s accelerated approval of selinexor is based on the results of a multicenter, single-arm IIb SADAL study that evaluated 134 patients with relapsed or refractory diffuse large B-cell lymphoma, including those with germinal center B cells or non-germinal center B-cell lymphoma patients. They had received a median of 2 previous systemic treatments (range = 1-5). Patients were given a fixed dose of 60 mg selinexor orally twice a week.
The SADAL study reached the primary endpoint, with an overall response rate of 29%, including 18 patients (13%) with complete response and 21 patients (16%) with partial response. Secondary endpoints included the median response duration of responding patients: 56% of patients maintained remission at 3 months, 38% at 6 months, and 15% at 12 months.
All 134 patients were included in the safety analysis. The most common treatment-related adverse events were cytopenia and gastrointestinal and constitutional symptoms, which were usually reversible and can be controlled by adjusting the dose and/or standard supportive treatment. The most common non-hematological adverse events were fatigue (63%), nausea (57%), decreased appetite (37%) and diarrhea (37%), mainly grade 1 or grade 2 events. No less than 15% of patients with grade 3 and 4 laboratory abnormalities include thrombocytopenia, lymphopenia, neutropenia, anemia and hyponatremia. Grade 4 laboratory abnormalities in patients not less than 5% were thrombocytopenia (18%), lymphopenia (5%) and neutropenia (9%).
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-selinexor-multiple-myeloma
针对癌细胞生长所需蛋白质的药物berzosertib与化疗结合，对卵巢癌有益 (6/27/2020)
Chemotherapy in combination with berzosertib, which targets proteins required for cancer cell growth, benefited ovarian cancer
Berzosertib和化疗合用治疗高度浆液性卵巢癌比仅接受化疗患者的生存时间更长。
癌细胞的无节制生长需要不间断DNA复制, 某些癌细胞依赖于ATR蛋白*协助复制过程, 当这些癌症用化学疗法治疗时，这种依赖性变得更大，ATR蛋白协调细胞周期的暂停，以检查DNA是否完整或需要修复。抑制ATR的药物berzosertib可以使肿瘤细胞失去这种修复作用, 而可能对某些癌症有效。
这是一项随机II期临床试验，11个癌症中心的研究人员招募了70例对铂类化疗耐药的高度浆液性卵巢癌患者。一半参与者被随机分配为单独接受标准化疗药物吉西他滨，另一半接受吉唑他滨联合berzosertib。
中位随访为53.2周。中位无进展生存期对仅接受吉西他滨的患者为14.7周。对接受吉西他滨和berzosertib治疗的患者，为22.9周（危险比0.57，90％CI, 0.33-0.98；单侧对数秩检验p = 0.044）。在对铂具有耐药性的肿瘤患者（即那些在先前铂类化疗后3个月内进展的患者）中位无进展生存期之间的差异更大：吉西他滨为9周，而吉西他滨加berzosertib为27.7周。
与治疗相关的最常见的3级或4级不良事件是嗜中性粒细胞计数降低（吉西他滨单药组39％，吉西他滨加berzosertib组47％）和血小板计数降低 （6％相对于24％）。吉西他滨组因败血症发生了1例与治疗有关的死亡，而吉西他滨加berzosertib组因肺炎引起了1例与治疗有关的死亡。
*ATR是一种丝氨酸/苏氨酸特异性蛋白激酶，能感知DNA损伤并激活DNA损伤检查点，从而导致细胞周期停滞。
Combination of berzosertib with chemotherapy for highly serous ovarian cancer achieved a longer progression-free survival than patients receiving chemotherapy alone.
The uncontrolled growth of cancer cells requires uninterrupted DNA replication. Some cancer cells rely on the ATR protein* to assist in the replication process. When these cancers are treated with chemotherapy, this dependence becomes even greater and the ATR protein can cause cell cycle arrest to check if DNA is intact or needs to be repaired. The ATR-inhibiting drug berzosertib results in the loss of repair ability of tumor cells, and may be effective for certain cancers.
In one study, researchers at 11 cancer centers recruited 70 patients with highly serous ovarian cancer patients who were resistant to platinum-based chemotherapy. Half of the participants were randomly assigned to receive the standard chemotherapy drug gemcitabine alone, and the other half received gemcitabine in combination with berzosertib.
Median follow-up was 53.2 weeks The median progression-free survival was 14.7 weeks for patients receiving gemcitabine alone, and it was 22.9 weeks for patients receiving gemcitabine plus berzosertib (hazard ratio 0.57, 90% CI, 0.33–0.98; one-sided log-rank test p =0.044).. The difference in patients with platinum-resistant tumors (ie, those who progressed within 3 months after the previous platinum-based chemotherapy) was 9 weeks for gemcitabine alone, while it was 27.7 weeks for gemcitabine plus berzosertib.
The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (39% in the gemcitabine alone group vs 47% in the combination group) and decreased platelet count (6% vs 24%). There was one treatment-related death in the gemcitabine alone group due to sepsis and one treatment-related death in the combination group due to pneumonitis.
*ATR is a serine/threonine-specific protein kinase that senses DNA damage and activates DNA damage checkpoints, leading to cell cycle arrest.
参考文献 Reference Konstantinopoulos PA et a. Lancet Onc 2020; June 15. https://doi.org/10.1016/S1470-2045(20)30180-7
Niraparib加上贝伐单抗可改善复发性卵巢癌的临床疗效 (6.21.2020)
Niraparib and bevacizumab combination improved clinical outcome among recurrent ovarian cancer
这是一项开放标签，随机的临床试验（AVANOVA）, 有97位复发性卵巢癌病人参加，包括对铂敏感的上皮性卵巢癌，输卵管癌或腹膜癌，以及高度浆液性或子宫内膜样癌。允许接受过多种治疗（包括贝伐单抗）的患者入选。分层因素包括同源重组缺陷状态（阳性相对于阴性）和无化疗间隔（6-12 相对于 > 12个月）。她们按1：1比例随机分配至联合用药组（Niraparib加上贝伐单抗）（n = 48）或单药用药组（贝伐单抗, n = 49）。所有患者均接受每日300 毫克Niraparib治疗，联合组患者每3周接受贝伐单抗15 毫克/公斤治疗，直至疾病进展或出现毒性。
这项开放标签，随机试验的结果最初于2019年在《柳叶刀肿瘤》上发表，根据生存数据更新结果，在2020 ASCO摹拟科学计划上报告。平均随访24.7个月。贝伐单抗/Niraparib联合治疗组与Niraparib对照组相比，第二次进展或死亡有统计学上的显著改善，中位数分别为20.5和15.7个月（HR，0.56； 95％CI，0.35-0.89； P = .015）。 联合用药组的中位无进展生存期为12.5个月，而单药用药组则为5.5个月。疾病进展或死亡的风险降低了66％（HR，0.34； 95％CI，0.21-0.54）。尽管这项研究无法检测总生存率的差异，但联合用药组与单药用药组相比有改善的趋势，中位数分别为29.4个月和27.8个月（HR，0.75； 95％CI，0.44- 1.28）。
与单独组相比，联合用药组的不良反应（高血压和蛋白尿）发生率显著增加。与治疗相关的不良事件导致停用Nirapari分别为13％和10％。
This is an open-label, randomized clinical trial (AVANOVA) involving 97 patients with recurrent ovarian cancer patients. Participants included platinum-sensitive epithelial ovarian cancer, fallopian tube cancer, or peritoneal cancer, as well as high-grade serous or endometrioid cancer. Patients who had received multiple treatments (including bevacizumab) are allowed. Stratification factors include homologous recombination defect status (positive vs. negative) and chemotherapy-free interval (6-12 vs. >12 months). They were randomly assigned to combination group (Niraparib plus bevacizumab) (n = 48) or monotherapy group (Niraparib, n = 49) in a 1:1 ratio. All patients received 300 mg of Niraparib daily, and patients in the combination group received bevacizumab 15 mg/kg every 3 weeks until disease progression or toxicity.
The results of this trial were originally published in The Lancet Oncology in 2019, and were recently reported at the 2020 ASCO Virtual Scientific Program based on updated survival data. The average follow-up was 24.7 months. Compared with the Niraparib control group, the bevacizumab/Niraparib combination group had a statistically significant improvement in the second progression or death, with a median of 20.5 and 15.7 months (HR, 0.56; 95% CI, 0.35 -0.89; P = .015). The median progression-free survival for the combination group was 12.5 months, compared with 5.5 months of the control group. The risk of disease progression or death was reduced by 66% (HR, 0.34; 95% CI, 0.21-0.54). Although this study could not detect differences in overall survival, the combination group had a tendency to improve compared to the single-agent group, with a median of 29.4 months vs. 27.8 months (HR, 0.75; 95% CI, 0.44 -1.28).
Compared with the control group, the incidence of adverse reactions (hypertension and proteinuria) in the combination group was significantly increased. Adverse events related to treatment led to discontinuation of Nirapari was 13% and 10%, respectively.
参考文献 Reference Mirza MR et al. J Clin Oncol. 2020;38(suppl 15):6012. doi:10.1200/JCO.2020.38.15_suppl.6012 Mirza MR et al. Lancet Oncol. 2019; 20:1409
FDA批准了Lurbinectedin治疗进展的转移性小细胞肺癌(6/20/2020)
FDA granted accelerated approval to Lurbinectedin for metastatic small cell lung cancer
6月15日，FDA批准了lurbinectin*（Zepzelca）治疗铂类化疗治疗后进展的转移性小细胞肺癌。
这项功效在一项PM1183-B-005-14试验中得到了证实，该试验是一项多中心，开放标签，多队列研究，纳入了105例转移性小细胞肺癌的患者，这些患者的病情在铂类化疗之后开始。患者每21天通过静脉输注接受lurbinectin 3.2 毫克/平方米，直到疾病进展或出现不可接受的毒性。治疗的主要目标为总响应率。
在105例患者中，总响应率为35％（95％置信区间[CI] = 26％–45％），中位响应期为5.3个月（95％CI = 4.1–6.4）。根据独立审核委员会的总体响应率为30％（95％CI = 22％–40％），中位响应时间为5.1个月（95％CI = 4.9–6.4）。
最常见的不良反应（≥20％），包括实验室异常（骨髓抑制，肌酐增加，丙氨酸转氨酶增加，葡萄糖增加，白蛋白减少，钠减少，镁减少），恶心，呕吐，便秘，腹泻，食欲下降，疲劳，骨骼肌肉疼痛，呼吸困难和咳嗽。骨髓抑制是最常见的不良事件：3/4级副作用为44％的中性粒细胞减少、12％的发热性中性粒细胞减少和8％3/4级血小板减少症。
*Lurbinectin是一种合成化合物（生物碱类似物）, 可以共价结合到DNA的残基上，可能导致S期进程延迟，G2/M期细胞周期停滞以及细胞死亡。
On June 15, the FDA approved lurbinectin* (Zepzelca) to treat metastatic small cell lung cancer that has progressed after platinum-based chemotherapy.
This efficacy was confirmed in a PM1183-B-005-14 trial, a multi-center, open-label, multi-cohort study that included 105 patients with metastatic small cell lung cancer whose had progressed after platinum-based chemotherapy. Patients received lurbinectin 3.2 mg/m² by intravenous infusion every 21 days until disease progression or unacceptable toxicity. The main efficacy outcome measures overall response rate.
In 105 patients, the overall response rate was 35% (95% confidence interval [CI] = 26%–45%), and the median response duration was 5.3 months (95% CI = 4.1–6.4). According to the independent review committee, the overall response rate was 30% (95% CI = 22%–40%), and the median response time was 5.1 months (95% CI = 4.9–6.4).
The most common adverse reactions (≥20%) included laboratory abnormalities (myelosuppression, increased creatinine, increased alanine aminotransferase, increased glucose, decreased albumin, decreased sodium, decreased magnesium), nausea, vomiting, constipation, diarrhea, decreased appetite, fatigue, musculoskeletal pain, breathing difficulty, and cough. Bone marrow suppression is the most common adverse event: grade 3/4 side effects are 44% neutropenia, 12% febrile neutropenia, and 8% grade 3/4 thrombocytopenia.
*Lurbinectin is a synthetic compound (alkaloids analog) that can be covalently bound to DNA residues, which may cause the delay of the S phase process, G2/M phase cell cycle arrest and cell death.
参考文献 Reference https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-lurbinectedin-metastatic-small-cell-lung-cancer
一种血液中循环的巨噬细胞融合细胞可判断非小细胞肺癌患者预后 (6/14/2020)
Circulating giant tumor-macrophage fusion cells are independent prognostic factor of non-small cell lung cancer
在一项前瞻性试验中，研究者收集血液中各种与癌症相关的细胞。 有一种细胞具有上皮和髓样表型（epithelial and myeloid phenotype）的独特的多形核细胞称为肿瘤-巨噬细胞融合细胞（TMF）。 确定TMF大于或等于30μm，同时具有上皮（细胞角蛋白8、18或19，或上皮细胞粘附分子阳性）和髓样或巨噬细胞阳性（CD14或CD45阳性）, 并且具有至少一个4’，6-diamidino-2-phenylindole 核。
115例非小细胞肺癌患者中有88例发现有循环TMF（平均为3.052；中位数为2 [0-17]];但在长期吸烟且无癌的患者中很少见（87例中有6例[6.9％] ]； 0.081； 0 [0-2]）。在20个健康对照者中不存在。比较非小细胞肺癌患者和无癌症吸烟者中TMF的存在，特异性为93.1％（95％置信区间：85.6–97.4％）; 敏感性为76.5％（95％置信区间：67.7％–83.9％）。 TMF计数与肺癌分期相关。更重要的是，I至IIIA期根治性切除后，如果患者有不止一种TMF和巨型TMF（> 50μm）, 与显著缩短的总生存时间和无癌症生存率（p <0.05）相关。通过多变量分析，大于或等于50μm的巨型TMF是独立的生存预测指标。其生物学作用将需要进一步研究。
In a prospective trial, the researchers collected various cancer-related cells in the blood. There is a unique polymorphonuclear cell with epithelial and myeloid phenotype called tumor-macrophage fusion cell (TMF). It is determined that TMF is greater than or equal to 30 μm, and has both epithelial (cytokeratin 8, 18 or 19, or epithelial cell adhesion molecule positive) and myeloid or macrophage positive (CD14 or CD45 positive), and has at least one 4′, 6-diamidino-2-phenylindole core.
Circulating TMF was found in 88 of 115 patients with non-small cell lung cancer (average 3.052; median 2 [0-17]]; but it is rare in patients who have smoked for a long time and have no cancer (87 patients 6 cases [6.9%]]; 0.081; 0 [0-2]). Not present in 20 healthy controls. Comparing the presence of TMF in non-small cell lung cancer patients and cancer-free smokers, the specificity was 93.1% ( 95% confidence interval: 85.6–97.4%); sensitivity is 76.5% (95% confidence interval: 67.7%–83.9%). TMF count is related to lung cancer stage. More importantly, after radical resection in stages I to IIIA, If the patient has more than one TMF and giant TMF (>50μm), it is associated with significantly shortened overall survival time and cancer-free survival rate (p<0.05). By multivariate analysis, giant TMF greater than or equal to 50μm is independent survival Predictive indicators. Their biological role will require further study.
参考文献 Reference Manjunath M. et al. J Thorac Onc 2020; DOI: https://doi.org/10.1016/j.jtho.2020.04.034VB-111（ofranergene obadenovec）用于耐受铂类的卵巢癌（6/13/2020）
VB-111 used in platinum-refractory ovarian cancer
VB-111是一种靶向抗癌基因疗法，具有双重作用机制：抗血管生成/血管破裂和诱导抗肿瘤定向免疫反应。
这是一项开放标签，剂量递增研究I/II期试验（NCT01711970）, 有21位复发的耐受铂类的卵巢癌患者参加, 中位年龄为65（41-79）岁，曾接受中位3（1-4）线以往治疗。评估VB-111与紫杉醇联合使用的最终结果。在研究的第一阶段，患者接受逐步增加剂量的静脉内VB-111和紫杉醇治疗。在第2阶段，患者接受了治疗剂量的每8星期一次VB-111 （1x 1013病毒颗粒）和每星期一次紫杉醇（80毫克/平方米）的治疗。评估包括安全性，总生存期，无进展生存期，肿瘤响应（CA-125和RECIST）和组织病理学。
患者平均接受2.3±1.8重复剂量的VB-111。 17/21名患者接受了治疗剂量。一半的受试者为铂类难治性患者，另一半曾接受抗血管生成药物治疗。没有观察到剂量限制性毒性。 VB-111具有良好的耐受性，通常伴有轻微的流感样症状。在治疗剂量队列中，可评估患者中观察到持久响应, 和58％的CA-125 GCIG（Gynecologic Cancer InterGroup）响应率，在铂类难治性疾病和抗血管生成药物治疗后的患者中均观察到 响应。治疗剂量患者的中位总生存期为498天，而亚治疗剂量的173天（p = 0.028）。治疗后采集的肿瘤标本显示肿瘤有细胞毒性CD8 T细胞浸润和凋亡癌细胞区域。
结论：VB-111联合每周紫杉醇治疗是安全且耐受性良好的。肿瘤响应和总体生存结果与诱导免疫治疗效果相关，表现为肿瘤被CD-8 T细胞浸润。关键的OVAL研究中进一步探索, 该研究计划招募约400名患者。在ASCO 2000会议上，据报道前60名可随机评估的患者的CA-125响应率为53％。 在治疗后发烧（VB-111治疗后经常观察到发烧）的患者中，CA-125响应率为69％。
VB-111 is an anti-cancer gene therapy with a dual mechanism of action: anti-angiogenesis/vascular rupture and induction of anti-tumor directed immune response.
This was initially an open-label, dose-escalation, phase I/II trial (NCT01711970) and the results were first reported in 2019. Twenty-one patients with relapsed platinum-resistant ovarian cancer participated. The median age was 65 (41-79) years old. They received a median 3 (1-4) line of previous treatment. In the first phase of the study, patients received intravenous VB-111 at increment doses and paclitaxel. In stage 2, patients received a therapeutic dose of VB-111 (1x 1013 virus particles) every 8 weeks and paclitaxel (80 mg/m2) once a week. End points of study include safety, overall survival, progression-free survival, tumor response (CA-125 and RECIST), and histopathology.
Patients received an average of 2.3 ± 1.8 repeated doses of VB-111. A total of 17/21 patients received therapeutic dose. Half of the subjects were platinum-refractory, and the other half had received anti-angiogenic drugs. No dose limiting toxicity was observed. VB-111 was well tolerated and was usually accompanied by mild flu-like symptoms. In the therapeutic dose cohort, a durable response was observed among the assessable patients, and a response rate of 58% of CA-125 GCIG (Gynecologic Cancer InterGroup) was observed in patients who were platinum-refractory or received anti-angiogenesis drugs. The median overall survival of patients with therapeutic dose was 498 days, while the sub-therapeutic dose was 173 days (p = 0.028). Tumor specimens collected after treatment showed that the tumor was infiltrated with cytotoxic CD8 T cell and apoptotic cancer area.
Conclusion: VB-111 combined with weekly paclitaxel treatment is safe and well tolerated. Tumor response and overall survival results were related to the effect of induced immunotherapy, which is manifested by tumor infiltration by CD-8 T cells. The results were further explorex in the phase III OVAL study, which plans to recruit approximately 400 patients. At the 2000 ASCO meeting, it was reported that the first 60 randomly assessable patients had a CA-125 response rate of 53%. In patients with fever after treatment (fever was often observed after VB-111 treatment), the CA-125 response rate was 69%.
参考文献 Reference https://www.globenewswire.com/news-release/2020/06/01/2041367/0/en/VBL-Presents-Positive-Interim-Data-from-the-OVAL-Phase-3-Pivotal-Study-in-Ovarian-Cancer-at-the-ASCO20-Annual-Meeting-Showing-58-or-Higher-Objective-Response-Rate.html Cohen YC et al. J Clin Onc 2019; 37: suppl5542
Selinexor / Bortezomib /地塞米松三联体改善多发性骨髓瘤的无进展生存期 (6/7/2020)
Selinexor added to Bortezomib/dexamethasone improved PFS in recurrent multiple myeloma
与每周两次的硼替佐米（Bortezomib）和地塞米松（Vd）相比，每周一次的selinexor，硼替佐米和地塞米松（SVd）治疗复发/难治性多发性骨髓瘤显著改善了无进展生存期。
这是一项全球性III期临床试验（BOSTON），多发性骨髓瘤患者己接受过1-3种治疗, 中位年龄为66.5岁（范围：38-90岁）, 57.2％是男性。他们分为两组, 患者接受每周两次Vd（硼替佐米1.3 毫克/平方米和地塞米松20 毫克）（207例患者）, 或每周一次SVd（Selinexor 100毫克, 195例患者）。 在24周时，研究人员在selinexor组将硼替佐米的剂量降低了40％，将地塞米松的剂量降低了25％。研究的主要终点是无进展生存期，次要终点包括总响应率，总生存期，反应持续时间，周围神经病变率和预后。
中位无进展生存期分别为13.9（SVd）和9.5（Vd）个月 （HR = 0.70; P = 0.0075）, 而且在所有患者亚组中均一致观察到无进展生存期的改善, 包括17p缺失患者和以前服用过来那度胺（lenolidomide）的患者。在所有亚组中，SVd组总响应率显著较高（76.4％相比于62.3％； P = 0.0012）。中位总生存期在selinexor组尚未达到, 相比于Vd组的25个月（HR = 0.84； 95％CI，0.57-12.3； P = 0.19）。
研究人员使用欧洲癌症研究与治疗组织的问卷调查，发现了SVd组的2级或更高的周围神经病变率显著降低（21.0相比于34.3％； P = 0.0013）。
最常见的与治疗相关的3级或更高的不良事件是血小板减少症（39.5％vs 17.2％），疲劳（13.3％相比于 1.0％）和恶心（7.7％相比于 0％）。 SVd组因不良事件而停药的比例为17％，Vd组为11％。
SVd作为多发性骨髓瘤的治疗方法正在研究中, 最佳组合还有待确定。
Compared with twice-weekly Bortezomib and Dexamethasone (Vd), once-weekly selinexor, plus Bortezomib and Dexamethasone (SVd) significantly improved progression-free survival in relapsed/refractory multiple myeloma.
This is a global phase III clinical trial (BOSTON). Patients with multiple myeloma have received 1-3 lines of treatments were eligible. The median age was 66.5 years (range: 38-90 years), and 57.2% were men. They were divided into two groups. They received either Vd twice a week (bortezomib 1.3 mg/m² and dexamethasone 20 mg) (207 patients), or once a week SVd (Selinexor 100 mg, 195 patients). At 24 weeks, the researchers reduced the bortezomib dose by 40% and the dexamethasone dose by 25% in the selinexor group. The primary endpoint of the study was progression-free survival, and secondary endpoints included overall response rate, overall survival, duration of response, peripheral neuropathy, and prognosis.
The median PFS was 13.9 (SVd) and 9.5 (Vd) months (HR = 0.70; P = 0.0075), and improvement in PFS was consistently observed in all subsets, including those with 17p deletion and those who had previously taken lenolidomide. In all subgroups, the total response rate of the SVd group was significantly higher (76.4% compared to 62.3%; P = 0.0012). The median overall survival was not reached in the selinexor group, compared with 25 months in the Vd group (HR = 0.84; 95% CI, 0.57-12.3; P = 0.19).
The researchers used an European cancer research and treatment organization questionnaire and found that the rate of grade 2 or higher peripheral neuropathy in the SVd group was significantly reduced (21.0% compared to 34.3%; P = 0.0013).
The most common treatment-related adverse events of grade 3 or higher were thrombocytopenia (39.5% vs 17.2%), fatigue (13.3% vs. 1.0%) and nausea (7.7% vs. 0%). The proportion of discontinuation due to adverse events was 17% in the SVd group and 11% in the Vd group.
SVd is being studied as a treatment for multiple myeloma, and the best combination has yet to be determined.
参考文献 Reference Dimopoulos MA et al. 2020 ASCO Virtual Scientific Program; May 29, 2020. Abstr 8501.
二次减细胞手术延长对铂敏感的复发性卵巢癌女性的生存 (6/6/2020)
Secondary cytoreductive surgery may extend overall survival among platinum-sensitive ovarian cancer patients
DESKTOP III成为第一个III期前瞻性随机试验，显示二次细胞减灭术（secondary cytoreductive surgery）对铂敏感的复发性卵巢癌妇女的总生存期的益处。
参与的卵巢癌患者在铂类药物治疗后第一次复发间隔时间≥6 月，而且其AGO评分为阳性（ECOG功能状态为 0，腹水≤500 毫升，并在初次手术时完全切除），她们被随机分配至第二线单药化疗, 或细胞减灭术后再进行化学疗法。中期分析结果报告如下：从2010-2014年一共有407位病人参加。两组的第一次复发间隔时间超过12个月分别为75％和76％。203位病人随机分配到非手术组的，8.9％仍进行了手术; 而204位手术组中的6.9％并未进行手术。 67％的患者完成了完全切除； 87％和88％的患者接受了含铂的二线治疗。 中位数无进展生存期分别为手术组的18.4个月，相对于非手术组的14.0 个月（HR 0.66，95％CI 0.54-0.84，p < 0.001）。开始进行二线后续治疗的中位时间为21个 月相对于13.9 个月，有利于手术组（HR 0.61，95％CI 0.48-0.77， p < 0.001）。第1次和第2次复发之间的第2次无进展生存期等于超过第1次复发前的无进展生存期，在手术后的占26％，而没有手术的只有16％。手术组的中位总生存期为53.7个月，而非手术组为46个月 (HR 0.75, 95% CI 0.58-0.96, P = 0.02)。这意味着降低了25％的风险。
手术组和非手术组的60天死亡率分别为0和0.5％。在手术组中进行了7例（3.5％）的再次开腹手术。除骨髓抑制（在非手术组中更常见）外，3级以上急性不良事件方面没有观察到进一步的显著差异。
DESKTOP III became the first phase III prospective randomized trial to show the benefit of overall survival with secondary cytoreductive surgery of platinum-sensitive women with recurrent ovarian cancer.
Participating ovarian cancer patients had a first relapse interval of ≥ 6 months after platinum-based therapy, and their AGO score was positive (ECOG function status was 0, ascites ≤ 500 ml, and their tumor was completely removed at the initial surgery). They were randomly assigned to second-line single-agent chemotherapy, or chemotherapy after cytoreductive surgery. From 2010 to 2014, a total of 407 patients participated. The first relapse interval over 12 months in the two groups was 75% and 76%, respectively. Of the 203 patients randomly assigned to the non-surgical group, 8.9% still underwent surgery; and 6.9% of the 204 surgical groups did not undergo surgery. Of all, 67% of patients completed a complete resection; 87% and 88% of patients received platinum-containing second-line treatment. The median progression-free survival was 18.4 months in the surgical group, compared with 14.0 months in the non-surgical group (HR 0.66, 95% CI 0.54-0.84, p < 0.001). The median time to start second-line treatment was 21 months versus 13.9 months, which was beneficial to the surgical group (HR 0.61, 95% CI 0.48-0.77, p <0.001). The second progression-free survival between the first and second recurrences equal to the progression-free survival before the first recurrence, accounted for 26% in the surgical group versus only 16% in the non-surgical group. The median overall survival in the surgical group was 53.7 months, compared with 46 months in the non-operative group (HR 0.75, 95% CI 0.58-0.96, P = 0.02). This means a 25% reduction in risk.
The 60-day mortality rates in the surgical and non-surgical groups were 0 and 0.5%, respectively. Seven patients (3.5%) underwent laparatomies again in the surgery group. With the exception of myelosuppression (more common in the non-surgical group), no further significant differences were observed in acute adverse events above grade 3.
参考文献 Reference Du Bois, A. et al. JCO 2017; 35: (suppl) 5501 Du Bois, A et al. ASCO 2020 virtual meeting
第二代双特异性抗体在难治性淋巴瘤中显示出活性 (5/31/2020)
Second-generation bispecific antibodies shows promising activity in refractory lymphoma
新一代的双特异性抗体迎来了CAR-T治疗失败者的新时代。
Mosunetuzumab与恶性B细胞表面的CD20以及细胞毒性T细胞表面的CD3结合，导致T细胞受体交联并随后激活免疫性T细胞应答。
这是一项I期临床试验, 对270例预后不良的患者进行了治疗，其中许多人以前曾接受过CAR T细胞疗法。在193例可评估疗效的患者中，有124例（65％）患有侵袭性（aggressive）淋巴瘤，有67例（35％）患有惰性（indolent）淋巴瘤（但他们的癌症对其他疗法无反应）。侵袭性淋巴瘤患者的客观缓解率为37％，其中19％完全缓解。在惰性淋巴瘤患者中，客观缓解率为63％，完全缓解率为43％。在先前接受过CAR T细胞治疗的30例患者中，有18例是可评估的，其中39％缓解，23％完全缓解。完全缓解组中的一些患者现在已经脱离了mosunetuzumab。有人认为是Mosunetuzumab可能有助于重新接合CAR T细胞并增强先前CAR T细胞治疗的效果。
5.5％的患者发生了导致停药的不良事件。细胞因子释放综合征和神经毒性大多限于1级和2级。
另一个双特异性抗体是REGN1979，它也靶向CD20和CD3。 它可在与CD20阳性B细胞接触后交联并激活表达CD3的T细胞，从而杀死与T细胞受体识别无关的CD20阳性肿瘤细胞， 该研究纳入了110例先前曾接受过抗CD20抗体治疗后复发性或难治性非霍奇金淋巴瘤患者（55％为弥漫性大B细胞淋巴瘤），包括抗CD19 CAR T细胞治疗后疾病进行性的患者。患者每周接受12剂REGN1979静脉注射，然后每2周给药12剂（共36周）。
对接受≥80 毫克治疗的患者在12周时进行了扫描，评估其反应。对于弥漫性大B细胞淋巴瘤患者，总缓解率为58％，其中42％为完全缓解。 在数据截断（5.5个月的中位随访）后，所有完全应答者仍保持完全应答。
在未接受CAR T细胞治疗的患者中，缓解率升至71％，并且均为完全缓解。在先前接受过CAR T细胞治疗的患者中，总缓解率和完全缓解率分别为50％和25％。在滤泡性淋巴瘤患者中，有95％有缓解，有77％达到完全缓解。滤泡性淋巴瘤亚群的无进展生存期中位数为11.4个月。
最常见的治疗性不良事件为发热，细胞因子释放综合征，发冷，疲劳和贫血。最常见的≥3级不良事件是贫血，低磷酸盐血症，淋巴细胞减少和中性粒细胞减少，在大约四分之一的患者中观察到。 6名患者由于毒性而终止治疗。据报道有50％的患者有感染。 20％是3或4级。在数据截止时，八名患者经历了3级免疫相关反应/细胞因子释放综合征，没有报道的4级或5级事件。 扩展队列中的一名患者死于肿瘤溶解综合征。 该患者患有套细胞淋巴瘤。
A new generation of bispecific antibodies usher in a new era of therapy for refractory lymphoma patients including those who failed CAR-T treatment.
Mosunetuzumab binds to CD20 on the surface of malignant B cells and CD3 on the surface of cytotoxic T cells, resulting in cross-linking of T cell receptors and subsequent activation of immune T cell responses.
This is a phase I clinical trial that treated 270 patients with poor prognosis, many of whom had previously received CAR T cell therapy. Of the 193 evaluable patients, 124 (65%) had aggressive lymphomas and 67 (35%) had indolent lymphomas (failed other therapies). The objective response rate for patients with aggressive lymphoma was 37%, of which 19% was complete remission. Among patients with indolent lymphoma, the objective response rate was 63% and the complete response rate was 43%. Of the 30 patients who had previously received CAR T cell therapy, 18 were evaluable, with 39% remission and 23% complete remission. Some patients in the complete remission group were no long on mosunetuzumab. Some people hypothesize that mosunetuzumab may help to rejoin CAR T cells and enhance the effect of previous CAR T cell therapy.
A total of 5.5% patients experienced adverse events that led to drug withdrawal. Cytokine release syndrome and neurotoxicity were mostly limited to grade 1 and 2.
Another bispecific antibody is REGN1979, which also targets CD20 and CD3. It can cross-link and activate CD3 expressing T cells after contact with CD20 positive B cells, thereby killing CD20 positive tumor cells unrelated to T cell receptor recognition. The study included 110 patients with relapsed or refractory NHL (55% with diffuse large B-cell lymphoma) previously treated with anti-CD20 antibodies, including patients with progressive disease after anti-CD19 CAR T-cell therapy. Patients received 12 doses of REGN1979 intravenously every week and then 12 doses every 2 weeks (total 36 weeks).
Patients who received ≥80 mg of treatment were scanned at 12 weeks to assess their response. For patients with diffuse large B-cell lymphoma, the overall remission rate was 58%, of which 42% was complete remission. After data cutoff (median follow-up of 5.5 months), all complete responders remained in complete response.
In patients who did not receive CAR T cell therapy, the remission rate rose to 71%, and all were complete remissions. Among patients who had previously received CAR T cell therapy, the overall and complete remission rates were 50% and 25%, respectively. Among patients with follicular lymphoma, 95% had remission and 77% achieved complete remission. The median progression-free survival of follicular lymphoma subgroup was 11.4 months.
The most common treatment-related adverse events were fever, cytokine release syndrome, chills, fatigue and anemia. The most common ≥ grade 3 adverse events were anemia, hypophosphatemia, lymphopenia, and neutropenia, which were observed in approximately a quarter of patients. Six patients discontinued treatment due to toxicity. According to reports, 50% of patients had infections/infestation, 20% was grade 3 or 4. At the time of data cut-off, eight patients experienced a grade 3 immune-related reaction/cytokine release syndrome, and no grade 4 or 5 events were reported. One patient in the expanded cohort died of tumor lysis syndrome. This patient has mantle cell lymphoma.
参考文献 Reference ASCO Post April 2020 Schuster SJ et al. 2019 ASH Ann Meeting & Exposition Dec 2019; Abstr 6. Bannerji R et al. 2019 ASH Ann Meeting & Exposition Dec 2019; Abstr 762.
术前后使用pembrolizumab有益于早期三阴性乳腺癌 (5/30/2020)
Neoadjuvant and adjuvant pembrolizumab benefited early stage triple-negative breast cancer
在术前化疗中加用pembrolizumab以及术后使用pembrolizumab与安慰剂相比可改善早期三阴性乳腺癌女性的病理完全响应率和无事件生存率。
这是一项III期临床试验，有来自21个国家/地区的181个地点的1,174名三阴性乳腺癌患者参加, 她们先前未接受过治疗, 被随机分配为（2:1）pembrolizumab/化学治疗组（n = 784）或安慰剂/化疗组（n = 390）。术前疗法包括每3周一次200 毫克的pembrolizumab或安慰剂, （共四个周期），再加上紫杉醇（每周一次80 毫克/平方米）和卡铂（AUC=5，在最初的12周每3周一次; 或AUC=1.5, 在最初的12周中每周一次），然后进行4个周期的pembrolizumab或安慰剂加化疗: 阿霉素（60 毫克/平方米）或表柔比星（epirubicin , 90 毫克/平方米）加环磷酰胺（ 600 毫克/平方米），每3周一 次，在手术后，患者每3周接受一次pembrolizumab或安慰剂治疗，共9个周期。试验的主要终点是手术时的病理完全缓解和意向治疗人群的无事件生存率。无事件生存包括任何事件如疾病进展，复发或第二原发肿瘤以及任何原因导致的死亡。
在第一次中期分析中，在随机分配的首批602例患者中（pembrolizumab组401人，安慰剂组202例），pembrolizumab组中64.8％的患者取得了病理完全缓解，而安慰剂组为51.2％（95％置信区间[CI] = 5.4–21.8％，P <.001）。 pembrolizumab的益处在各亚组中基本一致，包括程序性细胞死亡配体1（PD-1）表达亚组。
在意向性治疗人群中位随访15.5个月（范围= 2.7–25.0个月）后，首次无事件生存期评估（第二次中期分析），在任何一组中均未达到中值无事件生存期。在18个月时，pembrolizumab组的估计无事件生存率为91.3％，而安慰剂组为85.3％。
在术前治疗阶段，相关的≥3级不良反应发生在pembrolizumab组中的占76.8％，而安慰剂组为72.2％。与治疗相关的严重不良事件发生率分别为32.5％和19.5％。在所有阶段中，与治疗相关的≥3级不良事件发生率分别为78.0％和73.0％。 pembrolizumab组中与治疗相关的不良事件导致三名患者（0.4％）死亡（一名因肺栓塞，一名败血症和多器官功能障碍综合症，一名由肺炎引起）和安慰剂组一名患者（0.3％）死亡（败血性休克）。
The addition of pembrolizumab in neoadjuvant and adjuvant setting compared with placebo can improve pathological complete response rate and event-free survival in women with early triple-negative breast cancer.
This is a phase III clinical trial involving 1,174 triple-negative breast cancer patients from 181 locations in 21 countries/regions who have not previously received treatment. They were randomly assigned to (2: 1) pembrolizumab / chemotherapy group (n = 784) or placebo / chemotherapy group (n = 390). Preoperative therapy includes 200 mg of pembrolizumab or placebo every 3 weeks (for a total of four cycles), plus paclitaxel (80 mg / m² once a week) and carboplatin (AUC = 5 during the first 12 weeks once every 3 weeks; or AUC = 1.5, once a week for the first 12 weeks), then 4 cycles of pembrolizumab or placebo plus chemotherapy: doxorubicin (60 mg / m²) or epirubicin (90 mg / m²) plus cyclophosphamide (600 mg / m²) every 3 weeks. After surgery, patients received pembrolizumab or placebo every 3 weeks for 9 cycles. The primary endpoint of the trial was complete pathological remission at the time of surgery and event-free survival in the intention-to-treat population. Event-free survival events consisted of disease progression precluding definitive surgery, local or distant recurrence or second primary tumor, and death from any cause.
In the first interim analysis, of the first 602 patients randomly assigned (401 in the pembrolizumab group and 202 in the placebo group), 64.8% in the pembrolizumab group achieved complete pathological remission, compared with 51.2 in the placebo group % (95% CI= 5.4–21.8%, P <.001). The benefits of pembrolizumab are basically the same across all subgroups, including that of PD-1 expression.
At the first event-free survival assessment (second interim analysis) after median follow-up of 15.5 months (range = 2.7–25.0 months) among all patients in the intent-to-treat population, median event-free survival had not been reached in either group. At 18 months, the estimated event-free survival rate in the pembrolizumab group was 91.3%, compared with 85.3% in the placebo group.
In the neoadjuvant phase, grade treatment-related grade ≥3 adverse reactions occurred in 76.8% of the pembrolizumab group, compared with 72.2% in the placebo group. The incidence of treatment-related serious adverse events was 32.5% versus 19.5%, respectively. Across all phases, the incidence of treatment-related ≥3 adverse events were 78.0% and 73.0%, respectively. Treatment-related adverse events in the pembrolizumab group led to death death in three patients (0.4%) in pembrolizumab group (one from pulmonary embolism, one from sepsis and multiple organ dysfunction syndrome, and one from pneumonia) and one death in the placebo group ( 0.3%) (septic shock).
参考文献 Reference Schmid P et al. NEJM 2020; 382: 810
Trifluridine/Tipiracil联合贝伐单抗用于化疗难治性转移性大肠癌 (5/24/2020)
Trifluridine/Tipiracil in combination with bevacizumab for chemo-refractory colorectal cancer
将贝伐单抗加到三氟吡啶/替普拉西酯（也称TAS-102）中，可显着改善化疗难治性转移结直肠癌患者的无进展生存期。
在一项开放标签的多中心II期临床试验中，从2017年8月至2018年10月之间随机分配了93名RAS野生型结直肠癌患者, 他们对5-氟嘧啶，伊立替康，奥沙利铂和西妥昔单抗或帕尼单抗难治或不耐受。47名患者每天两次口服三氟哌啶/替吡酯（35 毫克/平方米, 每28天的第1至5天和第8至12天）; 46名患者在第1和15天以5毫克/公斤的剂量接受三氟吡啶/替普拉西酯加贝伐单抗, 直至疾病进展或不可接受的毒性。允许先前接受过贝伐单抗，aflibercept, ramucirumab或 regorafenib患者参加治疗。主要终点是研究者评估的无进展生存期。
中位随访时间为10.0个月。联合组中位无进展生存期为4.6个月，而三氟吡啶/替普拉西酯组为2.6个月（HR = 0.45，P = .0015）。当调整研究中心的分层因素和RAS突变状态后，差异仍然很显着（HR = 0.47，P = .0015）。联合组中位总生存期为9.4个月，相对于6.7个月（HR = 0.55，P = .028； 调整分层因素后，HR = 0.58，P = .048）。疾病控制率是67％和51％（P = .14）。
联合治疗组中最常见的与治疗相关的≥3级不良事件是中性粒细胞减少（67％相对于38％）；最常见的与治疗相关的≥3级非血液学不良事件是腹泻（9％相对于0％）。严重不良事件发生率为41％相对于45％。没有观察到与治疗相关的死亡。
Adding bevacizumab to trifluoropyridine/tipiracil ester (also known as TAS-102) can significantly improve the progression-free survival of patients with chemo-refractory metastatic colorectal cancer.
In an open-label multi-center phase II clinical trial, 93 patients with RAS wild-type colorectal cancer were randomly assigned between August 2017 and October 2018. They were refractory or intolerant to 5-fluoropyrimidine, irinotecan, Oxaliplatin and cetuximab or panitumumab. 47 patients received trifluoperidine / tipiramate twice daily (35 mg / m², on days 1 to 5 and 8 to 12 every 28 days); 46 patients received 5 mg/kg bevacizumab on days 1 and 15 plus trifluoropyridine / tipiracilate, until disease progression or unacceptable toxicity. Patients who had previously received bevacizumab, aflibercept, ramucirumab or regorafenib were allowed to participate in the trial. The primary endpoint was progression-free survival assessed by the investigator.
The median follow-up was 10.0 months. The median progression-free survival was 4.6 months in the combination group, and 2.6 months in the trifluoropyridine/tipiracil group (HR = 0.45, P = .0015). When analysis was adjusted for the stratification factors of study center and RAS mutation status, the difference was still significant (HR = 0.47, P = .0015). The median overall survival of the combined group was 9.4 months, versus 6.7 months (HR = 0.55, P = .028; after adjusting for stratification factors, HR = 0.58, P = .048). The disease control rates were 67% and 51% (P = .14).
The most common grade ≥3 treatment-related adverse event in the combination group was neutropenia (67% vs. 38%); the most common treatment-related grade ≥3 nonhematological adverse event was diarrhea (9 % vs. 0%). The incidence of serious adverse events was 41% versus 45%. No treatment-related deaths were observed.
参考文献 Reference Pfeiffer P et al. Lancet Onc 2020; 21: 412Atezolizumab被FDA批准用于一线治疗某些转移性非小细胞肺癌患者 (5/23/2020)
FDA has just approved Atezolizumab for first-line therapy on certain non-small cell lung cancer patients
FDA批准atezolizumab用于一线治疗转移性非小细胞肺癌患者，这些患者的肿瘤具有PD-L1高表达（PD-L1染色≥肿瘤细胞的50％）（TC≥50）或PD-L1染色的肿瘤浸润免疫细胞覆盖≥10％的肿瘤区域（IC≥10），他们没有EGFR或ALK基因组肿瘤异常。
IMpower110（NCT02409342）是一项多中心，国际，随机，开放标签试验，参加者为IV期非小细胞肺癌，肿瘤表达PD-L1（TC≥1％或IC≥1％）且未接受过化疗。患者被随机分配（1：1）为每3周接受1200 毫克的atezolizumab，或接受铂类化疗, 直到疾病进展或出现不可接受的毒性为止。主要功效结局指标是总生存期。
该试验表明，与接受铂类化疗的患者相比，接受atezolizumab治疗的PD-L1肿瘤高表达患者的总生存期在统计学上有显著改善。 Atezolizumab组患者的总生存期中位数为20.2个月（95％CI：16.5-未达到），而化疗组患者的中位总生存期为13.1个月（95％CI：7.4-16.5）（HR 0.59; 95％CI：0.40-0.89; p = 0.0106）。在中期或最终分析中，其他两个PD-L1亚组（TC≥5％或IC≥5％； TC≥1％或IC≥1％）的总生存期差异无统计学意义。
该试验的每个研究者（investigator）的中位无进展生存期在atezolizumab组为8.1个月（95％CI：6.8-11.0），在铂类化疗组中为5.0个月（95％CI：4.2-5.7）（HR 0.63; 95） ％CI：0.45-0.88）。每位研究者的确诊总体响应率分别为38％（95％CI：29-48）和29％（95％CI：20-39）。
单药使用atezolizumab最常见的不良反应（≥20％）是疲劳。
FDA has approved atezolizumab for first-line treatment of patients with metastatic non-small cell lung cancer whose tumors have high expression of PD-L1 (PD-L1 staining ≥50% of tumor cells) (TC≥50) or tumor infiltration of PD-L1 stain Immune cells cover ≥ 10% of the tumor area (IC ≥ 10) with no EGFR or ALK genomic tumor abnormalities.
IMpower110 (NCT02409342) is a multi-center, international, randomized, open-label trial. Participants had stage IV non-small cell lung cancer. The tumor expresses PD-L1 (TC ≥ 1% or IC ≥ 1%) and had not received chemotherapy. Patients were randomly assigned (1: 1) to receive either 1200 mg of atezolizumab every 3 weeks or platinum-based chemotherapy until disease progression or unacceptable toxicity. The main efficacy outcome measure was overall survival.
The trial demonstrated a statistically significant improvement in overall survival in patients with high expression of PD-L1 tumors treated with atezolizumab compared with those receiving platinum-based chemotherapy. The median overall survival of patients in the Atezolizumab group was 20.2 months (95% CI: 16.5-not reached) while the median overall survival of patients in the chemotherapy group was 13.1 months (95% CI: 7.4-16.5) (HR 0.59; 95% CI: 0.40-0.89; p = 0.0106). In the interim or final analysis, there was no statistically significant difference in the overall survival of the other two PD-L1 subgroups (TC ≥ 5% or IC ≥ 5%; TC ≥ 1% or IC ≥ 1%).
The median progression-free survival of each investigator in the trial was 8.1 months in the atezolizumab group (95% CI: 6.8-11.0) and 5.0 months in the platinum-based chemotherapy group (95% CI: 4.2 -5.7) (HR 0.63; 95)% CI: 0.45-0.88). The overall response rate of each investigator’s diagnosis was 38% (95% CI: 29-48) and 29% (95% CI: 20-39).
The most common adverse reaction (≥20%) of single drug atezolizumab is fatigue.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-first-line-treatment-metastatic-nsclc-high-pd-l1-expression May 18, 2020
Sacituzumab govitecan-hziy用于转移性三阴性乳腺癌 (5/17/2020)
Sacituzumab govitecan-hziy for triple-negative breast cancer
FDA在2020年4月批准了sacituzumab govitecan-hziy用于转移性三阴性乳腺癌。
Sacituzumab govitecan-hziy靶向Trop-2（一种泛上皮癌抗原）释放SN-38（化疗药伊立替康的活性代谢产物）。 与母体化合物伊立替康相比，该药物的优势在于，在临床前研究模型中，它可以将SN-38的含量提高136倍。它的有效性在IMMU-132-01（NCT 01631552）临床试验中得到证实，IMMU-132-01是一项多中心，单组，I/II期试验, 纳入研究的108例转移性三阴性乳腺癌患者，至少接受过两次转移性疾病的治疗。患者每21天在第1天和第8天静脉内接受10 毫克/公斤的sacituzumab govitecan-hziy静脉注射。每8周进行一次肿瘤成像，并对患者进行治疗直至疾病进展或对治疗不能耐受。主要疗效指标是客观响应率和响应持续时间。
接受sacituzumab govitecan-hziy患者的客观响应率为33.3％（95％CI：24.6-43.1）。中位缓解时间为7.7个月（95％CI：4.9-10.8）。中位无进展生存期为5.5个月，而12个月无进展生存期为15.1％。 中位总生存期为13.0个月，而12个月的估计生存率为51.3％。
3级或4级不良事件（在≥10％的患者中观察到）包括贫血和中性粒细胞减少。 此外，有10例患者（9.3％）患有发热性中性粒细胞减少症。
III期试验ASCENT是验证sacituzumab govitecan在转移性三阴性乳腺癌中观察到的安全性和有效性。 该研究的主要终点是无进展生存期，次要终点包括总体生存期和客观反应等。 由于达到功效，该公司于2020年4月宣布该研究被终止。
FDA approved sacituzumab govitecan-hziy for metastatic triple-negative breast cancer in April 2020.
Sacituzumab govitecan-hziy targets Trop-2 (a pan-epithelial carcinoma antigen) to release SN-38 (the active metabolite of the chemotherapeutic drug irinotecan). Compared with the parent compound irinotecan, the antibody-drug conjugate has the advantage to increase the content of SN-38 by 136 times in the preclinical research model. Its effectiveness was confirmed in the clinical trial of IMMU-132-01 (NCT 01631552). This is a multi-center, single-arm, phase I / II trial with 108 metastatic triple negative breasts in the study. Cancer patients had received at least two prior lines of treatment for metastatic disease. The patient received intravenous sacituzumab govitecan-hziy at 10 mg/kg intravenously on days 1 and 8 every 21 days. Tumor imaging is performed every 8 weeks, and the patient is treated until disease progression or intolerance to treatment. The primary endpoint of the trial are objective response rate and response duration.
The objective response rate of patients receiving sacituzumab govitecan-hziy was 33.3% (95% CI: 24.6-43.1). The median response time was 7.7 months (95% CI: 4.9-10.8). The median progression-free survival was 5.5 months, while the 12-month progression-free survival was 15.1%. The median overall survival is 13.0 months, while the estimated survival rate at 12 months is 51.3%.
Grade 3 or 4 adverse events (observed in ≥10% of patients) include anemia and neutropenia. In addition, 10 patients (9.3%) had febrile neutropenia.
The ASCENT Phase III trial is to verify the safety and effectiveness of sacituzumab govitecan observed in the phase I/II trial in metastatic triple-negative breast cancer. The primary endpoint of the study was progression-free survival, and secondary endpoints included overall survival and objective response. Due to its effectiveness, the company announced in April 2020 that the study was terminated.
参考文献 Reference Bardia A et al. N Engl J Med 2019; 290:741Immunomedics Announces ASCENT Study to be Stopped for Compelling Efficacy. Morris Plains, NJ. Published April 6, 2020. immunomedics.com/our-company/news-and-events/immunomedics-announces-ascent-study-to-be-stopped-for-compelling-efficacy
KRAS突变可能预测某些卵巢癌中MEK抑制剂的益处 (5/16/2020)
KRAS mutation status may predict benefit of MEK inhibitor in certain ovarian cancer
III期MILO试验的事后分析发现，对于患有复发性或持续性低度浆液性卵巢癌的女性，KRAS突变可预测Binimetinib的治疗益处。
从2013年开始，III期MILO / ENGOT-ov11试验在17个国家招收了341例复发性低度浆液性卵巢癌患者, 她们以2:1随机分为两组，一组接受口服MEK抑制剂Binimetinib（340 毫克, 每天两次）; 另一个组接受医师选择的化疗方案（脂质体阿霉素，紫杉醇或拓扑替康）。所有妇女以前都接受过外科手术，大多数是白人（91％），三分之一的妇女接受过激素治疗。研究组中位年龄为54岁，而化疗组中位年龄为50岁。两组之间存在KRAS突变的情况相似，Binimetinib组为32％，化疗组为34％。研究主要终点为无进展生存期。
总体而言，两组各有24％的患者有客观响应，包括3％用Binimetinib治疗的患者和1％接受化疗的患者完全响应。此外，有60％和54％的人疾病稳定。通过中央评估, 在整个研究人群中的分析未能证明binimetinib有无进展生存期益处: 10.4个月，相对于化疗组的11.5个月（HR 1.15， 95％CI 0.76-1.74）。但是在Binimetinib组中，具有KRAS突变的女性的中位无进展生存期显增加，为17.7个月，而患有野生型KRAS肿瘤的女性为10.8个月（P = 0.006）。
接受Binimetinib治疗的患者中有76％的患者发生了3/4级事件（腹泻，皮疹，外周水肿和肌酸升高），而接受化疗的患者中有44％的患者发生了这种事件，因副作用而停止治疗的患者中，Binimetinib组发生率是后者的两倍（20％比11％）。
A post-hoc analysis of the phase III MILO trial found that for women with recurrent or persistent low-grade serous ovarian cancer, KRAS mutation could predict the therapeutic benefit of Binimetinib.
Starting in 2013, the phase III MILO / ENGOT-ov11 trial enrolled 341 patients with recurrent low-grade serous ovarian cancer in 17 countries. They were randomly assigned 2:1 in two groups. One group received oral MEK inhibitors Binimetinib (340 mg, twice a day); another group received chemotherapy regimen chosen by the treating physician (liposome doxorubicin, paclitaxel or topotecan). All women have undergone surgery before, most of whm are white (91%), and one-third of women have received hormone therapy. The median age of the study group was 54 years, while the median age of the chemotherapy group was 50 years. The KRAS mutation was similar between the two groups, with 32% in the Binimetinib group and 34% in the chemotherapy group. The primary endpoint of the study was progression-free survival.
Overall, 24% of patients in each group responded objectively, including 3% of patients treated with Binimetinib and 1% of patients treated with chemotherapy achieved complete response. In addition, 60% and 54% of people had stable disease. Through central assessment, it was found in the entire study population binimetinib failed to demonstrate progression-free survival benefit: 10.4 months, compared to 11.5 months in the chemotherapy group (HR 1.15, 95% CI 0.76-1.74). However, in the Binimetinib group, the median progression-free survival of women with KRAS mutations was significantly increased at 17.7 months, compared with 10.8 months for women with wild-type KRAS tumors (P = 0.006).
A total of 76% patients receiving Binimetinib experienced grade 3/4 events (diarrhea, rash, peripheral edema and increased creatine), while 44% patients receiving chemotherapy experienced such events. Among patients who discontinued treatment due to side effects, the incidence in the Binimetinib group was twice that of the chemotherapy group (20% vs. 11%).
参考文献 Reference Grisham RN et al. Society Gyne Onc 2020; Abstract 41.
术前Durvalumab / Olaparib用于HER2阴性乳腺癌 (5/10/2020)
Durvalumab/Olaparib combination with chemotherapy in preoperative HER-2-negative breast cancer
在高危HER2阴性疾病的患者中，检查点抑制剂durvalumab，PARP抑制剂（olaparib）和紫杉醇联合阿霉素/环磷酰胺作为新辅助疗法可改善病理完全反应。
I-SPY试验是一系列多中心II期试验，评估作为乳腺癌新辅助疗法的新型药物，其主要终点是病理完全应答。多个并发臂使用共享控制臂进行测试， 当在适当的生物标志物组中进行的具有300位患者的III期新辅助试验中的贝叶斯预测成功概率达到至少85％时, 则可以认为实验方案已经毕业，有待进一步测试。
在动物研究中，PARP抑制剂可增加肿瘤中程序性细胞死亡配体1（PD-L1）蛋白的表达，还可能产生吸引和激活免疫细胞的信号。预期抗PD-L1检查点抑制剂durvalumab将增加抗肿瘤免疫反应。
参加的患者均患有HER2阴性乳腺癌，肿瘤至少2.5 cm，患有激素受体阳性疾病的患者也必须按照MammaPrint分析法确定具有高风险。 病理完全缓解的定义为在乳房或淋巴结中无残留浸润癌, 是试验的终点。
在实验组（73例患者，包括21例三阴性疾病）中，治疗包括每4周1,500 毫克 durvalumab的治疗，共3个周期，第1至11周以100 毫克 / 天的奥拉帕尼和每周80 毫克/平方米的紫杉醇×12，然后进行4个周期的阿霉素/环磷酰胺。对照组（299名患者）每周接受紫杉醇治疗12周，随后进行4个周期的阿霉素/环磷酰胺治疗。在第3周和第12周收集成像数据。针对三个预先定义的生物标志，分别计算了未来III期试验成功的可能性。
在HER2阴性的癌症中，病理完全缓解率从20％增加到37％；在三阴性癌症中，它从27％增加到47％；在HER2阴性/激素受体阳性人群中，这一比例从14％增至28％。在所有亚组中，实验组优于单独化疗的估计概率大于98％。 Durvalumab和olaparib不仅提高了病理学完全缓解率，还将残余癌症负荷类别向更低的值转移。
在初步毒性分析中，包括实验组的43例患者和对照组的251例患者，实验组中58％的患者报告了3或4级不良事件，而对照组中则为41％。据报道，实验组有更多的发热性中性粒细胞减少，结肠炎和肝酶升高。在实验组中有19％的人报告了3级免疫相关不良事件，而对照组中有1.6％。
In patients with high-risk HER2-negative breast cancer, the checkpoint inhibitor durvalumab, PARP inhibitor (olaparib) and paclitaxel combined with doxorubicin/cyclophosphamide as neoadjuvant therapy could improve the pathological complete response.
The I-SPY trial is a series of multi-center phase II trials evaluated as novel neoadjuvant therapies, and its primary endpoint is a complete pathological response. Multiple concurrent arms were tested using a shared control arm when the Bayesian predicted probability of success group reached at least 85% in a phase III neoadjuvant trial with 300 patients under appropriate biomarkers. It can then be considered that the experimental program has graduated and may need further testing.
In animal studies, PARP inhibitors has been shown to increase the expression of programmed cell death ligand 1 (PD-L1) protein in tumors, and may also produce signals that attract and activate immune cells. The anti-PD-L1 checkpoint inhibitor durvalumab is expected to increase the anti-tumor immune response.
The tumor size in participating HER-2-negative breast cancer patients is at least 2.5 cm, and patients with hormone receptor positive disease must also be determined to have a high risk according to MammaPrint analysis. PCR is the end point of the trial.
In the experimental group (73 patients, including 21 triple-negative disease), treatment included 1,500 mg durvalumab every 4 weeks for a total of 3 cycles, with 100 mg/day of olaparib and weekly paclitaxel (80 mg / m² ) × 12, followed by 4 cycles of doxorubicin/cyclophosphamide. Control group (299 patients) received paclitaxel treatment for 12 weeks per week, followed by 4 cycles of doxorubicin/Cyclophosphamide. Imaging data were collected at weeks 3 and 12. For three pre-defined biomarkers, the probability of a successful phase III trial is calculated separately.
In HER2-negative cancers, the pCR rate increased from 20% in control group to 37% in experiment group; in triple-negative cancers, it increased from 27% to 47%; in HER2-negative / hormone receptor positive populations, this pCR proportion increased from 14% to 28%. In all subgroups, the estimated probability that the experimental group is superior to chemotherapy alone is greater than 98%.
In the preliminary toxicity analysis, including 43 patients in the experiment group and 251 patients in the control group, 58% in the experiment had grade 3 or 4 side-effects, versus 41% in control group. The experiment group had more febrile neutropenia, colitis and increased liver enzymes. According to reports, 19% in the experiment group reported grade 3 immune-related adverse events, compared with 1.6% in control group.
参考文献 Reference Pusztai L et al. 2020 AACR Virtual Annual Meeting abstrCT011
Onvansertib在KRAS突变型转移性大肠癌中有前景 (5/9/2020)
Onvansertib plus FOLFIRI/Bevacizumab appeared promising in metastatic colorectal cancer with KRAS mutation
Onvansertib是丝氨酸/苏氨酸酶的第三代口服高选择性三磷酸腺苷抑制剂，根据临床前研究表明，该药物与伊立替康的组合具有协同作用针对具有KRAS 突变的细胞。
在1b期剂量递增阶段，已经清除了两个剂量水平（12和15 毫克/平方米）。第三剂量水平（18毫克/平方米）正在招募中；迄今为止尚未达到最大耐受剂量。Onvansertib的1b / 2期临床试验与FOLFIRI和贝伐单抗联合用于KRAS突变转移性结直肠癌患者的二线治疗。
截至数据截止日期，在8位可评估患者中，有7位（88％）观察到了临床反应：3例患者出现部分缓解，4例患者患有稳定疾病, 1名患者成功接受了治愈手术。迄今为止，无进展生存期为6.5个月，尚有6名患者接受治疗。血浆KRAS突变水平的降低是治疗反应的早期标志。
根据安全性评估，研究中有超过2位患者发生了不良事件。除3/4级腹痛和中性粒细胞减少外，大多数不良事件均为1级或2级。最常见的1/2级不良事件是疲劳（88％），恶心（50％）和胃痛（38％）。研究人员认为，该组合耐受性良好。
Ib期研究处于第二次剂量递增，还有一个剂量递增。一旦研究的第二阶段开始，研究的主要终点将是客观缓解率，次要终点将包括完全缓解的受试者人数，部分缓解，稳定疾病，无进展生存期和KRAS等位基因液体活检负担减少的人数。
Onvansertib is a third-generation, highly selective oral ATP inhibitor of serine/threonine polo-like-kinase 1 (PLK1) enzyme. According to preclinical studies, the combination of this drug and irinotecan has a synergistic effect on cells with KRAS mutations.
In the phase 1b dose escalation phase, two dose levels have been cleared for safety (12 and 15 mg / m2). The third dose level (18 mg / m²) is enrolling; so far the maximum tolerated dose has not been reached. Phase 1b / 2 clinical trial in combination with FOLFIRI and bevacizumab is used for second-line treatment for patients of metastatic colorectal cancer with KRAS mutation.
As of the data cutoff date, 7 (88%) of 8 evaluable patients had achieved a clinical response: 3 patients had partial remission, 4 patients had stable disease, and 1 patient successfully underwent curative surgery. To date, progression-free survival was 6.5 months, and 6 patients are still receiving treatment. The decrease of plasma mutated KRAS level is an early sign of treatment response.
Based on the safety assessment, more than 2 patients in the study experienced adverse events. With the exception of grade 3/4 abdominal pain and neutropenia, most adverse events were grade 1 or grade 2. The most common grade 1/2 adverse events were fatigue (88%), nausea (50%), and stomach pain (38%). The researchers believe that the combination is well tolerated.
The Phase Ib study is in its second dose escalation, and there will be another dose escalation. Once the second phase of the study begins, the primary endpoint of the study will be the objective response rate, and the secondary endpoint will include the number of subjects with complete remission, partial remission, stable disease, progression-free survival, and number of participants with reduced KRAS allelic burden on liquid biopsy.
参考文献 Reference Barzi A. AACR 2020; oral presentation April 27
现成的CAR T细胞对非霍奇金淋巴瘤安全和有效 (5/3/2020)
Off-the-shelf CA-T product appears safe and effective for non-Hodgkin lymphoma
根据I期试验结果，使用现成的嵌合抗原受体（CAR）T细胞产品可用于复发/难治性B细胞恶性肿瘤患者。
这项临床试验检查了2个队列。队列1包括异体造血干细胞移植后复发/难治性的患者（n = 7）。队列2包括符合自体造血干细胞条件的复发/难治性B细胞恶性肿瘤患者，并在移植后接受CAR-T细胞巩固治疗（n = 3）。分析中总共包括5名急性B淋巴细胞白血病患者，4例非霍奇金淋巴瘤和1例慢性淋巴细胞性白血病。 非霍奇金淋巴瘤患者中有3人组成第二个队列，其余患者则在第1组中接受治疗。
在队列1中有57％的患者发生了响应，在队列2中有100％的患者发生了响应。接受第三方供体细胞（CAR-T）治疗的患者中有83％有响应。所有慢性淋巴细胞性白血病和非霍奇金淋巴瘤患者均有响应，而急性B淋巴细胞白血病患者响应为40％。非霍奇金淋巴瘤患者的反应最为明显。符合自体造血干细胞资格的3例患者，包括2例原发性纵隔大B细胞淋巴瘤和1例弥漫性大B细胞淋巴瘤，在移植前的PET阳性疾病的Deauville评分为4。这些患者数据报告时仍然没有疾病。 一个Burkitt淋巴瘤患者接受异体造血干细胞移植后18天复发, 但在接受了第三方供体细胞4年后仍无病。在分析时，所有患有非霍奇金淋巴瘤或慢性淋巴细胞性白血病的患者均存活且无疾病。 非霍奇金淋巴瘤患者的中位随访时间为33.9个月。接受第三方供体细胞的患者中，中位随访时间为26.9个月。
该疗法具有良好的耐受性，队列1中的1名患者患有1级皮肤移植物抗宿主病（GVHD）和1级细胞因子释放综合征。在队列2中，观察到1例1级GVHD和1例肺炎/低氧血症，除1例以外，其余均发生在接受第三方捐赠的患者中。没有观察到严重的细胞因子释放综合征或神经毒性事件。
从健康捐赠者那里收集B细胞，并用实验室EBV株感染了它们。 将EBV抗原呈递细胞与单采术共培养, 最终得到的是不会引起GVHD的EBV特异性和非变态反应性供体细胞。 在细胞库中制备了HLA相容系，患者必须至少具有2/10的HLA相容性。T细胞输注的中位剂量为2.2×106 ，大多数患者能够接受1次以上的输液。
现成的CAR T细胞的优势包括无需等待收集和生产时间,成本降低, 以及从健康供体中获得更高质量的T细胞。
According to Phase I study results, the use of off-the-shelf chimeric antigen receptor (CAR) T cell products can be used in patients with relapsed/refractory B-cell malignancies.
This clinical trial examined two cohorts. Cohort 1 included patients who had relapsed/refractory disease after allogeneic hematopoietic stem cell transplantation (n = 7). Cohort 2 included patients with relapsed/refractory B-cell malignancies eligible for autologous hematopoietic stem cells and received CAR-T cell consolidation therapy after transplantation (n = 3). A total of 5 patients with acute B-lymphocytic leukemia, 4 cases of non-Hodgkin’s lymphoma and 1 case of chronic lymphocytic leukemia were included in the analysis. Three of the patients with non-Hodgkin’s lymphoma joined the second cohort, and the remaining patients were treated in cohort 1.
A total of 57% of patients in cohort 1 responded, while 100% of the patients in cohort 2 responded. Of all, 83% of patients treated with third-party donor cells (CAR-T) responded. All patients with chronic lymphocytic leukemia and non-Hodgkin’s lymphoma responded, while 40% patients with acute B-lymphocytic leukemia responded. Patients with non-Hodgkin’s lymphoma had the most objective response. Three patients eligible for autologous hematopoietic stem cells, including two primary mediastinal large B-cell lymphoma and one diffuse large B-cell lymphoma, had a Deauville score of 4 for PET-positive disease before transplantation. These patients are disease-free at the time of data reporting. A patient with Burkitt lymphoma relapsed 18 days after receiving allogeneic hematopoietic stem cell transplantation, but was still disease-free 4 years after receiving third-party donor cells. At the time of analysis, all patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia were alive and disease-free. The median follow-up time for patients with non-Hodgkin’s lymphoma was 33.9 months. Among patients receiving third-party donor cells, the median follow-up time was 26.9 months.
The therapy was well tolerated, and one patient in cohort 1 had grade 1 skin graft versus host disease (GVHD) and grade 1 cytokine releasing syndrome. In cohort 2, one case of grade 1 GVHD and one case of pneumonia/hypoxemia were observed. Except for one case, the rest occurred in patients receiving donor cells from third parties. No serious cytokine releasing syndrome or neurotoxic events were observed.
Methodically, B cells were collected from healthy donors and infected with laboratory EBV strains. Co-cultivation of EBV antigen-presenting cells and apheresis will ultimately result in EBV-specific and non-alloreactive donor cells that should not cause GVHD. HLA compatible lines were made in the cell bank, and the patient must have at least 2/10 of HLA compatibility. The median dose of T cell infusion is 2.2×106, and most patients could receive more than one infusions.
The advantages of off-the-shelf CAR T cells include better logistics with no need to wait for collection and production time, cost reduction, and higher quality T cells from healthy donors.
参考文献 Reference Curran KJ. 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020. abstr 120
卡博替尼加Atezolizumab对转移性去势抵抗性前列腺癌有活性 (5/2/2020)
Cabozantinib and Atezolizumab were active in metastatic castration-resistant prostate cancer
COSMIC-021是一个多中心开放标签研究, 在1b阶段 , 参与者中除了许多不同类型的实体瘤外，还有44名转移性去势抵抗性前列腺癌患者, 他们曾接受过恩杂鲁胺（enzalutamide），阿比特龙（abiraterone）或两者同时治疗, 而疾病进展。他们被安排接受卡博替尼（Cabozantinib）, 每日剂量为40毫克，Atezolizumab的剂量为每3周1200毫克。在数据分析时，已对患者进行了平均12.6个月的随访。
作为单一药物，酪氨酸激酶抑制剂卡博替尼或PD-L1抑制剂atezolizumab的治疗只达到低客观响应率, 在该患者人群中分别为5％和0％。 但是该44名接受卡博替尼加Atezolizumab参与者中有32％达到了客观响应。总体疾病控制率为80％，其中稳定疾病率为48％，部分缓解率为27％，完全缓解率为5％。中位缓解时间为8.3个月。在36例具有高风险内脏和/或盆腔外淋巴结转移的患者中，客观响应为33％。
卡波替尼加阿特珠单抗具有可耐受的安全性。 59％的患者发生3或4级的治疗相关不良事件，而9.1％的患者发生3或4级的免疫相关不良事件。其中包括疲劳（7％），腹泻（7％）和低钠血症（7％）。
COSMIC-021 is a multi-center open-label study. In 1b phase, in addition to patients with many different types of solid tumors, there were 44 patients with metastatic castration-resistant prostate cancer. They had received enzalutamide, abiraterone or both, and then the disease progressed. They were arranged to receive Cabozantinib at a daily dose of 40 mg and Atezolizumab at a dose of 1200 mg every 3 weeks. At the time of data analysis, patients had a median followed up of 12.6 months.
As a single drug, tyrosine kinase inhibitor carbotinib or PD-L1 inhibitor atezolizumab was found to achieve only a low objective response rate, which was 5% and 0% in this patient population, respectively. However, 32% of the 44 participants who received Cabozantinib and Atezolizumab achieved an objective response. The overall disease control rate was 80%, with a stable disease of 48%, a partial response rate of 27%, and a complete response rate of 5%. The median response duraton was 8.3 months. Among 36 patients with high-risk visceral and/or extrapelvic lymph node metastasis, the objective response was 33%.
Carbotinib plus atezumab demonstrated tolerable safety. A total of 59% patients had grade 3 or 4 treatment-related adverse events, while 9.1% of patients had grade 3 or 4 immune-related adverse events. These include fatigue (7%), diarrhea (7%) and hyponatremia (7%).
参考文献 Reference Agarwal N et al. 2020 GU cancer Symposium, San Francisco 2020, abstr 139
新的靶向药物治疗浆液性子宫癌 (4/26/2020)
New drug targeting uterine serous carcinoma
浆液性子宫癌约占子宫癌的10％, 但高达40％子宫癌的死亡是由于浆液性子宫癌。Adavosertib是定向WEE1的疗法, 在复发性浆液性子宫癌患者的试验中，产生了可观的响应。
超过90％的浆液性子宫癌具有TP53基因突变，G1 / S细胞周期检查点的频繁丢失和失调以及癌基因驱动的复制应激的存在。当丢失了G1 / S检查点时，对G2 / M检查点的依赖性就会增加，而这取决于一种名为WEE1的蛋白质。 如果该检查点被阻止，则将导致大量DNA损伤的积累，从而导致癌细胞死亡。Adavosertib就是一个靶向WEE1的新药。一项新的试验是该药物首次在浆液性子宫癌患者中进行测试（该药物已在乳腺癌和卵巢癌症中进行了测试）。
这是一项II期临床试验, 该试验涉及35名复发性患者（不包括癌肉瘤），参与者的中位年龄为70.2岁（58.9-88.5），并且接受过3项以前的疗法（范围为1-8）。所有患者先前均已接受过铂类化疗。参加试验的患者在21天周期的第1至5天和8至12天每天接受300毫克adavosertib的治疗。 在3.8个月的中位随访中，客观响应率为29.4％，包括所有部分响应，另外8.8％的患者病情稳定至少6个月。截止数据截止，有1名患者仍在接受治疗超过12个月。
最常见的治疗相关不良事件包括腹泻（76.5％），恶心（55.9％），贫血（55.9％），疲劳（55.9％），血小板计数下降（47.1％）和中性粒细胞计数下降（44.1％）。 3级或以上的治疗相关不良事件最常出现中性粒细胞减少（32.4％），贫血（20.6％），疲劳（17.6％）和血小板减少（14.7％）。 这些可以通过中断或减少剂量来控制。
Serous uterine cancer accounts for about 10% of uterine cancer, but up to 40% of uterine cancer deaths are due to serous uterine cancer. Adavosertib is a targeted WEE1 therapy that produced a considerable response in trials with patients with recurrent serous uterine cancer.
More than 90% of serous uterine cancer has TP53 gene mutations, frequent loss and imbalance of G1 / S cell cycle checkpoints, and the presence of oncogene-driven replication stress. When the G1 / S checkpoint is lost, the dependence on the G2 / M checkpoint increases, which depends on a protein called WEE1. If this checkpoint is blocked, it will lead to the accumulation of a large amount of DNA damage, which will lead to the death of cancer cells. Adavosertib is a new drug targeting WEE1. A new trial is the first time the drug has been tested in patients with serous uterine cancer (previously tested in breast and ovarian cancers).
This is a phase II clinical trial involving 35 relapsed patients (excluding carcinosarcoma). The median age of the participants was 70.2 years (58.9-88.5), and they had received 3 previous therapies (range 1-8). All patients had previously received platinum-based chemotherapy. Participants received 300 mg of adavosertib every day on days 1 to 5 and 8 to 12 of the 21-day cycle. At a median follow-up of 3.8 months, the objective response rate was 29.4%, including all partial responses, and another 8.8% of patients had stable disease for at least 6 months. As of the data cut-off, one patient was still receiving treatment for more than 12 months.
The most common treatment-related adverse events included diarrhea (76.5%), nausea (55.9%), anemia (55.9%), fatigue (55.9%), thrombocytopenia (47.1%), and decreased neutropenia (44.1%). Grade 3 or above side-effects most frequently occurred included neutropenia (32.4%), anemia (20.6%), fatigue (17.6%), and thrombocytopenia (14.7%). These can be controlled by interrupting or reducing the dose.
参考文献 Reference Liu JF. SGO webinar published on April 23, 2020. https://bit.ly/2Kwn33c
术前T-VEC用于高危黑色素瘤 (4/25/2020)
Adjuvant T-VEC in high-risk melanoma
与单独手术相比，使用talimogene laherparepvec（T-VEC）辅助治疗提高可切除的高危黑色素瘤患者的无复发生存率和总生存率。
这是一项开放性II期临床试验， 研究人员在9个国家/地区招募了150例IIIB/IVM1a期高危黑色素瘤患者。然后将患者随机分配至即刻手术（n = 74）或病灶内T-VEC注射，然后在第13周进行手术（n = 76）。
在T-VEC组中，有33.5％的患者1年无复发，而仅接受手术的患者无复发为21.9％（HR，0.73； 80％CI，0.56-0.93； P = .048）。在排除了手术切缘阳性的患者后，并且对数据进行了敏感性测试，T-VEC组有更大的差异（HR，0.63； 80％CI，0.47-0.83； P = .024）。在1年时还活着的患者为95.9% （T-VEC）相比对于85.8％（仅手术）（HR，0.47； 80％CI，0.27-0.82； P = .076），但在分析时，差异尚未达到统计学意义。在接受T-VEC治疗的57例患者中，有13例（22.8％）出现了病理完全缓解。在意向治疗人群中接受T-VEC患者的病理完全缓解率为17.1％。在中位随访31.2个月时，T-VEC组的2年总生存率为88.9％，而单独手术组为77.4％（HR，0.49； 80％ CI，0.30-0.79； P ＝ 0.05）。
最常观察到的治疗紧急不良事件是流感样症状。T-VEC组术后不良事件发生率为33.3％，立即手术组为46.4％。 T-VEC组的术后严重不良事件发生率为14.0％，即时手术组为2.9％。 T-VEC组的3级不良事件包括2例蜂窝织炎，以及各1例无胚胎妊娠，胆囊炎，装置闭塞，流行性感冒和伤口感染。在立即手术组中，3级不良事件包括1例周围性栓塞和伤口脓肿。
正在进行的Ib/III期MASTERKEY-265/KEYNOTE-034试验（NCT02263508）正在评估患有不可切除的IIIB/IVM1期疾病的患者，这些疾病被分配给pembrolizumab加T-VEC或安慰剂。
Compared with surgery alone, the use of talimogene laherparepvec (T-VEC) adjuvant therapy improves recurrence-free survival and overall survival of patients with resectable high-risk melanoma.
This is an open label, phase II clinical trial in which150 patients with stage IIIB / IVM1a high-risk melanoma were recruited from 9 countries. Patients were then randomly assigned to immediate surgery (n = 74) or intralesional T-VEC injection followed by surgery performed at week 13 (n = 76).
In the T-VEC group, 33.5% of patients had no recurrence at 1 year, and those who only received surgery had no recurrence of 21.9% (HR, 0.73; 80% CI, 0.56-0.93; P = .048). After patients with positive surgical margins were excluded and sensitivity tests were performed on the data, the T-VEC group had greater differences (HR, 0.63; 80% CI, 0.47-0.83; P = .024). A total of 95.9% (T-VEC) patients were alive at 1 year compared to 85.8% (surgical only) (HR, 0.47; 80% CI, 0.27-0.82; P = .076), although at the time of analysis, the difference has not reached statistical significance. Of the 57 patients receiving T-VEC treatment, 13 (22.8%) had a complete pathological remission. In the intention-to-treat population, the complete pathological response of patients receiving T-VEC was 17.1%. At a median follow-up of 31.2 months, the 2-year overall survival rate in the T-VEC group was 88.9%, compared with 77.4% in the surgery alone group (HR, 0.49; 80% CI, 0.30-0.79; P = 0.05).
The most frequently observed adverse event for R-VEC was flu-like symptoms. The incidence of postoperative adverse events was 33.3% in the T-VEC group and 46.4% in the immediate surgery group. The incidence of serious adverse events in the T-VEC group was 14.0%, and that in the immediate surgery group was 2.9%. Grade 3 adverse events in the T-VEC group included 2 cases of cellulitis, and 1 case each of anembryonic pregnancy, cholecystitis, device occlusion, influenza, and wound infection. In the immediate surgery group, grade 3 adverse events included 1 case of peripheral embolism and wound abscess.
The ongoing phase Ib / III MASTERKEY-265 / KEYNOTE-034 trial (NCT02263508) is evaluating patients with unresectable stage IIIB / IVM1 disease, which is assigned to pembrolizumab plus T-VEC or placebo.
参考文献 Reference Dummer R et al. Pigment Cell Melanoma Res. 2020;33(1):148-255. doi: 10.1111/pcmr.12834.
验血测试早期发现胃肠道癌症 (4/19/2020)
Blood test for early detection of gastrointestinal cancers
一项基于血液的试验在不同阶段检测多种类型的癌症（包括胃肠道癌）的功效。
一项前瞻性，多中心，观察性, 病例对照的无细胞基因组研究包括273位无癌参与者和654位患者，包括超过20种不同类型和阶段的肿瘤: 食道/胃癌（n = 67），胰腺/胆囊/肝外胆管癌（n = 95），肝/肝内胆管癌（n = 29）和结直肠癌（n = 121）。 研究者使用了交叉验证的靶向甲基化测序测定法来评估血浆无细胞DNA（cfDNA）。他们组合了跨越目标基因组区域的甲基化片段，并确定了癌症以及特定起源组织的相对概率。
报告显示，基于血液的测定对I至III期疾病的敏感性为72％，对IV期疾病为96％。以血液为基础的分析显示，对于所有胃肠道癌症类型，特异性均大于99％，总体敏感性为82％（95％CI，77-86）。对I至III期疾病的敏感性为72％，对IV期疾病的敏感性为96％。该测试显示，对于所有胃肠道癌症，预测起源组织的准确性为92％（95％CI，88-95）。具体而言，预测食道癌/胃癌的组织起源准确度为87％（I-III期为86％； IV期为89％），胰腺/胆囊/肝外胆管癌（I-III期为为94％； IV期为91％），肝/肝内胆管癌为78％（I-III期为85％，IV期为70％）; 结直肠癌则为98％（I-III期为96％； IV期为100％）。
数据显示，评估血液样本中无细胞DNA的甲基化可能以良好的敏感性和低的假阳性率检测到各种胃肠道癌。这种方法有可能更早地诊断出胃肠道癌症，以更容易治愈它们。
A blood-based pilot test proved the efficacy of detecting multiple types of cancer (including gastrointestinal cancer) at different stages.
A prospective, multicenter, observational, case-control cell-free genomic study included 273 cancer-free participants and 654 patients, including more than 20 different types and stages of tumors: esophageal / gastric cancer (n = 67), pancreatic / gallbladder / extrahepatic cholangiocarcinoma (n = 95), liver / intrahepatic cholangiocarcinoma (n = 29) and colorectal cancer (n = 121).
The researchers used a cross-validated targeted methylation sequencing assay to evaluate plasma cell-free DNA (cfDNA). They combined methylated fragments across targeted genome and determined the relative probability of cancer and specific tissue of origin.
The report shows that blood-based assays have a sensitivity of 72% for stage I to III disease and 96% for stage IV disease. Blood-based analysis showed that for all gastrointestinal cancer types, the specificity was greater than 99%, and the overall sensitivity was 82% (95% CI, 77-86). The sensitivity to stage I to III disease was 72%, and the sensitivity to stage IV disease was 96%. The test showed that for all gastrointestinal cancers, the accuracy of predicting the tissue of origin was 92% (95% CI, 88-95). Specifically, the tissue origin accuracy of esophageal cancer / gastric cancer was 87% (86% in stage I-III, 89% in stage IV); pancreatic / gallbladder / extrahepatic cholangiocarcinoma (94% in stage I-III, 91% for stage IV), 78% for liver / intrahepatic cholangiocarcinoma (85% for stage I-III, 70% for stage IV); 98% for colorectal cancer (96% for stage I-III, 100% for stage IV).
The data shows that assessing the methylation of cell-free DNA in blood samples may detect various gastrointestinal cancers with good sensitivity and a low false positive rate. This method makes it possible to diagnose gastrointestinal cancer earlier in order to deliver more curative care.
参考文献 Reference Wolpin DM et al. 2020 Gastrointestinal Cancer Symp San Francisco abstr 283
免疫调节剂可增强晚期头颈癌的免疫治疗反应 (4/18/2020)
Immune-restorative agents may boost response to immunotherapy in head-neck cancer
使用检查点抑制剂的免疫治疗在晚期头颈部鳞状细胞癌中的有益作用仅限于少数患者。最近的研究表明，具有免疫调节作用的药物IRX-2可能有助于克服肿瘤介导的免疫抑制。
IRX-2, 主要是一种细胞源性免疫修复剂，由人细胞因子（主要是白细胞介素2）组成，可作用于多种细胞类型以克服肿瘤介导的免疫抑制作用。这是一项期临床II期随机试验, 口腔癌患者手术前3周进行了IRX-2分配方案，该方案由环磷酰胺（起始剂量300 毫克/平方米），10天局部淋巴周围IRX-2细胞因子注射和每日消炎痛, 锌和奥美拉唑组成（实验组），与没有IRX-2细胞因子的相同方案（对照组）相比。将总共96例可评估的可切除口腔癌患者随机分配（2：1）到两个研究组之一。研究人员从39例患者（32个所有数据点）中收集了治疗前和治疗后的标本，并分析了肿瘤微环境中肿瘤浸润淋巴细胞的T细胞亚群的变化。
将浸润肿瘤的CD-8阳性淋巴细胞增加至少10细胞/平方毫米的患者称为“免疫应答者”。该定义源自先前对228名口腔癌患者的研究: 预处理样品中T细胞密度每增加10个细胞，死亡风险就会降低15％。
与对照组相比，实验组与治疗后CD8阳性细胞浸润的增加显著相关（P = 0.01），这表明肿瘤相关的巨噬细胞（CD68阳性）的增加趋势，P = .11）。接受IRX-2方案的19例患者中有14例（74％）有免疫应答，而对照组的13例患者中有4例（31％）有免疫应答。由于六名p16阳性疾病患者中有五名被随机分配到实验组，研究人员在去除了p16阳性疾病患者后重复了肿瘤浸润淋巴细胞的分析。结果显示, 在p16阴性癌症患者中，实验组中CD8阳性和整体肿瘤浸润淋巴细胞增加更显著。
研究者将继续在该试验中收集更长的随访数据，以确定肿瘤浸润淋巴细胞的变化与临床结果之间的关系。
The beneficial effect of immunotherapy using checkpoint inhibitors in advanced head and neck squamous cell carcinoma is limited to a small proportion of patients. Recent studies have shown that the immunomodulatory agent IRX-2 may help to overcome tumor-mediated immunosuppression.
IRX-2, mainly a cell-derived immune restorative agent, is composed of human cytokines (mainly interleukin 2) and can act on a variety of cell types to overcome tumor-mediated immunosuppression. This is a phase II randomized trial. Oral cancer patients were given an IRX-2 regime 3 weeks before surgery. The regime consisted of cyclophosphamide (starting dose 300 mg / m²) and 10 days of perilymphatic injection of IRX- 2 cytokine and daily indomethacin, zinc and omeprazole (Experiment Group), compared with the same regimen without IRX-2 cytokine (Control Group). A total of 96 evaluable patients with resectable oral cancer were randomly assigned (2: 1) to one of the two study groups. The researchers collected specimens from 39 patients (all 32 data points) before and after treatment, and analyzed the changes of T-cell subsets in the population with tumor-infiltrating lymphocytes in the tumor microenvironment.
Patients whose tumor-infiltrating CD-8 positive lymphocytes are increased by at least 10 cells / mm2 are called “immune responders.” This definition is derived from a previous study of 228 oral cancer patients: for every 10 cells increase of T cell density in the pretreated sample, the risk of death is reduced by 15%.
Compared with the control group, the experimental group was associated with significantly increased infiltration of CD8-positive cells after treatment (P = 0.01), which indicated an increasing trend of tumor-associated macrophages (CD68-positive) (P = .11). Of the 19 patients who received the IRX-2 regimen, 14 (74%) had were immune responders, while 4 of the 13 patients in the control group (31%) were immune responders. Since five of the six patients with p16 positive disease were randomly assigned to the experimental group, researchers repeated the analysis of tumor-infiltrating lymphocytes after removing patients with p16 positive disease. The results showed that among p16-negative cancer patients, significant increases in CD8-positive and overall tumor-infiltrating lymphocytes were evident in the experimental arm.
Researchers will continue to collect longer follow-up data in this trial to determine the relationship between tumor-infiltrating lymphocyte changes and clinical outcome.
参考文献 Reference Wolf GT et al. 2020 Multidisciplinary Head and Neck Cancers Symposium. 2020; Abstr 2
Tucatinib组合可延长HER2阳性转移性（包括脑转移）乳腺癌的生存期 (4/12/2020)
Tucatinib in combination with trastuzumab, and capecitabine effective in breast cancer with brain metastases
对于先前用曲妥珠单抗，帕妥珠单抗和阿妥曲妥珠单抗（T-DM1）治疗过而进展的HER2阳性转移性乳腺癌，没有确立的治疗标准。这些患者中有超过50％会发生脑转移。Tucatinib（一种最近被FDA授予突破疗法称号的口服药物）是HER2酪氨酸激酶的高度选择性抑制剂，在经过多线治疗的HER2阳性转移性乳腺癌患者（包括脑转移）中，与曲妥珠单抗/卡培他滨合用后，其死亡风险降低了三分之一，疾病进展或死亡的风险降低了一半。
HER2CLIMB是一项国际性，随机安慰剂对照的双盲试验，在北美，欧洲，亚洲和澳大利亚的15个国家/地区的155个地点招募了612例有或无基线脑转移的转移性HER2阳性乳腺癌患者。 总共410名患者被分配接受每日两次口服300 毫克Tucatinib加曲妥珠单抗/卡培他滨，而202名患者被分配接受曲妥珠单抗/卡培他滨加安慰剂的治疗。脑转移患者（治疗或未治疗）占研究人群的47.5％。
在中位随访14个月时，Tucatinib组中33％的患者还活着，而且病情没有恶化，而对照组为12％（P <.001）。Tucatinib组中的中位无进展生存期为7.8个月，安慰剂组为5.6个月。 Tucatinib组从开始治疗起的2年总生存率为45％，安慰剂组为27％（P = .005）。在基线时有脑转移的患者中，Tucatinib组中有25％的患者在开始治疗后1年还活着，没有疾病的迹象，而对照组中则没有（P <.001）。这些患者的中位无进展生存期分别为7.6个月和5.4个月。
在Tucatinib组中，最常见的不良反应是腹泻，手足掌红斑感觉异常，恶心，疲劳和呕吐。与安慰剂相比，Tucatinib组中3或更高级的腹泻和肝酶水平升高更为常见。短期服用止泻药可以控制腹泻，肝酶升高是短暂且可逆的。但Tucatinib组中只有不到6％的患者中止治疗，而安慰剂组中为3％。双臂患者中约有10％停用卡培他滨。
Tucatinib联合曲妥珠单抗和卡培他滨有可能成为有或无脑转移患者的新治疗标准。
There is no established standard therapy for HER2-positive metastatic breast cancer patients who progressed on trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). More than 50% of these patients eventually developed brain metastases. Tucatinib (awarded breakthrough therapy by the FDA recently) is a highly selective inhibitor of HER2 tyrosine kinase. In patients with HER2-positive metastatic breast cancer (including brain metastases) after multi-line therapy, the combination of trastuzumab / capecitabine reduced the risk of death by one third and the risk of disease progression by half.
HER2CLIMB is an international, randomized, placebo-controlled, double-blind trial recruiting 612 metastatic HER2-positive breasts cancer patients with or without baseline brain metastasis at 155 locations in 15 countries in North America, Europe, Asia, and Australia Cancer. A total of 410 patients were assigned to receive twice daily 300 mg (oral) of Tucatinib plus trastuzumab / capecitabine, while 202 patients were assigned to receive trastuzumab / capecitabine plus placebo. Patients with brain metastases (treated or untreated) accounted for 47.5% of the study population.
At a median follow-up of 14 months, 33% of patients in the Tucatinib group were alive and with no worsening of their disease, compared with 12% in the control group (P <.001). The median progression-free survival was 7.8 months in the Tucatinib group and 5.6 months in the placebo group. The 2-year overall survival from the start of treatment in the Tucatinib group was 45% and 27% in the placebo group (P = .005). Among patients with brain metastases at baseline, 25% of patients in the Tucatinib group were alive 1 year after the start of treatment, with no signs of disease, and none in the control group (P <.001). The median progression-free survival of these patients was 7.6 months and 5.4 months, respectively.
In the Tucatinib group, the most common adverse reactions were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue and vomiting. Compared with placebo, grade 3 or higher diarrhea and elevated liver enzyme were more common in the Tucatinib group. Short-term use of antidiarrheal drugs can control diarrhea; elevated liver enzymes are transient and reversible. Less than 6% of patients in the Tucatinib group discontinued treatment, compared with 3% in the placebo group. About 10% of patients in both arms discontinued capecitabine.
Tucatinib in combination with trastuzumab and capecitabine may become a new standard of treatment for patients with or without brain metastases.
参考文献 Reference Murthy RK et al. N Eng J Med 2020; 382:586
系统性轻链淀粉样变性和心脏受累患者的双重单克隆抗体治疗 (4/11/2020)
Dual monoclonal antibody for systemic AL amyloidosis with cardiac involvement
报告包括19例轻链淀粉样变性（AL amyloidosis）的患者接受daratumumab（抗CD38）作为一线治疗, 其中9例同时接受daratumumab和NEOD001（抗淀粉样蛋白）* 双重单克隆抗体治疗。9名接受双重单克隆抗体治疗的患者在33天内的平均血液学客观响应率很高（100％）。在不到3个月的联合治疗中，八项中的七项达到了心脏响应标准。 十名仅接受达拉他单抗治疗的患者血液和器官响应率也很高。 对双重单克隆抗体治疗没有明显的毒性。
结论 是具有明显不同靶标的单克隆抗体可以安全地联合用于 轻链淀粉样变性和心脏受累患者。并有较高的血液学和心脏响应。
*NEOD001是一种人源化单克隆抗体，靶向循环的可溶性淀粉样蛋白, 和沉积在组织上的不溶性淀粉样蛋白，这些蛋白在AL淀粉样变性中积累。 FDA在2014年12月授予NEOD001快速通道称号。
A report described 19 patients with light chain amyloidosis (AL amyloidosis) receiving daratumumab (anti-CD38) as first-line treatment. Among them, 9 patients received both daratumumab and NEOD001 (anti-amyloid) * dual monoclonal antibody therapy. The average hematological objective response rate of 9 patients receiving dual monoclonal antibody treatment within 33 days was very high (100%). In less than 3 months of combined therapy, seven of the eight items met the cardiac response criteria. The blood and organ response rates of ten patients who received only daltuzumab were also very high. There is no obvious toxicity to dual monoclonal antibody treatment.
The conclusion is that monoclonal antibodies with significantly different targets can be safely combined for patients with light chain amyloidosis and cardiac involvement. A high hematology and cardiac response was detected.
* NEOD001 is a humanized monoclonal antibody that targets circulating soluble amyloid and insoluble amyloid deposited in tissues. These proteins accumulate in AL amyloidosis. FDA awarded the NEOD001 Fast Track title in December 2014.
参考文献 Reference Godara A et al. Clin Lymphoma, Myeloma & Leuk 2020; 20: 184
编辑RNA可提供对（小鼠）三阴性乳腺癌精确治疗(4/5/2020)
Editing RNA provides accurate target in triple-negative breast cancer in mouse model
三阴性乳腺癌细胞有大量microRNA-21, 由于其在转移中的作用而被称为致癌RNA, 它和低生存率有关。一种创新的化合物靶向这个致癌RNA的序列并将其去除，能杀死癌细胞并阻止其在小鼠模型中扩散，同时保持健康细胞不受感染。
大多数药物通过与蛋白质结合起作用。几年前，人们开发了一种可识别RNA结构并和其结合的化合物的工具，称为Inforna。发现的新化合物首先特异性结合microRNA前体（参与关闭基因转录）, 该化合物并包含一个杂环，该杂环可募集并激活microRNA前体的核糖核酸酶（RNA切割酶），从而在化学计量上影响其裂解并随后阻止小鼠模型中乳腺癌向肺的转移。靶向RNA的化合物与靶向蛋白质的化合物一样具有选择性，人们将这种精确的瞄准与破坏系统称为RIBOTAC（针对核糖核酸酶的嵌合体）。该工具代表了一种基因表达编辑器，可从RNA精确删除与疾病相关序列。
Triple negative breast cancer cells have a large amount of microRNA-21, which is called oncogenic RNA because it is associated with a low survival. An innovative compound targets this carcinogenic RNA sequence and subsequently removes it, killing cancer cells and preventing their spread in mouse models. Healthy cells are left intact.
Most drugs work by binding to proteins. A few years ago, people developed a tool for compounds that can recognize and bind specific RNA structures, called Inforna. The new compound thus discovered specifically binds to the microRNA precursor (involved in silencing gene transcription). The compound contains a heterocycle that recruits and activates the ribonuclease of the microRNA precursor, to substoichiometrically effect its cleavage and subsequently impede metastasis of breast cancer cells to the lungs in a mouse model. Compounds that target RNA are as selective as compounds that target proteins. People call this precise targeting and destruction system RIBOTAC (ribonuclease-targeting chimeras). This tool represents a gene-expression editor that can precisely delete disease-related sequences from RNA.
参考文献 Reference Costales MG et al. PNAS 2020; 117:2406
针对B细胞恶性肿瘤的多抗原靶向CAR NK细胞治疗 (4/4/2020)
Novel CAR NK cell therapy targeting multiantigen in B-cell malignancies
一种名为FT596的新型嵌合抗原受体自然杀伤细胞（CAR-NK）产品可能是治疗B细胞恶性肿瘤的有效方法。该药物旨在克服CAR T细胞疗法的若干挑战，包括CD19抗原逃逸。
FT596是第一个现成的（不是来自患者自己的基因修饰细胞）细胞免疫疗法，其基因工程改造包含三种活性抗肿瘤方式：针对B细胞抗原CD19的专有嵌合抗原受体; 高亲和力，不可裂解的CD16 Fc受体，已被修饰以增强抗体依赖性细胞的细胞毒性； IL-15受体融合（IL-15RF）以增强NK细胞的活性。FT596有望克服现有CAR T细胞疗法所面临的若干挑战，包括制造过程需要等待数周，高昂的治疗成本，可及性有限以及制造中的问题等。FT596源自工程改造的人类诱导多能干细胞，可以从这些细胞创建主细胞库，并反复分化以生成抗癌免疫细胞，例如天然杀伤细胞和T细胞，从而产生均质的工程化细胞产品。每剂的制造成本低至2500美元。该药品直接输注，是一种真正的现成产品，可以在门诊患者中使用。
在临床前研究中，FT596在杀死体内癌细胞方面与现有的CAR T细胞平台一样有效，并且FT596与利妥昔单抗的组合杀死了由于失去了CD19抗原靶标而不再对CAR T细胞疗法产生响应的淋巴瘤。
FT596已获得FDA授予研究新药的资格，首次人体试验将于2020年上半年开始。
A new chimeric antigen receptor natural killer cell (CAR-NK) product called FT596 may be an effective way to treat B-cell malignancies. The drug is designed to overcome several challenges of CAR T cell therapy, including CD19 antigen escape.
FT596 is the first off-the-shelf (not the patient’s own gene-modified cells) cellular immunotherapy that is genetically engineered to include three active anti-tumor modalities: a proprietary chimeric antigen receptor against the B cell antigen CD19; a high affinity, non-cleavable CD16 Fc receptor has been modified to enhance antibody-dependent cellular toxicity; IL-15 receptor fusion (IL-15RF) to enhance the activity of NK cells. FT596 is expected to overcome several challenges faced by existing CAR T-cell therapies, including the need to wait several weeks in the manufacturing process, high treatment costs, limited accessibility, and manufacturing issues. FT596 is derived from engineered human induced pluripotent stem cells. From these cells, a master cell bank can be created and differentiated repeatedly to generate anti-cancer immune cells, such as natural killer cells and T cells, resulting in homogeneous engineered cell products. Manufacturing costs are as low as $ 2,500 per dose. The drug is directly infused and is a truly off-the-shelf product that can be used in outpatients.
In preclinical studies, FT596 was as effective in killing cancer cells in vivo as the existing CAR T cell platform, and the combination of FT596 and rituximab killed lymphoma cells that were no longer responding to CAR T cell therapy due to the loss of the CD19 antigen.
FT596 has been approved by the FDA to study new drugs, and the first human trial will begin in the first half of 2020.
参考文献 Reference Goodridge JP et al. ASH Ann Meeting 2019; abstr 301
Ribociclib/来曲唑在雌激素受体阳性/HER2-阴乳腺癌中与术前化疗效果相当 (3/29/2020)
Ribociclib/Letrozole vs neoadjuvant chemotherapy in post-menopausal ER-positive/HER2-negative breast cancer
激素受体阳性/HER2阴性乳腺癌在临床和生物学上是异质的。 PAM50管腔B型内在亚型占所有激素受体阳性/ HER2阴性乳腺肿瘤的30-40％，并且与10年远距离复发风险 > 10％相关。在无化学疗法的术前疗法（Ribociclib/来曲唑）后，几乎一半的高危luminal-B乳腺癌患者转化为低复发风险，在小型随机试验中达到了标准化疗的水平。
这是一项开放标签，多中心，随机2期试验临床试验（CORALLEEN, NCT03248427）, 招募了106例激素受体阳性/HER2阴性，I-IIIa期，管腔B型乳腺癌，肿瘤≥ 公分的绝经后妇女。患者被随机分为接受阿霉素/环磷酰胺化疗和紫杉醇的术前治疗6个月，或接受ribociclib和来曲唑的术前治疗。 治疗的终了目标为手术时低PAM50 复发风险（ROR）* 疾病的比例。次要终点包括乳房和腋窝的病理完全缓解，残余癌症负担,，PAM50内在亚型的变化，复发风险评分，Ki67评分和安全性。
数据分析包括100例。患者的中位年龄为63-64岁，大约80％患有T2肿瘤，而57-59％的淋巴结阴性。在化疗组中，复发风险评分中位数为77，在ribociclib和来曲唑组中为70。化疗组的11.1％和ribociclib/来曲唑组的15.4％具有中等复发风险；其余患高复发风险疾病。
主要终了目标分析显示，术前化疗和无化疗完成后，低复发风险（46.1％vs 46.9％），中度复发风险（30.8％vs 30.6％）和高复发风险（21.2％vs 22.5％）的发生率在两组中相似。中位复发风险评分从所有100例患者中的75分降低到化疗组的25分和ribociclib/来曲唑组的18分。在化疗组中，Ki67表达中值从35降低到10，在ribociclib/来曲唑组中从30降低到3。很少有患者达到病理完全缓解（总共3例，全部在化疗组中）。 手术时，接受术前化疗患者中有82.7％患有管腔A型乳腺癌，仍然有15.4％的患者患有管腔B型。在接受术前ribociclib/来曲唑治疗的患者中，有87.8％的患者降级为管腔A型，剩余8.2％的患者仍有管腔B型乳腺癌。
化疗组中有69.2％的患者发生≥3级不良事件，而ribociclib/来曲唑组中则为56.9％。 化疗组中最常见的≥3级不良事件是中性粒细胞减少和发热性中性粒细胞减少，而ribociclib/来曲唑组是中性粒细胞减少和肝酶增加。 导致停药的不良事件分别为19.2％和15.7％，导致剂量减少或中断的不良事件分别发生在82.7％和58.8％的患者中。 化疗组的严重不良事件发生率几乎是4倍（15.4％比3.9％）。
*由NanoString进行的Prosigna乳腺癌预后基因特征分析（PAM50）是一种基因组测试，用于分析早期激素受体阳性乳腺癌中某些基因的活性。 Prosigna分析结果以两种方式报告为复发风险（ROR）评分从0到100：1) 淋巴结阴性癌症分为低（0-40），中（41-60）或高（61-100）风险. 2) 淋巴结阳性癌症分为低（0-40）或高（41-100）风险
Hormone receptor-positive / HER2-negative breast cancers are clinically and biologically heterogeneous. The PAM50 lumen B intrinsic subtype accounts for 30-40% of all HR-positive / HER2-negative breast tumors and is associated with a 10-year risk of long-term recurrence> 10%. After chemotherapy-free neoadjuvant therapy (ribociclib / letrozole), almost half of patients with high-risk luminal-B breast cancer converted to a low risk of recurrence, reaching the level of standard chemotherapy.
This is an open-label, multi-center, randomized phase 2 clinical trial (CORALLEEN, NCT03248427), which recruited 106 HR-positive/HER2-negative, stage I-IIIa, luminal B-type breast cancer, tumors ≥ 2 cm postmenopausal women. Patients were randomized to 6 months of preoperative treatment with doxorubicin/cyclophosphamide chemotherapy and paclitaxel, or preoperative treatment of ribociclib/letrozole. The primary endpoint of trial is the proportion of low PAM50 risk of recurrence (ROR) * disease at the time of surgery. Secondary endpoints included complete remission of breast and axillary pathology, residual cancer burden, changes in PAM50 intrinsic subtypes, ROR, Ki67 score, and safety.
Data analysis included 100 cases. Patients had a median age of 63-64 years, approximately 80% had T2 tumors, and 57-59% had nodal nodes. The median risk of ROR was 77 in the chemotherapy group and 70 in the ribociclib/letrozole groups. 11.1% of the chemotherapy group and 15.4% of the ribociclib/letrozole group had a medium ROR; the rest had a high ROR.
The primary endpoint analysis showed that after the completion of neoadjuvant chemotherapy or no non-chemotherapy treatment, low ROR (46.1% vs 46.9%), moderate ROR (30.8% vs 30.6%), and high ROR (21.2% vs 22.5%) occurred. The rates were similar in both groups. The median ROR decreased from 75 in all 100 patients to 25 in the chemotherapy group and 18 in the ribociclib / letrozole group. In the chemotherapy group, the median Ki67 expression decreased from 35 to 10, and from 30 to 3 in the ribociclib / letrozole group. Few patients achieved pCR (3 in total, all in the chemotherapy group). At the time of surgery, 82.7% of patients receiving preoperative chemotherapy had luminal type A breast cancer, and 15.4% of patients still had luminal type B. Among patients receiving ribociclib/letrozole, 87.8% of patients were downgraded to luminal A, and the remaining 8.2% still had luminal B.
Grade 3 adverse events occurred in 69.2% of patients in the chemotherapy group and 56.9% in the ribociclib/letrozole group. The most common grade 3/4 adverse events in the chemotherapy group were neutropenia and febrile neutropenia, while in the ribociclib/letrozole group were neutropenia and increased liver enzymes. Adverse events leading to discontinuation were 19.2% and 15.7%, respectively, and adverse events leading to dose reduction or discontinuation occurred in 82.7% and 58.8% of patients, respectively. The incidence of serious adverse events in the chemotherapy group were almost four times as more (15.4% vs. 3.9%).
*The Prosigna Breast Cancer Prognostic Gene Signature Assay (PAM50), made by NanoString, is a genomic test that analyzes the activity of certain genes in early-stage, hormone-receptor-positive breast cancer. Prosigna assay results are reported as a risk of recurrence (ROR) score from 0 to 100 in two ways: 1) Node-negative cancers are classified as low (0-40), intermediate (41-60), or high (61-100) risk. 2) Node-positive cancers are classified as low (0-40) or high (41-100) risk
参考文献 Reference Prat A et al. Lancet Onc 2020; 21: 33.
乳腺癌化疗期间服用抗氧化剂和某些补品可能弊大于利 (3/28/2020)
Taking antioxidants and some supplements during chemotherapy may be harmful
一项小型研究发现，乳腺癌化疗期间服用抗氧化剂的患者发生癌症复发和死亡的机会更高。但是，服用常规的多种维生素并不会增加或减少风险。
这是一项临床试验（SWOG0221）内对随机分组乳腺癌病人的调查, 在患者注册时和治疗过程中被询问是否使用补充剂（n = 1,134）。 该研究中有18％的人每天使用任何类型的抗氧化剂，而44％的人服用了多种维生素。使用针对临床和生活方式变量进行Cox比例风险回归调整。 入组后6个月，采用标志性方法对复发和生存进行了索引。
结果研究表明，在治疗之前和治疗期间使用任何抗氧化剂补充剂（包括维生素A，C和E；类胡萝卜素；辅酶Q10）与复发风险增加（风险比经调整为1.41； 95％CI为0.98-2.04； P = .06），并在较小程度上导致死亡（调整的风险比为1.40； 95％CI，0.90-2.18； P = .14）。 与个别抗氧化剂的关系较弱，可能是因为数量较少。 对于非抗氧化剂，在化疗之前和期间使用维生素B12与无病生存期较差（调整的风险比为1.83； 95％CI，1.15-2.92； P < .01）和总生存期（调整的风险比为2.04； 95％CI， 1.22至3.40； P < .01）。 化疗期间铁的使用与复发率显着相关（调整的风险比为1.79； 95％CI，1.20至2.67； P < .01），与治疗前和治疗期间使用铁一样（调整的风险比为1.91； 95％CI，0.98至3.70； P = .06）。 总体存活率的结果相似。 多种维生素的使用与生存结果无关。
这项新研究是第一个研究乳腺癌治疗期间补充剂使用情况的研究。
A small study found that patients taking antioxidants during breast cancer chemotherapy were more likely to have cancer recurrence and death. However, taking a regular multivitamin does not increase or decrease the risk.
This is survey within the randomized arms of a clinical trial (SWOG0221). Patients were asked whether they used supplements at the time of registration and during treatment (n = 1,134). Eighteen percent of the patients in the study used any type of antioxidant daily, while 44% took a multivitamin. Cox proportional hazard regression adjustments were used for clinical and lifestyle variables. Six months after enrollment, recurrence and survival were indexed using landmark methods.
There were indications that use of any antioxidant supplement (including vitamins A, C, and E; carotenoids; coenzyme Q10) before and during treatment increased the risk of relapse (adjusted hazard ratio, 1.41; 95% CI, 0.98- 2.04; P = .06) and, to a lesser extent, death (adjusted hazard ratio, 1.40; 95% CI, 0.90-2.18; P = .14). Relationship with individual antioxidants was weaker which may be due to small numbers. For non-antioxidants, the use of vitamin B12 before and during chemotherapy is worse for disease-free survival (adjusted hazard ratio, 1.83; 95% CI, 1.15-2.92; P <.01) and overall survival (adjusted hazard ratio, 2.04; 95% CI, 1.22 to 3.40; P < .01). Iron use during chemotherapy was significantly associated with recurrence rates (adjusted hazard ratio, 1.79; 95% CI, 1.20 to 2.67; P < .01), as was the use of iron before and during treatment (adjusted hazard ratio 1.91; 95% CI, 0.98 to 3.70; P = .06). Results for overall survival were similar. Multivitamin use was not associated with survival outcomes.
This is the first study about the use of supplements during breast cancer treatment.
参考文献 Reference Ambrosone CB et al. J Clin Onc 2020; Mar 10;38(8):804-814. doi: 10.1200Tipifarnib可在HRAS突变型头颈部鳞状细胞癌中获得完全疾病控制 (3/22/2020)
Tipifarnib had complete control of HRAS-mutant head and neck squamous cell carcinoma
信号转导抑制剂（signal transduction inhibitor, STI）Tipifarnib能控制所有HRAS突变型头颈部鳞状细胞癌（HNSCC）和高等位基因频率（variant allele frequency, VAF）患者的疾病。
这是一项II期临床试验, 具有HRAS突变且尚无治愈方法的复发性实体瘤病人都可以参加。患者被分配到2个队列：1) 甲状腺癌患者；2) 患有任何其他实体瘤类型的患者，但后来被修改为仅是HNSCC, 由于在该人群中观察到明显的信号。Tipifarnib初始剂量为每天两次口服900 毫克，第1至7天，第15至21天, 每28天为一个周期。在前17例HRAS突变型HNSCC患者中，尽管对先前的化疗，西妥昔单抗或免疫疗法耐药，但仍观察到快速而持久的反应。一部分患者也需要降低剂量，并且在第1周期结束时，患者接受的中位剂量降低到每天两次600 毫克。研究人员发现，大多数主要响应者是等位基因频率≥20％的患者，而那些出现频率≥35％的患者则有更大的响应。
基于这些观察，该试验被进一步修改为包括30例HNSCC患者，并且仅限于HRAS VAF≥20％和血清白蛋白≥3.5 克/分升或HRAS VAF≥35％的患者。并且添加了第三个患者队列，包括非HNSCC的鳞状细胞癌。
总共21例接受过治疗的HNSCC患者中，中位年龄为64岁，男性为66.7％，既往抗癌方案的中位数目为2，原发灶部位为口腔的占一半左右（52.4％ ）, 除2名患者外，其他所有患者均接受过先前的铂类治疗（90.5％），免疫治疗13例（61.9％）；和11例西妥昔单抗（52.4％）。在18例可评估的高VAF患者中，有10例具有客观响应（56％； 95％CI，0.31-0.78）。其他8例患者病情稳定，其中2例未证实部分响应。 在有响应的患者中，中位无进展生存期为8.3个月，而疾病稳定者为4.5个月。值得注意的是，这些响应中有许多相当持久, 4个主要响应者持续了一年，有6者持续了6个月。
治疗中发生的紧急不良事件与已知的Tipifarnib的安全性一致，大多数≥3级的事件是血液学的。
这些数据导致了国际上多中心，开放标签的II期AIM-HN / SEQ-HN研究，以评估Tipifarnib在HRAS突变型HNSCC中的安全性和有效性。也正在探索将Tipifarnib与免疫疗法，化学疗法或靶向药物联合使用的机会。
Signal transduction inhibitor (STI) Tipifarnib could control the disease in all patients with HRAS-mutant head and neck squamous cell carcinoma (HNSCC) and a high variant allele frequency (VAF).
This is a phase II clinical trial. Patients with relapsed solid tumors with HRAS mutations and no potential for cure could participate. Patients were assigned to 2 cohorts: 1) patients with thyroid cancer; 2) patients with any other solid tumor type, was later modified to include HNSCC only, as a clear signal of response was observed in this population. The initial dose of Tipifarnib was 900 mg orally twice daily for days 1 to 7 and days 15 to 21, in a cycle of every 28 days. In the first 17 HRAS-mutant HNSCC patients, a rapid and long-lasting response was observed despite resistance to previous chemotherapy, cetuximab, or immunotherapy. Some patients needed to reduce the dose, and at the end of the first cycle, the median dose that patients received was 600 mg twice daily. The researchers found that most of the major responders were patients with an allele frequency of ≥20%, and those with a frequency of ≥35% had a greater response.
Based on these observations, the trial was further modified to include 30 HNSCC patients and was limited to patients with HRAS VAF ≥ 20% and serum albumin ≥ 3.5 g / dL or HRAS VAF ≥ 35%. A third patient cohort was added, including non-HNSCC squamous cell carcinoma.
A total of 21 HNSCC treated patients had a median age of 64 with 66.7% male. The median number of previous anti-cancer regimens was 2. The primary site was oral cavity (52.4%). With the exception of 2 patients, all other patients had previously received platinum therapy (90.5%). 13 had immunotherapy (61.9%), and 11 had cetuximab (52.4%). Of the 18 evaluable patients with high VAF, 10 had an objective response (56%; 95% CI, 0.31-0.78). The other 8 patients were stable, and 2 of them did not have a partial response. Among patients who responded, the median progression-free survival was 8.3 months, compared with 4.5 months in patients with stable disease. It is worth noting that many of these responses were quite long-lasting, with four main responders lasting one year and six lasting six months.
Emergency adverse events during treatment were consistent with the known safety of Tipifarnib, and most grade ≥3 events were hematological.
These data have led to an international multicenter, open-label phase II AIM-HN / SEQ-HN study to evaluate the safety and effectiveness of Tipifarnib in HRAS-mutant HNSCC. Opportunities for using Tipifarnib in combination with immunotherapy, chemotherapy or targeted drugs are also being explored.
参考文献 Reference Ho AL et al. AACR-NCI-EORTC Intl Conf Mole Targets and Cancer Therap 2019; Abstr PR08
绝经后妇女单独使用雌激素有保护作用(?)，但雌激素加孕激素有害 (3/21/2020)
Estrogen alone protective to postmenopausal women (?) while estrogen plus progesterone harmful
没有乳腺癌的绝经后妇女单独使用雌激素可以降低乳腺癌的风险，但雌激素加孕激素与乳腺癌的发病率增加有关。
一项随机妇女健康计划（包括10,000多名绝经后妇女）的19年随访显示，单独使用雌激素可将乳腺癌的发生率降低23％，乳腺癌死亡人数也减少了44％，而各种原因导致的乳腺癌死亡人数也减少了25％。而雌激素与孕激素联合使用则可使患乳腺癌的风险增加29％。妇女暴露于雌激素/孕激素达5.6年，但这种风险持续长达20年。
妇女健康计划将1993年至1998年的妇女纳入两项随机试验。绝经后妇女被随机分配接受雌激素加甲羟孕酮相对于安慰剂（子宫完整的患者为16,608名），她们的中位暴露时间为5.6年; 或者单独接受雌激素相对于安慰剂（先前子宫切除者为10,739人），她们的中位暴露时间为7.2年。所有参与者的中位随访时间分别为18.3年和16.1年。
在最新分析中，仅进行雌激素比较，单独使用雌激素的女性中有231例乳腺癌患者，而接受安慰剂的女性中则有289例乳腺癌（风险比[HR] = 0.77； P = .005）。单独分配给雌激素的妇女因乳腺癌而死亡的风险也降低了（HR = 0.56； P = .02），而乳腺癌患者的死亡风险也降低了（HR = 0.75； P = .06）。按亚组，雌激素受体阳性/孕激素阴性疾病患者的发病率降低了55％。
相比之下，在雌激素加孕激素试验中，分配给该组合的妇女中诊断出572例乳腺癌，而分 配给安慰剂的妇女中则诊断出431例（HR = 1.29； P <.0001）。接受联合疗法的患者，因疾病而死亡（HR = 1.45; P = .06）和乳腺癌后死亡的风险（HR = 1.29; P = .03）也增加。
在长达5.6年的激素干预期结束后，与单独使用雌激素有关的发病率降低的风险就持续了数十年（HR = 0.83； 95％置信区间[CI] = 0.57-1.20）。同样，雌激素/孕激素的风险继续增加（HR = 1.30； 95％CI = 0.99-1.70）。
这项发现与 “乳腺癌激素因素” 合作小组和 ”百万妇女研究” 近年发表的结果直接矛盾。 协作小组研究是一项对58项观察性研究的荟萃分析，其中女性使用激素治疗7到10年（包括单独使用雌激素以及雌激素和孕激素）均与乳腺癌风险显着增加相关。 在 ”百万妇女研究” 中，两种激素治疗均与乳腺癌死亡率显著增加有关。
The risk of breast cancer in postmenopausal women without breast cancer could be reduced by using estrogen alone, but estrogen plus progestin was associated with an increased incidence of breast cancer.
A 19-year follow-up of a randomized Women’s Health Initiative (including more than 10,000 post-menopausal women) showed that the use of estrogen alone could reduce the incidence of breast cancer by 23% and the number of breast cancer deaths by 44%. The number of deaths from breast cancer was also decreased by 25%. The combination of estrogen and progesterone increases the risk of breast cancer by 29%. When women were exposed to estrogen/progestin for 5.6 years, their risk persisted for up to 20 years.
The Women’s Health Initiative included women from 1993 to 1998 in two randomized trials. Postmenopausal women were randomly assigned to receive estrogen plus medroxyprogesterone versus placebo (16,608 patients with intact uterus) and their median exposure was 5.6 years; or they received estrogen alone versus placebo (10,739 patients had previous hysterectomy), and their median exposure was 7.2 years. The median follow-up for all participants was 18.3 years and 16.1 years, respectively.
In the latest analysis of those who took only estrogen vs placebo was performed. There were 231 breast cancer patients in women who took estrogen alone, and 289 breast cancers in women who received placebo (risk ratio [HR] = 0.77; P =. 005). Women assigned to estrogen alone also had a lower risk of dying from breast cancer (HR = 0.56; P = .02), and breast cancer patients also had a lower risk of death (HR = 0.75; P = .06). By subgroup, the incidence of patients with estrogen receptor-positive/progesterone-negative diseases was reduced by 55%.
In contrast, in the estrogen plus progestin trial, 572 breast cancers were diagnosed in women assigned to the combination, and 431 were diagnosed in women assigned to placebo (HR = 1.29; P <.0001 ). Patients receiving combination therapy also had an increased risk of death from disease (HR = 1.45; P = .06) and death from breast cancer (HR = 1.29; P = .03).
The risk of reduced morbidity associated with estrogen use alone persists for decades beyond the 5.6 years of hormonal intervention (HR = 0.83; 95% confidence interval [CI] = 0.57-1.20). Similarly, the risk of estrogen/progestin continues to increase (HR = 1.30; 95% CI = 0.99-1.70).
This finding directly contradicts the results of Collaborative Group on Hormone Factors in Breast Cancer and the Million Women Study published in recent year. The collaborative group study is a meta-analysis of 58 observational studies in which women treated with hormones for 7 to 10 years (including estrogen alone as well as estrogen and progesterone) have been associated with significantly increased breast cancer risk. In the Million Women Study, both hormone treatments were associated with a significant increase in breast cancer mortality.
参考文献 Reference Chlebowski RT et al. 2019 San Antonio Breast Cancer Symp Abstr GS5-00
具有或不具有Veliparib的化疗在BRCA/PALB2 +胰腺癌中的作用 (3/15/2020)
Gemcitabine/cisplatin with or without veliparib highly active in pancreatic adenocarcinoma patients with known germline BRCA/ PALB2 mutation
吉西他滨加顺铂加或不加Veliparib都对胰腺导管腺癌既有BRCA/PALB2种系突变的患者有很高的活性。
这是一项随机的，跨国的II期临床试验，入选标准包括未经治疗的III/IV胰腺导管腺癌期疾病，并有种系BRCA/PALB2突变。有42例患者（84％）患有IV期疾病，其中24％患有BRCA1突变，70％患有BRCA2突变，6％患有PALB2突变。 74％的人发现肝转移。两组患者随机接受吉西他滨/顺铂 组合, 或吉西他滨/顺铂加Veliparib（三联体）。研究中的两组都是实验性的。在三联体治疗组（n = 27）中，患者在第3天和第10天接受顺铂25 毫克/平方米加吉西他滨600 毫克/平方米，在第1天至第12天, 每天两次接受veliparib 80 毫克，共3周，并可选择维持性veliparib治疗。在双联组（n = 23）中，在每个21天周期的第1天和第8天，以与三联组相同的剂量给予顺铂和吉西他滨。
三联体治疗的患者的总响应率为74.1％，而接受吉西他滨/顺铂双联体治疗的患者的总体缓解率为65.2％（P = .55），两组疾病控制率分别为100％和78.3％（P = .02）。两组之间的中位无进展生存期无显着差异，三联组为10.1个月（95％CI，6.7-11.5），而双联组为9.7个月（95％CI，4.2-13.6； P = 0.74）。两组之间的中位总生存期也相似，三联组为15.5个月（95％CI，12.2-24.3），双联组为16.4个月（95％CI，11.7-23.4）（P = 0.61）。
联合两组的探索性分析显示，有BRCA1突变的患者的中位无进展生存期为6.8个月（95％CI，2.8-10.1），总生存期的中位数为14个月（95％CI，8.1-18.5）; 有BRCA2突变的患者, 它们分别为11.3个月（95% CI，9.8-12.8）和20.2个月（95％CI，12.3-24.4）。联合队列的2年生存率是31％（95％CI，17.7-44.4）； 3年生存率是18％（95％CI，8.1％-30.7％）。根据研究者，这些生存率是所有胰腺癌随机试验中报告的最长记录之一。
用三联体治疗的患者中, 有52％发生了3/4级发生贫血，而接受双联体治疗的患者中只有35％。血小板减少比例分别为55％和9％；中性粒细胞减少分别占48％和30％。三联组和二联组中有90％和17%的患者需要减少剂量。两个治疗组之间的非血液学毒性发生率相似。
研究人员认为,铂类疗法后维持PARP抑制剂治疗（或继续进行细胞毒性疗法）是种系BRCA/PALB2突变胰腺导管腺癌患者最佳的一线治疗方法。
Gemcitabine plus cisplatin with or without Veliparib is highly active in patients with pancreatic ductal adenocarcinoma with BRCA/PALB germline mutations.
This is a randomized, international, phase II clinical trial that enrolls untreated stage III/IV pancreatic ductal adenocarcinoma with germline BRCA / PALB2 mutations. Forty-two patients (84%) had stage IV disease, of which 24% had BRCA1 mutation, 70% had BRCA2 mutation, and 6% had PALB2 mutation. There were 74% people with liver metastases. Patients were randomized to receive either gemcitabine/cisplatin combination, or gemcitabine / cisplatin plus Veliparib (triplet). Both groups in the study were considered experimental. In the triplet arm (n = 27), patients received cisplatin 25 mg/m 2 plus gemcitabine 600 mg/m 2 on days 3 and 10, and received twice a day on days 1 to 12 veliparib 80 mg for 3 weeks, and had an option of maintenance veliparib. In the double arm (n = 23), cisplatin and gemcitabine were given at the same dose as in the triplet group on days 1 and 8 of each 21-day cycle.
The overall response rate of patients treated with triplet was 74.1%, while that of patients of the doublet arm was 65.2% (P = .55), and the disease control rates were 100% and 78.3 in the two groups % (P = .02). There was no significant difference in median progression-free survival between the two groups, with 10.1 months in the triplet group (95% CI, 6.7-11.5) and 9.7 months in the doublet group (95% CI, 4.2-13.6; P = 0.74). The median overall survival was similar between the two groups, with 15.3 months in the triplet group (95% CI, 12.2-24.3) and 16.4 months in the doublet group (95% CI, 11.7-23.4) (P = 0.61).
An exploratory analysis combining the two groups showed that patients with BRCA1 mutation had a median progression-free survival of 6.8 months (95% CI, 2.8-10.1) and a median overall survival of 14 months (95% CI 8.1-18.5); In patients with BRCA2 mutation, they were 11.3 months (95% CI, 9.8-12.8) and 20.2 months (95% CI, 12.3-24.4). The 2-year survival rate in the combined cohort was 31% (95% CI, 17.7-44.4); the 3-year survival rate was 18% (95% CI, 8.1% -30.7%). According to researchers, these survival rates were among the longest ever reported in any randomized trial of pancreatic cancer.
Anemia of grade 3/4 occurred in 52% of patients in the triplet arm, compared to only 35% in the doublet arm. Thrombocytopenia rates were 55% and 9%, respectively; neutropenia accounted for 48% and 30%. Dose reductions were 90% and 17% in the triplet and duplet respectively. The incidence of non-hematological toxicity was similar between the two treatment groups.
Researchers believe that front line cisplatin and gemcitabine followed by maintenance PARP inhibitor (or continuing cytotoxic therapy) represents an optimal first-line treatment in patients of pancreatic ductal adenocarcinoma with germline BRCA/PALB2 mutation.
参考文献 Reference O’Reilly EM et al. J Clin Oncol. 2020;38(suppl 4;abstr 639)
白血病药物有望治疗耐药性肺癌 (3/14/2020)
Leukemia drugs offer hope for drug-resistant lung cancer
两种白血病药物对耐药性的肺癌可能有活性。
酪氨酸激酶抑制剂是针对肺癌靶向受体的的特定突变，但肿瘤很快会获得新的突变并具有耐药性。例如, 三分之一的肺癌患者使用奥西替尼（osimertinib），在六至九个月治疗后将会产生耐药性的C797S突变。
研究者开发的细胞平台直接在活细胞中测试潜在的药物分子，名为MaMTH-DS （Mammalian Membrane Two-Hybrid Drug Screen）, 可以鉴定既进入细胞又靶向自然环境受体的候选药物。 此外，MaMTH-DS不仅识别靶向受体激酶活性，还靶向其与其他细胞蛋白相互作用的药物分子。研究小组寻找了可靶向EGFR三联突变中赋予耐药性的C797S突变的小分子。通过对近3,000个分子的筛选，发现了四种对正常受体没有影响的有前途的化合物，这意味着这些药物伤害健康细胞的可能性较小。
研究者使用已批准用于特定形式白血病患者的两种药gilteritinib 和 midostaurin作为对具有三重突变的表皮生长因子受体（EGFR）的肺癌患者的潜在治疗方法。这些患者的肿瘤对现有疗法高度耐药。预计将于今年晚些时候在多伦多和 Zagreb, Croatia开始临床试验评估其中一种药物。
Two leukemia drugs may be active against drug-resistant lung cancer.
Tyrosine kinase inhibitors target specific mutations of lung cancer, but tumors will soon acquire new mutations and become resistant. For example, one-third of lung cancer patients taking osimertinib will develop drug-resistant C797S mutations after six to nine months of treatment.
The cell platform developed by the researchers tests potential drug molecules directly in living cells, called MaMTH-DS (Mammalian Membrane Two-Hybrid Drug Screen). It can identify drug candidates that both enter cells and target receptors in a natural environment. In addition, MaMTH-DS not only recognizes targeted receptor kinase activity, but also targets drug molecules that interact with other cellular proteins. The team looked for small molecules that could target the C797S mutation in drug-resistant triplets EGFR mutants. Screening of nearly 3,000 molecules revealed four promising compounds that have no effect on normal receptors, which means that these drugs are less likely to harm healthy cells.
Researchers use two drugs, gilteritinib and midostaurin, that have been approved for patients with specific forms of leukemia as a potential treatment for lung cancer patients with triple-mutated EGFR. These patients’ tumors are highly resistant to existing therapies. Clinical trials evaluating one of these drugs are expected to begin later this year in Toronto and Zagreb, Croatia.
参考文献 Reference Saraon P et al. Nature Chem Biol 2020; DOI: 10.1038/s41589-020-0484-2
抗抑郁药可能是复发性前列腺癌的新疗法 (3/8/2020)
Anti-depression drug may be able to treat recurrent prostate cancer
一种MAO抗抑郁药, 苯乙肼（phenelzine）在癌症患者中的首次临床试验显示，能使超过一半的参与者的PSA水平降低。 在前列腺癌中，MAO抑制剂会破坏雄激素受体信号传导-前列腺癌的主要生长途径。先前对动物和人类前列腺癌细胞系的研究表明，MAO抑制剂会降低前列腺癌的生长和扩散。
这是一项开放标签的单臂临床试验, 招募了前列腺切除术后生化复发性（PSA升高）的前列腺癌患者，定义为PSA ≥ 0.4 ng/ ml; 或放射治疗后生化复发性, PSA高于最低点的2 ng/ ml, 他们有正常的雄激素水平, 但没有影像学上转移的证据。 受试者每天两次口服苯乙肼30毫克。 使用医院焦虑抑郁评分（HADS）问卷评估情绪症状。 主要终点是PSA从基线下降≥50％的患者比例。
参加的20名患者的平均年龄66.9岁和PSA 4.7±5.8 ng/ ml。 在25％（n = 5）和10％（n = 2）的受试者中分别观察到最大PSA下降≥30％和≥50％, 最大的PSA下降是74％。 在第12周时，仍有17名接受治疗的受试者PSA分别下降≥30％和≥50％。 治疗相关的常见1/2级副作用包括头晕，高血压和浮肿。 有1次发作的4级高血压（第4周期）和2次发作的3级晕厥（第12周期和第14周期）需要停药。 HADS问卷表明，治疗后焦虑症状显著减轻，而抑郁症状却没有改变。
研究人员认为，这项研究的主要局限性包括缺乏安慰剂比较和小样本量。尚在计划进一步的研究。
The first clinical trial of a MAO antidepressant, phenelzine, in cancer patients has shown that PSA levels can be reduced in more than half of the participants. In prostate cancer, MAO inhibitors disrupt androgen receptor signaling, a major growth pathway for prostate cancer. Previous studies of animal and human prostate cancer cell lines have shown that MAO inhibitors reduce the growth and spread of prostate cancer.
This is an open-label, single-arm clinical trial that recruited patients with biochemically recurrent (elevated PSA) prostate cancer after prostatectomy, defined as PSA ≥ 0.4 ng/ml; or biochemically recurrent patients after radiation therapy, with PSA levels 2 ng/ml higher than their lowest point, they must have normal androgen levels, but there is no imaging evidence of metastases. Subjects took 30 mg of phenelzine orally twice daily. Emotional symptoms were assessed using the Hospital Anxiety and Depression Score (HADS) questionnaire. The primary endpoint was the proportion of patients with PSA ≥50% from baseline.
The mean age of the 20 participants was 66.9 years and PSA was 4.7 ± 5.8 ng/ml. In 25% (n = 5) and 10% (n = 2) subjects, a maximum PSA decrease of ≥30% and ≥50% was observed, and a maximum PSA decrease was 74%. At week 12, there were still 17 treated subjects with PSA reductions of ≥30% and ≥50%, respectively.
Common treatment-related grade 1/2 side effects included dizziness, hypertension, and edema. There were one episode of hypertension (cycle 4) and two episodes of grade 3 syncope (cycle 12 and cycle 14) that required discontinuation. The HADS questionnaire demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment.
The researchers commented that the main limitations of the study included a lack of placebo and small sample sizes. Further research is planned,
参考文献 Reference Gross ME et al. Prostate cancer and prostate diseases 2020; March 3
AKT抑制剂Capivasertib和氟维司群用于对芳香化酶抑制剂耐药的晚期雌激素受体阳性乳腺癌 (3/7/2020)
AKT inhibitor and fulvestrant used in advanced ER-positive breast cancer refractory to aromatase inhibitor
Capivasertib是一种有效的选择性口服药物，可抑制所有三种同工型AKT激酶。在具有对芳香酶抑制剂抗药性，雌激素受体阳性, HER2阴性的绝经后乳腺癌病人中，在内分泌治疗中使用氟维司群（fulvestrant）和AKT抑制剂capivasertib可以延长无进展生存期。
这是一项多中心双盲临床试验（FAKTION II）, 她们都在使用芳香化酶抑制剂后复发或疾病进展。每28天随机分配140名，每28天肌内注射500 毫克氟维司群（第1周期的第15天接受负荷剂量），从第1个周期的第15天开始，以每星期4天/（3天不服用）的时间表, 每天两次口服400 毫克capivasertib（n = 69）或安慰剂（n = 71）。治疗持续至疾病进展或不可接受的毒性。主要终点是意图治疗人群的无进展生存期。对患者进行随访直到所有患者均接受了至少6个月的随访，并已确认至少98个疾病进展事件。
中位随访时间为4.9个月。在对无进展生存期进行初步分析时，发生了112例总无进展生存事件，在capivasertib组中有49例患者（占71％），而在安慰剂组中有63例患者（占89％）。中位无进展生存期为10.3个月对4.8个月（危险比[HR] = 0.58，95％置信区间= 0.39–0.84，P = 0.0018）。在99位可测量的疾病 (measurable disease) 患者中, 中位无进展生存期为7.6个月相对3.2个月（HR = 0.61，P = .030）; 在41位基线时无法测量的疾病患者中, 为13.4个月相对于7.9个月（HR = 0.47，P = .046）。客观响应率为29％相对于8％（优势比= 4.42，P = .0031）。总体生存数据尚不成熟；接受12个月随访后，发生死亡的患者为30％相对于44%。
Capivasertib组最常见的3或4级不良事件是高血压（32％相对于安慰剂组24％），皮疹（20％相对于0％），腹泻（14％相对于 4％），感染（6％相对于3％）和疲劳（1％相对于4％）。仅在capivasertib组中观察到严重的不良事件，其中三例为腹泻。两名患者分别患有急性肾损伤和皮疹；和高血糖，意识丧失，败血症和呕吐分别在一名患者中发生。非典型肺部感染导致的死亡被认为可能与capivasertib治疗有关。
研究人员得出结论：接受capivasertib者的无进展生存期明显长于接受安慰剂的受试者。Capivasertib和氟维司群的组合值得在III期临床试验中进一步研究。
Capivasertib is an effective selective oral drug that inhibits all three isoforms of AKT kinase. In ER-positive and HER2 negative postmenopausal breast cancer patients with resistance to aromatase inhibitors, the combination of fulvestrant and AKT inhibitor capivasertib in endocrine therapy can prolong progression-free survival.
This is a multi-center, double-blind clinical trial (FAKTION II). They all relapsed or progressed after using aromatase inhibitors. Every 28 days enrolled 140 randomly assigned patients. They received intramuscular injection of 500 mg fulvestrant every 28 days (a loading dose was given on day 15 of cycle 1). Starting on day 15 of cycle 1, one cohort received orally 400 mg of capivasertib (n = 69), twice daily 4 days per week (off for 3 days) , or placebo (n = 71). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival in the intent-to-treat population. Patients were followed until all patients had been followed for at least 6 months, and at least 98 disease progression events were identified.
The median follow-up time was 4.9 months. In a preliminary analysis of progression-free survival, 112 total progression-free survival events occurred, with 49 patients (71%) in the capivasertib group and 63 patients (89%) in the placebo group. . The median progression-free survival was 10.3 months vs 4.8 months (hazard ratio [HR] = 0.58, 95% confidence interval = 0.39–0.84, P = 0.0018). Among 99 patients with measurable disease, the median progression-free survival was 7.6 months vs. 3.2 months (HR = 0.61, P = .030); among 41 patients with disease that could not be measured at baseline , PFS was 13.4 months vs. 7.9 months (HR = 0.47, P = .046). Objective response rate was 29% versus 8% (odds ratio = 4.42, P = .0031). Overall survival data are still immature. After 12 months of follow-up, 30% of patients died compared to 44%.
The most common grade 3 or 4 adverse events in the capivasertib group were hypertension (32% vs. 24% in the placebo group), rash (20% vs. 0%), diarrhea (14% vs. 4%), and infection (6% vs. 3%) and fatigue (1% vs.4%). Serious adverse events that were observed only in the capivasertib group included three patients with diarrhea, two patients had acute kidney injury and rash, respectively. Hyperglycemia, loss of consciousness, sepsis, and vomiting occurred in one patient each. Deaths from atypical lung infections are thought to be related to capivasertib treatment.
The researchers concluded that progression-free survival was significantly longer in subjects receiving capivasertib than in placebo group. The combination of capivasertib and Fulvestrant deserves further study in a phase III clinical trial.
参考文献 Reference Jones RH et al. Lancet Onc 2020; February 05 DOI:https://doi.org/10.1016/S1470-2045(19)30817-4
新的药物组合和顺序对治疗胰腺癌有希望 (3/1/2020)
New drug combination and sequencing shows promise in pancreatic cancer treatment
靶向药物palbociclib和化疗联合按并正确的顺序给药, 可能会增强胰腺癌治疗的有效性。
研究发现，palbociclib是一种细胞周期蛋白依赖性激酶（CDK）4和6抑制剂，可以阻止癌细胞进入S期，从而阻止其增殖。 它们还可以防止癌细胞修复由各种DNA破坏剂引起的DNA损伤。
最初发现在化疗的同时使用CDK 4/6抑制剂, 会阻止癌细胞进入DNA复制的细胞周期阶段，因此会干扰S期或有丝分裂靶向药物。而使胰腺肿瘤对化学疗法获得抵抗力。若首先给小鼠palbociclib, 然后给紫杉醇会使化疗破坏更少的癌细胞。相反，若小鼠先服用紫杉醇，再给予palbociclib会降低胰腺癌细胞的生长。这个结果, 在胰腺导管腺癌细胞，患者来源的异种移植小鼠, 以及在KRAS G12V和Cdkn2a-null突变（胰腺导管腺癌细胞中经常观察到）的基因工程小鼠都观察到。
这一观察将为临床治疗提供指导。
The combination of targeted drug palbociclib and chemotherapy in the correct sequence may increase the effectiveness of pancreatic cancer treatment.
Studies have found that palbociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, which can prevent cancer cells from entering S phase and thereby stop their proliferation. They can also prevent cancer cells from repairing DNA damage caused by various DNA-damaging agents.
It was initially discovered that the use of CDK 4/6 inhibitors in conjunction with chemotherapy actually prevents cancer cells from entering the cell cycle phase of DNA replication and therefore interferes with S-phase or mitotic targeted drugs, and make pancreatic tumors resistant to chemotherapy. If palbociclib is given to mice before paclitaxel, chemotherapy will destroy fewer cancer cells. Conversely, if mice were given paclitaxel first and then palbociclib, the growth of pancreatic cancer cells was reduced. This result was observed in pancreatic ductal adenocarcinoma cells, patient-derived xenograft mice, and genetically engineered mice with KRAS G12V and Cdkn2a-null mutations (often observed in pancreatic ductal adenocarcinoma).
This observation will provide guidance to clinical treatment.
参考文献 Reference Salvador-Barbero B et al. Cancer Cell 2020; Feb 27 DOI:https://doi.org/10.1016/j.ccell.2020.01.007治疗透明细胞肾癌靶向癌症驱动分子的药物 (2/29/2020)
A new drug targeting cancer driver molecule in clear cell renal cell cancer
绝大多数患有透明细胞肾癌的患者有一种称为von Hippel-Lindau（VHL）的蛋白质。具有这种缺陷的VHL蛋白的结果是激活缺氧诱导因子（HIF）2α蛋白，该蛋白在肿瘤细胞内积聚，错误地发出氧气不足的信号并激活血管的形成，从而助长了肿瘤的生长。
这是一项I/II期临床试验, 有55位晚期透明细胞病人参加, 中位年龄为62岁，患者中有44名是男性。 患者曾接受过3种先前的全身性治疗方案，而34名接受过3种或更多种先前的治疗。 绝大多数（93％）患者接受了包括血管内皮生长因子（VEGF）抑制剂和免疫检查点抑制剂（73％）。 三分之二的患者同时接受了抗PD-1和抗VEGF疗法。患者每日口服一次HIF-2α抑制剂,MK-6482。
最常见的3级副作用是贫血（26％）和缺氧（15％）。2例患者共发生4种4级副作用（高钙血症，败血症，心脏骤停和呼吸衰竭）。4例患者由于疾病进展而亡。 试验期间未发生致命的与治疗有关的不良事件。
总响应率为24％，所有响应都是部分响应。临床受益率（稳定疾病加响应疾病）达到80％, 中位随访时间为13个月。III期临床试验研究正在进行。
The great majority of patients with clear cell renal cancer have a protein called von Hippel-Lindau (VHL). The outcome of this defective VHL protein is the activation of hypoxia-inducible factor (HIF) 2α protein, which accumulates in tumor cells, falsely signals a lack of oxygen and activates blood vessel formation, thereby promoting tumor growth.
This is a phase I / II clinical trial involving 55 patients with advanced clear cells renal cancer, with a median age of 62 years and 44 of the patients were male. Patients had received 3 prior systemic treatments, and 34 patients had received 3 or more previous treatments. The majority (93%) of the patients received vascular endothelial growth factor (VEGF) inhibitors and immune checkpoint inhibitors (73%). Two-thirds of patients received both anti-PD-1 and anti-VEGF therapy. Patients took HIF-2α inhibitor, MK-6482 orally once a day, and the total response rate was 24%.
The most common grade 3 side effects were anemia (26%) and hypoxia (15%). A total of 4 grade 4 side effects (hypercalcemia, sepsis, cardiac arrest, and respiratory failure) occurred in 2 patients. Four patients died due to disease progression. No fatal treatment-related adverse events occurred during the trial.
All responses were partial responses. The clinical benefit rate (stable disease plus response) reached 80%, and the median follow-up was 13 months. Phase III clinical trial research is underway.
参考文献 Reference Choueiri T et al. Genitourinary Cancers Symposium 2020; Abstr 611
奥西替尼和Savolitinib组合在EGFR阳性/MET扩增的晚期非小细胞肺癌有抗肿瘤活性 (2/23/2020)
Osimertinib and savolitinib combination has potential in EGFR-mutated and MET amplified advanced NSCLC
在EGFR阳性，而MET扩增的晚期非小细胞肺癌中，EGFR酪氨酸激酶抑制剂（TKI）加上MET 酪氨酸激酶抑制剂, 对于具有MET驱动, 获得耐药的EGFR突变阳性的肺癌是一种可能的治疗方法。
这是一项多中心，开放标签，1b期研究期临床试验（TATTON）, 包括2组中的1组（B和D部分）。B部分有144位先前接受过第三代EGFR 酪氨酸激酶抑制剂的患者和先前未接受第三代EGFR 酪氨酸激酶抑制剂且患有Thr790Met阴性或Thr790Met阳性疾病的患者。 D部分（n = 42）包括先前未接受第三代EGFR 酪氨酸激酶抑制剂治疗的患者，其疾病为Thr790Met阴性。
B部分的患者每天接受80毫克奥西替尼（osimertinib）和600毫克Savolitinib。在2018年3月12日进行方案修订后，体重≤55公斤的患者接受了300 毫克Savolitinib治疗。 D部分的患者接受了80毫克奥西替尼加300毫克Savolitinib。主要终点是安全性和耐受性，次要终点包括客观响应患者的百分比。最终，B部分中的138例患者接受了奥西替尼加600毫克savolitinib（n = 130）或300 毫克（n = 8）的治疗，而D部分中的42例患者接受了奥美替尼加300毫克savolitinib 的治疗。
B组中有79名（57％）≥3级的不良事件，D部分中有16名（38％）。 与savolitinib有关的不良事件在 B部分有115名（83％）患者; D部分有25名（60％）。值得注意的是，B部分中有2种不良事件导致患者死亡，被认为可能与治疗有关。
客观部分响应在B部分和D部分，分别为66（48％; 95％CI，39-56）和23（64％; 95％CI，46-79）。
研究者认为, 奥美替尼和savolitinib的组合在MET扩增，EGFR突变阳性，晚期非小细胞肺癌的患者中具有可接受的风险-获益特征，并具有抗肿瘤活性。
In EGFR-mutated and MET-amplified advanced non-small cell lung cancers, EGFR tyrosine kinase inhibitors (TKI) plus MET TKIs, for MET-driven, EGFR TKI-resistant lung cancer is a potential treatment.
This is a multicenter, open-label, Phase 1b clinical trial (TATTON), which includes one of the two groups (Parts B and D). Part B includes 144 patients who had previously received a third-generation EGFR TKI and patients who had not previously received a third-generation EGFR TKI and had Thr790Met-negative or Thr790Met-positive disease. Part D (n = 42) includes patients who had not previously been treated with a third-generation EGFR TKI and whose disease is Thr790Met negative.
Part B patients received 80 mg of osimertinib and 600 mg of savolitinib daily. Following a protocol revision on March 12, 2018, patients weighing ≤55 kg received 300 mg of savolitinib. Part D patients received 80 mg of osimertinib plus 300 mg of savolitinib. Primary endpoints were safety and tolerability; secondary endpoints included percentage of patients who responded objectively. In the end, 138 patients in Part B received osimertinib plus 600 mg of savotitinib (n = 130) or 300 mg (n = 8), while 42 patients in Part D received osimertinib and 300 mg of savolitinib.
There were 79 (57%) grade 3 adverse events in group B, and 16 (38%) in part D. Savolitinib-related adverse events occurred in 115 patients (83%) in Part B; 25 patients (60%) in Part D. It is worth noting that there were 2 adverse events in Part B that led to the death and were thought to be related to treatment.
The objective partial responses were in Part B and D were 66 (48%; 95% CI, 39-56) and 23 (64%; 95% CI, 46-79) respectively.
Researchers concluded that the combination of osimertinib and savolitinib has acceptable risk-benefit ratio and displayed antitumor activity in patients with MET amplification, EGFR mutation-positive advanced non-small cell lung cancer.
参考文献 Reference Sequist LV et al. Lancet Onc 2020; Feb 3. pii: S1470-2045(19)30785-5Trifluridine/Tipiracil对转移性胃癌的疗效与先前的胃切除术无关(2/22/2020)
Efficacy of Trifluridine/Tipiracil in metastatic gastric cancer with or without gastrectomy
这是一项3期随机，安慰剂对照的临床试验（TAGS）的亚组分析。 有507位转移性胃癌或胃食管连接癌患者参加, 中位年龄为62.5岁, 男性369 位（72.8％）。221例（43.6％）接受了胃切除术和286例（56.4%） 的人没有接受胃切除术。这些患者曾接受过至少2种先前的化疗方案。干预措施在每个28天的治疗周期的第1- 5天和第8 – 12天进行，以2：1的比例将患者随机分组, 每天两次接受口服Trifluridine/Tipiracil（FTD/TPI, TAS-102）35 毫克/平方米或安慰剂，并给予最佳支持。主要终点是总体生存率。进行此亚组分析是为了检查潜在趋势，在亚组中评估功效和安全终点。
在胃切除术亚组中，FTD / TPI组与安慰剂组的总生存危险比（HR）为0.57（95％CI，0.41-0.79），无进展生存率HR为0.48（95％CI，0.35- 0.65）。在无胃切除术亚组中，FTD / TPI组与安慰剂组的总生存危险比HR为0.80（95％CI，0.60-1.06），无进展生存危险比为0.65（95％CI，0.49-0.85）。
在接受FTD / TPI治疗的患者中，胃切除术亚组的145例患者中的122例（84.1％）发生了3级或更高的任何原因的不良事件，未进行胃切除术亚组的190例中有145例（76.3％）发生不良事件。在胃切除术亚组中，有94例（64.8％）由于不良事件而改变了剂量，而在非胃切除术亚组中有101例（53.2％）。胃切除术组中有15例（10.3％），无胃切除术组中的28例（14.7％）因不良事件而中止了治疗。两组之间的治疗剂量暴露相似。
FTD / TPI治疗是可以耐受的, 与安慰剂相比改善了总生存率和无进展生存期, 而与先前的胃切除术无关。
This is a subgroup analysis of a phase 3 randomized, placebo-controlled clinical trial (TAGS). A total of 507 patients with metastatic gastric cancer or GE junction cancer participated, The median age was 62.5 years and 369 were males (72.8%). A total of 221 patients (43.6%) underwent gastrectomy and 286 (56.4%) did not undergo gastrectomy. These patients received at least 2 previous chemotherapy regimens.
The interventions were carried out on days 1-5 and 8-12 of each 28-day treatment cycle. Patients were randomly divided into groups of 2: 1 and received oral Trifluridine / Tipiracil (FTD / TPI, TAS- 102) 35 mg / m² or placebo with optimal support. The primary endpoint was overall survival. This subgroup analysis was performed to examine potential trends and assess efficacy and safety endpoints in the subgroup.
In the gastrectomy subgroup, the overall survival hazard ratio (HR) of the FTD / TPI group vs. the placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35- 0.65). In the subgroup where patients had not undergone gastrectomy, the overall survival HR of the FTD / TPI group vs. the placebo group was 0.80 (95% CI, 0.60-1.06) and the progression-free survival hazard ratio was 0.65 (95% CI, 0.49-0.85).
Among patients receiving FTD / TPI, 122 of the 145 patients in the gastrectomy subgroup (84.1%) had adverse events of grade 3 or higher for any reason, vs.145 out of 190 (76.3%) in the subgroup who had not undergone gastrectomy. In the gastrectomy subgroup, 94 patients (64.8%) had dose modification due to adverse events, while in the subgroup who had not undergone gastrectomy, 101 patients (53.2%). Fifteen patients (10.3%) in the gastrectomy group and 28 patients (14.7%) in the non-gastrectomy group discontinued treatment due to adverse events. The therapeutic dose exposure was similar between the two groups.
FTD / TPI treatment was tolerable and improved overall survival and progression-free survival compared to placebo, whether or not the patients had undergone previous gastrectomy.
参考文献 Reference Ilson DH JAMA 2020; 6: 49
Sitravatinib加上尼诺单抗对晚期尿路上皮癌有活性 (2/16/2020)
Sitravatinib in combination with Nivolumab has activity in locally advanced or metastatic urothelial carcinoma
Sitravatinib可有效抑制受体酪氨酸激酶的TAM家族（Tyro3，Axl和MerTK），据称可调节免疫微环境， 它还抑制血管内皮生长因子受体2和c-Met，后者在抗肿瘤免疫中发挥作用。
这是一项II期临床试验，报导的是该研究队列1的结果，其中包括33例局部晚期（9％）或转移性（91％）尿路上皮癌的患者, 中位年龄为68岁（47-83）, 男性为70％。他们都曾接受过铂的化疗并在检查点抑制剂治疗后进展。患者在转移或晚期环境中接受了中位数为两次（1-4次）的治疗。患者在28天为1周期中每天接受120 毫克口服Sitravatinib，再每2周接受240毫克静脉nivolumab（或每4周接受480 毫克 ）。研究人员每8周评估一次肿瘤。客观响应率是主要目标。次要目标包括安全性，反应持续时间，临床受益率，无进展生存期，生存期和Sitravatinib的药代动力学。
在22位可评估的患者中，客观响应率为27％, 6名患者已确认完全（n = 1）或部分（n = 5）响应, 有21位（95％）表现出完全/部分响应或疾病稳定。19名患者（86％）的完全/部分响应或疾病稳定持续时间超过12周，而八名（36％）患者的肿瘤消退率超过30％。
最常见不良事件包括疲劳（58％），腹泻（48％），食欲下降（33％），发音障碍（33％），恶心（33％）和丙氨酸转氨酶增加（21％）。超过一名患者的与3级不良事件包括疲劳（12％），高血压（12％），腹泻（9％）和脂肪酶升高（9％）。没有报道与治疗相关的4级或5级不良事件。
Sitravatinib与抗PD-1疗法的组合具有可接受的毒性，并且在先前接受过抗PD-1/PD-L1疗法后进展的局部晚期或转移性尿路上皮癌患者中仍显示出临床活性，包括肿瘤消退和治疗持续时间。
Sitravatinib effectively inhibits the TAM family of receptor tyrosine kinases (Tyro3, Axl, and MerTK), which can modulate immune microenvironment. It also inhibits vascular endothelial growth factor receptor 2 and c-Met, which plays a role in anti-tumor immunity.
This is a phase II clinical trial. The results of cohort 1 of this study was reported. The cohort included 33 patients with locally advanced (9%) or metastatic (91%) urothelial cancer, with a median age of 68 years (47-83) and 70% were men. They have all received platinum-based chemotherapy and progressed after checkpoint inhibitor treatment. Patients received a median of two (1-4) treatments in metastatic or advanced settings. Patients received 120 mg of oral Sitravatinib per day for 28 days as a cycle, and received 240 mg of intravenous nivolumab every 2 weeks (or 480 mg every 4 weeks). Researchers evaluated tumors every 8 weeks. Objective response rate is the main goal. Secondary goals include safety, duration of response, clinical benefit rate, pharmacokinetics, PFS, and OS.
Of the 22 evaluable patients, the objective response rate was 27%, 6 patients had confirmed complete response (n = 1) or partial response (n = 5), and 21 (95%) showed complete or partial response or stable disease. Nineteen patients (86%) had a complete or partial response or stable disease lasted more than 12 weeks, while eight (36%) patients had a tumor regression rate of more than 30%.
The most common adverse events included fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%), and increased alanine aminotransferase (21%). Grade 3 adverse events in more than one patient included fatigue (12%), hypertension (12%), diarrhea (9%), and elevated lipase (9%). No treatment-related grade 4 or 5 adverse events were reported.
The combination of Sitravatinib with anti-PD-1 therapy has reasonable toxicity and shows clinical activity including tumor regression and prolonged duration of treatment in patients with locally advanced or metastatic urothelial cancer that has progressed after previous anti-PD-1/PD-L1 therapy.
参考文献 Reference Doshi GK et al. JCO 2019; DOI: 10.1200/JCO.2019.37.7_suppl.TPS498
下一代针对BCMA的 CAR T细胞疗法治疗多发性骨髓瘤 (2/15/2020)
Next generation BCMA-targeted CAR-T cell therapy for multiple myeloma
在患有复发性或难治性多发性骨髓瘤的患者中，新型的双靶嵌合抗原受体（CAR）T细胞策略可产生早期且持久的反应，与第一代CAR T细胞产品相比，细胞因子释放综合征和神经毒性更少。
这是一项Ib/II 期临床试验（CARTITUDE-1）, 主要目的是评估JNJ-4528的安全性，并确认源自先前LEGEND-2试验的相同构建体LCAR-B38M的II期剂量。 JNJ-4528经过基因工程改造，包含一个4-1BB刺激域和两个附着在B细胞成熟抗原（BCMA）上的蛋白质，可赋予它们亲和力。每位患者均对JNJ-4528有响应（100%），并且每位患者的副蛋白均降低了; 其中69％的患者有完全反应。此外，可评估的患者中, 100％为最小残留病（MRD）阴性，并且在经过6个月的中位随访后，29位多线治疗过的患者中有27位没有疾病进展。JNJ- 4528最近获得了美国食品和药物管理局的突破性治疗称号，用于治疗复发性或难治性多发性骨髓瘤患者。
In patients with relapsed or refractory multiple myeloma, the novel dual-target chimeric antigen receptor (CAR) T-cell strategy produces an early and long-lasting response compared to first-generation CAR T-cell products. The new generation product has less cytokine release syndrome and neurotoxicity.
This is a phase Ib / II clinical trial (CARTITUDE-1). The main purpose is to evaluate the safety of JNJ-4528 and confirm the phase II dose of the same construct LCAR-B38M from the previous LEGEND-2 trial. JNJ-4528 is genetically engineered to contain a 4-1BB co-stimulatory domain and two proteins attached to B-cell maturation antigen (BCMA), which confers avidity. Each patient responded to JNJ-4528 (100%), and the paraprotein in each patient was reduced; 69% of them had a complete response. In addition, 100% of the evaluable patients were negative for minimal residual disease (MRD), and after a median follow-up of 6 months, 27 of the 29 heavily-treated patients had no disease progression. JNJ-4528 recently received the US Food and Drug Administration’s Breakthrough Therapy designation for patients with relapsed or refractory multiple myeloma.
参考文献 Reference Madduri D et al. 2019 ASH Annual Meeting & Exposition Abstr 577
西妥昔单抗对肝转移可切除的结直肠癌生存期不利 (2/10/2020)
Cetuximab may shorten overall survival in resectable colorectal liver metastases
长期随放结果显示，在围手术期化疗中添加西妥昔单抗（cetuximab）会降低可手术肝转移的结直肠癌患者的生存率。
这是一项III期临床试验（New EPOC）,从2007年到2012年，将257例可手术肝转移的KRAS野生型结直肠癌患者按1：1比例随机分配接受单独化疗（n=128）或西妥昔单抗加化疗（n=129）。患者的中位年龄约为65岁，大多数患有N1或N2疾病（分别为65％相比于60％）和≤3个转移部位（80％相比于75％）。在对照组中，57％发生同步转移，而在西妥昔单抗组中则为68％。
两组之间的术前反应或病理切除状态的次要结果无显着差异。经过5年以上的随访，单纯化疗组中位总生存期为81.0个月（59.6-未达到），化疗加西妥昔单抗组为55.4个月（43.5-71.5）（风险比率 1.45，95％置信区间, 1.02-2.05 ，P = 0.036）。化疗-西妥昔单抗组中有4例死亡被认为可能与治疗有关，而单纯化疗组中有1例死亡。在亚组分析中，具有良好特征的患者中, 西妥昔单抗的总生存期结局较差。那些具有不良特征的患者, 即分化不良的癌症，N2状态或≥4转移病灶, 用西妥昔单抗并没有改善，但也没有受到伤害。
作者建议西妥昔单抗不宜用于可切除肝转移的结直肠癌患者。
Long-term follow-up results show that addition of cetuximab to perioperative chemotherapy can reduce overall survival in colorectal patients with resectable liver metastases.
This is a phase III clinical trial (New EPOC). From 2007 to 2012, 257 patients with KRAS wild-type colorectal cancer with operable liver metastases were randomly assigned to receive either chemotherapy alone (n = 128), or cetuximab plus chemotherapy (n = 129). Median age was approximately 65 years, and most had N1 or N2 disease (65% vs. 60%, respectively) and ≤ 3 metastatic sites (80% vs. 75%). In the control group, 57% had synchronous = metastases, compared with 68% in the cetuximab group.
There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. After more than 5 years of follow-up, the median overall survival was 81.0 months (59.6-not reached) in the chemotherapy alone group, and 55.4 months (43.5-71.5) in the chemotherapy plus cetuximab group (HR 1.45, 95% CI, 1.02-2.05, P = 0.036). Four deaths in the chemotherapy-cetuximab group were considered to be treatment-related, while one death was in the chemotherapy-only group. In the subgroup analysis, the overall survival outcomes of cetuximab were poor in patients with good characteristics. Patients with adverse characteristics, i.e. poorly differentiated cancers, N2 status, or ≥4 metastatic sites, showed no improvement with cetuximab, but were not harmed.
The authors advised that cetuximab should not be used in colorectal cancer patients with resectable liver metastases.
参考文献 Reference Bridgewater JA et al. Lancet Onc 2020; Jan 31, DOI:https://doi.org/10.1016/S1470-2045(19)30798-3
APR-246和Azacitidine对有TP53突变的骨髓增生异常综合症的安全性和有效性 (2/8/2020)
Safety and efficacy of combination therapy of APR-246 and azacytidine towards MDS with TP53 mutation
骨髓增生异常综合症（MDS）是造血干细胞恶性肿瘤，其骨髓不能产生足够数量的健康血细胞。大约30-40％的MDS患者发展为急性髓细胞性白血病（AML），p53抑癌蛋白的突变被认为与疾病进展有关。在多达20％的MDS患者中发现p53突变，并且与总体预后不良有关。
这是由美国和法国进行的一项Ib/II期临床试验, 在临床试验的Ib期部分中，患者在导入期（第-14天到第-10天），以3+3次剂量递增设计（50、75、100 毫克/公斤瘦体重）静脉接受APR-246 ，然后每天使用相同剂量的APR-246（第1-4天）和Azacitidine 75 毫克/平方米 皮下 / 静脉每7天（第4-10或4-5和8-12天）, 每28天为1周期。 在临床试验的II期阶段，患者每天接受4500 mg固定剂量静脉的APR-246（第1-4天）和每天Azacitidine接受7天（第4-10或4-5和8-12天）。 每28天为1周期。
对33位可评估的MDS患者进行了评估，总缓解率为88％，完全缓解率为61％。中位随访时间为10.8个月，中位缓解时间为8.4个月，中位完全缓解持续时间为7.3个月。 17名（52％）可评估的MDS患者中止了治疗以进行干细胞移植。所有入组患者（n = 55）的中位总生存期为10.8个月。有响应的患者与无响应的患者的中位总生存期分别为13.7和3.9个月。不良事件大多为1/2年级。 ≥20％的患者发生的3级以上不良事件仅限于血细胞减少和感染，与患者本身的造血系统恶性肿瘤一致，并且未观察到Azacitidine相关安全性状况恶化。
APR-246是一个小分子，已通过恢复野生型p53构象和功能而展示了突变和失活的p53蛋白的再活化，从而诱导了人类癌细胞的程序性细胞死亡。
APR-246和Azacitidine用于TP53突变MDS的一线治疗的3期临床试验正在进行中。 APR-246已获得FDA授予的MDS孤儿药和快速通道认证，以及孤儿药认证。
该网站未报告该临床试验中的AML结果。
Myelodysplastic syndrome (MDS) is a hematopoietic stem cell malignancy where bone marrow cannot produce a sufficient number of healthy blood cells. Approximately 30-40% of patients with MDS develop acute myeloid leukemia (AML), and mutations in TP53, a tumor suppressor gene are thought to be associated with disease progression. TP53 mutations are found in up to 20% of patients with MDS and are associated with a poor overall prognosis.
This is a phase Ib / II clinical trial conducted by investigators in the United States and France. In the phase Ib part of the clinical trial, patients were designed in 3 + 3 dose escalation manner during the lead-phase (days -14 to -10). Patients receive APR-246 at 50, 75, 100 mg / kg lean body weight intravenously, and then received the same dose of APR-246 (days 1-4) and Azacitidine 75 mg / m2 subcutaneously /intravenously every 7 days (day 4 -10 or 4-5 and 8-12 days). Every 28 days is a cycle. During the Phase II phase of the clinical trial, patients received 4500 mg of fixed-dose intravenous APR-246 daily (days 1-4) and daily Azacitidine for 7 days (days 4-10 or 4-5 and 8-12). Every 28 days is a cycle.
Thirty-three evaluable MDS patients were evaluated with an overall response rate of 88% and a complete response rate of 61%. The median follow-up time was 10.8 months, the median response time was 8.4 months, and the median complete response duration was 7.3 months. Seventeen (52%) of evaluable MDS patients discontinued treatment for stem cell transplantation. The median overall survival for all enrolled patients (n = 55) was 10.8 months. The median overall survival for responding and non-responding patients was 13.7 and 3.9 months, respectively. Adverse events were mostly grade 1/2. Grade 3 adverse events occurred in ≥20% of patients and were limited to hemocytopenia and infection, consistent with the patient’s own hematopoietic malignancies, while no deterioration in Azacitidine-related safety status was observed.
APR-246 is a small molecule that has demonstrated the ability to reactivate mutant and inactivated p53 proteins by restoring the conformation and function of wild-type p53, thereby inducing programmed cell death in human cancer cells.
A phase 3 clinical trial of APR-246 and Azacitidine for first-line treatment of TP53 mutant MDS are ongoing. APR-246 has received MDS Orphan Drug and Fast Track deesignation from the FDA.
The trial results in AML were not included in the above.
参考文献 Reference Cluezeau T et al. Blood 2019; 134: (suppl-1) 677
HIV蛋白酶抑制剂nelfinavir联合放化疗治疗不可切除的IIIA / IIIB期非小细胞肺癌 (2/2/2020)
Combination of HIV protease inhibitor nelfinavir and chemo-radiation in unresectable ST IIIA/IIIB NSCLC
HIV蛋白酶抑制剂Nelfinavir（放射增敏剂）与放化疗联合治疗对局部晚期非小细胞肺癌患者具有良好的耐受性，并有希望实现长期的局部控制和生存。
这是一项期I/II临床试验, 有35位IIIA/IIIB期非小细胞肺癌病人参加 （16名女性和19名男性）, 中位年龄为60岁（39-79）。患者在化疗和放疗7至14天之前开始口服Nelfinavir, 并与放化疗同时进行。中位随访时间为6.8年，所有幸存者的随访时间至少为5年。其中5名患者每天两次服用625毫克，30名患者每日两次服用1250毫克。
没有观察到剂量限制的毒性作用。没有观察到4级或更高的非血液学毒性作用。 35例患者中有33例为可评估（CT），客观响应率为94％（31/33； 95％CI, 86-100）。局部失败的累积发生率为39％（95％CI，30.5-47.5）。中位无进展生存期为11.7个月（95％CI，6.2-17.1）。所有患者的平均总生存时间为41.1个月（95％CI，19.0-63.1）。
这项研究表明，Nelfinavi可以增强标准放化疗的疗效, 与放化疗联合使用具有可接受的毒性作用，应在随机第3期设置中进行测试。
The combination of HIV protease inhibitor Nelfinavir (radiosensitizer) and chemoradiotherapy is well tolerated in patients with locally advanced non-small cell lung cancer, and offers hope to achieve long-term local control and survival.
This is a phase I / II clinical trial involving 35 patients with stage IIIA / IIIB non-small cell lung cancer (16 women and 19 men) with a median age of 60 (39-79). Patients started taking Nelfinavir orally 7 to 14 days before chem-radiotherapy, and then concurrently with chemo-radiation. The median follow-up was 6.8 years, and all survivors were followed for at least 5 years. Five patients took 625 mg twice daily and 30 patients took 1250 mg twice daily.
No dose-limiting toxic effects were observed. No grade 4 or higher non-hematological toxicity was observed. Of the 35 patients, 33 were evaluable by CT. Objective response rate was 94% (31/33; 95% CI, 86-100). The cumulative incidence of local failure was 39% (95% CI, 30.5-47.5). The median progression-free survival was 11.7 months (95% CI, 6.2-17.1). The average overall survival for all patients was 41.1 months (95% CI, 19.0-63.1).
This study shows that Nelfinavi can enhance the efficacy of standard chemoradiotherapy with acceptable toxicity when used in combination with chemo-radiation. The regime should be tested in randomized phase 3 setting.
参考文献 Reference Regan R et al. JAMA 2019; 5: 1464-72
Atezolizumab 加上贝伐单抗对无法切除的肝细胞癌有希望 (2/1/2020)
Atezolizumab plus Bevacizumab offers hope for unresectable hepatocellular carcinoma
在Atezolizumab加上贝伐单抗的临床试验亚组疗效分析中，对先前未经治疗，无法切除的肝细胞癌患者观察到了临床上有意义且持久的客观反应。
这是一项Ib期临床试验（GO30140）, 有104位无法切除的肝细胞癌病人参加, 入选的大多数患者是男性（81％），中位年龄为62岁，其中57％来自亚洲（日本除外）。 49％的患者患有乙型肝炎，30％的患者患有丙型肝炎。 88％的患者存在肝外扩散或大血管侵犯。Child-Pugh评分最高为B7。每3周给患者静脉给予atezolizumab 1200 毫克静脉注射，每3周给予贝伐单抗15 毫克/公斤静脉注射。 主要终点是治疗安全性和客观响应率。次要终点包括响应持续时间和无进展生存期，一些关键的次要端点的数据将在即将召开的会议上提供。
在研究组中，客观响应率为36％，其中12％的患者获得了完全缓解。响应持续时间为1.6个月至31个月。超过一半的患者（54％）的反应持续时间超过9个月，76％的反应仍在进行中，并且未达到反应的中位时间。
Atezolizumab和贝伐单抗的组合产生的中位无进展生存期在3个分析中一致：66％的患者为7.3个月; 72％为7.4个月。中位总体生存期为17.1个月，6个月总体生存率为82％，12个月总体生存期为63％。 在患者亚组中，无论PD-L1的状态如何，都观察到了临床活性。
最常见的不良事件为蛋白尿（37％），食欲下降（ 35％）和疲劳（28％）。患者中39％具有3/4级与治疗相关的不良事件，3％的患者为5级。最常见的3/4级副作用是高血压（14％）。有24％的患者患有与治疗相关的严重不良事件，包括发热（5％），胆管炎（3％）和上消化道出血（3％）。与atezolizumab相关的最常见的特殊关注不良事件是皮疹（23％），贝伐单抗是蛋白尿（37％）。有15名患者（14％）对atezolizumab产生不良事件后的30天内需要全身性激素治疗。AST和ALT水平升高（每例患者的3％）是最常见的肝脏事件，需要在30天内全身应用类固醇。
这种atezolizumab和贝伐单抗的组合可能成为无法切除的肝细胞癌患者的有希望的治疗选择。一项III期研究（IMbrave150 , NCT03434379）正在进一步评估这种组合的有效性。
The combination of atezolizumab plus bevacizumab produced clinically meaningful and durable objective response in patients of previously untreated, unresectable hepatocellular carcinoma.
This is a phase Ib clinical trial (GO30140). A total of104 patients with unresectable hepatocellular carcinoma participated. The majority of patients enrolled were men (81%) with a median age of 62 years, of which 57% were from Asia (except Japan). Among them, 49% patients had hepatitis B and 30% had hepatitis C. 88% of patients had extrahepatic spread or macrovascular invasion. The highest Child-Pugh score is B7. Patients were given atezolizumab 1200 mg and bevacizumab 15 mg / kg every 3 weeks. The primary endpoints were treatment safety and objective response rate. Secondary endpoints include response duration and progression-free survival. Data for some key secondary endpoints will be presented at upcoming meetings.
In the study group, the objective response rate was 36%, with 12% of patients achieving a complete response. Response durations ranged from 1.6 months to 31 months. More than half of the patients (54%) had a response lasting longer than 9 months, 76% were still on-going and had not reached the median response time.
The median progression-free survival produced by the combination of Atezolizumab and bevacizumab was consistent across the three analyses: 66% of patients were 7.3 months; 72% were 7.4 months. Median overall survival was 17.1 months, 6-month overall survival was 82%, and 12-month overall survival was 63%. In these subgroups, clinical activity was observed regardless of the PD-L1 status.
The most common adverse events were proteinuria (37%), decreased appetite (35%), and fatigue (28%). 39% of patients had grade 3/4 treatment-related adverse events, and 3% of patients had grade 5. The most common grade 3/4 side effect is hypertension (14%). Treatment-related serious adverse events occurred in 24% of patients, including fever (5%), cholangitis (3%), and upper gastrointestinal bleeding (3%). The most common adverse event of concern associated with atezolizumab was rash (23%), and with bevacizumab was proteinuria (37%). Fourteen patients required systemic hormone therapy within 30 days of an adverse event on atezolizumab. Elevated AST and ALT levels (3% for each) were the most common liver events and required steroids therapy within 30 days.
This combination of atezolizumab and bevacizumab may become a promising treatment option for patients with unresectable hepatocellular carcinoma. A phase III study (IMbrave150, NCT03434379) is further evaluating the effectiveness of this combination.
参考文献 Reference Lee KH et al. 13th Ann Conf of Internat Liver Cancer Asso 2019; Abstr 0-32凝血蛋白和血小板可以促进免疫逃逸和癌症进展 (1/26/2020)
Thrombin can promote platelet in cancer progression and evading immunotherapy
凝血酶（血液中的一种凝结蛋白）可以使血小板释放转化生长因子-β1（TGF-β1），该因子可促进乳腺癌，前列腺癌，结直肠癌和其他癌症的疾病进展，并抑制肿免疫系统对癌症的反应。 另外，TGF-β1是导致癌症患者免疫治疗（例如PD1抑制剂）失败的主要原因。
这项研究利用癌症患者的血液样本，细胞系和动物模型，研究了成熟TGF- β1释放的潜在机制以及阻止这种释放作为癌症免疫疗法的方法。他们发现:
- 凝血酶裂解在血小板表面发现称为GARP（glycoprotein A repetitions predominant）主要是糖蛋白A重复）的分子;
- GARP裂解导致血小板释放成熟的TGF-β1；
- 只有通过GARP裂解才能激活血小板TGF- β1；
- 使用抑制剂dabigatran etexilate阻断凝血酶的作用能极大地改变肿瘤的微环境，并增加了肿瘤浸润性T细胞，自然杀伤细胞和中性粒细胞的数量和活性。
结果研究显示，阻断GARP裂解可能是克服癌症对免疫疗法的抵抗力的有效治疗策略。
Thrombin (a coagulation protein in the blood) allows platelets to release transforming growth factor-β1 (TGF-β1), which promotes the progression of breast cancer, prostate cancer, colorectal cancer, and other cancers, and suppresses immune System response to cancer. In addition, TGF-β1 is the main cause of failure of immunotherapy (such as PD1 inhibitors) in cancer patients.
This study used blood samples from cancer patients, cell lines, and animal models to study the underlying mechanisms of mature TGF-β1 release and the significance of preventing this release as a way of cancer immunotherapy. They found:
• Thrombin cleavages a molecule called GARP (glycoprotein A repetitions predominant) on the surface of platelets;
• GARP cleavage results in release of mature TGF-β1 from platelets;
• This cleavage is required to activate platelet TGF-β1;
• Blocking thrombin using the inhibitor dabigatran etexilate greatly change the microenvironment of the tumor, and increased the number and activity of tumor infiltrating T cells, natural killer cells and neutrophils.
This study has shown that blocking GARP cleavage may be an effective treatment strategy to overcome cancer’s resistance to immunotherapy.
参考文献 Reference Metelli A et al Sci Transl Med 2020; 12: eaay4860
治疗晚期胆管癌药物infigratinib获得FDA快速治疗指定 (1/25/2020)
Infigratinib received fast track and orphan drug designation for first line treatment of advanced cholangiocarcinoma
Infigratinib已获得FDA快速治疗（Fast track designation）和孤儿药指认（orphan drug designation）作为第一线治疗晚期或转移性胆管癌。
PROOF试验是infigratinib第一线治疗胆管癌的3期试验, 目前正在招募中。 患有胆管癌的病人中约有15％至20％存在FGFR2（fibroblast growth factor receptor.）基因融合或易位。 该试验将招募约384名患有FGFR2融合或易位的胆管癌患者。患者将按2：1的比例随机分配至Infigratinib（每天口服125 mg，连续3周，然后休息1周）或标准的护理化疗方案, 包括吉西他滨（第1天和第8天静脉滴注1000 毫克/平方米, 21天为一个周期）和顺铂（第1天和第8天静脉注射25 毫克/平方米 , 21天为一个周期）。主要终点指标是无进展生存期。在该试验中，如果分配接受标准护理的患者对化疗无响应，将被允许跨过接受infigratinib治疗。
Infigratinib has received FDA Fast track designation and orphan drug designation as first-line treatment for advanced or metastatic cholangiocarcinoma.
The PROOF trial is a phase 3 trial of infigratinib as a first-line treatment of cholangiocarcinoma and is currently recruiting patients. FGFR2 (fibroblast growth factor receptor) gene fusion or translocation is present in about 15% to 20% of patients with cholangiocarcinoma. The trial will enroll approximately 384 patients with cholangiocarcinoma that harbors FGFR2 fusion or translocation. Patients will be randomly assigned to either infigratinib (125 mg orally daily for 3 weeks and then rest for 1 week), or standard care chemotherapy regimen, including gemcitabine (intravenous infusion of 1000 mg/m2 on days 1 and 8, on a 21-day cycle) and cisplatin (25 mg / m2 intravenously on days 1 and 8 on a 21-day cycle). The primary endpoint is progression-free survival. In this trial, patients who are assigned to receive standard care and are not responding to chemotherapy will be allowed to crossover and receive infigratinib treatment.
新的纳米颗粒疗法在治疗三阴性乳腺癌方面比 Protein Bound Paclitaxel（Abraxane）更有效 (1/19/2020)
New nanoparticle drug more effective than standard therapy for triple-negative breast cancer
一种新的纳米颗粒药物制剂DART，靶向癌细胞上的特定受体，比目前治疗转移性三阴性乳腺癌的标准纳米颗粒疗法Abraxane更有效。新的纳米颗粒绕过健康细胞和组织，并与肿瘤细胞结合，在整个肿瘤中均匀分散，同时释放出化疗药物紫杉醇。
Abraxane是一种含有紫杉醇的纳米制剂，但它不能选择性地将紫杉醇仅递送至体内的癌细胞。一种新的纳米颗粒平台表面，附着一种称为ITEM 4的单克隆抗体，因为它能和Fn14特异性结合，而许多三阴性乳腺癌都表达高水平的Fn14, 从而为进入癌细胞提供了关键。另外, 纳米颗粒的表面也涂有聚乙二醇，以使它们在血液和淋巴系统中循环直至到达肿瘤，被防止其迅速冲出体外。
许多药物递送载体除了靶向患病细胞外，还表现出与健康细胞和组织的非特异性结合，这通常会导致意外的副作用或毒性。 这个DART纳米颗粒平台具有独特的功能，可以改善向体内难于治疗的部位的治疗效果，而不会增加对患者的副作用。
在一组患有三阴性乳腺癌的小鼠实验中，将紫杉醇填充了优化的DART纳米颗粒制剂，并和Abraxane相比较。结果研示，与Abraxane治疗（45天）相比，DART制剂可显著提高中位总生存期（68天）。在比较植入脑部乳腺肿瘤（类似于转移性脑瘤）的动物的治疗方法时，使用DART纳米颗粒也有明显好处。
A new nanoparticle drug formulation, DART, targets specific receptors on cancer cells and appears more effective than Abraxane, which is the current standard nanoparticle therapy for metastatic triple-negative breast cancer. The new nanoparticles bypass healthy cells and tissues and bind to tumor cells. They spread evenly throughout the tumor, while releasing the chemotherapy drug paclitaxel.
Abraxane is a nano-formulation containing paclitaxel, but it cannot selectively deliver paclitaxel only to cancer cells in the body. A new nanoparticle platform has on its surface a monoclonal antibody, ITEM 4, which specifically binds to Fn14, as many triple-negative breast cancer cells express high levels of Fn14. Thus, the binding provides access to cancer cells. In addition, the surface of the nanoparticles is also coated with polyethylene glycol, so that they circulate in the blood and lymphatic system until they reach the tumor, preventing them from being eliminated out of the body.
In addition to targeting diseased cells, many drug delivery vehicles also exhibit non-specific binding to healthy cells and tissues, which often leads to unwanted side effects or toxicity. The DART nanoparticle platform has a unique feature that can improve the therapeutic effect on difficult-to-treat parts of the body without increasing side effects on patients.
In a mouse model of triple-negative breast cancer, paclitaxel was filled with an optimized DART nanoparticle formulation and its effect was compared with Abraxane. The results showed that DART preparation could significantly improve the median overall survival (68 days) compared with Abraxane (45 days). There is also clear benefit to deliver DART nanoparticles in animal models where the brain was implanted with breast tumors (similar to metastatic brain tumors).
参考文献 Reference Dancy JG et al. Sci Advance 2020; 6: eaax39312020年数据报告显示最大单年度癌症死亡率下降 (1/18/2020)
2020 statistic report shows largest one year drop in cancer mortality
根据美国癌症协会的年度统计报告，1991年至2017年，美国癌症死亡率下降了29％，其中2016年至2017年下降了2.2％，是有记录以来的最大单年度下降。肺癌死亡人数的下降推动了记录的下降。
在过去的26年中，死亡率的下降趋势一直稳定。在2008年至2017年期间，整体癌症死亡率平均每年下降1.5％。这意味着自1991年（死亡率最高）以来避免了290万例死亡。预计到2020年，美国总共将有1,806,590例新癌症病例和606,520例死亡，即每天约4,950例新病例和1600例死亡。
总体癌症死亡人数连续26年下降是由于四种最常见的癌症类型（肺癌，结直肠癌，乳腺癌和前列腺癌）的死亡率长期下降所致。由于吸烟减少以及早期发现和治疗的进步，减少肺癌死亡的进展有所改善。但是，减少结直肠癌，乳腺癌和前列腺癌的进展已经放缓。这4种癌症也占癌症死亡人数最多。在所有癌症死亡中，几乎四分之一是肺癌，大于乳腺癌，前列腺癌和结肠直肠癌的总和。
- 从1990年至2017年，男性肺癌死亡率下降了51％，从2002年至2017年女性下降了26％。从2013年到2017年，男性新发肺癌病例每年下降5％，女性每年下降4％。这些差异反映了烟草使用的历史模式，在这种模式下，女性比男性晚很多年才开始吸烟，而且戒烟速度较慢。但是，吸烟模式似乎不能解释女性与1960年代左右出生的男性相比有更高的肺癌发生率。
- 从1989年到2017年，女性的乳腺癌死亡率下降了40％。
- 从1993年到2017年，男性前列腺癌的死亡率下降了52％。
- 从1980年至2017年，男性大肠癌死亡率下降了53％，而从1969年至2017年女性下降了57％。
治疗进展的结果: 黑色素瘤皮肤癌的癌症死亡率下降幅度最大，部分原因是2011年FDA批准了免疫疗法药物ipilimumab和vemurafenib。2013-2017年间，黑色素瘤的总体死亡率每年下降7％ 。
The death rate from cancer in the US declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop ever recorded, according to annual statistics reporting from the American Cancer Society. The decline in deaths from lung cancer drove the record drop.
The decline in the death rate over the past 26 years has been steady. Overall cancer death rates dropped by an average of 1.5% per year between 2008 and 2017. This translates to more than 2.9 million deaths avoided since 1991, when rates were at their highest. A total of 1,806,590 new cancer cases and 606,520 deaths are expected in the US in 2020, which is about 4,950 new cases and more than 1,600 deaths each day.
The 26-year decline in overall cancer deaths is due to long-term drops in death rates in the 4 most common cancer types: lung, colorectal, breast, and prostate. Progress in reducing lung cancer deaths has improved due to declines in smoking and advances in early detection and treatment. However, progress in reducing colorectal, breast, and prostate cancers has slowed.
These 4 cancers also account for the greatest numbers of cancer deaths. Almost one-quarter of all cancer deaths are due to lung cancer, more than breast, prostate, and colorectal cancers combined.
- Lung cancer death rates declined by 51% from 1990 to 2017 among men and 26% from 2002 to 2017 among women. From 2013 to 2017, the rates of new lung cancer cases dropped by 5% per year in men and 4% per year in women. The differences reflect historical patterns in tobacco use, where women began smoking in large numbers many years later than men and were slower to quit. However, smoking patterns do not appear to explain the higher lung cancer rates being reported in women compared with men born around the 1960s.
- Breast cancer death rates declined 40% from 1989 to 2017 among women.
- Prostate cancer death rates declined 52% from 1993 to 2017 among men.
- Colorectal cancer death rates declined 53% from 1980 to 2017 among men and by 57% from 1969 to 2017 among women.
Advances in treatment: The steepest declines in cancer deaths occurred for melanoma skin cancer, due in part to the immunotherapy drugs ipilimumab and vemurafenib, which the FDA approved in 2011. The overall melanoma death rate dropped by 7% per year during 2013-2017 in people ages 20 to 64.
参考文献 Reference Siegel RL et al. CA: A Cancer J for Clinicians 2020; https://doi.org/10.3322/caac.21590
白介素-1β可以关闭胰腺癌细胞的抗癌免疫反应 (1/12/20)
Interleukin-1β can turn off the anti-cancer immune response towards pancreatic cancer
由胰腺肿瘤细胞产生和释放的免疫信号蛋白白介素-1β（IL-1β）可以降低抗癌免疫反应，从而促进胰腺导管腺癌的生长。
尽管检查点抑制剂对多种癌症有效，但在胰腺癌中却不成功，其局限性归因于CD8 + T细胞浸润和免疫抑制均差。在这项研究中，若在抗PD-1抗体治疗中添加抗IL-1β抗体, 结果使T细胞向胰腺导管腺癌的浸润加倍，并使PD-1阻断剂的抗肿瘤活性提高40％, 导致肿瘤生长降低32％。。
通过对缺少IL-1β基因的胰腺导管腺癌模型的小鼠进行试验，首次发现胰腺癌细胞产生IL-1β，这对于胰腺导管腺癌的持续生长至关重要。 实验发现细菌产物可激活癌细胞表面上称为“ toll样受体” 的蛋白质，该蛋白质可引发癌细胞产生IL-1β所需的链式反应。该研究小组还发现，较高的IL-1β产生量会导致附近的胰腺星状细胞增加致密的结构蛋白（如胶原蛋白）的产生。在胰腺肿瘤附近发生的这种纤维组织的过度生长，与治疗抵抗力有关。 实验还发现活跃的星状细胞触发一种信号蛋白的产生，这些信号蛋白将巨噬细胞吸引到肿瘤中，并使其编程成为抑制免疫反应的类型（M2）。较高的IL-1β和M2巨噬细胞水平以及成纤维细胞的异型增生，会降低杀死癌细胞的CD8 +T细胞进入肿瘤的能力。
这项工作提供了有力的证据，证明阻断IL-1β的作用可使T细胞更好地穿透肿瘤并杀死癌细胞，这种机制具有克服胰腺癌治疗中免疫疗法的局限性。
An immune signaling protein interleukin-1β (IL-1β) produced and released by pancreatic tumor cells was found to reduce anti-cancer immune response, thereby promote the growth of pancreatic ductal adenocarcinoma.
Though effective against many cancers, checkpoint inhibitors have failed in pancreatic cancer, and the limitations attributed to poor CD8+ T cell infiltration and immune suppression. In the current study, adding anti-IL-1β antibodies to anti-PD-1 antibody treatment doubled the infiltration of such T cells into pancretica tumors and increased the anti-tumor activity of PD-1 blockade by 40 percent and a 32% reduction in tumor growth.
By engineering mice with versions of pancreatic ductal cancer (PDA) that lack the IL-1β gene, it was found for the first time that pancreatic cancer cells produce IL-1β, and that it is essential for the continued growth of PDA tumors.
Bacterial products were found to activate proteins on the cancer cell surfaces called toll-like receptors, which set off chain reactions that were required for IL-1β production in cancer cells. It was also found that higher IL-1β production caused nearby pancreatic stellate cells to increase production of dense, structural proteins such as collagen. Desmoplasia is the overgrowth of such fibrous tissue that often occurs near pancreatic tumors, and which has been linked to treatment resistance. Active stellate cells were also found to trigger production of the signaling proteins that attract immune cells called macrophages into tumors and programs them to become the type (M2) that suppresses immune reactions. Experiments also confirmed that higher IL-1β and M2 macrophage levels, along with fibroblast-driven desmoplasia, reduced the ability of CD8+ T cells, that kill cancer cells, from entering tumors.
This work provides strong evidence that blocking the action of IL-1β allows T cells to better penetrate tumors and kill cancer cells, a mechanism that may overcome the limitations of immunotherapy in the treatment of pancreatic cancer.
参考文献 Reference Das S et al. ancer Res 2019 DOI: 10.1158/0008-5472.CAN-19-2080
尼武单抗（Nivolumab）和贝伐（bevacizumab）联合治疗对复发性卵巢癌安全有效 (1/11/2020)
Combination of Nivolumab and bevacizumab is safe and effective for relapsed ovarian cancer
这项研究包括38名女性（平均年龄63岁），患有铂类耐药（n = 18）或铂类敏感（n = 20）复发的上皮性卵巢癌。所有妇女在最近一次以铂类为基础的治疗后的12个月内都经历了疾病复发，并且接受了多达三线的先前治疗。
这些妇女每两周一次接受240毫克尼武单抗和10毫克/公斤贝伐单抗。客观响应率是研究的主要终点。通过对铂敏感性，无进展生存期，安全性以及肿瘤PD-L1与治疗响应之间的关联分析进行客观响应率作为次要终点。
结果显示有11个已确认的响应，客观响应率为28.9％（95％CI，15.4-45.9）。客观响应率在对铂敏感的女性中（40%; 95％CI，19.1-64）比对铂耐药的女性（16.7％; 95％CI，3.6-41.4）更高。中位缓解时间为6个月，中位无进展生存期为8.1个月（95％CI，6.3-14）。对铂类耐药的女性的中位反应持续时间长于患有铂类敏感疾病的女性（12.3个月对5.6个月），但中位无进展生存期较短（5.3个月对9.4个月）。
有34名妇女（占89.5％）经历了一项或多项与治疗相关的不良事件，其中9名发生了3级或更高的不良事件。常见的不良事件包括疲劳（n = 18），头痛（n = 11），肌痛（n = 11），血清淀粉酶水平升高（n = 11），天冬氨酸转氨酶水平升高（n = 10）和高血压（n = 10 ）。
对36个组织学样本进行的PD-L1测试显示22名女性的PD-L1肿瘤百分比低于1，而14名女性的百分比为1或更高。 研究人员观察到PD-L1肿瘤<1% 的女性中有10个响应，百分率为1或更高的女性中有2个响应。
样本量小且缺乏随机性是该研究的主要限制。
The study included 38 women (mean age 63 years) who had relapsed epithelial ovarian cancer with platinum resistance (n = 18) or platinum sensitivity (n = 20). All women experienced relapses within 12 months of the most recent platinum-based treatment and received up to three lines of previous treatment.
These women received 240 mg nivolumab and 10 mg / kg bevacizumab every two weeks. Objective response rate (ORR) was the primary endpoint of the study. ORR by platinum sensitivity, PFS, safety, and analysis of the association between tumor PD-L1 with response to therapy served as secondary endpoints.
The results showed 11 confirmed responses with an ORR of 28.9% (95% CI, 15.4-45.9). The ORR was higher in women sensitive to platinum (40%; 95% CI, 19.1-64) than in women resistant to platinum (16.7%; 95% CI, 3.6-41.4). The median response time was 6 months, and the median progression-free survival was 8.1 months (95% CI, 6.3-14). The median duration of response to platinum-resistant women was longer than that of women with platinum-sensitive diseases (12.3 months vs. 5.6 months), but the median progression-free survival was shorter (5.3 months vs. 9.4 month).
A total of 34 women (89.5%) experienced one or more treatment-related adverse events, and 9 of them had grade 3 or higher adverse events. Common adverse events include fatigue (n = 18), headache (n = 11), myalgia (n = 11), elevated serum amylase levels (n = 11), and elevated aspartate aminotransferase levels (n = 10) and hypertension (n = 10).
PD-L1 tests on 36 histological samples showed that the percentage of PD-L1 tumors in 22 women was less than 1, while the percentage of 14 women was 1 or higher. Researchers observed 10 responses in women with tumor PD-L1 <1%, and 2 responses in women with a percentage of 1 or higher.
The small sample size and lack of randomization were the main limitations of the study.
参考文献 Reference Liu JF et al. JAMA Oncol 2019; doi:10.1001/jamaoncol.2019.3343
关键的研究评估了第四线治疗晚期胃肠道间质瘤（GIST）的TKI (1/5/2020)
Pivotal study of a TKI for fourth line therapy for GIST
Ripretinib是一种酪氨酸激酶抑制剂（TKI），可广泛抑制KIT和PDGFRα突变的激酶, 与安慰剂相比, 在第四线或更晚的环境中改善了无进展生存期。
这是一个III期临床试验（INVICTUS）, 有129位局部晚期GIST病人参加, 患者接受过至少伊马替尼，舒尼替尼和雷戈非尼的治疗，病人以2：1方式随机分配为接受ripretinib或安慰剂。与安慰剂相比，ripretinib显著降低了疾病进展或死亡的风险达85％。Ripretinib组的中位无进展生存期为6.3个月，安慰剂组为1.0个月（危险比= 0.15，95％置信区间= 0.09 –0.25，P <.0001）。6个月的无进展生存率分别为51％和3％，1年总生存率达到了65％。在所有评估的患者亚组中，无进展生存期的获益是一致的。
Ripretinib耐受性良好, 但大约一半的患者可见脱发，约五分之一的患者出现手足综合症。与治疗相关的3或4级不良事件发生在ripretinib组的患者中为49％，而安慰剂组为44％。
对于接受标准疗法治疗后进展的晚期GIST患者，ripretinib可能代表了一种新的护理标准。
Ripretinib is a tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRα-mutated kinases. It was reported to improve progression-free survival in the fourth-line or later setting compared with placebo.
This is a Phase III clinical trial (INVICTUS), which involved 129 patients with locally advanced GIST, who had received at least imatinib, sunitinib, and regorafenib. Patients were randomzed to receive ripretinib or placebo (2:1). Compared to placebo, ripretinib significantly reduced the risk of disease progression or death by 85%. The median progression-free survival was 6.3 months in the ripretinib group and 1.0 months in the placebo group (hazard ratio = 0.15, 95% confidence interval = 0.09 -0.25, P <.0001). The 6-month progression-free survival rates were 51% and 3%, respectively, and the 1-year overall survival rate reached 65%. The benefits of progression-free survival were consistent across all subgroups of patients evaluated.
Ripretinib is well tolerated, but hair loss is seen in about half of patients, and hand-foot syndrome occurs in about one in five patients. Treatment-related grade 3 or 4 adverse events occurred in 49% of patients in the ripretinib group and 44% in the placebo group.
For patients with advanced GIST who have progressed after receiving standard therapies, ripretinib may represent a new standard of care.
参考文献 Referencevon Mehren M et al. ESMO Congress 2019; Abstr LBA87
抗CD73抗体在晚期癌症治疗中的希望 (1/4/2020)
Anti-CD73 antibody in advanced stage solid tumors
CPI-006是一种具有免疫调节作用的抗CD73抗体, 将近一半能够进行评估的患者肿瘤消退。
CPI-006除了增加抗原CD86和HLA-DR在细胞上的表达外，还诱导激活淋巴细胞的免疫调节活性，并影响T细胞和B细胞的运输。
这是一个I/Ib期剂量递增/剂量扩展临床试验, 有24例接受CPI-006单药治疗的患者和16例接受CPI-006加上ciforadenant（一种腺苷A2A受体小分子免疫检查点抑制剂）参加。患者曾接受中位数为四种的晚期癌症治疗后经历了疾病进展，其中包括结直肠癌（n = 12），肾细胞癌（n = 6），胰腺癌（n = 6），前列腺癌（n = 6），头部癌颈部鳞状细胞癌（n = 5），非小细胞肺癌（n = 3），膀胱癌（n = 1）和肉瘤（n = 1）。患者接受每21天以从1 -24毫克/公斤的六个剂量水平之一进行CPI-006单药治疗。联合治疗组通过静脉注射接受1 -18 毫克/公斤的CPI-006，外加固定剂量每日两次的100 毫克ciforadenant。
没有发生剂量限制性毒性。三名患者发现生了1级输注反应。其他1级或2级不良事件包括恶心和疲劳。一名患者经历了3级贫血，一名患者患有3-4级腹泻
一些患者在接受CPI-006单药治疗或与ciforadenant组合使用时肿瘤消退。在接受6 毫克/公斤或更高剂量CPI-006后能够进行评估的9例患者中，有4例发生了肿瘤消退，其中1例（1/2）为转移性去势抵抗性（castration-resistant）前列腺癌, （肿瘤减少了18.2％），2例（2/5）为肾细胞癌（减少分别为7％和21.3%）, 1例为非小细胞肺癌（1/2）（减少了5.8％）。
CPI-006 is an anti-CD73 antibody with immunomodulatory effects. Nearly half of evaluable patients experienced tumor regression.
In addition to increasing the expression of the CD86 and HLA-DR antigens on cells, CPI-006 also induces immunoregulatory activity of activated lymphocytes and affects the transport of T and B cells.
This is a Phase I /Ib dose escalation/dose extension clinical trial with 24 patients receiving CPI-006 monotherapy and 16 patients receiving CPI-006 plus ciforadenant (a small molecule immune checkpoint inhibitor of adenosine A2A receptor). Patients experienced disease progression following a median of four lines of prior therapy. They had advanced cancers, including colorectal cancer (n = 12), renal cell carcinoma (n = 6), pancreatic cancer (n = 6), prostate cancer ( n = 6), head cancer, neck squamous cell carcinoma (n = 5), non-small cell lung cancer (n = 3), bladder cancer (n = 1), and sarcoma (n = 1). Patients received CPI-006 monotherapy every 21 days at one of six dose levels from 1-24 mg / kg. The combination treatment group received 1-18 mg / kg of CPI-006 by intravenous injection, plus a fixed dose of 100 mg ciforadenant twice daily.
No dose-limiting toxicity occurred. Three patients were found to have a grade 1 infusion response. Other grade 1 or 2 adverse events include nausea and fatigue. One patient experienced grade 3 anemia and one patient had grade 3-4 diarrhea
Some patients had tumor regression when receiving CPI-006 monotherapy or in combination with ciforadenant. Of the 9 evaluable patients after receiving CPI-006 at 6 mg / kg or higher, 4 had tumor regression, of which 1 (1/2) was cast-resistant prostate cancer (tumor reduction by 18.2%), 2 cases (2/5) were renal cell carcinoma (7% and 21.3% reduction), and 1 case was non-small cell lung cancer (1/2) (reduction of 5.8%).
参考文献 Reference
https://www.healio.com/hematology-oncology/gastrointestinal-cancer/news/online/%7B4d2d76bf-104b-4780-a831-91ebae610347%7D/anti-cd73-antibody-agent-appears-safe-shows-promise-in-advanced-cancers