2019

Leronlimab用于转移性乳腺癌 (12/29/2019)

Leronlimab promising for metastatic breast cancer

Leronlimab（PRO 140）是一种CCR5拮抗剂，初步数据表明其对转移性乳腺癌的结果令人鼓舞。

这是一个1b/2期临床试验, 来自第一名转移性三阴性乳腺癌癌症患者的数据显示，在用leronlimab治疗11周后，外周血中没有可检测到的循环肿瘤细胞，并且表达CCR5的相关癌细胞进一步降低。第二名患者是4期HER2阳性乳腺癌患者, 转移到肝，肺和脑。该患者接受赫赛汀和帕妥珠单抗超过1.5年。该患者于11月25日接受了第一次leronlimab注射，每周一次700毫克。3星期后扫描结果表明，肿瘤缩小，脑水肿减轻，并且一些转移性肿瘤明显消失。

Leronlimab在临床试验中未报告严重不良反应。

研究表明CCR5在肿瘤的侵袭和转移中起着重要的作用。 它的表达增加是几种癌症疾病状态的指标。 阻断CCR5可以减少侵袭性乳腺癌和前列腺癌动物模型中的肿瘤转移。 Leronlimab在鼠异种移植模型中将人类乳腺癌的转移减少了98％以上。 因此，该公司正在转移性三阴性乳腺癌中进行2期人类临床试验，并于2019年5月获得FDA快速通道称号。

Leronlimab (PRO 140) is a CCR5 antagonist, and preliminary data suggested encouraging results in metastatic breast cancer.

This is a phase 1b / 2 clinical trial. Data from the first patient with metastatic triple-negative breast cancer showed that after 11 weeks of treatment with leronlimab, there were no detectable circulating tumor cells in the peripheral blood, and CCR5 expressing cancer cells were further reduced. The second patient was a stage 4 HER2-positive breast cancer patient with metastases to the liver, lung and brain. This patient had received trastuzumab and pertuzumab for more than 1.5 years. The patient received the first leronlimab injection on November 25, 700 mg once a week. Scan results after three weeks showed that the tumors shrank, brain edema was reduced, and some metastatic tumors disappeared significantly.
Leronlimab has not reported serious adverse reactions in clinical trials.

CCR5 plays an important role in tumor invasion and metastasis. Its increased expression is an indicator of the disease state of several cancers. Blocking CCR5 can reduce tumor metastasis of invasive breast and prostate cancer in animal models. Leronlimab reduced metastasis in human breast cancer by more than 98% in a mouse xenograft model. As a result, the company is conducting a phase 2 human clinical trial in metastatic triple-negative breast cancer and was awarded fast track designation by FDA in May 2019.

参考文献 Reference

https://www.precisiononcologynews.com/drug-discovery-development/cytodyn-sees-promising-early-responses-two-breast-cancer-patients Dec. 24 2019

 

FDA批准trastuzumab deruxtecan用于HER2阳性乳腺癌 (12/28/2019)

FDA approved trastuzumab deruxtecan in HER2-positive breast cancer

FDA批准了trastuzumab deruxtecan用于曾接受过两种或两种以上抗HER2治疗的患者。

在DESTINY-Breast01（NCT03248492）多中心单臂临床试验中，有184位病人参加, 她们患有HER2阳性，不可切除和/或转移性乳腺癌，这些患者曾接受过两种或多种先前抗HER2治疗。患者每3周静脉输注trastuzumab deruxtecan 5.4 毫克/公斤，直至出现不可接受的毒性或疾病进展。

主要疗效结果的量度是客观响应率。 客观响应率为60.3％（95％CI：52.9、67.4），完全响应率为4.3％，部分响应率为56％。中位响应持续时间为14.8个月（95％CI：13.8、16.9）。

最常见的不良反应（≥20％）为恶心，疲劳，呕吐，脱发，便秘，食欲下降，贫血，中性粒细胞减少，腹泻，白细胞减少，咳嗽和血小板减少症。 “盒装警告” 包括间质性肺病。 2.6％的患者发生了间质性肺病导致的致命结局。

FDA has approved trastuzumab deruxtecan for patients who have received two or more lines of anti-HER2 treatments.

In the DESTINY-Breast01 (NCT03248492) multi-center single-arm clinical trial, 184 patients participated. They had HER2-positive, unresectable, and / or metastatic breast cancer. These patients had received two or more prior anti- HER2 treatment. Patients were intravenously infused with trastuzumab deruxtecan 5.4 mg / kg every 3 weeks until unacceptable toxicity or disease progression.

The primary end point of the trial is objective response rate. The objective response rate was 60.3% (95% CI: 52.9-67.4), Complete response rate was 4.3%, and partial response rate was 56%. The median response duration was 14.8 months (95% CI: 13.8-16.9).

The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, hair loss, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough, and thrombocytopenia. “Boxed warnings” include interstitial lung disease. Fatal outcomes from interstitial lung disease occurred in 2.6% of patients.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer

 

Niraparib 用于新诊断的卵巢癌 (12/23/2019)

Niraparib in newly diagnosed advanced ovarian cancer

Niraparib是一种多聚腺苷二磷酸[ADP]-核糖）聚合酶（PARP）的抑制剂，用于对铂类化疗响应之后, 可增加复发性卵巢癌患者的无进展生存期，无论她们是否存在BRCA突变。

在这项随机的双盲，3期临床试验中，733例新诊断的晚期卵巢癌患者, 在铂类化疗响应后, 以2:1的比例随机分配为接受Niraparib或安慰剂。主要终点是具有同源重组缺陷肿瘤（HRD）的患者和总体人群的无进展生存期。

患者中，有373例（50.9％）的肿瘤有同源重组缺陷。在这些患者中，Niraparib组的中位无进展生存期显著长于安慰剂组（21.9个月相对于10.4个月；疾病进展或死亡的危险比为0.43； 95％置信区间，0.31至0.59； P <0.001）。在总体人群中，不论是否存在同源重组缺陷, 相应的无进展生存期分别为13.8个月和8.2个月（危险比，0.62； 95％CI，0.50至0.76； P <0.001）。在24个月的中期分析中，Niraparib组的总生存率为 84％，安慰剂组为77％（危险比，0.70； 95％CI，0.44至1.11）。 3级或4级的最常见不良事件是贫血（占31.0％的患者），血小板减少症（占28.7％）和中性粒细胞减少症（占12.8％）。没有发生与治疗有关的死亡。

从以提到的三项PARP抑制剂试验中，一线铂类化疗后无BRCA或HRD的卵巢癌患者是否应接受PARP抑制剂作为维持治疗应与医生讨论，似乎有人倾向于用于所有的病人。

Niraparib is an inhibitor of poly(adenylation diphosphate [ADP] -ribose polymerase (PARP). It led to an increase in progression-free survival in patients with recurrent ovarian cancer who platinum-based chemotherapy, regardless whether they carry BRCA mutations or not.

In this randomized, double-blind, phase 3 clinical trial, 733 newly diagnosed patients with advanced ovarian cancer were randomly assigned to receive Niraparib or placebo at a 2: 1 ratio after a response to platinum chemotherapy. The primary endpoint was progression-free survival in patients with homologous recombination-deficient (HRD) and the general population.

Among those patients, 373 (50.9%) tumors had HRD. Among these patients, the median progression-free survival in the Niraparib group was significantly longer than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death was 0.43; 95% CI, 0.31 to 0.59; P < 0.001). In the general population, regardless of the presence of homologous recombination defects, the corresponding progression-free survival was 13.8 months vs. 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P <0.001). In the 24-month interim analysis, overall survival was 84% ​​in the Niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or 4 were anemia (31.0% of patients), thrombocytopenia (28.7%), and neutropenia (12.8%). No treatment-related deaths occurred.

From the three PARP inhibitor trials presented over the last 3 days, whether ovarian cancer patients without BRCA or HRD after first-line platinum-based chemotherapy should receive PARP inhibitor as maintenance therapy should be discussed with their treating physicians. It appears that some people feel like to use it for all patients.

参考文献 Reference

González-Martín A et al. NEJM 2019; 381: 2891-2402

 

奥拉帕尼加上贝伐单抗维持治疗改善晚期卵巢癌无进展生存期 (12/22/2019)

Addition of olaparib to maintenance bevacizumab increased PFS in advanced ovarian cancer

对晚期卵巢癌病人, 一线铂类化疗和贝伐单抗治疗后, 在贝伐单抗维持治疗中添加聚（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕尼（olaparib）可显著改善无进展生存期。

这是一个III期随机临床试验（PAOLA-1 / ENGOT-ov25）,有806位病人参加, 她们患有III期或IV期高级浆液性或子宫内膜样卵巢癌，输卵管或原发性腹膜癌;在接受标准铂类化疗联合贝伐单抗后均处于临床完全或部分缓解状态。她们被随机分配为2：1）用奥拉帕尼（n = 537）加贝伐单抗; 或2）安慰剂（n = 269）加贝伐单抗（n = 269）维持。 口服奥拉帕尼300 毫克长达24个月，贝伐单抗15 毫克/公斤持续15个月。意向性治疗人群中的无进展生存期是研究的主要终点。

奥拉帕尼组的中位随访时间为24个月，安慰剂组的中位随访时间为22.7个月。
结果显示，与安慰剂组相比，奥拉帕尼组的中位无进展生存期明显延长（22.1个月相对于16.6个月； HR = 0.59； 95％CI，0.49-0.72）。在携带BRCA突变的肿瘤患者中，奥拉帕尼组的中位无进展生存期为37.2个月，相对于21.7个月（HR = 0.31； 95％CI，0.2-0.47）。在没有BRCA突变的女性中，奥拉帕尼组的中位无进展生存期为18.9个月，相对于安慰剂组为16个月（HR = 0.71； 95％CI，0.58-0.88）。

有同源重组缺陷阳性（HRD）疾病的女性，奥拉帕尼的中位无进展生存期为37.2个月，而安慰剂为17.7个月（HR = 0.33; 95％CI，0.25-0.45）。无BRCA突变且HRD阳性的女性，奥拉帕尼组的中位无进展生存期为28.1个月，安慰剂组为16.6个月。具有HRD阴性或未知状态的女性，奥拉帕尼的中位无进展生存期为16.9个月，安慰剂为16个月。

奥拉帕尼组中57％的女性和安慰剂组中51％的患者发生3级或更高级别的不良事件。 奥拉帕尼组中有54％的病人由于不良事件而中断了剂量，而安慰剂组中为24％。

For patients with advanced ovarian cancer, the addition of poly (ADP-ribose) polymerase (PARP) inhibitor olaparib to bevacizumab maintenance therapy after first-line platinum chemotherapy and bevacizumab treatment significantly improved progression-free survival.

This is a phase III randomized clinical trial (PAOLA-1/ENGOT-ov25), with 806 patients, who had stage III or IV advanced serous or endometrioid ovarian cancer, fallopian tube or primary peritoneal cancer. After receiving standard platinum chemotherapy combined with bevacizumab, they were in clinical complete or partial remission. They were randomly assigned 2: 1 in two groups: 1) maintenance with olaparib (n = 537) plus bevacizumab; or 2) placebo (n = 269) plus bevacizumab (n = 269). The dose for Olaparib was 300 mg orally for up to 24 months and for bevacizumab was 15 mg / kg for 15 months. PFS in the intent-to-treat population was the primary endpoint of the study.

The median follow-up time for the olaparib group was 24 months, and that for the placebo group was 22.7 months. The results showed that the median PFS was significantly longer in the olaparib group compared to the placebo group (22.1 months versus 16.6 months; HR = 0.59; 95% CI, 0.49-0.72). Among patients with tumors carrying BRCA mutations, the median PFS of the olaparib group was 37.2 months, compared to 21.7 months (HR = 0.31; 95% CI, 0.2-0.47). In women without BRCA mutations, the median progression-free survival of the olaparib group was 18.9 months, compared to 16 months in the placebo group (HR = 0.71; 95% CI, 0.58-0.88).

Women with homologous recombination deficiency-positive (HRD) disease had a median PFS of 37.2 months for olaparib and 17.7 months for placebo (HR = 0.33; 95% CI, 0.25-0.45). Women without BRCA mutations but HRD-positive had a median PFS of 28.1 months in the olaparib group and 16.6 months in the placebo group. Women with HRD-negative or unknown status had a median PFS of 16.9 months for olaparib and 16 months for placebo.

Grade 3 or higher adverse events occurred in 57% in the olaparib group and 51% in the placebo group. 54% in the olaparib group discontinued treatment due to adverse events, compared with 24% in the placebo group.

参考文献 Reference

Ray-Coquard IL, et al. Eur Soc for Med Oncol Congress 2019; Spain, Abstract LBA2_PR

 

Veliparib加化疗并维持veliparib单药治疗延长卵巢癌的无进展生存期 (12/21/2019)

Incorporation of Veliparib extends PFS in high-grade serous ovarian cancer

这是一个III期随机临床试验（VELIA/GOG-3005）,有1,140位高度浆液性卵巢癌病人参加,  她们无中枢神经系统转移。大约四分之一（26％）具有BRCA突变，一半以上（55％）具有同源重组缺陷（homologous recombination deficiency）。患者按1:1:1的比例随机分配到以下三种治疗方案之一：化疗加安慰剂，然后进行安慰剂维持治疗（对照组,  375人）；化疗加veliparib, 然后进行安慰剂维持治疗（383人）；或化疗加veliparib，然后维持veliparib（382人）。每个方案包括36个周期。6周期化疗（每3周为1周期）包括每3周1次卡铂（AUC=6），和每周紫杉醇（80毫克/平方米）, 或每3周的剂量为175 毫克/平方米。Veliparib的剂量为每天两次，每次150毫克, 在30个周期的维持阶段，每天两次，每次400 毫克。主要研究终点是接受整个36周期veliparib组和对照组之间的无进展生存期差异。次要终点包括接受整个36周期veliparib组与对照组之间的总生存期差异, 和仅接受化疗期间veliparib组与对照组之间无进展生存期差异。

数据显示，接受整个veliparib组的女性中位无进展生存期均明显高于对照组。
在具有BRCA突变的女性中, 无进展生存期为34.7个月相比于22个月（风险比率 = 0.44; 95％置信区间，0.28-0.68），具有同源重组缺陷的女性中位值为31.9个月相比于20.5个月（风险比率 = 0.57; 95%置信区间,0.43-0.76）。  在意向性治疗人群中的所有患者无进展生存期为23.5个月相比于17.3个月（风险比率 = 0.68； 95％置信区间，0.56-0.83）。 在veliparib联合化疗但未接受维持治疗者，虽然反应率增加。但与对照组相比，该组的无进展生存期没有改善 。

在接受卡铂/紫杉醇治疗的3级或4级不良事件的发生率中，接受velipiparib治疗的女性中血小板减少发生率更高（27％比8％）; 其余副作用相似。

This is a phase III randomized clinical trial (VELIA/GOG-3005) involving 1,140 women with high-degree serous ovarian cancer who did not have central nervous metastases. About a quarter (26%) have BRCA mutations, and more than half (55%) have homologous recombination deficiency (HRD). Patients were randomly assigned to one of three treatment regimens in a 1: 1: 1 ratio: chemotherapy plus placebo and then placebo maintenance (control group, n = 375); chemotherapy plus veliparib, and then placebo maintenance (n = 383); or chemotherapy plus veliparib and then maintaining veliparib (n = 382). Each program consists of 36 cycles. 6 cycles of chemotherapy (1 cycle every 3 weeks) include carboplatin (AUC = 6) every 3 weeks, plus paclitaxel (80 mg / m2) per week, or 175 mg / m2 every 3 weeks. The dose of Veliparib is 150 mg twice daily during chemotherapy, and 400 mg twice daily during the 30-cycle maintenance phase. The primary endpoint was the difference in progression-free survival between the two groups receiving veliparib and the control group. Secondary endpoints included differences in overall survival between the two groups receiving veliparib and the control group.

The data showed that the median progression-free survival of the two groups receiving veliparib was significantly higher than that of the control group.
Among women with BRCA mutations, progression-free survival was 34.7 months compared to 22 months (HR = 0.44; 95% CI, 0.28-0.68), and the median value for women with HRD was 31.9 months compared to 20.5 months (HR = 0.57; 95% CI , 0.43-0.76).  In all patients in the intent-to-treat population PFS was 23.5 months compared to 17.3 months (HR = 0.68; 95% CI, 0.56-0.83) . Those who received chemotherapy in veliparib but did not receive maintenance treatment, although the response rate increased. However, there was no improvement in progression-free survival in this group compared to the control group.

Among patients who received carboplatin / paclitaxel with grade 3 or 4 adverse events, the rate of thrombocytopenia was higher in women receiving veliparib (27% vs. 8%); the remaining side effects were similar.

参考文献 Reference

Coleman RL, et al.  Eur Soc for Med Onc Congress 2019; Spain, Abstract LBA3

 

每周剂量密集化疗无益于上皮性卵巢癌的一线治疗 (12/15/2019)

First-line weekly dose-dense chemotherapy not beneficial to epithelial ovarian cancer

与标准的每周3周的化学疗法相比,  每周剂量密集的化疗，在（主要为）欧洲人群 中，没有显着改善上皮性卵巢癌的无进展生存期。
日本JGOG3016试验显示，每周剂量密集的紫杉醇/卡铂相比于每3周一次, 可显著改善无进展生存期和总体生存率，每周治疗导致中位无进展生存期延长11个月，中位总生存期延长38个月。在ICON8试验中，研究小组旨在比较主要在欧洲患有上皮性卵巢癌的人群中，每周一次剂量密集方案与标准3周化疗的疗效和安全性。

ICON8是III期试验, 1,566名IC-IV期上皮性卵巢癌妇女被随机分为3组: 第1组，每3周用卡铂AUC5或AUC6, 和175 毫克/平方米紫杉醇治疗；第2组，每3周用卡铂AUC5或AUC6治疗，每周用80 毫克/平方米紫杉醇治疗，或第3组, 每周接受卡铂AUC2和80毫克/平方米紫杉醇治疗。患者在初次手术后立即接受治疗, 或在术前辅助化疗之前接受治疗并推延迟初次手术。 研究的主要结果是无进展生存期和总生存期。比较是在对照组（第1组）和第2组和第3组之间进行。

两种方案均未观察到每周剂量密集化疗显著增加无进展生存期。平均生存时间受限 [第1组为24.4个月（97.5％CI 23.0-26.0），第2组为24.9个月（24.0-25.9），第3组为25.3个月（23.9-26.9）]。第1组的中位无进展生存期为17.7个月（IQR 10.6 –未达到），第2组的为20.8个月（11.9–59.0），第3组的为21.0个月（12.0-54.0）。

研究者认为, ICON8和JGOG3016之间结局不一致的结果可能是种族药物基因组学差异; 每周剂量密集的紫杉醇治疗仍可被视为日本上皮性卵巢癌女性的一线治疗选择。但是，不建议将每周剂量密集的紫杉醇/卡铂作为非日本族裔女性一线上皮性卵巢癌治疗。

Compared to standard 3 weekly chemotherapy, weekly dose-intensive chemotherapy has not significantly improved the progression-free survival of epithelial ovarian cancer in the (mostly) European population.

The Japanese JGOG3016 trial showed that weekly dose-dense paclitaxel / carboplatin significantly improved progression-free survival and overall survival compared to once every 3 weeks. Weekly treatment resulted in a prolonged median progression-free survival of 11 months. The median overall survival was extended by 38 months. In the ICON8 trial, the research team aimed to compare the efficacy and safety of a once-weekly dose-intensive regimen with standard 3-week chemotherapy in people with epithelial ovarian cancer patients, mainly in Europe.

ICON8 is a phase III trial. 1,566 women with stage IC-IV epithelial ovarian cancer were randomly divided into 3 groups: group 1, treated with carboplatin AUC5 or AUC6 every 3 weeks, and 175 mg / m2 paclitaxel; group 2, treated with carboplatin AUC5 or AUC6 every 3 weeks, with 80 mg / m2 paclitaxel per week, or group 3, treated with carboplatin AUC2 and 80 mg / m2 paclitaxel per week. Patients were treated immediately after the initial surgery, or before the neo-adjuvant chemotherapy and the initial surgery was delayed. The primary goals of the study were progression-free survival and overall survival. The comparison was made between the control group (group 1) and groups 2 and 3.

Neither dose-dense weekly regimen resulted in a significant increase in progression-free survival. Mean survival time was limited [24.4 months (97.5% CI 23.0-26.0) in group 1, 24.9 months (24.0-25.9) in group 2, and 25.3 months (23.9-26.9) in group 3]. The median progression-free survival of group 1 was 17.7 months (IQR 10.6 – not reached), group 2 was 20.8 months (11.9–59.0), and group 3 was 21.0 months (12.0-54.0).

Researchers believe that the outcome of the inconsistent outcome between ICON8 and JGOG3016 may be a racial pharmacogenomic difference; weekly dose-dense paclitaxel treatment can still be considered a first-line treatment option for Japanese women with epithelial ovarian cancer. However, weekly dose-dense paclitaxel / carboplatin is not recommended as a first-line epithelial ovarian cancer treatment for non-Japanese women.

参考文献

Clamp AR, et al. Lancet; Published online 29 November 2019.DOI: https://doi.org/10.1016/S0140-6736(19)32259-7

 

Imprime PGG和pembrolizumab用于难治性三阴性乳腺癌患者 (12/14/2019)

Combination of Imprime PGG and pembrolizumab in chemo-refractory triple-negative breast cancer

一种称为Imprime PGG的药物，与抗PD-1抗体pembrolizumab结合使用, 有益于化疗难治性转移性三阴性乳腺癌。Imprime PGG是通过全身递送的dectin受体激动剂，可触发抗癌免疫反应。

这是一个II期临床试验（IMPRIME 1）, 截至2019年11月11日的数据显示，在所有使用Imprime PGG和pembrolizumab联合治疗的44名转移性三阴性乳腺癌患者中，总缓解率为15.9％，其中一位证实为完全缓解（2.3％）, 并在另外六名患者中确认了部分缓解（13.6％）。另外17名（38.6%）患者具有稳定的疾病。疾病控制率为25％。根据Kaplan-Meier估计，目前的平均总生存时间为16.4个月，中位随访时间为19.1个月。 12个月的总生存率为57.6％。

基线时，患者基本上没有活化的T细胞。外周血分析显示，在治疗三周之初就发现激活了的CD8 T细胞。在治疗六周后，肿瘤活检显示活化的髓样和T细胞深入浸润到肿瘤组织中。这些免疫效应变化与总生存率明显相关。

A drug called Imprime PGG, in combination with the anti-PD-1 antibody pembrolizumab, was beneficial for chemotherapy-refractory metastatic triple negative breast cancer. Imprime PGG is a systemically delivered dectin receptor agonist that triggers an anti-cancer immune response.

This is a Phase II clinical trial (IMPRIME 1). Data as of November 11, 2019 show a total response rate of 15.9% among all 44 patients with metastatic triple negative breast cancer treated with Imprime PGG and pembrolizumab.  One of them confirmed a complete response (2.3%), and partial response was confirmed in another six patients (13.6%). Another 17 (38.6%) patients had stable disease. The disease control rate is 25%. According to Kaplan-Meier estimates, the current average overall survival time is 16.4 months, and the median follow-up time is 19.1 months. The overall survival rate at 12 months was 57.6%.

At baseline, patients were essentially devoid of activated T cells. Peripheral blood analysis showed that activated CD8 T cells were found at the beginning of three weeks of treatment. After six weeks of treatment, a tumor biopsy revealed infiltration of activated myeloid and T cells into the tumor tissue. These changes in immune pharmacodynamic changes correlated with a greater overall survival.

参考文献

https://www.globenewswire.com/news-release/2019/12/11/1959602/0/en/Biothera-Pharmaceuticals-Presents-Updated-Phase-2-Data-for-Chemo-refractory-Triple-Negative-Breast-Cancer-Patients-at-San-Antonio-Breast-Cancer-Symposium.html

San Antonio Breast Cancer Symp 2019, Dec. abstr PD1-02

 

腺病毒基因疗法用于膀胱癌 (12/8/2019)

Gene therapy for bladder cancer

Nadofaragene firadenovec是一种基于腺病毒的基因疗法，这基因编码产生免疫刺激蛋白干扰素α-2b。含有该基因的病毒载体每三个月通过导管送入膀胱，然后被吸收到器官壁的细胞中并开始刺激干扰素。 这样, 限制了病毒载体和干扰素的全身暴露和干扰素的副作用。

该临床试验招募了157例膀胱癌患者，这些患者尚未扩散到肌肉壁，但卡介苗疫苗的治疗已经不再有效。在103例膀胱壁浅表肿瘤患者中，一半以上的患者在三个月时完全缓解，六个月时为41％，一年后为24％。 在一组48例癌症已扩散到膀胱外结缔组织的患者中，有73％的患者在三个月时没有复发，而在12个月时降至44％。

但在这种类型的膀胱癌中，没有安慰剂对照的单臂试验,  仅完全缓解不足以被FDA批准, 还需要3期试验。 Pembrolizumab是治疗浅表性膀胱癌的另一种有前景的药物。在Keynote-057试验中，该免疫肿瘤药在相似的人群中的完全缓解率为39％。但它必须每三周静脉注射, 以及有潜在的全身性副作用。目前尚不清楚上述两种药物中的哪一种将最终胜出。

Nadofaragene firadenovec is an adenovirus-based gene therapy that encodes the interferon α-2b, which encodes the immunostimulatory protein. A viral vector containing the gene is delivered into the bladder through a catheter every three months, and is then absorbed into cells in the bladder wall and begins to stimulate interferon. In this way, the systemic exposure of viral vectors and interferons are limited, and the side effects of interferons are avoided.

The clinical trial enrolled 157 bladder cancer patients whose cancer has not spread to the muscle wall. However, these patient no longer responded the BCG treatment. Of the 103 patients with superficial bladder cancer, more than half of them had a complete remission at three months, 41% at six months, and 24% after one year. In a group of 48 patients with cancer that had spread to the connective tissue outside the bladder, 73% had no recurrence at three months, and that percentage fell to 44% at 12 months.

However, in the clinical trial of this type of bladder cancer where there is no placebo-controlled arm, complete remission alone is not enough to be approved by the FDA. A phase 3 trial is needed. Pembrolizumab is another promising drug for superficial bladder cancer. In the Keynote-057 trial with a similar population of patients, the complete response rate was 39%. But it must be given intravenously every three weeks, and there are potential systemic side effects. It is yet to be seen which of the above two drugs will be the winner at the end of the day.

参考文献

 National Cancer Institute. Cancer Stat Facts: Bladder Cancer. Available at: https://cts.businesswire.com/ct/CT?id=smartlink&url=https%3A%2F%2Fseer.cancer.gov%2Fstatfacts%2Fhtml%2Furinb.html&esheet=52132164&newsitemid=20191125005439&lan=en-US&anchor=https%3A%2F%2Fseer.cancer.gov%2Fstatfacts%2Fhtml%2Furinb.html&index=7&md5=669e7404d653256915b3ce94fff599db’, ‘https://seer.cancer.gov/statfacts/html/urinb.html’);”>https://seer.cancer.gov/statfacts/html/urinb.html. Last accessed: December 2019

 

Abemaciclib有益于HER2阳性乳腺癌患者 (12/7/2019)

Abemaciclib benefits HER2-positive breast cancer
细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂Abemaciclib，曲妥珠单抗和氟维司群联合治疗, 对雌激素受体阳性， HER2阳性乳腺癌患者有益处。这是关于CDK4/6抑制剂和内分泌疗法与HER2导向治疗激素受体阳性/HER2阳性晚期乳腺癌的第一个II期研究。

MonarcHER临床试验招募了237名激素受体阳性，HER2阳性的晚期乳腺癌女性，她们先前曾接受过至少两种HER2定向治疗（必须包括trastuzumab Emtansine, 或T-DM1）和紫杉烷类药物，但不能包括CDK4/6抑制剂和氟维司群。患者被随机分配为1：1：1至A组：每天两次的150毫克abemaciclib,  加每21天的曲妥珠单抗，和每28天氟维司群； B组: abemaciclib加曲妥珠单抗; C组: 曲妥珠单抗加研究者选择的化疗。主要终点是无进展生存期（A组相对于 C组，然后B组相对于C组）。

A组的无进展中位生存期为8.3个月，而C组为5.7个月（危险比 = 0.673； P = 0.05）。B组的中位无进展生存期为5.6个月，于C组的相似（危险比= 0.943; P = 0.77）。 Abemaciclib，曲妥珠单抗和氟维司群联合治疗可将疾病进展或死亡的风险降低33％。 Abemaciclib三联治疗组还改善了意向性治疗人群的反应率，从对照组的13.9％增至32.9％。在临床前模型中，显示出用abemaciclib抑制这些途径可增强HER2定向药物的活性，并使耐药肿瘤对HER2阻断重新敏感。

治疗相关的3级副作用为56％（Abemaciclib三联治疗组）相对于33％（C组）。 3​​级或以上的血小板减少症更为常见（10.3％相对于2.8％），腹泻也很常见（9.0％相对于2.8％）。但这并没有导致更多的治疗中断（7.7％相对于8.3％）。

Cyclin-dependent kinase 4 and 6 (CDK4 / 6) inhibitor Abemaciclib, plus trastuzumab, and fulvestrant is are beneficial for patients with ER-positive and HER2-positive breast cancer. This is the first phase II study of CDK4 / 6 inhibitors in combination with endocrine therapy and HER2-oriented therapy for hormone receptor-positive / HER2-positive advanced breast cancer.

The MonarcHER clinical trial recruited 237 women with ER-positive and HER2-positive advanced breast cancer who had previously received at least two HER2-oriented therapies (must include trastuzumab Emtansine, or T-DM1) and taxanes, but had never received CDK4 / 6 inhibitors or fulvestrant. Patients were randomly assigned to 1:1:1 to either group A: 150 mg abemaciclib twice daily, plus trastuzumab every 21 days, and fulvestrant every 28 days; or group B: abemaciclib plus trastuzumab; or group C: trastuzumab plus chemotherapy as per investigators’ choice. The primary endpoint was progression-free survival (group A vs. C, then group B vs. C).

The median PFS was 8.3 months in group A and 5.7 months in group C (HR = 0.673; P = 0.05). The median PFS of group B was 5.6 months, which was similar to that of group C (HR = 0.943; P = 0.77). Abemaciclib, trastuzumab, and fulvestrant combination treatment reduced the risk of disease progression or death by 33%. The Abemaciclib triple treatment also improved the response rate of the intention-to-treat population, from 13.9% in the control group to 32.9%. In preclinical studies, it has been shown that inhibition of these pathways with abemaciclib enhances the activity of HER2-targeted drugs and re-sensitizes resistant tumors to HER2 blockade.

Treatment-related grade 3 side effects were 56% (Abemaciclib triple therapy group) versus 33% (group C). Grade 3 or higher adverse effects were more common (10.3% vs. 2.8%), and so was diarrhea (9.0% vs. 2.8%). However, this did not result in more treatment interruptions (7.7% versus 8.3%).

参考文献

Tolaney SM et al. ESMO Congress 2019. Abstract LBA23

术前化疗免疫疗法可诱导肺癌亚群中较高的病理响应率 (12/1/2019)

Neoadjuvant chemoimmunotherapy induced high rates of pathological response in subset of lung cancer patients

在可切除的IIIA期非小细胞肺癌患者中，使用术前nivolumab和化疗诱导了从未见过的完全病理响应。

这是一个II期单臂临床试验，包括了IIIA期非小细胞肺癌的46位成年人（中位年龄为63岁； 74％为男性； ECOG功能状态为0的占54％）。所有参与者均为现吸烟者或以前吸烟者，61％患有腺癌，83.5％患有合并疾病，89.3％患有N2疾病。 患者接受术前nivolumab，每三周一次，剂量为360 mg ，并加上每3周一次化疗紫杉醇（200 毫克/平方米）和卡铂（AUC为6），术后接受nivolumab治疗1年。 在完成术前治疗后和手术前所有患者的肿瘤都予以评估。在第三个术前治疗的第21天后的第三或第四周，患者接受了手术。

研究的主要终点为24个月时的无进展生存期。以客观的病理反应标准来评估疗效。中位随访时间为17.1个月。没有患者因疾病进展或治疗毒性而在手术前退出研究。 41例患者接受了手术切除，其中37例接受了术后辅助治疗。

在接受切除的41例患者中，有34例（83％; 95％置信区间 = 68-93）达到了重大病理响应，包括24例（59％; 95％置信区间 = 42-74）完全病理响应，7例（17％; 95％ 置信区间 = 7-32）残留的存活肿瘤组织少于10％。

在意向性治疗人群中，研究人员观察到12个月时的无进展生存期为96％（95％置信区间 = 84-99），而18个月时为81％（95％置信区间 =61-91）。意向治疗人群的总生存率在12个月时为98％（95％置信区间 = 85-100），在18个月时为91％（95％置信区间 = 73-97） 。术前化疗后少于10％的残留肿瘤组织与存活率之间有很强的联系。残存存活肿瘤介于1％至10％之间的患者表现出的死亡风险比率为1，残存肿瘤介于71％至100％之间的患者的风险比率增加至4.78（95％置信区间 = 2.06-11.11）。

非小细胞肺癌在诊断时，只有25％到30％的病例可以进行根治性手术。这项II期研究提供了很大希望。但将来有必要进行随机研究，主要包括III期患者，以解决纵隔响应的问题。

In patients with resectable stage IIIA non-small cell lung cancer, the use of preoperative nivolumab and chemotherapy induced an unprecedented rate of pathological complete response.

This is a phase II single-arm clinical trial involving 46 adults with stage IIIA non-small cell lung cancer (median age 63 years; 74% men; 54% with ECOG performance status 0). All participants were current or former smokers, 61% had adenocarcinoma, 83.5% had comorbidities, and 89.3% had N2 disease. The patient received preoperative nivolumab at a dose of 360 mg every three weeks, plus chemotherapy every three weeks with paclitaxel (200 mg / m 2) and carboplatin (AUC of 6), and received adjuvant  nivolumab for 1 year. Tumors were evaluated in all patients after completion of preoperative treatment and before surgery. The patient underwent surgery three or four weeks after the 21st day of the third preoperative treatment.

The primary endpoint of the study was progression-free survival at 24 months. Efficacy was evaluated by objective pathological response. The median follow-up time was 17.1 months. No patients withdrew from the study before surgery due to disease progression or treatment toxicity. Forty-one patients underwent surgical resection and 37 of them underwent adjuvant treatment.

Of the 41 patients who underwent resection, 34 (83%; 95% CI = 68-93) achieved a major pathological response, including 24 (59%; 95% CI = 42-74) complete pathological response. In 7 cases (17%; 95% CI = 7-32), less than 10% of the surviving tumor tissue remained.

In the intent-to-treat population, researchers observed 96% (95% CI = 84-99) progression-free survival at 12 months and 81% (95% CI = 61-91) at 18 months. The overall survival rate of the intent-to-treat population was 98% (95% CI = 85-100) at 12 months and 91% (95% CI =73-97) at 18 months. There is a strong correlation between less than 10% residual tumor tissue and survival after preoperative chemotherapy. Patients with residual tumors between 1% and 10% showed a risk of death of 1. Patients with residual tumors between 71% and 100% had increased HR to 4.78 (95% CI = 2.06- 11.11).

At the time of diagnosis, about 25-30% of NSCLC patients can undergo radical surgery. This phase II study offers great hope. However, it is necessary to conduct randomized studies in the future, mainly including stage III patients, to address the issue of mediastinal response.

参考文献

Provencio M et al. Intl Asso for the Study of Lung Cancer World Conference on Lung Cancer 2019 Sept 18.

 

放射治疗引起的严重口腔粘膜炎的最新有效治疗 (11/30/2019)

Most recent effective therapy for radiation-induced oral mucositis

新发现药物GC4419可中断放射治疗引起的严重口腔粘膜炎。
这是一个2b期随机，双盲，安慰剂对照的临床试验,  研究超氧化物歧化酶模拟物GC4419在口腔鳞状细胞癌患者中的疗效和安全性。有227例接受强度放射治疗加顺铂的患者参加, 在每次放疗前均接受过GC4419（30毫克和90毫克）或安慰剂的治疗，GC4419在每次放射治疗前以一小时静脉输注的形式提供，在完成输注后的一小时内提供了放射。在放疗期间每两周评估一次粘膜炎，在治疗后长达八周每周评估一次。主要终点为严重口腔粘膜炎的持续时间。

在接受90毫克GC4419的患者队列中，与安慰剂相比，可使严重口腔粘膜炎发生率降低34％，严重程度降低47％，严重的口腔粘膜炎的持续时间从19天减少到1.5天。 接受30毫克剂量的患者,  患有严重的口腔粘膜炎持续8天。除了可能产生轻度低血压外，未观察到明显的毒性反应。 目前正在进行的为期两年的随访结果分析正在进行中，对较早的Ib/IIa期试验的一年肿瘤控制结果的分析表明，GC4419不会损害抗肿瘤功效。

目前, 在美国和加拿大进行的III期ROMAN验证性试验继续招收病人入组。

The newly discovered drug GC4419 can interrupt severe oral mucositis caused by radiation therapy.

This is a phase 2b randomized, double-blind, placebo-controlled clinical trial to investigate the efficacy and safety of GC4419, that mimics the activity of human superoxide dismutase enzymes, in patients with oral squamous cell carcinoma. There were 223 patients who received intensive radiation therapy plus cisplatin, who had received GC4419 (30 mg or 90 mg) or placebo before each radiation treatment. GC4419 was given as an intravenous infusion for one hour before each radiation treatment. The radiation is provided within one hour after completing the infusion. Mucositis is evaluated every two weeks during radiation therapy and weekly for up to eight weeks after treatment. The primary endpoint was the duration of severe oral mucositis.

In the cohort of patients receiving 90 mg GC4419, the incidence of severe oral mucositis was reduced by 34% and the severity was reduced by 47% compared to placebo. The duration of severe oral mucositis was reduced from 19 days to 1.5 days. Patients receiving 30 mg dose had severe oral mucositis for 8 days. Except for the possibility of mild hypotension, no significant toxic effects were observed. Analysis of the two-year follow-up results is ongoing, and analysis of one-year tumor control results from earlier phase Ib / IIa trials showed that GC4419 does not impair anti-tumor efficacy.

Currently, phase III ROMAN confirmatory trial in the United States and Canada continues to enroll patients.

参考文献

Anderson CM et al. J Clin Onc 2019; doi:10.1200/JCO.19.01507.

 

阿妥珠单抗（atezolizumab)与贝伐单抗（bevacizumab）的组合可改善肝癌患者的总体生存率 (11/24/2019)

Atezolizumab and bevacizumab combination can improved overall survival in hepatocellular carcinoma

第一项III期临床试验研究显示，阿妥珠单抗与贝伐单抗组合与标准的索拉非尼（sorafenib）相比，无法切除肝细胞癌患者的总生存期和无进展生存期均有改善。

IMbrave150是一项全球性，多中心，开放标签的III期研究，研究对象是501名无法切除的肝细胞癌且未接受过先前全身治疗的患者, 按照2：1的比例随机接受阿妥珠单抗与贝伐单抗组合或索拉非尼。在每个21天周期的第1天静脉注射 阿妥珠单抗 1200 毫克，与15 毫克/公斤的贝伐单抗。在每个21天周期的第1-21天，口服索拉非尼400毫克，每天两次。人们接受了联合用药或对照组治疗，直到研究者确定不可接受的毒性或失去临床益处为止。主要终点是根据实体肿瘤版本1.1（RECIST v1.1）的反应评估标准通过独立审核工具进行的总生存率期和无进展生存期。

 

阿妥珠单抗与贝伐单抗联合使用, 与索拉非尼相比可将死亡风险降低42％（危险比 = 0.58； 95％置信区间：0.42-0.79； p = .0006）; 无进展生存期为6.8个月（阿妥珠单抗与贝伐单抗）相对于4.3个月（风险比率 =0.59; 95% 置信区间 = 0.47-0.76;  p < .0001）。

 

阿妥珠单抗与贝伐单抗的安全性与每种药物的已知安全性一致。接受阿妥珠单抗与贝伐单抗的患者中有57％发生了3-4级不良事件，接受索拉非尼的患者中有55％发生了3-4级不良事件。 5级不良事件分别发生在5％和6％的人群中。

 

结果将在2019年11月23日欧洲医学肿瘤学会（ESMO）亚洲大会的总统会议上介绍。

The first phase III clinical trial that compared the combination of  atezolizumab and bevacizumab with standard sorafenib showed overall survival and progression-free survival benefit in patients with unresectable hepatocellular carcinoma.

IMbrave 150 is a global, multi-center, open-label, phase III study of 501 unresectable hepatocellular carcinoma patients who have not received prior systemic therapy and randomized at a 2:1 ratio to combination of  atezolizumab and bevacizumab or sorafenib. On the first day of each 21-day cycle, intravenous atezolizumab of 1200 mg, and 15 mg/kg of bevacizumab. Sorafenib (400 mg) was administered orally twice daily on days 1-21 of each 21-day cycle. Treatment with a combination or control group continued until the investigator determined unacceptable toxicity or loss of clinical benefit. The primary end point was overall survival and progression-free survival by independent review tools based on the response evaluation criteria for solid tumor version 1.1 (RECIST v1.1).

In the combination group the risk of death was reduced by 42% compared with sorafenib (HR = 0.58; 95% CI: 0.42-0.79; p = .0006). PFS was 6.8 months (atezolizumab and bevacizumab) relative to 4.3 months (HR = 0.59; 95% CI = 0.47-0.76; p < .0001).

The safety of atezolizumab and bevacizumab is consistent with the known safety of each drug. Of those patients who received atezolizumab and bevacizumab, 57% had grade 3-4 adverse events, and 55% of patients who received sorafenib had grade 3-4 adverse events. Grade 5 adverse events occurred in 5% and 6% in each group.

The results will be presented at the Presidential Meeting of the European Medical Oncology Society (ESMO) Asia Conference on November 23, 2019.

参考文献

To be presented at ESMO 2019; Nov. 23, abstr LBA3

 

口服前列腺癌药物relugolix与现有GnRH受体拮抗剂药物相匹配 (11/23/2019)

Oral relugolix is non-inferior compared with current available GnRH antagonists

Relugolix的制药公司宣布在前列腺癌的HERO试验中已达到其主要目标。

这是一个3期临床试验, 有934位患有晚期前列腺癌的男性参加，其中三分之二的患者随机每天口服GnRH受体拮抗剂relugolix,其余三分之一接受了亮丙瑞林（leuprolide）的贮库（depot）注射，亮丙瑞林是接受雄激素剥夺治疗的标准护理。

从试验第5周到第48周，在relugolix组中， 96.7%的患者睾丸激素抑制达到阉割（castration）水平。FDA要求至少90％的患者达到抑制才能获得批准。Relugolix还在五个次要终点优于亮丙瑞林，包括在第4和15天迅速抑制睾丸激素，在第15天彻底抑制睾丸激素，在第15天迅速抑制前列腺特异性抗原（PSA），以及第24周时抑制卵泡刺激性激素（FSH）。

在试验的两组中，不良反应和由于药物停药的发生率相似。

该制药公司将“响应者”定义为从第5周到第48周，实现并维持睾丸激素抑制率小于或等于50 ng / dL （毫微克/分升）。一些医生希望看到FDA判断雄激素剥夺疗时, 能将睾丸激素水平降低到20 ng/dL以下，因为它可能具有更好的预后。该公司将在2020年第二季度提交FDA批准申请的数据。

Relugolix’s pharmaceutical company announced that it has achieved its primary goal in the HERO trial of prostate cancer.

This is a phase 3 clinical trial involving 934 men with advanced prostate cancer. Two-thirds of the patients were randomized to once daily oral relugolix, an GnRH receptor antagonist, and the remaining one third received leuprolide depot injection. Leuprolide is the standard care for androgen deprivation therapy.

From the 5th week to the 48th week of the treatment in the relugolix group, 96.7% of patients achieved testosterone inhibition at the castration level. The FDA requires at least 90% of patients achieving inhibition in order to be approved.

Relugolix also outperformed leuprolide in five secondary endpoints, including rapid inhibition of testosterone on days 4 and 15, complete inhibition of testosterone on day 15, rapid inhibition of prostate specific antigen (PSA) on day 15, and inhibition of follicle stimulating hormone (FSH) at week 24.

In the two groups tested, the incidence of adverse reactions and drug withdrawal were similar.

The pharmaceutical company defined “responders” as achieving and maintaining testosterone inhibition rates of less than or equal to 50 ng / dL from week 5 to week 48. Some doctors hope to see the FDA can reduce testosterone levels below 20 ng/dL as it may have a better prognosis. The company will submit data for FDA approval in the second quarter of 2020.

参考文献

https://www.biospace.com/article/myovant-s-relugolix-hits-primary-endpoint-in-prostate-cancer-trial

 

CASPIAN临床试验中期分析：Durvalumab改善广泛期小细胞肺癌的生存率 (11/17/19)

Midterm analysis of CASPLAN trial showed improved analysis in extensive stage small cell lung cancer

CASPIAN试验是一项随机，开放标签，全球性的III期试验，805名患广泛期小细胞肺癌患者，参加第一线治疗，中位年龄为62-63岁，10％的病人有脑转移。该试验比较免疫疗法（durvalumab，抗PD-L1抗体）联合化疗（依托泊苷和顺铂或卡铂）相对于单纯化疗。在实验组中，患者接受了四个周期化疗和免疫治疗，然后接受每四星期一次的维持性durvalumab。相比之下，对照组最多可以进行六个周期（56.8％）的化疗和预防性颅脑照射。

过去的数据显示，在中位随访14.2个月后，durvalumab联合化疗的总生存期为13.0个月相对于化疗的10.3个月（风险比为0.73，p = .0047）。

在2019年的ESMO大会的中期分析报告中，两组总的疾病进展情况相似，但疾病进展的绝对人数在免疫化疗组要比单纯化疗组要少，如新的肿瘤病灶为41.4%（免疫化疗组）相对于47.2%（化疗组），脑转移灶的数目在两组都相同（11.6 ％相对于11.5％），但只有化疗组的病人才接受预防性颅脑放射，而免疫化疗组的病人并不能。报告者认为该试验已达到了主要终点目标，即生存期。

只有5.1%的病人肿瘤PD-L1表达＞ 1％，22.4％的免疫细胞PD-L1表达＞ 1％，数据显示PD-L1并不能预测对免疫化疗的疗效。

这个试验的第三组，Durvalumab加tremelimumab（抗CTL-4抗体）联合化疗，在预先计划的中期分析之后，仍然继续双盲，要等待最后的分析。

Interim analysis of CASPIAN clinical trial: Durvalumab improves survival in extensive-stage small cell lung cancer

The CASPIAN trial was a randomized, open-label, global phase III trial in which 805 patients with extensive-stage small cell lung cancer underwent first-line therapy with a median age of 62-63 years and 10% of patients had brain metastases. This trial compared immunotherapy (durvalumab, an anti-PD-L1 antibody) with chemotherapy (etoposide plus cisplatin or carboplatin) versus chemotherapy alone. In the experimental group, the patient received four cycles of chemotherapy and immunotherapy followed by maintenance durvalumab every four weeks. In contrast, the control group could receive up to six cycles (56.8%) of chemotherapy and prophylactic brain irradiation.

Past data showed that after a median follow-up of 14.2 months, the overall survival of durvalumab combined with chemotherapy was 13.0 months vs. 10.3 months for chemotherapy (hazard ratio 0.73, p = .0047).

In the interim analysis of the ESMO conference in 2019, the overall disease progression was similar in both groups, but the absolute number of patients with disease progression was less in the immunochemotherapy group than in the chemotherapy alone group, with 41.4% of new tumor lesions (immune chemotherapy group vs 47.2% (chemotherapy group). The number of brain metastases was the similar in both groups (11.6% vs. 11.5%). Of note, only patients in the chemotherapy group received prophylactic cranial radiation, while patients in the immunochemotherapy group did not. The researchers believe that the trial has reached its primary endpoint, the overall survival.

Only 5.1% of patients had tumor PD-L1 expression >1%, and 22.4% of immune cells had PD-L1 expression > 1%. The data showed that PD-L1 could not predict the efficacy of immunochemotherapy.

In the third group of this trial, Durvalumab plus tremelimumab (anti-CTL-4 antibody) combined with chemotherapy, continued to remain double-blind after a pre-planned interim analysis. It awaits the final analysis.

参考文献

Paz-Aves L et al. 2019 ESMO Congress, 2019, abstr LBA 62

Paz-Aves L et al. 2019 ESMO Congress, 2019, abstr OA02.02

 

Margetuximab治疗HER2阳性转移性乳腺癌中期生存数据 (11/9/2019)

Survival data on mid-term analysis of Margetuximab in HER2-positive breast cancer

与接受曲妥珠单抗和化疗的患者相比, margetuximab和化疗延长了生存期。

SOPHIA研究（NCT02492711）是一项随机，开放标签的III期临床试验，评估了HER2阳性转移性乳腺癌患者接受margetuximab加化疗与曲妥珠单抗加化疗相比的情况, 患者必须在转移性环境中至少接受过两线抗HER2定向治疗。所有研究的患者先前都接受过曲妥珠单抗和帕妥珠单抗，约90％的患者先前接受了T-DM1。该研究招募了536名患者，这些患者按1：1的比例随机分配，接受每三周静脉注射15 毫克/公斤的margetuximab（n = 266）或以6 毫克/公斤（或8 毫克/公斤）静脉注射曲妥珠单抗（n = 270）每三周一次，与标准剂量的四种化疗药物（卡培他滨，eribulin，吉西他滨或长春瑞滨）组合使用。根据转移部位（≤2或> 2），转移性疾病先前治疗的行数（≤2或> 2）和化学疗法的选择对患者进行分层。

与接受曲妥珠单抗和化疗的患者相比，接受margetuximab和化疗的患者的中位总生存期延长了1.8个月（21.6相对于19.8个月；危险比 = 0.885； 95％CI：0.693-1.130； p ＝ .326）。预先确定的目的是评估CD16A等位基因变异对margetuximab活性的影响。在大约85％的带有CD16A 158F等位基因的患者中，与曲妥珠单抗组相比，margetuximab组的中位总生存期延长了4.3个月（23.7相对于19.4个月； HR = 0.793； 95％CI：0.607-1.035； p = .087）。在大约16％的CD16A 158V等位基因纯合患者中， margetuximab组比曲妥珠单抗组更好。计划在385个事件发生后进行最终的预先指定的总生存期分析，预计将在2020年发生。

Margetuximab联合化疗的总体安全性总体上与曲妥珠单抗联合化疗的总体安全性相当。Margetuximab组的145（55％）患者发生了3级或更高级别的不良事件，而曲妥珠单抗组的140名（53％）患者发生了3级或更严重的不良事件。Margetuximab组发生严重不良事件的人数为45（17％），而曲妥珠单抗组则为50（19％）。与曲妥珠单抗相比，margetuximab组发生与输注相关的反应更为常见（13％比3％），大多为1级或2级且与首剂相关。

SOPHIA试验的第二次中期生存结果在12月在的圣安东尼奥乳腺癌研讨会（SABCS）上进行口头报告。

Margetuximab and chemotherapy prolonged survival compared with patients receiving trastuzumab and chemotherapy.

The SOPHIA study (NCT02492711) is a randomized, open-label, phase III clinical trial evaluating patients with HER2-positive metastatic breast cancer who received margetuximab plus chemotherapy versus trastuzumab plus chemotherapy. Patients must receive,  in the metastatic setting, at least two lines of anti-HER2 directed therapy previously. All patients in the study had previously received trastuzumab and pertuzumab, and approximately 90% of patients had previously received T-DM1. The study enrolled 536 patients who were randomized in a 1:1 ratio and received intravenous 15 mg/kg margetuximab (n = 266) or 6 mg/kg (or 8 mg/kg) intravenous trastuzumab (n = 270)  every three weeks, in combination with standard dose of one of the four chemotherapeutic drugs (capecitabine, eribulin, gemcitabine or vinorelbine). Patients were stratified according to the number of lines (≤ 2 or > 2) of the previous treatment , or the sites of the metastatic disease (≤ 2 or > 2) and the choice of chemotherapy.

The median overall survival of patients receiving margetuximab and chemotherapy was extended by 1.8 months compared with patients receiving trastuzumab and chemotherapy (21.6 vs. 19.8 months; hazard ratio = 0.885; 95% CI: 0.693-1.130; p = .326). The pre-determined objective was to assess the effect of CD16A allelic variation on margetuximab activity. In approximately 85% of patients with the CD16A 158F allele, the median overall survival of the margetuximab group was extended by 4.3 months compared with the trastuzumab group (23.7 vs. 19.4 months; HR = 0.793; 95% CI: 0.607-1.035; p = .087). In approximately 16% of patients with homozygous CD16A 158V allele, the margetuximab group fared even better than the trastuzumab group. A final pre-specified overall survival analysis is planned for 385 events and is expected to occur in 2020.

The overall safety of Margetuximab in combination with chemotherapy is generally comparable to that of trastuzumab in combination with chemotherapy. Grade 3 or higher adverse events occurred in 145 (55%) patients in the Margetuximab group, and in 140 (53%) patients in the trastuzumab group. The number of serious adverse events was 45 (17%) in the Margetuximab group and 50 (19%) in the trastuzumab group. Compared with trastuzumab, the infusion-related reactions in the margetuximab group were more common (13% vs. 3%), mostly grade 1 or 2 and were associated with the first dose.

The second mid-term survival outcome of the SOPHIA trial will be presented orally at the San Antonio Breast Cancer Symposium (SABCS) in December, 2019.

参考文献 Reference

MacroGenics announcement. Published October 22, 2019. https://bit.ly/32GPSl3

Rugo HS et al J Clin Oncol. 2019;37(15 suppl; abstr 1000)

 

Trilaciclib在转移性三阴性乳腺癌的化疗中的应用 (11/2/2019)

Trilaciclib in combination with chemotherapy in triple negative breast cancer

细胞周期抑制剂trilaciclib加入吉西他滨/卡铂化疗, 不会增加三阴性乳腺癌女性化疗期间严重中性粒细胞减少的持续时间或发生率。在接受trilaciclib的患者中观察到潜在的生存获益。

这是一项II期开放标签试验, 研究包括来自五个国家的33个站点的102位患者。在2017年2月至2018年5月之间，她们被随机分配成3组（1：1：1）: 1) 第1天和第8天接受吉西他滨（1,000毫克/平方米）和卡铂（AUC=2 ）（34人）; 2) 第1天和第8天吉西他滨/卡铂加静脉内trilaciclib（240毫克/平方米）（33人）; 3) 第2天和第9天接受吉西他滨/卡铂, 并在第1, 2, 8和9天接受trilaciclib（35人），一周期为21天。继续治疗直至疾病进展，或不可接受的毒性。主要终点是第1周期间严重中性粒细胞减少的持续时间和治疗期间严重中性粒细胞减少的发生率。总体而言，在转移环境中，有37％的患者先前接受过一到两行化疗。

第1组的中位随访时间分别为8.4个月，12.7个月，12.9个月。在第1周期中，第1组的严重中性粒细胞减少的平均持续时间为0.8天，第2组为1.5天，第3组为1.0天（第3组相对于第1组的P = 0.70）。在治疗过程中，第1组的34名患者中有9名（26％）发生严重的中性粒细胞减少，第2组的33名中有12名（36％），第3组的35名中有8名（23％）（第3组相对于第1组P = .70）。

3组的中位无进展生存期为5.7个月，9.4个月，和7.3个月。中位总生存期为12.6个月，20.1个月（第2组相对于第1组，P = .028）和17.8个月（第3组相对于第1组，P = .0023）。

不良事件: 第一组的最常见不良反应是贫血（73％），中性粒细胞减少症（70％）和血小板减少症（60％）。第2组的中性粒细胞减少症（82％），血小板减少症（55％）和贫血（52％）；第3组中的中性粒细胞减少症（66％），血小板减少症（63％）和恶心（49％）。未观察到与治疗相关的死亡。

研究人员的结论：在转移性三阴性乳腺癌患者中，trilaciclib联合吉西他滨和卡铂的骨髓抑制终点无明显差异；总体生存结果令人鼓舞。

The addition of cell cycle inhibitor trilaciclib to gemcitabine/carboplatin chemotherapy did not increase the duration or incidence of severe neutropenia during chemotherapy in women with triple-negative breast cancer. Potential survival benefits were observed in patients receiving trilaciclib.

This is a Phase II open-label trial that included 102 patients from 33 sites in five countries. Between February 2017 and May 2018, they were randomly assigned to 3 groups (1:1:1): 1) Gemcitabine (1,000 mg/m2) and carboplatin (AUC=2) on Days 1 and 8. (n = 34); 2) Gemcitabine/carboplatin plus intravenous trilaciclib (240 mg/m2) on days 1 and 8 (n = 33); 3) trilaciclib on days 1, 2, 8 and 9 and Gemcitabine/carboplatin on days 2 and 9 (n=35) for a cycle of 21 days. Treatment continued until disease progression, or unacceptable toxicity. The primary endpoint was the duration of severe neutropenia during the first cycle and the incidence of severe neutropenia during treatment. Overall, 37% of patients in the metastatic setting had previously received one or two lines of chemotherapy.

The median follow-up time for the three groups was 8.4 months, 12.7 months, and 12.9 months, respectively. During the first cycle, the average duration of severe neutropenia in Group 1 was 0.8 days, 1.5 days in Group 2, and 1.0 days in Group 3 (P = 0.70 for Group 3 vs. Group 1). During treatment, 9 (26%) of the 34 patients in the first group developed severe neutropenia, 12 of the 33 in the second group (36%), and 8 out of 35 in the third group (23%) (P = .70  for Group 3 vs Group 1).

The median progression-free survival of the three groups was 5.7 months, 9.4 months, and 7.3 months. The median overall survival was 12.6 months, 20.1 months (group 2 vs. group 1, P = .028) and 17.8 months (group 3 vs. group, P = .0023).

Adverse events: The most common adverse reactions in the first group were anemia (73%), neutropenia (70%), and thrombocytopenia (60%); in Group 2,  neutropenia (82%), thrombocytopenia (55%) and anemia (52%); in group 3, neutropenia (66%), thrombocytopenia (63 %) and nausea (49%). No treatment-related deaths were observed.

The researchers concluded that in patients with metastatic triple-negative breast cancer, there was no significant difference in the endpoint of myelosuppression with trilaciclib in combination with gemcitabine and carboplatin, while the overall survival was encouraging.

参考文献 Reference

Tan AR et al. Lancet Onc 2019; September 28. DOI:https://doi.org/10.1016/S1470-2045(19)30616-3

 

FDA将Navicixizumab作为快速通道药物用于反复治疗过的卵巢癌 (10/27/2019)

FDA granted fast track designation for Navicixizumab to be used in heavily treated ovarian cancer

FDA已将navicixizumab纳入快速通道，用于治疗已接受过至少3种先前治疗和/或贝伐单抗患者的高级卵巢癌，原发性腹膜或输卵管癌。

 

Navicixizumab是一种抗DLL4（anti-Delta-like ligand）/VEGF（血管内皮生长因子）的双特异性抗体，设计来用于抑制Notch癌症干细胞途径中的Delta样配体4（DLL4）以及血管内皮生长因子（VEGF），从而诱导有效的抗肿瘤应答，同时减轻某些血管生成相关的毒性。。在临床前期研究中，在包括结肠癌，卵巢癌，肺癌和胰腺癌在内的多种实体肿瘤的异种移动物中, navicixizumab显示出体内抗肿瘤功效。在单药的Ia阶段研究中，所有患者的中位年龄为60岁，其中68％为女性。 该试验中最常见的肿瘤类型是卵巢癌（12人）和结直肠癌（11人）。观察到最常见的与治疗相关的不良事件是高血压（57.6％），头痛（28.8％），疲劳（25.8％）和肺动脉高压（18.2％）。肺动脉高压在较高剂量时更为严重。仅观察到1种剂量限制性毒性，因此未达到最大耐受剂量。 研究人员选择了7.5毫克/公斤作为扩展队列中使用的剂量。

一些共在4例患者中观察到部分反应，其中3例患有卵巢癌，另外17例患者病情稳定。 总体而言，有19名患者实现了目标病变的缩小。 4例患者接受了超过300天的治疗，而2例接受了超过500天的治疗。

Navicixizumab加紫杉醇的Ib阶段剂量递增和扩展研究已完成。44例耐铂类药的卵巢癌患者参加研究，这些患者在两次治疗前均无效或/和接受过贝伐单抗治疗。 截至2019年第一季度末的最新中期数据分析，未确认的响应率为41％。 接受贝伐单抗治疗的患者的响应为30％; 未经贝伐单抗治疗的患者未证实的响应率为64％。 所有患者的中位无进展生存期为7.3个月。 任何等级中最常见的相关不良事件是高血压（68％），疲劳（46％），头痛（25％），中性粒细胞减少症（21％），腹泻（18％），肺动脉高压（14％），呼吸困难（14 ％）和周围水肿（14％）。 特别引起关注的其他相关不良事件为1例1级心力衰竭，1例3级和1例4级血小板减少, 和1例4级胃肠道穿孔。

FDA has granted navicixizumab as Fast Track designation for the treatment of advanced ovarian cancer, primary peritoneal or fallopian tube cancer in patients who have received at least 3 prior treatments and/or bevacizumab.

Navicixizumab is a bispecific antibody against DLL4 (anti-Delta-like ligand)/VEGF (vascular endothelial growth factor) designed to inhibit DLL4 and vascular endothelium in the Notch cancer stem cell pathway and VEGF to induce an effective anti-tumor response while attenuating certain angiogenesis-related toxicities. In preclinical studies, navicixizumab exhibits in vivo antitumor efficacy in xenografts of various solid tumors including colon, ovarian, lung, and pancreatic cancers. In a single-agent phase Ia study, the median age of all patients was 60 years, of which 68% were women. The most common tumor types in this trial were ovarian cancer (n = 12) and colorectal cancer (n = 11). The most common treatment-related adverse events observed were hypertension (57.6%), headache (28.8%), fatigue (25.8%), and pulmonary hypertension (18.2%). Pulmonary hypertension is more severe at higher doses. Only one dose-limiting toxicity was observed, so the maximum tolerated dose was not reached. The researchers chose 7.5 mg/kg as the dose used in the expansion cohort.
Partial response was observed in 4 patients, 3 of whom had ovarian cancer.  17 patients were stable. Overall, 19 patients achieved a reduction in target lesions. Four patients received more than 300 days of treatment, while two received more than 500 days of treatment.
The dose escalation and expansion study of Navicixizumab plus paclitaxel has been completed. Forty-four patients with platinum-resistant ovarian cancer were enrolled in the study. These patients failed greater than two lines of prior therapy and/or received prior bevacizumab. As of the latest interim data analysis at the end of the first quarter of 2019, the unconfirmed response rate was 41%. The unconfirmed response was 30% for those who received prior bevacizumab and 64% in bevacizumab-naïve patients. The median progression-free survival of all patients was 7.3 months. The most common treatment-related adverse events at any grade were hypertension (68%), fatigue (46%), headache (25%), neutropenia (21%), diarrhea (18%), pulmonary hypertension (14%), dyspnea (14%) and peripheral edema (14%). Other related adverse events of special interest were 1 case of grade 1 heart failure, 1 case of grade 3 and 1 case of grade 4 thrombocytopenia, and 1 case of grade 4 gastrointestinal perforation.

参考文献 Reference

Mereo BioPharma Group plc; October 7, 2019. https://bit.ly/31V3l8o. Accessed October 7, 2019.

 

尼武单抗联合易普利姆玛第一线治疗非小细胞肺癌 (10/26/2019)

Nivolumab plus ipilimumab as first-line non-chemotherapy for NSCLC

CheckMate 227是一项开放式，多部分，全球性的III期临床试验，在该试验中，给IV期或复发性非小细胞肺癌（非鳞状和鳞状）病人的第一线 治疗中, 比较尼武单抗（nivolumab）加易普利姆玛（ipilimumab）方案与铂类双重化疗对生存期的影响。

在该试验的第1部分中，有2个队列研究。

在1a部分，病人PD-L1表达>1％, 有3组: A) 尼武单抗加易普利姆玛（396人）; B) 尼武单抗单一疗法（177人）;与C) 单纯化疗（397人）进行了比较。

在1b部分，病人PD-L1表达<1％, 有3组: A) 尼武单抗加易普利姆玛（187人）; B) 尼武单抗加化疗（396人）;与C) 单纯化疗（186人）进行了比较。

在PD-L1表达水平为1％或更高的患者中，接受尼武单抗加易普利姆玛的中位总生存时间为17.1个月（95％置信区间 = 15.0-20.1），接受化疗的为14.9个月（95％置信区间 = 12.7至16.7）（P = .007），两年总生存率分别为40.0％和32.8％。尼武单抗加易普利姆玛的中位反应持续时间为23.2个月，化疗为6.2个月。

在PD-L1表达水平低于1％的患者中，接受尼武单抗加易普利姆玛的中位总生存时间为17.2个月（95％置信区间 = 12.8-22），接受化疗的为12.2个月（95％置信区间 = 9.2-14.3）。

在该试验的所有患者中，无论其PD-L1状态如何，接受尼武单抗加易普利姆玛的中位总生存时间为17.1个月（95％置信区间 = 15.2-19.9），接受化疗的为13.9个月（95％置信区间 = 12.2-15.1）。

尼武单抗加易普利姆玛治疗的患者中具有3级或4级治疗相关不良事件的总比例为32.8％，化疗组为36.0％。

结论是，与化疗相比，两种免疫疗法第一线联合治疗晚期非小细胞肺癌患者可提高总体生存率，并为部分患者提供无化疗一线治疗选择。

CheckMate 227 is an open label, multi-part, global phase III clinical trial in which patients are given first-line of nivolumab plus ipilimumab in comparison with chemotherapy for stage IV or recurrent non-small cell lung cancer (non-squamous and squamous) patients. .

In the first part of the trial, there were two cohorts.
In section 1a, patients with PD-L1 expression >1%, there were 3 groups: A) nivolumab plus ipilimumab (N=396); B) nivolumab monotherapy (N=177); and C) Chemotherapy alone (N=397) . In the 1b section, the patient’s PD-L1 expression was <1%, with 3 groups: A) nivolumab plus ipilimumab (N=187); B) nivolumab plus chemotherapy (N=396); and C) Chemotherapy alone (N=186).

In patients with PD-L1 expression levels of 1% or higher, the median overall survival of combination of nivolumab plus ipilimumab was 17.1 months (95% confidence interval = 15.0-20.1), versus 14.9 months in those who received chemotherapy (95% confidence interval = 12.7 -16.7) (P = .007).  The two-year OS was 40.0% and 32.8% respectively. The median response duration of nivolumab plus ipilimumab was 23.2 months vs 6.2 months in chemotherapy group.

In patients with PD-L1 expression levels below 1%, the median OS of nivolumab plus ipilimumab was 17.2 months (95% confidence interval = 12.8-22) vs 12.2 months (95% confidence interval = 9.2-14.3) in chemotherapy group.

In all patients in the trial, regardless of their PD-L1 status, the median OS of nivolumab plus ipilimumab  was 17.1 months (95% confidence interval = 15.2-19.9), vs 13.9 months (95% confidence interval = 12.2-15.1) in chemotherapy group.

Grade 3 or 4 treatment-related adverse events accounted for 32.8% in patients treated with nivolumab plus ipilimumab vs 36.0% in the chemotherapy group.

The conclusion is that, compared with chemotherapy, first line of two immunotherapy agents can improve overall survival for untreated advanced NSCLC patients. It provides some patients with an option of non-chemotherapy.

参考文献 Reference

Hellmann MD et al. NEJM 2019; September 28, 2019 DOI: 10.1056/NEJMoa1910231

 

真菌可以促进胰腺癌发生 (10/20/2019)

Fungi may accelerate the development of pancreatic cancer

肠道细菌性失衡 (dysbiosis) 被认为与胰腺导管腺癌的发病机理有关。

最新报告指出, 真菌从肠腔迁移到胰腺，可能与胰腺导管腺癌的发病机制有关。与正常的胰腺组织相比，患这种胰腺导管腺癌的人和小鼠模型中, 肿瘤内真菌增加约3,000倍。基于α-和β-多样性指数 (α-,β- diversity indices），胰腺导管腺癌肿瘤的真菌的组成与肠道或正常胰腺的组成不同。具体而言，渗入胰腺导管腺癌肿瘤的真菌群落明显富集了马拉色菌（Malassezia）。这在小鼠和人类中都一样。在胰腺导管腺癌的缓慢进展和侵袭性模型中，真菌基因组的消融可防止肿瘤生长，马拉色菌属物种（而非念珠菌，酿酒酵母或曲霉属中的物种）的繁殖可加速肿瘤发生。报告还发现，甘露糖结合凝集素（MBL）与真菌壁的聚糖结合以激活补体级联反应，是致癌性进展所必需的。而瘤外区MBL或C3的缺失, 或敲除C3aR的肿瘤细胞,  都可以防止肿瘤生长。此外，在Mbl-（也称为Mbl2）或C3缺陷型小鼠中，对真菌基因组的重编程不会改变胰腺导管腺癌的进程。

研究表明，致病真菌通过激活MBL来驱动补体级联反应，从而促进胰腺导管腺癌的生长。

Bacterial dysbiosis is thought to be involved in the pathogenesis of pancreatic ductal adenocarcinoma.
A latest report indicates that the migration of fungi from the intestinal lumen to the pancreas may be related to the pathogenesis of pancreatic ductal adenocarcinoma. In human and mouse models of pancreatic ductal adenocarcinoma, intratumoral fungi increased approximately 3,000-fold compared to normal pancreatic tissue. Based on the α- and β-diversity indices, the composition of fungi of pancreatic ductal adenocarcinoma tumors is different from that of the intestinal or normal pancreas. Specifically, the fungal colonies that infiltrated the pancreatic ductal adenocarcinoma tumors were significantly enriched in Malassezia spp. This is the same in both mice and humans. In a slow-progressive and invasive model of pancreatic ductal adenocarcinoma, ablation of the fungal genome prevents tumor growth, and reproduction of Malassezia species (rather than Candida, Saccharomyces or Aspergillus) accelerates tumorigenesis . The report also found that mannose-binding lectin (MBL) binds to glycans of the fungal wall to activate the complement cascade, which is required for carcinogenic progression. The absence of MBL or C3 in the extratumoral  area, or the knockdown of C3aR tumor cells, can prevent tumor growth. Furthermore, in Mbl- (also known as Mbl2) or C3-deficient mice, reprogramming of the fungal genome does not alter the progression of pancreatic ductal adenocarcinoma.

In summary, this study has shown that pathogenic fungi promote the growth of pancreatic ductal adenocarcinoma by driving the complement cascade through the activation of MBL.

参考文献 Reference

Aykut B et al. Nature 2019; 574: 264-7

 

Pembrolizumab加lenvatinib联合治疗晚期子宫内膜癌 (10/19/2019)

Combination of pembrolizumab and lenvatinib in advanced endometrial cancer

KEYNOTE-146/111研究（NCT02501096）是一项1b/2期，单臂试验, 有108例转移性子宫内膜癌患者参加，她们均经过至少一项先前的全身性治疗后进展，并且不适合进行根治性手术或放疗。94位患者的肿瘤不是微卫星不稳定性（MSI-H）或错配修复缺失（dMMR），11位患者的肿瘤是MSI-H或dMMR，三位患者的肿瘤状态未知。患者每天口服20毫克lenvatinib（一种口服激酶抑制剂）, 加上每三周一次200 毫克 pembrolizumab（抗PD-1）。平均随访18.7个月。

主要终点为第24周的客观响应率。主要和次要终点为响应持续时间，无进展生存期，疾病控制率，临床受益率 ，数据截止时（2019年1月10日）的安全性和耐受性。主要终点和次要终点的肿瘤响应由每个研究者根据irRECIST评估。

在108名患者的全部研究人群中，无论是MSI-H还是dMMR状态，联合治疗组在第24周的客观响应率均为38.0％（41人） （95％CI：28.8％-47.8％）。完全响应率为7.4％（8人），部分响应率为31.5％（34人）。 响应持续时间中位数为21.2个月（范围从1.2+至35.6+个月）。

在94位非MSI-H或dMMR的患者中，联合治疗组在第24周时的客观响应率为36.2％（34人）（95％CI：26.5％-46.7％），完全响应率为 7.4％（7人），部分响应率为29.8％（28人）。中位响应持续时间不可估算（范围从1.2+至33.8+个月）。

在11名患有MSI-H或dMMR的肿瘤患者中，联合治疗组在第24周的客观响应率为63.6％（7人）（95％CI：30.8％-89.1％）。完全响应率为9.1％（1人），部分响应率为54.5％（6人）。 响应持续时间中位数为21.2个月（范围从6.1+至35.6+个月）。

在预先指定的探索性分析中，由独立影像检查（RECIST 1.1）评估了肿瘤响应。在108名患者的全部研究人群中,  中位响应持续时间为14.8个月（范围：1.2+至35.6+个月）。中位无进展生存期为7.5个月（95％CI：5.0-8.3），中位总生存期为16.7个月（95％CI：15.0-不可估算） 。

在94名非MSI-H或dMMR的肿瘤患者中，中位响应持续时间不可估算（范围：1.2+至33.1+个月）。中位无进展生存期为5.4个月（95％CI：4.4-7.6），中位总生存期​​为16.4个月（95％CI：13.5-25.9）。

在11例MSI-H或dMMR肿瘤患者中，中位响应持续时间不可估算（范围：2.1+至35.6+个月）。 中位无进展生存期为18.9个月（95％CI：3.9-不可估算），中位总生存期不可估计（95％CI：7.4-不可估算）。

联合治疗组中, 18.5％（20人）的患者停药。 与治疗相关的3-4级副作用占69.4％（75人）。 最常见的是高血压（32.4％），疲劳（8.3％）腹泻（6.5％）和蛋白尿（3.7％）。

这种治疗组合为晚期子宫内膜癌提供了有希望的治疗方案。

The KEYNOTE-146/study111 (NCT02501096) is a phase1b/2, one-arm trial involving 108 patients with metastatic endometrial cancer who progressed after at least one systemic treatment and were not candidates for radical surgery or radiotherapy. The tumors of 94 patients were either microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). The tumors of 11 patients were MSI-H or dMMR, and the tumor status of the three patients was unknown. Patients were given daily 20 mg of lenvatinib (an oral kinase inhibitor), plus 200 mg/m 2 of pembrolizumab (anti-PD-1) every three weeks. The median follow-up was 18.7 months.

The primary endpoint was objective response rate (ORR) at Week 24. Secondary endpoints included response duration, progression-free survival (PFS), disease control rate, clinical benefit rate, and safety and tolerability at the data cut-off (January 10, 2019). Tumor responses at primary and secondary endpoints were assessed by each investigator based on irRECIST.

In all the study populations of 108 patients, whether being MSI-H or dMMR, the ORR at week 24 was 38.0% (41 patients) (95% CI: 28.8%-47.8%). The CR rate was 7.4% (8 people) and the PR rate was 31.5% (34 people). The median duration of response was 21.2 months (range from 1.2+ to 35.6+ months).

In 94 patients with non-MSI-H or dMMR status, the ORR at week 24 was 36.2% (34) (95% CI: 26.5%-46.7%) and the CR rate was 7.4%. (7 people), the PR rate was 29.8% (28 people). The median response duration was not estimable (ranging from 1.2+ to 33.8+ months).

In 11 tumor patients with MSI-H or dMMR, the ORR at week 24 was 63.6% (7 patients) (95% CI: 30.8%-89.1%). The CR rate was 9.1% (1 person) and the PR rate was 54.5% (6 persons). The median response duration was 21.2 months (range from 6.1+ to 35.6+ months).

Tumor response was also assessed by an independent imaging test (RECIST 1.1) in a pre-specified exploratory analysis. The median response duration was 14.8 months (range: 1.2+ to 35.6+ months) in all study populations of 108 patients. The median PFS was 7.5 months (95% CI: 5.0-8.3) and the median OS was 16.7 months (95% CI: 15.0 – not measurable).

In 94 patients with non-MSI-H or dMMR tumors, the median response duration was not estimable (range: 1.2+ to 33.1+ months). The median PFS was 5.4 months (95% CI: 4.4-7.6) and the median OS was 16.4 months (95% CI: 13.5-25.9).

In 11 patients with MSI-H or dMMR tumors, the median response duration was not estimable (range: 2.1+ to 35.6+ months). The median PFS was 18.9 months (95% CI: 3.9 – not measurable) and the median OS was not estimable (95% CI: 7.4 – not measurable).

In the combination treatment group, 18.5% (20 patients) discontinued the drug. Grade 3-4 side effects associated with treatment accounted for 69.4% (n=75). The most common are hypertension (32.4%), fatigue (8.3%) diarrhea (6.5%) and proteinuria (3.7%).

This combination of treatments provides a promising therapeutic regimen for advanced endometrial cancer.

参考文献 Reference

Makker V et al. ESMO 2019; abstr 994O

 

转移性结直肠癌的三线治疗的发展 (10/13/2019)

Promising development in third-line therapy in metastatic colorectal cancer

雷戈非尼（regorafenib）加尼武单抗（nivolumab) 用于三线治疗晚期大肠癌或胃癌患者。

在一项开放标签，剂量确定和剂量扩展1b期试验（REGONIVO，EPOC1603）
研究中，先前治疗过的50位晚期胃癌或结直肠癌的患者, 在剂量寻找阶段接受了雷戈非尼加尼武单抗，以估计最大耐受剂量。在剂量扩大阶段招募了其他患者，以进一步确定安全性并确定初步疗效。雷戈非尼的剂量为80至160毫克，每天服用一次，间隔21天/停药7天，每2周静脉给予尼武单抗3毫克/ 公斤。主要终点是在第一个周期（4周）内的剂量限制毒性，以估算最大耐受剂量和推荐剂量。

截至2018年10月，共入选50人（结直肠癌25人； 胃癌25人）。先前治疗的中位数为3（范围2-8）。在剂量递增期间，当雷戈非尼为160毫克时, 观察到3种剂量限制毒性，包括3级斑丘疹，蛋白尿和结肠穿孔，而80毫克或120毫克没有剂量限制毒性。在雷戈非尼120毫克的剂量增加队列中，由于频繁的3级皮肤毒性，剂量减少至80毫克。 17人发生≥3级与治疗相关的不良事件；常见事件（> 5％）是皮疹（14％），手/脚掌-红斑感觉异常（10％）和蛋白尿（8％）。观察到的客观肿瘤响应为19人（38％），包括11个微卫星稳定 胃癌，7个微卫星稳定 结直肠癌和1个微卫星不稳定性高 结直肠癌，胃癌的响应率为44％，微卫星稳定 结直肠癌为29％。 7个曾接受抗PD-1治疗的胃癌患者中有3个获得了部分响应。

雷戈非尼与尼武单抗的组合具有可控制的安全性，并在微卫星稳定胃癌和结直肠癌 患者中具有令人鼓舞的抗肿瘤活性。

Regorafenib plus nivolumab is used for third-line treatment of patients with advanced colorectal or gastric cancer.In an open label, dose-finding and dose-expansion phase 1b trial (REGONIVO, EPOC1603), 50 patients with advanced gastric cancer or colorectal cancer received regorafenib and nivolumab at the dose-finding stage to estimate the maximum tolerated dose. Additional patients were recruited during the dose-expansion phase to further determine safety and determine initial efficacy. The dose of regorafenib was 80 to 160 mg, taken once daily, on a schedule of 21 days on/ 7 days off, with nivolumab 3 mg/kg administered intravenously every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during the first cycle (4 weeks) to estimate maximum tolerated dose (MTD) and recommended dose.As of October 2018, a total of 50 people (25 colorectal cancer; 25 gastric cancer) were enrolled. The median previous treatment line was 3 (range 2-8). During dose escalation phase, when regorafenib was given at 160 mg, three DLTs were observed, including grade 3 maculopapular rash, proteinuria and colonic perforation, while at 80 mg or 120 mg, there o DLT. In the dose escalation phase of 120 mg dose of regorafenib, the dose was reduced to 80 mg due to frequent grade 3 skin toxicity. There were  ≥3 grade treatment-related adverse events in 17 patients; common events (> 5%) were rashes (14%), palmar-plantar erythrodysesthenia (10%), and proteinuria (8%). The observed objective tumor response was 19 (38%), including 11 microsatellite stable (MSS) gastric cancer, 7 MSS colorectal cancer, and 1 MMI-H colorectal cancer. The response rate of gastric cancer was 44%. For MMS colorectal cancer, it was 29%. Three of seven anti-PD-1 treated gastric patients achieved partial response.The combination of regorafenib and nivolumab has controllable safety and has an encouraging anti-tumor activity in MMS gastric and colorectal cancer patients参考文献 Reference

Hara H et al. Ann Onc ESMO 21st World Congress GI Cancer，2019: oral abstr #SO-007

 

Alpelisib用于雌激素受体阳性晚期乳腺癌 (10/12/2019)

Alpelisib for ER–Positive Advanced Breast Cancer

在雌激素受体（ER）阳性，HER2阴性的乳腺癌患者中，约40％有PIK3CA突变。在这个患者人群中, PI3Kα特异性抑制剂alpelisib与氟维司群 (fulvestrant) 联用, 显示出对晚期乳腺癌患者有抗肿瘤活性。

这是一项随机的3期临床试验（SOLAR-1），总共572例患者接受了随机分组，她们患有ER阳性HER2阴性晚期乳腺癌, 先前曾接受内分泌治疗。其中341例证实了肿瘤组织有PIK3CA突变。PIK3CA突变的癌症患者队列分成两组，一组接受alpelisib（每天300 毫克）, 加氟维司群（每28天500 毫克，第15天加一次）; 另一组接受安慰剂加氟维司群。试验主要终点是无进展生存期。次要终点包括总体反应和安全性。

Alpelisib-氟维司群组中位随访为20个月, 无进展生存期为11.0个月（95％置信区间 =为7.5-14.5）。安慰剂-氟维司群组为5.7个月（95％置信区间 = 3.7-7.4）（进展或死亡的危险比，0.65； 95％置信区间= 0.50-0.85； P <0.001）；在没有PIK3CA突变癌症的队列中，危险比为0.85（95％置信区间 = 0.58-1.25）。在PIK3​​CA突变的队列中，接受alpelisib-氟维司群患者的总响应率比安慰剂-氟维司群的要好（26.6％相比于12.8％）。

最常见的3级或4级不良事件是高血糖症（alpelisib-氟维司群组为36.6％，而安慰剂-氟维司群组为0.7％）和皮疹（9.9％vs. 0.3％）。 Alpelisib-氟维司群组6.7％的患者发生3级腹泻，而安慰剂-氟维司群组为0.3％；没有4级腹泻。因不良事件而停用alpelisib和安慰剂的患者百分比分别为25.0％和4.2％。

In estrogen receptor (ER)-positive, HER2-negative breast cancer patients, approximately 40% have PIK3CA mutations. In this patient population, the PI3Kα specific inhibitor alpelisib, when combined with fulvestrant, shows anti-tumor activity in patients with advanced disease.
This was a randomized phase 3 clinical trial (SOLAR-1) in which a total of 572 patients were enrolled. They had ER-positive, HER2-negative advanced breast cancer who had previously received endocrine therapy. Among them, the tumor tissue from 341 patients had PIK3CA mutation. Those with PIK3CA mutation were randomized. One group received alpelisib (300 mg per day), and fulvestrant (500 mg every 28 days, plus once on day 15); the other group received placebo plus fulvestrant . The primary endpoint was progression-free survival. Secondary endpoints include overall response and safety.

The median follow-up of the Alpelisib- fulvestrant group was 20 months and the progression-free survival was 11.0 months (95% CI = 7.5-14.5). The placebo- fulvestrant group was 5.7 months (95% CI = 3.7-7.4) (risk ratio of progression or death, 0.65; 95% CI = 0.50-0.85; P < 0.001). In the cohort of women without PIK3CA mutation, the hazard ratio was 0.85 (95% CI = 0.58-1.25). In the PIK3CA mutation cohort, the overall response rate for patients receiving alpelisib- fulvestrant was better than that of placebo-fulvestrant (26.6% vs. 12.8%).
The most common grade 3 or 4 adverse events were hyperglycemia (36.6% in the alpelisib- fulvestrant group, 0.7% in the placebo- fulvestrant group) and rash (9.9% vs. 0.3%). Grade III diarrhea occurred in 6.7% of patients in the alpelisib- fulvestrant group, compared with 0.3% in the placebo- fulvestrant group; there was no grade 4 diarrhea. The percentage of patients who discontinued alpelisib and placebo due to adverse events were 25.0% and 4.2%, respectively.

参考文献 Reference

Fabrice André E et al. N Eng J Med 2019: 380:1929-40

 

乳腺癌：CDK4/6抑制剂耐药后的治疗选择 (10/6/2019)

Breast cancer: Strategy after resistance to CDK4/6 Inhibition 

细胞周期特异性和非特异性机制都会导致转移性雌激素受体阳性乳腺癌对CDK4/6抑制剂产生抗药性。

CDK4/6抑制剂，包括palbeciclib, ralbiciclib and abemaciclib，结合抗䧳激素受体 (ER) 药物，在ER阳性疾病的首线治疗中发挥了主要作用。但三个CDK4/6抑制剂并不完全相等。细胞周期蛋白质D-CDK4/6 轴的第一步由 CDK4/6 驱动，第二步则由 CDK2 进行介导。Abemaciclib 阻止细胞周期蛋白E-CDK2 复合体。ER阳性乳腺癌可以通过利用CDK2来补偿对CDK4/6的抑制。针对CDK4/6 抑制剂耐药的情况，可以在未来开发CDK2。

细胞周期特异性的对CDK4/6抑制剂的抗药性机制可以由于视网膜母细胞瘤（RB）肿瘤抑制剂的丧失，和CDK4和CDK6的扩增。例如，FAT1 的功能丧失突变会引起 CDK6 显著升高而导致治疗效果较差。细胞周期非特异性抵抗机制可能包括ER和孕酮受体表达的丧失或FGFR通路的激活。这些异常也可以提供未来的治疗策略。

对于没有突变治疗的患者，依维莫司 (everolimus)与芳香化酶抑制剂或氟维司群 (fulvestrant)的组合可能对产生耐芳香化酶抑制剂的患者有新的作用。

在雌激素受体阳性乳腺癌的二线治疗中，一个重要目标是PIK3CA突变。在三期SOLAR-1试验中，Alpelisib，一种PI3Kα特异性抑制剂，与氟维司群 合用于有PIK3CA突变的患者，改善了无进展生存期，相比于对照组（11.0 相对于5.7个月，p =.001）。肿瘤的进展通过激活生长因子，往往使肿瘤变得不那么依赖ER，这就推动了PIK3CA通道的活性。

AKT 的改变也驱动 PI3K 通路，常见于 ER 阳性肿瘤。它可能成为有PTEN突变患者的治疗策略。FAKTION临床试验检查了选择性Akt1/3抑制剂capivasertib与富维斯特合用在芳香化酶抑制剂治疗失败后的效应。对照组的无进展生存期从4.8个月延长到联合组的10.3个月（P = .004）。

由于雌激素受体1（ESR1）的突变而产生抗药性在芳香化酶抑制剂治疗过的患者中很常见。在BOLERO-2试验中，ESR1突变患者的结果比野生型ESR1患者差，而ESR1 Y537S突变的患者结果最差。这些患者可能不会从依维莫司/exemestan联合治疗得到疗效。为ESR1突变病患者正在开发两类药物。一种为选择性 ER 降解剂 （SERD） ，它在 芳香化酶抑制剂 治疗失败后的患者中显示出希望，客观反应率为 23%，即使大量患者曽接受过许多治疗。目前正在进行第三阶段研究（NCT03778931）。

选择性 ERa 共价（covalent) 激动剂 （SERCA） H3B-6545，通过靶向半胱氨酸来使雌激素受体灭活，而半胱氨酸在其他细胞核激素受体中并不存在。该药正在晚期或转移性ER阳性、HER2阴性乳腺癌（NCT03250676）的妇女中进行调查。

本栏作者简要重组：

在CDK4/6抑制剂失败后的选择：

重新活检转移病灶，看有无新的突变。

1）若没有发现有基因突变，可以采用依维莫司加艾克斯坦（exemestan）。

2）有PlK3CA突变者，可以使用alpelisib加氟维司群。

3）参加临床试验，如针对有PTEN或ESR1突变的患者。

Both cell cycle-specific and nonspecific mechanisms lead to acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer.

CDK4/6 inhibitors, including palbeciclib, ralbiciclib and abemaciclib, in combination with anti-ER agents have played a major role in the frontline setting for ER-positive disease.

The three CDK4/6 inhibitors are not equal. The first step in the cyclin-D–CDK4/6 axis is driven by CDK4/6, and the second step is mediated by CDK2. Abemaciclib blocks the cyclin-E–CDK2 complex. The ER-positive breast cancers can compensate for CDK4/6 inhibition by utilizing CDK2. It is possible to target CDK2 in future development in case of CDK4/6 resistance.

Mechanism of cell cycle-specific resistance to CDK4/6 inhibitors can be due to loss of retinoblastoma (RB) tumor suppressors, and amplification of CDK4 and CDK6. For example, a loss of functional mutation in FAT1 causes a significant increase in CDK6 and results in a poorer therapeutic effect. Cell cycle non-specific resistance mechanisms may include loss of ER and progesterone receptor expression or activation of the FGFR pathway. These abnormalities can also provide future treatment strategies.

For patients who do not have additional mutations for treatment, the combination of everolimus with AIs or fulvestrant may play an emerging role in patients with resistance to AIs.

In the second-line setting, an important target is the PIK3CA mutation. Alpelisib, a PI3Ka-specific inhibitor, as shown in the phase III SOLAR-1 trial, improved PFS over placebo (11.0 vs 5.7 months) when combined with fulvestrant in patients with PIK3CA-mutated disease (HR, 0.65; 95% CI, 0.50-0.85; P <.001). Activation of growth-factor pathways that happen sequentially through the progression of the tumor as it becomes less ER-dependent is what drives the PIK3CA activity.

Alterations in AKT also drive the PI3K pathway and are commonly seen in ER-positive disease. It may become a good strategy for patients with PTEN mutations. The phase II FAKTION trial examined efficacy of the selective Akt1/3 inhibitor capivasertib plus fulvestrant in patients with ER-positive tumors following progression to an AI. PFS was extended in the intent-to-treat population from 4.8 months in the placebo arm to 10.3 months in the combination arm (P = .004).

Resistance medicated via mutated estrogen receptor 1 (ESR1) is common in AI-pretreated patients. In the BOLERO-2 trial, patients with ESR1 mutations had worse outcomes than those who had wild-type ESR1, and those with the ESR1 Y537S mutation had the worst outcomes overall. These patients may not derive benefit from the addition of everolimus to exemestan. Two classes of drugs are being developed for patients with ESR1-mutant disease. The selective ER degrader (SERD) elacestrant has shown promise in patients following AI therapy with an objective response rate of 23%, despite a large number of patients who were heavily pretreated. A phase III study is currently ongoing (NCT03778931).

A selective ERa covalent agonist (SERCA) H3B-6545, shows mechanistic and phenotypic effects that differ from those of SERDs in a phase II trial. SERCAs inactivate the estrogen receptor by targeting cysteine, which is not present in other nuclear hormone receptors. This agent is being investigated in women with locally advanced or metastatic ER-positive, HER2-negative breast cancer (NCT03250676).

Brief rearrangement by the author of this column:

Treatment choices following CDK4/6 inhibitor resistance:

Re-biopsy to see if there are new mutations.

1) If no new genetic mutation is found, use everolimus and  exemestan.

2) PlK3CA mutants, give alpelisib plus fulvestrant.

3) Participate in clinical trials, e.g. for patients with PTEN or ESR1 mutations.

 

参考文献 Reference

1. Juric D. Presented at: 18th Annual International Congress on The Future of Breast Cancer® East July 19-20, 2019.
2. Li Z, Razavi P, Li Q, et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway. Cancer Cell. 2018;34(6):893-905.e8. doi: 10.1016/j.ccell.2018.11.006.
3. Pandey K, An HJ, Kim SK, et al. Molecular mechanisms of resis- tance to CDK4/6 inhibitors in breast cancer: a review. Int J Cancer. 2019;145(5):1179-1188. doi: 10.1002/ijc.32020.
4. Kornblum N et al. J Clin Oncol. 2018;36: 1556-1563.
5. André F eat al. N Engl J Med. 2019;380(20):1929-1940.
6. Juric D et al. J Clin Oncol. 2019;37(suppl 15; abstr 1038).
7. Jones RH et a J Clin Oncol. 2019;37(suppl 15; abstr 1005).
8. Chandarlapaty S et al.2016;2: 1310-1315. 
9. Bardia A et al. Clin Oncol. 2017;35(suppl 15; abstr 1014). 

 

具有BRAF突变的可切除III期黑色素瘤的术前免疫治疗 (9/29/2019)

Neoadjuvant immunotherapy in BRAF-mutated stage III melanoma
这是一项单臂，开放标签，单中心II期研究，招募了35名黑色素瘤患者。 29/35（83％）患有IIIC期疾病。 中位年龄为56岁（46-64岁）； 15名（43％）是女性； 34（97％）例为BRAF / V600E突变阳性。 在这些患者中，有15位（54％）需要腹股沟或髂腹股沟淋巴结清扫术。 该研究的主要终点是缓解率。 次要终点是不良事件。 其他次要点包括肿瘤和血液生物标志物与反应和生存结果的关联。 患者每天口服两次150毫克dabrafenib，每天口服一次2毫克tramatenib，持续52周（术前12周，术后40周）。中位随访时间为27个月。 35名患者中没有一个有临床或影像学疾病进展的证据

全部35例患者在切除后均取得了病理反应。 其中17例（49％）达到病理完全缓解。 30人（86％）有RECIST反应，而16人（46％，95％置信区间 = 29-63）有完全反应。 对于代谢反应，18人（51％，95％CI + 34-69）有代谢完全反应。 这三种反应在21例患者中一致（60％）。 在事后分析中，获得完全缓解的患者与基线临床病理特征（包括年龄，性别，BRAF基因型AJCC分期，ECOG表现，基线LDH水平和疾病部位）之间没有关联。

作者认为,在RECIST可测量的, 可切除的III期黑色素瘤患者的治疗中, 可考虑术前dabrafenib联合tramatenib治疗，它导致高比例的患者实现了完全缓解，而且术前治疗期间疾病没有进展。

This is a single-arm, open-label, single-center, phase II study that enrolled 35 melanoma patients. Among them, 29/35 (83%) had stage IIIC disease. the median age was 56 (46-64); 15 (43%) were female; 34 (97%) were positive for BRAF/V600E mutation. Of those patients, 15 (54%) required an inguinal or ilioinguinal lymph node dissection. The primary end point of the study was response rate. Secondary end point was adverse events. Other secondary points included association of tumor and blood biomarkers with response and survival outcome. Patients received 150 mg dabrafenib twice daily and 2 mg tramatenib orally once daily for 52 weeks (12 weeks pre-operatively and 40 weeks after surgery).

The median follow-up was 27 months. None of the 35 patients had evidence of clinical or radiographic disease progression during neoadjuvant therapy. All 35 patients achieved a pathological response after resection. Among them, 17(49%) achieved pathological complete response. By RECIST criteria, 30 (86%) had a response, and 16 (46%, 95% CI = 29-63) had a complete response. For metabolic response, 18 (51%, 95% CI = 34-69) had a metabolic complete response. All three responses are concordant in 21 patients (60%). In a post-hoc analysis, there was no association between patients who achieved a complete response and baseline clinical pathological features, including age, sex, BRAF genotype AJCC stage, ECOG performance, baseline LDH levels and disease sites.

Authors thought neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response, with no progression during neoadjuvant therapy.

参考文献 Reference

Long GV et al. lancet Onc 2019; http://dx.doi.org/10.1016/S1470-2045(19)30331-6

 

AXL抑制剂bemcentinib和pembrolizumab在非小细胞肺癌中的疗效 (9/28/2019)

AXL inhibitor and pembrolizumab effective in chemo-refractory non-small cell lung cancer

非小细胞肺癌患者化疗后接受选择性AXL抑制剂bemcentinib和pembrolizumab的联合治疗, 显示出有希望的临床活性，特别是AXL阳性肿瘤患者。

AXL激酶是细胞膜受体，是威胁生命疾病的生物学机制的重要介质。 在癌症中，AXL抑制人体对肿瘤的免疫反应，并可导致癌症治疗失败。 因此，AXL抑制剂在癌症联合治疗中具有潜在的价值。

这项II期临床试验（BGB008，NCT03184571）包括两种类型的研究。在研究的初始阶段，参加者患有铂类难治性非小细胞肺癌且先前未接触过PD-1 / PD-L1抑制剂（48人）; 第二组研究正在进行招募，将评估PD-1 / PD-L1抑制剂-难治性非小细胞肺癌患者，预期纳入58位患者。使用选择性AXL抑制剂bemcentinib和抗PD-1抗体pembrolizumab在晚期非小细胞肺癌患者中进行。符合条件的患者在组织学或细胞学上均已证实为IV期腺癌，并且有足够的新鲜肿瘤组织用于评估PD-L1和AXL的表达。治疗包括200毫克的Pembrolizumab和400毫克的bemcentinib负荷剂量，然后每天200毫克一次。该试验的终了目标为客观响应率。次要终点包括疾病控制率，缓解持续时间，无进展生存期，以及12个月生存率。

结果表明，通过组合使用，客观缓解率为40％，中位总生存期为12.2个月。超过了单一PD-1抑制剂作为二线治疗的历史基准，尤其是在PD-L1低表达患者中。

联合治疗耐受性好。最常见的治疗相关不良事件包括转氨酶升高（35％），乏力（30％）和腹泻（26％）。转氨酶升高是可逆的。

研究者认为, 该研究主要针对PD-L1阴性（53％）患者，他们不太可能受益于pembrolizumab单药治疗; 以及AXL阳性（58％）患者。联合bemcentinib和pembrolizumab用药有临床活性, 总体耐受性良好。

Non-small cell lung cancer patients who received a combination of the selective AXL inhibitor bemcentinib and pembrolizumab after chemotherapy showed promising clinical activity, particularly in patients with low PD-1 expression and AXL-positive tumors.
AXL kinase is a cell membrane receptor. It is an important mediator of biological mechanisms of certain life-threatening diseases. In cancer, AXL inhibits the body’s immune response to tumors and can also lead to cancer treatment failure. Therefore, AXL inhibitors have potential value in cancer combination therapy.
This Phase II clinical trial (BGB008, NCT03184571) includes two types of studies. In the initial stage, participants had platinum-refractory non-small cell lung cancer and had not previously been exposed to PD-1/PD-L1 inhibitors (48 patients); the second phase is undergoing recruitment and will evaluate PD- 1/PD-L1 inhibitor – refractory non-small cell lung cancer patients (expected to include 58 patients). The selective AXL inhibitor bemcentinib and the anti-PD-1 antibody pembrolizumab were used in patients with advanced non-small cell lung cancer. Eligible patients have been confirmed as stage IV adenocarcinoma either histologically or cytologically. There is enough fresh tumor tissue to assess the expression of PD-L1 and AXL. Treatment consisted of 200 mg of Pembrolizumab and a loading dose of 400 mg of bemcentinib, followed by 200 mg once a day. The primary end point of the trial was the objective response rate. Secondary endpoints included disease control rate, duration of remission, progression-free survival, and 12-month survival.
The results showed that the objective response rate was 40% and the median overall survival was 12.2 months, which exceed the historic control of a single PD-1 inhibitor as a monotherapy in second-line setting, especially in patients with low PD-L1 expression.
The combination therapy is well tolerated. The most common treatment-related adverse events included elevated transaminases (35%), fatigue (30%), and diarrhea (26%). Elevase transaminase elevation is reversible.
This study is primarily directed at PD-L1 negative (53%) patients who are less likely to benefit from pembrolizumab monotherapy, and AXL positive (58%) patients. The combination of bemcentinib and pembrolizumab is clinically active and generally well tolerated.

参考文献 Reference

https://www.onclive.com/conference-coverage/wclc-2019/bemcentinibpembrolizumab-combo-active-in-chemorefractory-nsclc  

 

术前talazoparib在BRCA突变的可手术乳腺癌中诱导病理完全反应 (9/22/2019)

Neoadjuvant talazoparib induced pathological complete response in operable breast cancer with BRCA mutation

一项小型单臂导引试验研究结果显示，携带BRCA突变的患者, 术前接受talazoparib可导致相当高的病理完全响应率。

这是第一项在没有化疗的情况下单独进行靶向治疗的研究。有20位病人参加, 她们都有BRCA种系突变（BRCA1，16人; BRCA2，4人）。 中位年龄为38岁（23-58岁）, 试验目的为研究单剂talazoparib（Talzenna）和病理完全响应的关系。

其中15名女性患有三阴性乳腺癌，5名患有激素受体阳性疾病。大多数女性（12人）患有II期疾病，5名患有I期疾病。三名女性患有III期疾病，其中一名患有炎性乳腺癌，一名患有化生性软骨肉瘤 （metaplastic chondrosarcomatous carcinoma）。 她们每天接受1 毫克talazoparib, 治疗6个月而不进行化疗，然后由医生决定接受明确的手术和辅助治疗。

研究人员使用残余癌症负荷（residual cancer burden , RCB）计算器测量病理响应，范围从RCB-0（病理完全响应）到RCB-III。结果显示RCB-0率为53％（95％CI，32-73），RCB-0 / I率为63％（95％CI，41-81）。两名患者有RCB-I，五名患者有RCB-II，三名患者有RCB-III响应。一名治疗5个月后淋巴结肿大的妇女在手术前进行化疗，未纳入RCB分析。  研究人员观察到RCB-0或RCB-I发生在大多数BRCA1突变女性（53％; 95％CI，27-79）和所有BRCA2突变女性（100％; 95％CI，40-100），以及在激素受体阳性和三阴性乳腺癌的女性中。

11名妇女在1毫克剂量下完成治疗。血液学毒性导致两名女性的剂量减少至0.75 毫克，六名女性减少至0.5 毫克，一名女性减少至0.25 毫克。

A small one-arm pilot trial showed that BRCA-mutated breast cancer patients received talazoparib preoperatively had a quite high pathologic complete response rate.

This is the first study using target therapy alone without chemotherapy. There were 20 patients who had BRCA germline mutations (BRCA1, n=16; BRCA2, n=4). The median age was 38 years (23-58 years) and the goal of the trial was to investigate the relationship between single dose talazoparib (Talzenna) and pathological complete response.

Among these patients, 15 women had triple-negative breast cancer and 5 had hormone receptor-positive disease. Most women (12) had stage II disease and 5 had stage I disease. Three women had stage III disease, one with inflammatory breast cancer and one with metaplastic chondrosarcomatous carcinoma. They received 1 mg of talazoparib daily for 6 months without chemotherapy, folloed by definite surgery and adjuvant therapy at the discretion of the doctors.

The researchers used a residual cancer burden (RCB) calculator to measure pathological responses ranging from RCB-0 (pathologic complete response) to RCB-III. The results showed a RCB-0 rate of 53% (95% CI, 32-73) and a RCB-0/I rate of 63% (95% CI, 41-81). Two patients had RCB-I, five patients had RCB-II, and three patients had RCB-III response. A woman who had a swollen lymph node after 5 months of treatment received chemotherapy before surgery and was not included in the RCB analysis. The researchers observed that RCB-0 or RCB-I occurred in most BRCA1 mutant women (53%; 95% CI, 27-79) and all BRCA2 mutant women (100%; 95% CI, 40-100), and among women with hormone receptor-positive and triple-negative breast cancer.

Eleven women completed treatment at a dose of 1 mg. Hematological toxicity reduced the dose of two women to 0.75 mg, six women to 0.5 mg, and one woman to 0.25 mg.

参考文献 Reference

Litton JK, et al. J Clin Oncol. 2019; doi:10.1200/JCO.19.01304

 

两项临床试验的5年汇总分析: Nivolumab相比于泰索帝治疗非小细胞肺癌 (9/21/2019)

Pooled analysis from two phase III trials showed survival benefit of Nivoluman versus docetaxel in previously treated non-small cell lung cancer

两项随机III期临床试验（CheckMate 017和057）的汇总数据显示，与化疗泰索帝相比，对先前治疗过的非小细胞肺癌患者, 接受nivolumab使5年总生存率增加了5倍以上。
从历史上看，晚期非小细胞肺癌患者的预后较差，常规化疗后5年生存率低于5％。 Nivolumab于2015年获得美国FDA批准用于先前治疗过的晚期患者，CheckMate 017和057是第一个报告PD-1抑制剂在先前治疗过的晚期非小细胞肺癌中5年结果的III期试验。 有854名患晚期非小细胞肺癌，在一线铂类化疗期间或之后疾病进展被随机分配至nivolumab或泰索帝（1:1）, 直到疾病进展或不可接受的毒性。在完成初步分析后，泰索帝组中不再接受益处的患者可以交叉接受nivolumab。研究人员将总体生存率作为两项研究的主要终点。

5年后, 与泰索帝相比，Nivolumab继续显示长期总生存期和无进展生存获益，5年生存率为13.4％相对于 2.6％，无进展生存率为8％相对于 0％。在5年的随访中，nivolumab组中的50名患者和多西紫杉醇组中的9名患者存活。两组中5年生存者的基线特征与总体人群和存活不到1年的患者相似，除了功能状态（ECOG）为0或PD-L1表达>1%（nivolumab组）, 或除了功能状态（ECOG）为0和IIIB期（泰索帝组）。

在随访时间内，未发现新的安全信号。在3至5年的随访期间，31名接受nivolumab治疗的患者中有8名（26％）报告了治疗相关的不良事件，1名患者（3％）报告了3级或4级事件。最常见的选择性不良事件（具有潜在免疫原因的事件）与4名患者的皮肤有关（13％），没有3级或4级不良事件。

Pooled analyses from two randomized phase III clinical trials (CheckMate 017 and 057) showed that nivolumab increased the 5-year overall survival rate by more than 5 times in patients with previously treated non-small cell lung cancer (NSCLC) compared with Taxotere. .

Historically, patients with advanced NSCLC have a poor prognosis, with a 5-year survival rate of less than 5% after conventional chemotherapy. Nivolumab was approved by FDA for use in previously treated advanced patients in 2015. CheckMate 017 and 057 were the first phase III trials to report 5-year results of PD-1 inhibitors in previously treated advanced NSCLC. There were 854 patients with advanced NSCLC who were randomly assigned to nivolumab or docetaxel (1:1) during or after first-line platinum-based chemotherapy until disease progression or unacceptable toxicity. After completing the preliminary analysis, patients who no longer benefited from docetaxel can cross-over to receive nivolumab. Overall survival is the primary endpoint of both studies.

After five years, compared with docetaxel, Nivolumab continued to show long-term overall survival and progression-free survival benefit, with a 5-year survival rate of 13.4% versus 2.6% and a progression-free survival rate of 8% versus 0%. At 5-year of follow-up, 50 patients in the nivolumab group and 9 patients in the docetaxel group survived. The baseline characteristics of 5-year survivors in the two groups were similar to those in the overall population and those who survived less than 1 year, except for functional status (ECOG=0)  or PD-L1 expression >1% (nivolumab group), or functional status (ECOG=0) ) for the 0 and IIIB stage (docetaxel group).

No new safety signs were found during the follow-up period. During the 3 to 5-year follow-up, 8 (26%) of the 31 patients who received nivolumab reported treatment-related adverse events, and 1 patient (3%) reported grade 3 or 4 events. The most common adverse events (events with potential immunological causes) were associated with skin in 4 patients (13%) and no grade 3 or 4 adverse events.

参考文献 Reference

Press release. International Association for the Study of Lung Cancer. Published September 10, 2019. https://bit.ly/2kpO5jr.

新的治疗转移性胰腺癌的药物 (9/15/19)

A new drug, CPI-613, for metastatic pancreatic cancer

研究人员开发的一种新药物，名为CPI-613（Devimistat）, 其靶向参与胰腺癌细胞生长的酶，正与标准化疗方案（FOLFIRINOX）联合用于治疗胰腺癌。有望改善转移性胰腺癌的治疗。

CPI-613, 针对线粒体三羧酸（TCA）循环, 靶向参与癌细胞能量代谢的酶。这是一种选择性地针对肿瘤细胞增殖和存活至关重要的过程。 Devimistat还显著增加癌细胞对多种化学治疗剂的敏感性。这种协同作用使得devimistat能与较低剂量的有毒的化疗药物组合, 以降低副作用。美国FDA批准CPI-613在胰腺癌（AVENGER 500）中开展关键的3期临床试验，并指定devimistat作为治疗胰腺癌的孤儿药。

之前的第一阶段研究显示，与单独使用化疗相比，使用CPI-613与化疗组合的患者总生存期中位数为20个月。同一项研究显示联合治疗的肿瘤反应率为61％，而标准治疗方案则为近32％。

A new drug, called CPI-613 (Devimistat), targets enzymes involved in the growth of pancreatic cancer cells. It is being used in combination with a standard chemotherapy regimen (FOLFIRINOX) for the treatment of pancreatic cancer. It is expected to improve the treatment of metastatic pancreatic cancer.
CPI-613, targeting the mitochondrial tricarboxylic acid (TCA) cycle, targets enzymes involved in the energy metabolism of cancer cells. This is a process that is critical for the proliferation and survival of tumor cells. Devimistat also significantly increases the sensitivity of cancer cells to a variety of chemotherapeutic agents. This synergy allows devimistat to be combined with lower doses of toxic chemotherapy drugs to potentially reduce side effects. FDA has approved CPI-613 for a key phase 3 clinical trial in pancreatic cancer (AVENGER 500) and designated devimistat an orphan drug for the treatment of pancreatic cancer.

The previous Phase I study showed a median overall survival of 20 months in patients who received CPI-613 in combination with chemotherapy compared with chemotherapy alone. The same study showed a 61% tumor response rate for combination therapy and nearly 32% for the standard treatment regimen.

参考文献 Reference

https://news.stonybrook.edu/newsroom/press-release/medical/drug-designed-to-treat-metastatic-pancreatic-cancer-may-help-extend-life/

Alistar AT et al JCO 2019 doi/abs/10.1200/JCO.2019.37.4_suppl.TPS459?af=R

 

Pyrotinib联合卡培他滨治疗HER2阳性转移性乳腺癌 (9/14/2019)

Pyrotinib plus capecitabine for metastatic HER-2-positive breast cancer

Pyrotinib（不可逆的泛ErbB抑制剂）联合卡培他滨, 优于拉帕替尼加卡培他滨。

这是一个开放标签，多中心，随机II期临床试验, 有128位中国患者参加。她们患复发或转移性, HER2阳性乳腺癌, 先前接受过紫杉烷类，蒽环类抗生素和/或曲妥珠单抗治疗 。她们被随机分配到pyrotinib（每天口服一次400 毫克, 65人）或拉帕替尼（每天口服一次1.250 毫克,  63人）治疗组。两组都联合使用药卡培他滨（第1至14天每天口服1,000 毫克/平方米）。主要终点是研究者评估的总响应率。
Pyrotinib组的总反应率为78.5％（95％置信区间 = 68.5-88.5％），拉帕替尼组为57.1％（95％置信区间 = 44.9-69.4％）（治疗差异为21.3％;  95％ 置信区间= 4.0- 38.7％; p = .01）。使用pyrotinib的中位无进展生存期为18.1个月（95％置信区间 = 13.9个月- 未达到），拉帕替尼为7.0个月（95％置信区间 = 5.6至9.8个月）（校正风险比为0.36; 95％ 置信区间 = 0.23-0.58; p <.001）。

最常见的3/4级不良事件包括手足综合征为24.6%（pyrotinib组, 24.6％）, 相对于20.6%（拉帕替尼组）;腹泻为15.4％, 相对于4.8％; 中性粒细胞计数减少分别为9.2％和3.2％。

结论是, 对于先前用紫杉烷，蒽环霉素和/或曲妥珠单抗治疗的HER2阳性转移性乳腺癌女性，与拉帕替尼加卡培他滨相比，pyrotinib加卡培他滨在总体缓解率和无进展生存率方面具有统计学意义。

Pyrotinib (an irreversible pan-ErbB inhibitor) in combination with capecitabine is superior to lapatinib plus capecitabine.
This is an open-label, multicenter, randomized phase II clinical trial involving 128 Chinese patients. They have recurrent or metastatic, HER2-positive breast cancer who have previously been treated with taxane, anthracycline and/or trastuzumab. They were randomized to either pyrotinib (400 mg orally, once daily, 65 patients) or lapatinib (1.250 mg orally, once daily, 63 patients). Both groups were given the combination of capecitabine (1,000 mg/m 2 per day for days 1 to 14). The primary endpoint was the total response rate assessed by the investigators.

The overall response rate was 78.5% in the Pyrotinib group (95% CI = 68.5-88.5%) and 57.1% in the lapatinib group (95% CI = 44.9-69.4%) (treatment difference was 21.3%; 95% CI= 4.0- 38.7%; p = .01). The median progression-free survival with pyrotinib was 18.1 months (95% CI = 13.9 months – not achieved), and lapatinib was 7.0 months (95% CI = 5.6 to 9.8 months).  Adjusted hazard ratio is 0.36; (95% CI = 0.23-0.58; p <.001).
The most common grade 3/4 adverse events included  hand-foot syndrome (24.6%, pyrotinib group) vs. 20.6% (lapatinib group); diarrhea 15.4% vs. 4.8%; neutropenia were 9.2% and 3.2%, respectively.

In conclusion, for women with HER2-positive metastatic breast cancer previously treated with taxane, anthracycline and/or trastuzumab, pyrotinib plus capecitabine compared to lapatinib plus capecitabine showed a statistically significant benefit in terms of overall response rate and progression-free survival.

参考文献 Reference

MA F et al. J Clin Oncol. 2019 Aug 20:JCO1900108. doi: 10.1200/JCO.19.00108

 

可渗透血脑屏障的纳米免疫结合物诱导胶质母细胞瘤的局部免疫应答 (9/8/2019)

Nano particles carrying checkpoint inhibitors induce brain immune response for glioma

使用纳米组合技术治疗携带胶质母细胞瘤小鼠的存活显著延长。
使用检查点抑制剂, 如抗细胞毒性T淋巴细胞相关抗原4（CTLA-4）和程序性细胞死亡-1（PD-1）来治疗脑胶质瘤, 由于无法穿过血脑屏障而大多失败。研究者在天然生物聚合物（β-L-苹果酸）支架上, 共价连接了靶向免疫物，与细胞毒性T淋巴细胞相关抗原4抗体或程序性细胞死亡-1抗体, 可以全身递送, 并穿过血脑屏障而激活局部脑对肿瘤免疫反应。带有颅内GL261胶质母细胞瘤的小鼠, 在接受了这种纳米免疫结合物后, 导致CD8 阳性 的T细胞，自然杀手（NK）细胞和巨噬细胞的增加，同时脑肿瘤区域中的调节性T细胞减少。与用游离的细胞毒性T淋巴细胞相关抗原4抗体或程序性细胞死亡-1抗体治疗的动物相比，用纳米免疫结合物组合治疗的携带GBM的小鼠的存活显著延长。研究证明, 穿过血脑屏障递送的靶向检查点抑制剂, 可以通过激活全身和局部脑肿瘤免疫应答，作为有效的胶质母细胞瘤治疗。

Survival of mice bearing glioblastoma was significantly prolonged using nano-conjugates techniques.

Treatment of gliomas with checkpoint inhibitors such as anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1), fails for most part due to their inability to cross the blood-brain barrier. Researchers engineered the target immunogen with a CTLA-4 or a PD-1 antibody covalently attached to a natural biopolymer scaffold, poly (β-L-malic acid), which can be delivered systemically, and through the blood-brain barrier to activate the local anti-tumor immune response in the brain. When mice carrying intracranial GL261 glioblastoma received this nanoimmunoconjugate (NIC), there was an increase in CD8-positive T cells, natural killer (NK) cells and macrophages, and reduced regulatory T cells in the brain tumor areas. Survival of GBM-bearing mice treated with the combination of NIC was significantly prolonged compared to animals treated with single check-point inhibitor-bearing NICs or free CTLA-4 or PD-1 antibody. Studies have shown that targeted checkpoint inhibitors delivered across the blood-brain barrier can be used as effective glioblastoma treatment by activating both systemic and local brain tumor immune responses.

参考文献 Reference

Galstyan A et al. Nature Communocations 2019; 10: 3850      

 

组蛋白去乙酰化酶抑制剂abexinostat和pembrolizumab在多种实体肿瘤中的数据 (9/7/2019)

Phase Ib data about combination of histone deacetylase inhibitor abexinostat and pembrolizumab in solid tumors

美中肿瘤药物开发公司（Xynomic Pharma），宣布其正在进行的第1b期临床研究中期数据，该研究的主要候选药物abexinostat，为一种口服剂量，基于异羟肟酸的小分子组蛋白去乙酰化酶（HDAC）抑制剂，与pembrolizumab;联合用于治疗多种实体瘤。该试验正在旧金山加利福尼亚大学进行。中期数据也将在2019年8月30日至31日在北京举行的第三届中国免疫和基因治疗大会上发布。

该试验有7名患者参加研究的剂量递增部分, 他们之前曾接受抗PD1 / PD-L1治疗而疾病进展。肿瘤类型包括黑素瘤（3人），尿路上皮癌（2人），神经内分泌癌（1人）和食道鳞状细胞癌（1人）。先前全身治疗的中位数为3, 患者人群的中位年龄为61。在所测试的两个剂量水平（第1-4, 8-11天abexinostat 30 毫克/平方米和45 毫克/平方米） 与pembrolizumab联合使用（第1天静脉注射200毫克），没有剂量限制性毒性。未达到最大耐受剂量，推荐的2期剂量为第1天pembrolizumab 静脉注射200 毫克; 第1-4, 8-11天的 abexinostat 45毫克/平方米每天口服两次，21天为一周期。

没有治疗相关≥3级不良事件。最常见的1-2级不良事件是腹泻（3人），皮疹（2人），血小板减少症（1人）和味觉障碍（1人）。 7名患者中有2名（29％）疾病稳定> 6个月。这2名患者中有1名患有 pembrolizumab难治性尿路上皮癌，并且治疗6个月以上，肿瘤大小从基线开始减少20％。

该试验的剂量扩展部分的注册正在进行，以确定肿瘤类型的反应率和疾病控制率。该试验的目标是在美国招募约42名患者。
Abexinostat is an oral small molecule histone deacetylase  (HDAC) inhibitor, by Xynomic Pharma, Inc. The company announced its ongoing phase Ib clinical study, using abexinostat in combination with pembrolizumab, to treat a variety of solid tumors. The trial is being conducted at the University of California, San Francisco. The interim data will also be released at the 3rd China Immunization and Gene Therapy Conference in Beijing from August 30 to 31, 2019.

The trial included seven patients enrolled in a dose escalation section of the study. All patients had previously received anti-PD1 / PD-L1 treatment with subsequent disease progression. Tumor types include melanoma (3), urothelial carcinoma (2), neuroendocrine carcinoma (1 ), and esophageal squamous cell carcinoma (1). The median number of previous systemic treatments was 3, and the median age of the patient population was 61. At the two dose levels tested ( abexinostat 30 mg/m2 and 45 mg/m2 for days 1-4 and 8-11) in combination with pembrolizumab (200 mg intravenously on day 1). There was no dose-limiting toxicity . The maximum tolerated dose was not reached. The recommended phase 2 dose was pembrolizumab, 200 mg intravenously on day 1 and abexinostat, Bid 45 mg/m 2 on days 1-4 and 8-11. The treatment cycle was 21 days.
There were no treatment-related ≥3 adverse events. The most common grade 1-2 adverse events were diarrhea (3), rash (2), thrombocytopenia (1), and taste disorder (1). Two of the seven patients (29%) had stable disease > 6 months. One of the two patients had pembrolizumab refractory urothelial carcinoma, and remains on treatment for >6 months. The tumor size decreased by 20% from baseline.

The registration of the dose extension portion of the trial is ongoing to determine the response rate and disease control rate across tumor types. The goal of the trial was to recruit approximately 42 patients in the United States.

参考文献 Reference

http://obroncology.com/news-2/ 2019; August 30

 

难治性多发性骨髓瘤的新药Selinexor (9/1/2019)

Selinexor: A promising new drug for refractory multiple myeloma

Selinexor  （XPOVIO）, 一个选择性细胞核输出化合物的抑制剂, 并使细胞核内肿瘤抑制蛋白的积累和活化, 最近获得FDA批准，用于治疗难治性多发性骨髓瘤，这些病人对蛋白酶体抑制剂，免疫调节剂和抗CD38单克隆抗体（三级耐药）均无效。

一项在美国和欧洲进行的临床2b期试验（STORM）, 共有122名患者参加到意向治疗人群（初步分析），123名参加到安全人群。中位年龄为65岁，之前治疗方案的中位数为7; 共有53％的患者存在高风险的细胞遗传学异常。Selinexor（80 毫克）与地塞米松（20 毫克）每周两次联合使用。治疗终了目标是总体响应，定义为部分响应或更好，由独立审查委员会评估。

在26％的患者中观察到部分响应或更好（95％置信区间 = 19至35），包括两个严格的完全反应; 39％的患者取得最小响应或更好。中位响应持续时间为4.4个月，中位无进展生存期为3.7个月，中位总生存期为8.6个月。

治疗相关的副作用为疲劳，恶心和食欲降低是常见的，通常为1级或2级（高达25％的患者注意到3级事件，未报告4级事件）。 73％的患者出现血小板减少症（25％为 3级，33％为4级）。血小板减少导致6名患者出现3级或更高级别的出血事件。

Selinexor (XPOVIO), an inhibitor of selective nuclear export compounds, which enforces the accumulation and activation of tumor suppressor proteins inside the nucleus, recently received approval by the FDA for the treatment of refractory multiple myeloma, where a proteasome inhibitor, immunomodulators and anti-CD38 monoclonal antibodies (triple class  refractory) were ineffective.

In a clinical phase 2b trial (STORM) conducted in the United States and Europe, a total of 122 patients participated in the modified intent-to-treat population (primary analysis) and 123 participated in the safety population. The median age was 65 years, and the median of previous treatment regimens was 7; a total of 53% of patients had high-risk cytogenetic abnormalities. Selinexor (80 mg) was combined with dexamethasone (20 mg) twice a week. The primary end point was overall response, defined as partial response or better, as assessed by an independent review committee.

A partial response or better was observed in 26% of patients (95% CI = 19 – 35), including two strict complete responses; 39% achieved minimal response or better. The median response duration was 4.4 months, the median progression-free survival was 3.7 months, and the median overall survival was 8.6 months.

Treatment-related side effects including fatigue, nausea and loss of appetite are common, usually grade 1 or 2 (up to 25% of patients noticed a grade 3 event and no grade 4 event was reported). Thrombocytopenia occurred in 73% of patients (25% grade 3, 33% grade 4). Thrombocytopenia resulted in a grade 3 or higher bleeding events in 6 patients.

参考文献 Reference

Chari A. et al. N Eng J Med 2019; 38: 727-38

 

Lynch综合征的症致病性基因，年龄和性别相对于癌症风险 (8/31/2019)

Cancer risk by pathogenetic mismatch repair genes, gender and age in Lynch syndrome

一个Lynch综合征致病性基因，性别和年龄与癌症风险相关性的新见解。

研究者利用数据库的6,350名Lynch综合征致病性错配修复变基因（MLH1，MSH2，MSH6和PMS2），对它们和年龄及性别相对于癌症风险, 作前瞻性的研究。研究者使用4类或5类变体携带者的独立测试和验证队列, 进行了一项国际多中心观察研究。验证后，这些队列合并，提供6350名参与者和51,646名随访年（follow-up years）。

一共观察到1,808个前瞻性癌症。

• 致病性MLH1和MSH2变异导致高外显率显性癌症综合征，具有相似的结直肠癌，子宫内膜癌和卵巢癌风险。
• 但年龄较老的MSH2携带者具有更高的上尿路，上胃肠道，脑，特别是前列腺癌的风险。
• 致病性MSH6变异导致性别限制外显率，具有高子宫内膜癌风险，但结直肠癌风险仅在男女性别中适度增加。
• 致病性PMS2变体携带者的癌症风险并没有显著增加。患了结肠癌，子宫内膜癌或卵巢癌后的10年原始存活率超过80％。

研究者认为, Lynch综合征的管理指南可能需要根据这些不同的基因和性别特异性风险, 以及最常见相关癌症的预后进行修订。

A new insight of correlation of different pathogenic genes in Lynch syndrome, gender and age with cancer risks has been illustrated.
The researchers used a database of 6,350 Lynch syndrome with pathogenic mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) for a prospective study of their age and gender relative to cancer risk. The investigators conducted an international multicenter observational study using an independent test and validation cohort of class 4 or 5 variant carriers. After validation, these cohorts were merged, providing 6,350 participants and 51,646 follow-up years.

A total of 1,808 prospective cancers were observed.
1) Pathogenic MLH1 and MSH2 mutations result in high penetrance dominant cancer syndromes sharing similar risk of colorectal cancer, endometrial cancer and ovarian cancer.
2) Older MSH2 carriers have a higher risk of upper urinary tract, upper gastrointestinal tract, brain, and especially prostate cancer.
3) Pathogenic MSH6 mutations lead to sex-limited trait with a higher risk of endometrial cancer, but only a moderately increased risk of colorectal cancer among men and women.
4) There is no significantly increased cancer risk in pathogenic PMS2 variant carriers. The 10-year crude survival rate after colon cancer, endometrial cancer or ovarian cancer was over 80%.

The investigators believe that the management guidelines for Lynch syndrome may need to be revised based on these different genetic and gender-specific risks, as well as the prognosis of the most commonly associated cancers.

参考文献 Reference

Dominguez-Valentin M et al. Genetics in Medicine 2019;  https://doi.org/10.1038/s41436-019-0596-9

 

PARP抑制剂/化疗组合治疗复发性小细胞肺癌 (8/25/2019)

PARP inhibitor and chemotherapy for recurrent small cell lung cancer

根据一项I / II期临床试验结果，PARP抑制剂奥拉帕尼olaparib（Lynparza）与化疗药物替莫唑胺（Temodar）联合应用对复发性小细胞肺癌有效。

这项单臂试验于2015年10月至2018年4月期间招募了50名先前接受过中位数为两次治疗（1-7次）的复发性小细胞肺癌患者。 13名患者参加了I期剂量递增研究，主要目标是确定推荐的II期剂量。 37名患者参加了推荐的II期剂量扩张部分，主要目的是评估疗效。

患者在第1天至第7天（21天为一周期）口服奥拉帕尼和替莫唑胺, 重复该

周期直至疾病进展或不可接受的毒性。在I期部分评估四个剂量水平，推荐的II期剂量奥拉帕尼为每天两次200毫克，替莫唑胺为每天一次75毫克/平方米。

在该研究的两个部分中治疗的48名可评估患者的总体响应率为41.7％（20名部分响应，没有患者取得完全响应）。在参与该研究的所有50名患者中，中位无进展生存期和中位总生存期分别为4.2个月和8.5个月。在推荐的II期剂量治疗的可评估患者中（39名患者），总体响应率为41.0％。

最常见的治疗相关不良事件是血小板减少症（68％），贫血（68％）和中性粒细胞减少症（54％）。在研究的II期部分发生了两个5级不良事件，这可能归因于研药物的副作用（一个是由于肺炎，另一个是由于中性粒细胞减少性败血症）。

为了确定可能预测对奥拉帕利/替莫唑胺组合反应的分子特征，研究人员对来自22名患者的32例源自患者的异种移植模型进行了一项平行临床试验。研究人员确定，四种炎症反应基因（CEACAM1，TNFSF10，TGIF1和OAS1）的特征可以发现和验证队列中敏感模型和抗性模型。此外，这些基因的低基础表达与顺铂/依托泊苷的耐药性相关 。由于试验的单臂性，这些结果无法直接与其他治疗选择进行比较。

According to a phase I / II clinical trial, the PARP inhibitor olaparib (Lynparza ) is effective in combination with a chemotherapy drug temozar (Temodar) for relapsed small cell lung cancer.

This one-arm trial enrolled 50 patients with recurrent small cell lung cancer who had previously received a median of two lines (1-7) treatment between October 2015 and April 2018. Thirteen patients participated in the Phase I dose escalation study with the primary goal of identifying the recommended Phase II dose（RP2D）. Thirty-seven patients participated in the RP2D expansion, with the primary goal of assessing efficacy.

Patients were given oral olaparib and temozolomide from day 1 to day 7 (21 days/cycle) and the cycle was repeated until disease progression or unacceptable toxicity. Four dose levels were evaluated in Phase I. The RP2D of olaparib was 200 mg twice daily and temozolomide was 75 mg/m 2 once daily.

The overall response rate of the 48 evaluable patients treated in the two parts of the study was 41.7% (20 partial responses, no patients achieved complete response). Among all 50 patients enrolled in the study, median progression-free survival and median overall survival were 4.2 months and 8.5 months, respectively. Among the evaluable patients (39 patients) who were on RP2D, the overall response rate was 41.0%.

The most common treatment-related adverse events were thrombocytopenia (68%), anemia (68%), and neutropenia (54%). Two grade 5 adverse events occurred in the phase II of the study, which may be due to side effects of the study drug (one due to pneumonia and the other due to neutropenic sepsis).

To determine the molecular characteristics that might predict the combination therapy, the researchers performed a co-clinical trial of 32 patient-derived xenograft models from 22 patients. The researchers determined that the characteristics of the four inflammatory response genes (CEACAM1, TNFSF10, TGIF1, and OAS1) can identify and validate sensitive or resistant models in the cohort. In addition, the low basal expression of these genes is associated with drug resistance of platinum/etoposide. Due to the one-arm nature of the trial, these results cannot be directly compared to other treatment options in similar setting.

参考文献 Reference

Farago AF et al. Cancer Discovery 2019; Aug 15. DOI: 10.1158/2159-8290.CD-19-0582

 

DNA修复抑制剂加放化疗为对胰腺癌的影响 (8/24/2019)
DNA repair inhibitor plus chemoradiation for locally advanced pancreatic cancer

一项临床一期试验显示，DNA修复抑制剂（Wee1抑制剂）adavosertib (AZD1775)加化放疗性, 具有良好的耐受, 可能延长局部晚期胰腺癌患者的寿命。

研究人员招募了34名中位年龄为68岁的患者, 5名患者患有cT4N1M0期疾病，其余患者分期为cT4N0M0; 中位肿瘤大小为3.0厘米。治疗包括在每周期的第1天和第8天使用吉西他滨（1.000 毫克/平方米, 3周为一周期），在第1, 2, 8和9天剂量接受adavosertib （剂量递增100至175 毫克/天），并且在第 2, 3周期接受25次放射治疗（一周5次）。 该试验的主要目的是确定adavosertib的最大耐受剂量。次要终了目标为包括总生存率期，无进展生存期，以及免​​于局部和远处进展的自由。
毛囊活组织检查样品证实了Wee1抑制的证据，在推荐的II期剂量下（150 毫克/天），施用adavosertib后, 通过免疫组织化学降低了细胞周期蛋白依赖性激酶1染色的磷酸化。作者报告18名患者总共有27个3/4级治疗相关的不良事件。最常见的不良事件是发热性中性粒细胞减少症（4名患者），厌食/恶心呕吐（3名），疲劳（3名）和发烧（3名）。 1例患者出现胃肠道出血，1例出现心肌梗塞，1例出现肺栓塞，2例出现脓毒性休克。研究期间未发生与治疗相关的死亡。

中位随访15个月，34例患者的中位生存期为21.7个月，中位无进展生存期为9.4个月。相比之下，先前对化放疗的评估导致中位生存期为12至14个月。推荐的II期adavosertib剂量为150 毫克/天。

作者认为，adavosertib与吉西他滨和放射疗法的组合在一定剂量下具有良好的耐受性，并在替代组织中产生靶标反应。 总体存活率显着高于将吉西他滨与放射疗法相结合的先前结果。但需要进行额外的研究。

A phase I clinical trial showed that DNA repair inhibitor (Wee1 inhibitor) adavosertib (AZD1775) plus chemo-radiotherapy was well-tolerated and may prolong the lifespan of patients with locally advanced pancreatic cancer.
The researchers enrolled 34 patients with a median age of 68 years, 5 patients with cT4N1M0 disease, and the remaining patients with cT4N0M0; the median tumor size was 3.0 cm. Treatment consisted of the use of gemcitabine (1.000 mg/m2 for a 3-week cycle) on days 1 and 8 of each cycle and adatsertib on days 1, 2, 8 and 9 (dose increment 100 up to 175 mg/day) and 25 fractions of radiation treatments (5 times a week) during the 2nd and 3rd cycle. The main purpose of this trial was to determine the maximum tolerated dose of adavosertib. Secondary end goals include overall survival, progression-free survival, and freedom from local and distant progression.

Hair follicle biopsy confirmed evidence of Wee1 inhibition, and phosphorylation of CDK1 staining was reduced by immunohistochemistry after administration of adavosertib at the recommended phase II dose (150 mg/day). The authors reported a total of 27 grade 3/4 treatment-related adverse events in 18 patients. The most common adverse events were febrile neutropenia (4 patients), anorexia/nausea and vomiting (3), fatigue (3) and fever (3). One patient developed gastrointestinal bleeding, one patient developed myocardial infarction, one patient developed pulmonary embolism, and two patients developed septic shock. No treatment-related deaths occurred during the study.
At a median follow-up of 15 months, 34 patients had a median survival of 21.7 months and a median progression-free survival of 9.4 months. In contrast, previous assessments of chemoradiation resulted in a median survival of 12 to 14 months. The recommended dose of stage II adavosertib is 150 mg / day.

The authors conclude that the combination of adavosertib with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. Overall survival was significantly higher than previous reported results regarding combining gemcitabine with radiation therapy. However, additional research is needed.

参考文献 Reference

Cuneo KC et al. J Clin Onc 2019; Aug. 5. https://doi.org/10.1200/JCO.19.00730

 

一种新的输送系统可将药物输送到大脑 (8/18/209)

A new delivery system that carries drugs to the brain

研究人员开发了一种纳米级胶囊的药物输送系统，可以突破血脑屏障，用以治疗已经扩散到中枢神经系统的癌症。

对扩散到神经系统的癌症，有效治疗方案很少，一个原因是由于血脑屏障，它是防止有害物质进入大脑的天然防御系统，这种屏障还防止迄今为止开发的大多数小分子药物和抗癌大分子药物有效地治疗中枢神经系统的转移瘤。 研究人员制作了一个大约1纳米或十亿分之一米的胶囊（相当于一张纸厚度的十万分之一）, 胶囊上涂有一种叫做2-甲基丙烯酰氧基乙基磷酸胆碱的物质，能够使纳米级胶囊通过胆碱转运蛋白和乙酰胆碱受体转运，而穿过血脑屏障。这种物质组合允许胶囊在体液中缓慢降解，以提供足够的时间在整个身体内循环, 但在肿瘤周围的酸性微环境中快速释放包封的抗体。避免了不合时宜的释放。

研究人员将纳米胶囊加入抗B细胞淋巴瘤的癌药物利妥昔单抗（rituximab），然后将其给予患有转移至中枢神经系统的人类淋巴瘤的小鼠。并且追踪肿瘤在四个月内是如何生长或萎缩的。 当纳米胶囊用CXCL13（趋化因子受体CXCR5的配体, 这种配体经常在B细胞淋巴瘤上发现）进行功能化时，单剂量利妥昔单抗可以改善对小鼠移植模型中表达CXCR5的非霍奇金淋巴瘤的控制。
研究人员将进行其他研究，包括用纳米级胶囊携带FDA批准的药物, 针对已经扩散到中枢神经系统的癌症。

Researchers have developed a nano-capsule drug delivery system that penetrates the blood-brain barrier to treat cancer that has spread to the central nervous system.For cancers that spread to the central nervous system, there are few effective treatment options. One reason is due to the blood-brain barrier, which is a natural defense system that prevents harmful substances from entering the brain. This barrier also prevents most of the small molecule drugs developed so far, as well as macromolecular cancer drugs from effectively treating metastatic tumors in the central nervous system. The researchers made a capsule of about 1 nanometer or a billionth of a meter (a hundred-thousandth of the thickness of a piece of paper) coated with a type of 2-methacryloyloxyethyl phosphate substance that causes nano-capsules to go through the choline transporters and acetylcholine receptors to eventually penetrate the blood-brain barrier. This combination of surface materials also allows the capsule to slowly degrade in body fluids to provide sufficient time to circulate throughout the body, while rapidly release the encapsulated antibodies in the acidic microenvironment surrounding the tumor. Thus untimely release can be avoided.The researchers encapsulated anti-B cell lymphoma drug, rituximab, in the nano-capsule, and then administered it to mice that already have human lymphoma cells metastasized to the central nervous system. They tracked how the tumor cells grow or shrink within four months. When nano-capsules are functionalized with CXCL13 (a ligand for the chemokine receptor CXCR5, which is often found on B-cell lymphoma), a single dose of rituximab can improve the control of CXCR5-expressing non-Hodgkin’s lymphoma xenograft in a mouse model.Researchers will conduct further research, including testing FDA-approved drugs encapsulated in nano-capsules for metastatic cancers in the central nervous system.参考文献 ReferenceWen, J et al. Nature Biomed Engineer 2019; Aug. 5. https://doi.org/10.1038/s41551-019-0434-z

 

增加遗传性胰腺癌风险的新基因突变 (8/17/2019)

Identification of a new hereditary pancreatic cancer risk mutation

最近一项报导, 发现了一种被称为RABL3的遗传基因突变，它大大增加了胰腺和其他癌症的终生风险。

大约10％的胰腺癌具有家族性模式，在大多数情况下，致病遗传缺陷尚不清楚。已知一种可导致易患胰腺癌的遗传突变发生在BRCA2基因中，该基因也导致一些乳腺癌和卵巢癌。基因RABL3中新发现的突变同样增加了癌症在人一生中发展的可能性。

一个家庭中有五个亲属患有胰腺癌，该家族成员在48岁时患上了胰腺癌，而其父亲的叔叔则在80岁时被诊断出患有此病。多个家庭成员患有其他癌症，该分析包括测序一位家族成员的DNA，RABL3突变被确定,  在其他几位患有癌症的家庭成员中也发现了RABL3突变。 这种模式表明遗传性突变导致了患癌症的倾向。

通过流行病学方法以确认新的基因突变导致癌症,  通常需要许多年来寻找世界各地类似的家庭。因此，科学家转向斑马鱼（zebrafish）模型。通过重演斑马鱼群体中的基因突变，该团队可以在该动物模型中进行快速流行病学研究，以评估突变对癌症风险的影响。结果，与患者家族中的个体相似，携带RABL3突变的斑马鱼具有更高的癌症发病率。

RABL3中的突变是天生的癌症易感基因突变，增加了后天癌症发展的风险。研究人员发现，RABL3突变加速了细胞内胰腺癌蛋白KRAS的运动。这种改变有利于KRAS在细胞膜中的存在，并引发一系列促进癌症生长的事件。由于KRAS活性在大多数胰腺癌中发生了改变，因此研究RABL3突变对KRAS活性的影响可以提供关于胰腺癌发展的重要见解以及靶向治疗的新策略。

RABL3突变在一般人群中很少见，但对其进行检测, 以识别这些家族中的突变将有助于指导哪些亲属应该考虑胰腺癌筛查, 以及RABL3基因中可能的其他突变, 帮助揭示其他家族中遗传易感性。

A recent report found a genetic mutation called RABL3 that greatly increases the lifetime risk of pancreatic and other cancers.

About 10% of pancreatic cancers have a familial pattern, and in most cases, the genetic defect of the disease is unclear. A known genetic mutation that causes pancreatic cancer occurs in the BRCA2 gene, which also causes some breast and ovarian cancers. Newly discovered mutations in the gene RABL3 also increase the likelihood that cancer will develop throughout life.

Five relatives in a family have pancreatic cancer: a member of the family developed pancreatic cancer at the age of 48, and his father’s uncle was diagnosed with the disease at the age of 80. Multiple family members have other cancers. The analysis included sequencing the DNA of a family member, RABL3 mutations were identified, and RABL3 mutations were also found in several other family members with cancer. This pattern suggests that hereditary mutations lead to a tendency to develop cancer.

It is often necessary to search for similar families around the world for many years through epidemiological studies in order to confirm new genetic cancer-causing mutations. Therefore, scientists turned to the zebrafish model. By recapitulating genetic mutations in the zebrafish, the team could conduct rapid epidemiological studies in this animal model to assess the impact of mutations on cancer risk. In reality, zebrafish carrying the RABL3 mutation has a higher incidence of cancer, similar to individuals in the patient family.

Mutations in RABL3 are cancer susceptibility gene mutations born with and increase the risk of cancer development in later life. The researchers found that RABL3 mutations accelerate the movement of the intracellular pancreatic cancer protein KRAS. This change favors the position of KRAS in cell membrane and triggers a series of events that promote cancer growth. Since KRAS activity has changed in most pancreatic cancers, studying the effects of RABL3 mutations on KRAS activity can provide important insights into the development of pancreatic cancer as well as new strategies for targeted therapy.

RABL3 mutations are rare in the general population. Testing them to identify mutations in families will help guide which relatives should be considered for pancreatic cancer screening.  Finding other possible mutations in the RABL3 gene may help reveal other families with genetic susceptibility.

参考文献 Reference

Nissim S et al. Nature Genetics 2019; DOI: 10.1038/s41588-019-0475-y

 

第一个针对KRAS的活性癌症药物 (8/4/2019)

First time target drug against KRAS mutation showed activity 

KRAS G12C是最常见的KRAS突变，估计发生在13％的肺癌和1-3％的其他实体瘤中。然而，一般认为RAS蛋白质是不可遏制的，没有药物可以有效结合。 Amgen公司的AMG 510靶向KRAS G12C是第一种显示对KRAS突变活性的药物, 也是同类药物中第一种发布临床数据的药物。

在今年的ASCO会议上, AMG 510在10名可评估的非小细胞肺癌患者的5名患者中缩小了肿瘤，并在另外4名患者中停止了肿瘤生长。在结肠直肠癌患者中，近四分之三的可评估患者实现了稳定的疾病, 但数据没有显示对药物的响应。不过，Amgen在7月30日的第二季度财报报告中称，AMG 510在19名患有结直肠癌和2名患有阑尾癌的患者中进行了测试,  它缩小了患有结肠直肠癌和阑尾癌的患者的肿瘤。但但没有提供细节。该研究测试了四种剂量：180毫克，360毫克，720毫克和 最大值为960毫克。结肠直肠癌中的响应是以较高剂量出现的，大多数患者将接受960毫克治疗。

I / II期试验的单药治疗扩展队列的入组已经完成。该公司计划开始招募患者进入I/II期的第二阶段; 还正在将患有非小细胞肺癌的患者纳入AMG 510与PD-1抑制剂结合的组列中。

KRAS G12C is the most common KRAS mutation and is estimated to occur in 13% of lung cancers and 1-3% of other solid tumors. However, RAS proteins are generally considered to be undruggable and no drugs can effectively bind to it. Amgen’s AMG 510 targeting KRAS G12C is the first drug to show activity against KRAS mutations and is the first drug of its kind to release clinical data.

At this year’s ASCO meeting, AMG 510 shrank tumor size in five of the 10 evaluable non-small cell lung cancer patients and stopped tumor growth in four other patients. Nearly three-quarters of evaluable patients with colorectal cancer achieved stable disease, but the data did not show a response rate. However, Amgen said in the second quarter earnings report on July 30 that AMG 510 was tested in 19 patients with colorectal cancer and two patients with appendiceal cancer, and it reduced their tumor size too. But the company did not provide more details. The study tested four doses: 180 mg, 360 mg, 720 mg and a maximum of 960 mg. The response in colorectal cancer was achieved at higher doses, and most patients with colorectal and appendiceal cancer will receive 960 mg.

The enrollment of the monotherapy dose extension part of phase I/II trials has been completed. The company plans to begin recruiting patients into the second phase of Phase I/II. Patients with non-small cell lung cancer are also being included in the AMG 510 combination with PD-1 inhibitors.

参考文献 Reference

https://medcitynews.com/2019/07/amgen-cancer-drug-with-undruggable-target-shows-more-progress

 

Pembrolizumab与化疗结合用于手术前乳腺癌的3期研究（8/3/2019）

Pembrolizuman and chemotherapy combination in triple negative breast cancer reported to be successful

 

默克（Merck）公司宣布其药物pembrolizumab与化疗相结合，导致三阴性乳腺癌患者病理完全响应的统计学显著改善, 即在治疗和手术后采集的组织样本中没有癌症迹象。不管PD-L1蛋白质在患者肿瘤中表达如何，结果都可见。

这项由1,174名患者参加的研究（Keynote-522） , 病人在手术前得到pembrolizumab和化疗的组合, 或只是化疗，然后是手术后的pembrolizumab或安慰剂。治疗的终了目标为病理完全响应和无复发生存期。该公司现在将继续研究该方案是否达到其他主要目标，无事件生存,  延迟疾病进展或死亡。但该公司没有提供细节, 将在未来的医学会议上分享细节。

Merck announced that its drug, pembrolizumab, combined with chemotherapy resulted in a statistically significant improvement in the pathologic complete response rate of patients with triple-negative breast cancer, ie, no signs of live cancer cells in tissue samples taken after treatment and surgery. The outcome was not associated with the levels of PD-L1 protein expression in the patient’s tumor.

Altogether 1,174 patients participated the phase III study (Keynote-522). They were randomized to receive a combination of Keytruda and chemotherapy before surgery, or just chemotherapy, followed by post-operative Keytruda or placebo. The double endpoint of the trial is pathological complete response and event-free survival. The company will continue to study whether the study meets other major goals, effect-free survival, abd disease progression or death. However, the company did not provide details and will share details at future medical conference.

参考文献 Reference

https://investors.merck.com/news/press-release-details/2019/Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Chemotherapy-Met-Primary-Endpoint-of-Pathological-Complete-Response-pCR-in-Pivotal-Phase-3-KEYNOTE-522-Trial-in-Patients-with-Triple-Negative-Breast-Cancer-TNBC/default.aspx

 

长期使用邻苯二甲酸酯配制的药物与乳腺癌的风险 (7/28/2019)

Phthlate exposure and breast cancer risk

生活中与邻苯二甲酸酯（phthlate）接触无处不在，在由邻苯二甲酸酯配制的药物使用者中尤其高。体外实验显示, 一些邻苯二甲酸酯类似雌二醇，通过雌激素受体信号传导, 可能会促进乳腺癌。一项在丹麦进行的调查显示, 女性应避免长期使用邻苯二甲酸二丁酯配制的药物。
该研究使用丹麦药品管理局成分数据库确定了在丹麦销售的药物的邻苯二甲酸盐含量。 2005年1月1日，在丹麦全国范围内招募了112万名女性，这些女性有可能首次进行癌症诊断。通过将药物成分数据与丹麦国家处方登记处相结合，对年度累积邻苯二甲酸酯暴露进行了表征。然后，根据肿瘤雌激素受体状态，拟合多变量Cox回归模型来估计邻苯二甲酸酯暴露与浸润性乳腺癌之间的关联。

超过999万女性年的随访，大多数邻苯二甲酸酯暴露与乳腺癌发病率无关。接触高剂量邻苯二甲酸二丁酯（dibutyl phthalate, DBP, 累积超过1,000 mg）, 雌激素受体阳性乳腺癌发病率风险增加约2倍（风险比= 1.9; 95％置信区间 = 1.1-3.5）。与这种化合物体外的类雌激素作用的证据一致。但较低水平的DBP暴露与乳腺癌发病率无关。（应该注意的是，这个阈值可能并不是真正的阈值，而是代表高水平的接触）。据该文章报道，含有DBP的药物包括锂，dulcolax，diclofenac和多酶片。

2012年，美国FDA限制FDA批准的药品使用DBP; 然而，DBP并未在美国受到统一的监管，并且该指南不适用于膳食补充剂，DBP在美国仍普遍用于个人护理和消费品。这项研究引起了人们对高水平DBP暴露和乳腺癌风险的认识。

Exposure to phthlate is ubiquitous in life and is particularly high among drug users formulated with phthalates. In vitro experiments have shown that some phthalates are similar to estradiol and may promote breast cancer through estrogen receptor signal transduction. A survey conducted in Denmark showed that women should avoid long-term use of drugs formulated with dibutyl phthalate (DBP).

The study used the Danish Medicines Agency ingredient database to determine the phthalate content of drugs sold in Denmark. On January 1, 2005, 1.12 million women were recruited nationwide in Denmark, and these women are likely to have a risk for a first breast cancer diagnosis. Annual cumulative phthalate exposure through redeemed prescriptions was characterized by combining pharmaceutical ingredient data with the Danish National Prescription Registry. Then, based on the tumor estrogen receptor status, a multivariate Cox regression model was fitted to estimate the association between phthalate exposure and invasive breast cancer.

At more than 999,000 women-years of follow-ups, most phthalate exposures were not associated with breast cancer incidence. Exposure to high doses of DBP (accumulated more than 1,000 mg) increased the risk of estrogen receptor-positive breast cancer by approximately 2-fold (hazard ratio = 1.9; 95% CI = 1.1-3.5). This is consistent with the in vitro evidence of the estrogenic effects of this compound. However, lower levels of DBP exposure were not associated with breast cancer incidence. (It should be noted that this threshold may not be a true threshold, but rather a high level of exposure). According to the article, drugs containing DBP include lithium, dulcolax, diclofenac and multi-enzyme tablets.
In 2012, the US FDA restricted use of DBP in FDA-approved drugs. However, it was not consistently regulated in the United States, and the guidelines do not apply to dietary supplements. DBP is still widely used in personal care and consumer products in the US. This study raises awareness of high levels of phthalate exposure and breast cancer risk.

参考文献 Reference

Ahern TP et al. J Clin Onc 2019; 37:1800-9

 

新的抗癌免疫疗法抑制纤维化并增强卵巢癌和胰腺癌的化学敏感性 (7/27/2019)

New anticancer immunotherapy inhibits fibrosis and enhances chemosensitivity in ovarian and pancreatic cancer

一种新的单克隆抗体，用于阻断小鼠卵巢癌和胰腺癌周围细胞分泌的蛋白质的作用, 来抑制肿瘤的生长。

新开发的单克隆抗体靶向癌相关成纤维细胞分泌的一种蛋白质, 称为微纤维相关蛋白5（MFAP , microfibril associated protein 5）。肿瘤微环境包含新发展的血管和纤维结缔组织, 通过血管生成和纤维化过程产生, 为肿瘤提供食物和支持肿瘤。MFAP5蛋白已经被证明可以触发这些周围元素的形成，促进卵巢癌和胰腺癌的纤维化，纤维化促进进展，化疗耐药, 并降低患这些癌症的生存。在患有这两种癌症的患者中发现该蛋白质的水平很高，并且存活率降低。阻断它可以防止新的血管和多余的组织在微环境中形成，从而切断肿瘤的血液供应和支持。研究人员发现在小鼠模型中, 阻断MFAP5抑制卵巢癌和胰腺癌内微血管渗漏和增强紫杉醇生物利用度。抑制了小鼠模型中卵巢癌和胰腺癌的生长。这种新的免疫治疗药物的目标是靶向支持肿瘤周围的细胞，而不仅仅是肿瘤细胞。通过用抗体阻断这种分泌蛋白，可以通过靶向肿 瘤微 环境中的多种细胞类, 包括成纤维细胞和血管来治疗肿瘤。

研究人员正在设计和生产人源化抗MFAP5抗体，以进一步开发作为治疗卵巢和胰腺的治疗剂。

A new monoclonal antibody that blocks the proteins secreted by cells surrounding cancers could inhibit the growth of ovarian and pancreatic cancer in a mouse model

The newly developed monoclonal antibody targets a protein secreted by cancer-associated fibroblasts, called microfibril associated protein 5 (MFAP). The tumor microenvironment contains newly developed blood vessels and fibrous connective tissue, produced by angiogenesis and fibrosis processes, providing nutrients for the tumor and supporting the tumor. The MFAP5 protein has been shown to trigger the formation of these surrounding elements, promote fibrosis in ovarian and pancreatic cancers, promote progression of fibrosis, cause chemoresistance, and reduce survival. The level of this protein is found to be high in patients with both cancers and the survival rate is reduced. Blocking MFAP5 prevents new blood vessels and excess tissues from forming in the microenvironment, cutting off the blood supply and support of the tumor. The researchers found that blocking MFAP5 could inhibit microvascular leakage in ovarian and pancreatic cancers and enhance paclitaxel bioavailability in a mouse model. The growth of ovarian and pancreatic cancers in the mouse model was inhibited. The goal of this new immunotherapeutic drug is to target cells surrounding the tumor, not just tumor cells. By blocking this secreted protein with antibodies, tumors can be treated by targeting a variety of cell types in the tumor microenvironment, including fibroblasts and blood vessels.
Researchers are designing and producing humanized anti-MFAP5 antibodies to further develop therapeutic agents to treat ovarian and pancreatic cancer.

参考文献 Reference

Yeung T-L et al. J Clin Res 2019; Jule 22. DOI: 10.1158/1078-0432.CCR-19-0187

 

三药联用靶向治疗可改善有BRAF突变的晚期结直肠癌的生存率 (7/21/2019)

Triple-targeted therapy improves survival in advanced colorectal cancer with BRAF mutation

Encorafenib，binimetinib和西妥昔单抗的三种靶向药物联用显着改善了有BRAF突变的转移性结直肠癌患者的总生存期。

BRAF突变发生在约15％的转移性结直肠癌患者中，其中V600E是最常见的BRAF突变，这些患者的预后多为不良。这项国际临床研究（BEACON CRC）是由全球200多个中心参加, 开放标签性，三臂随机临床试验,  是第一个, 也是一个唯一旨在测试转移性结直肠癌和BRAF V600E突变患者联合靶向治疗的III期试验。由665例转移性结直肠癌患者参加, 他们都有BRAF V600E突变, 曾接受过一种或两种既往治疗后进展。他们随机接受三联疗法（224人），双联疗法（encorafenib和西妥昔单抗）（220人）或研究者选择决定[伊立替康, 或亚叶酸/氟尿嘧啶/伊立替康（FOLFIRI）和西妥昔单抗]（221人）。

三联靶向组合导致中位总生存期为9个月（95% 置信区间 = 8.0-11.4），而标准治疗组为5.4个月（95% 置信区间 = 4.8-6.6）(风险比率= 0.52; 95% 置信区间 = 0.39-0.70, p < .0001)。三联靶向治疗的客观缓解率为26％，而标准治疗仅为2％。 双联组合的中位总生存期为8.4个月（95％置信区间 = 7.5-11.0; 风险比相对于对照组= 0.60; 95％置信区间 = 0.45-0.79; p = .0003）。

没有化疗的三联靶向组合通常具有良好的耐受性，没有意外的毒性。三联治疗组中58％的患者出现三级或更高级不良事件，双联组组50％，标准治疗组61％。

未来的分析将探讨哪些患者最有可能从三联体与双联体组合中获益, 以及这种组合是否可作为一线治疗。正在进行的一项试验（ANCHOR-CRC）旨在研究三联疗法作为转移性BRAF V600E突变型结直肠癌患者的初始治疗的效果。

The combination of three targeted drugs with encorafenib, binimetinib and cetuximab significantly improved overall survival (OS) of patients with metastatic colorectal cancer and BRAF mutation.
BRAF mutation occurs in approximately 15% of patients with metastatic colorectal cancer, with V600E being the most common.  BRAF mutation often carries a poor prognosis. This international clinical study (BEACON CRC) is an open labelled, three-arm randomized clinical trial involving more than 200 centers worldwide. It is the first and the only one to test for patients with metastatic colorectal cancer and BRAF V600E mutations for targeted therapy. A total of 665 patients with metastatic colorectal cancer, and BRAF V600E mutations had undergone one or two previous treatments while disease progressed. They were randomized to triple therapy (224 patients), dual therapy (encorafenib and cetuximab) (220 patients) or investigators’ choise [irinotecan, or leucovorin/fluorouracil/irinotecan (FOLFIRI) and cetuximab] (221 patients).
The triple combination resulted in a median OS of 9 months (95% CI = 8.0-11.4), compared with 5.4 months for the current standard treatment group (95% CI = 4.8-6.6) (HR = 0.52; 95% CI = 0.39-0.70, p < .0001). The objective response rate for triple-targeted therapy was 26%, compared with only 2% for standard therapy. The median OS of the double combination was 8.4 months (95% CI = 7.5-11.0; HR relative to control group = 0.60; 95% CI = 0.45-0.79; p = .0003).

Triple targeted combination without chemotherapy was generally well tolerated with no unexpected toxicity. In the triple treatment group, 58% of patients had grade III or higher adverse events, 50% in the double group and 61% in the standard treatment group.
Future analysis will explore which patients are most likely to benefit from a combination of triplets and doublets, and whether this combination can be used as first-line therapy. An ongoing trial (ANCHOR-CRC) was designed to investigate the efficacy of triple therapy as the initial treatment for patients with metastatic BRAF V600E mutant colorectal cancer.

参考文献 Reference

Kopetz S et al. Ann Oncol 2019; 30; Suppl 4 abstr LBA-006

 

一个早期发育基因的表达阻止了免疫系统识别和攻击癌细胞 (7/20/2019)

Activation of an embryonic gene protects cancer from recognition by immune system

DUX4是一种植入前（preimplantation）胚胎转录因子, 通常在体细胞组织中消失; 当它在许多癌症中重新表达时，它可以防止癌症被免疫系统识别和破坏。

研究小组调查了来自33种不同癌症类型的近10,000种癌症的基因表达谱，发现DUX4是一种基因，其特征是与面肩肱型肌营养不良症（facioscapulohumeral dystrophy或FSHD）有关，它始终存在于许多不同的固体肿瘤中，包括膀胱癌，乳腺癌，肺癌，肾癌和胃癌。 DUX4通过阻断干扰素-γ介导的MHC I类诱导来阻止免疫细胞识别癌细胞，抑制抗癌免疫活性, 因此癌症表达基因的患者对免疫疗法的反应较小。由于DUX4在许多癌症中表达，阻断其活性可能会增加免疫检查点抑制剂的成功率。

研究小组的一位先前曾研究过DUX4在早期发育和FSHD肌营养不良症中的作用。该基因通常只在早期发育中表达，此时胚胎细胞需要逃避母体免疫系统的检测。这一研究结果，说明早期发育的快速但受调节的增长如何在癌症中重新激活为不受管制的细胞生长。研究表明，癌细胞表达DUX4可以劫持一种可以抑制抗癌免疫活性的正常早期发育计划。

研究小组希望他们的工作最终能够开发出针对DUX4的治疗方法，这将有助于提高各种癌症免疫疗法的成功率。

DUX4 is a preimplantation embryonic transcription factor that usually disappears in somatic tissues. It prevents cancer from being recognized and destroyed by the immune system when it is re-expressed in many cancers.

The team investigated the gene expression profiles of nearly 10,000 cancers from 33 different cancer types and found that DUX4 is a gene that is associated with facioscapulohumeral dystrophy or FSHD. The gene is always present in many solid tumors, including bladder, breast, lung, kidney and stomach cancer. DUX4 prevents immune cells from recognizing cancer cells by inhibiting anti-cancer immune activity by blocking interferon-gamma-mediated MHC class I induction, and thus patients with expression of DUX4 gene have less response to immunotherapy. Since DUX4 is expressed in many cancers, blocking its activity may increase the success rate of immunological checkpoint inhibitors.

One of the research team leads has previously studied the role of DUX4 in early development and FSHD muscular dystrophy. This gene is usually expressed only in early development, when embryonic cells need to escape the detection of the maternal immune system. The results of this study demonstrate how rapid but regulated growth in early development reactivates cancer into unregulated cell growth. Studies have shown that cancer cells expressing DUX4 can hijack a normal early developmental program that inhibits anti-cancer immune activity.

The research team hopes that their work will eventually lead to the development of treatments for DUX4, which will help improve the success rate of various cancer immunotherapy.

参考文献 Reference

Chew G-L et al. Developmental Cell, 2019; July 18, DOI: 10.1016/j.devcel.2019.06.011

 

Durvalumab在中期分析中提高了广泛性小细胞肺癌总生存期 (7/14/2019)

Durvalumab was shown to raise overall survival in extensive stage small cell lung cancer in mid-term analysis

这是一项开放标签，多中心，随机III期临床试验（CASPIAN），该试验将 1) durvalumab（抗PD-L1抗体）加铂类化疗（依托泊苷和顺铂或卡铂）, 或 2) durvalumab，tremelimumab（抗CTLA4抗体 ）双重免疫检查点阻断与化疗的组合, 和 3) 单独化疗相比较作为第一线治疗广泛性小细胞肺癌。该试验正在22个国家的200多个中心进行，包括美国，欧洲，南美，亚洲和中东。终了目标是总生存期。在试验组中，患者接受多达四个周期的化疗; 对照组允许多达六个周期的化疗和预防性头颅照射。

Durvalumab是一种人类单克隆抗体，可与PD-L1结合并阻断PD-L1与PD-1和CD80的相互作用，从而抵消肿瘤的免疫逃避并释放免疫应答的抑制作用。durvalumab已被批准用于包括美国，欧盟和日本在内的超过45个国家的不可切除的III期非小细胞肺癌。Tremelimumab是一种人类单克隆抗体，它靶向细胞毒性T淋巴细胞相关蛋白4（CTLA-4）的活性, 促进T细胞活化并增强对癌症的免疫应答。

由独立数据监测委员会进行的中期分析得出结论，该试验已经达到其主要终点，显示在durvalumab与标准化疗联合治疗的患者中，总生存期具有统计学意义和临床意义的改善。 这种durvalumab组合的安全性和耐受性与这些药物的已知安全性一致。

AstraZeneca 公司将在即将召开的医学会议上提交这些结果。

This is an open-label, multicenter, randomized phase III clinical trial (CASPIAN) that will compare 1) durvalumab (anti-PD-L1 antibody) plus platinum-based chemotherapy (etoposide and cisplatin or carboplatin), or 2 ) durvalumab, tremelimumab (anti-CTLA4 antibody) dual immunological checkpoint blockade combined with chemotherapy, with 3) chemotherapy alone as a first line treatment for extensive stage small cell lung cancer. The trial is being conducted in more than 200 centers in 22 countries, including the United States, Europe, South America, Asia and the Middle East. The end point is overall survival. In the experimental group, patients received up to four cycles of chemotherapy; the control group was allowed up to six cycles of chemotherapy and prophylactic cranial irradiation.

Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks the binding of PD-L1 to PD-1 and CD80, thereby counteracting the immune evasion of tumors and releasing the inhibition of immune responses. Durvalumab has been approved for unresectable stage III non-small cell lung cancer in more than 45 countries including the United States, the European Union and Japan. Tremelimumab is a human monoclonal antibody that targets the activity of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), promotes T cell activation and enhances immune responses to cancer.
An interim analysis by the Independent Data Monitoring Committee concluded that the trial had reached its primary endpoint, showing a statistically significant and clinically significant improvement in overall survival in patients treated with durvalumab in combination with standard chemotherapy. The safety and tolerability of the duvalalumab combination is consistent with the known safety of these drugs.
AstraZeneca will present these results at the upcoming medical conference.

参考文献 Reference

https://www.astrazeneca.com/media-centre/press-releases/2019/imfinzi-improves-overall-survival-at-interim-analysis-in-the-phase-iii-caspian-trial-in-1st-line-extensive-stage-small-cell-lung-cancer-27062019.html

 

普通感冒病毒用于治疗膀胱癌 (7/13/2019)

A common cold virus used in treating bladder cancer

一种引起普通感冒的柯萨奇病毒株（CVA21）用于治疗患有非肌肉浸润性膀胱癌，其中一名患者疾病消失。

这是一个I期临床试验（CANON），有15名患过CVA21病毒的非肌肉浸润性膀胱癌患者参加。患者在手术前一周通过导管直接将CAVATAK（CVA21的纯化制剂）接种到膀胱中。第一阶段，9名患者仅接受单剂CAVATAK；第二阶段，6名患者还同时接受了亚治疗剂量的丝裂霉素（mitomycin）C，因为已知它可以增强膀胱癌细胞的ICAM-1（细胞间粘附分子）的表达（与免疫力有关）。主要终点是确定患者安全性和最大耐受剂量。次要终点是病毒复制，炎性细胞因子的诱导，抗肿瘤活性和切除组织中病毒诱导变化的证据。

结果显示：CAVATAK的临床活性通过在多个患者中单次或多次施用CAVATAK后诱导肿瘤炎症和出血得到证明。无论是单独使用还是与丝裂霉素C联合使用，CAVATAK通过上调干扰素诱导基因以及诱导的细胞因子，与未治疗患者的膀胱癌组织相比, 在膀胱癌组织活检中引起显著的炎症变化。而且, 病毒只感染了癌细胞，患者的尿液样本表明病毒继续复制并攻击更多的癌细胞。有一名患者，在接受治疗后仅一周，在手术过程中没有发现任何癌症迹象。

无论是病毒还是联合治疗，任何患者均未发现明显的毒性反应。

结论：CAVATAK的安全性，病毒靶向，复制和肿瘤细胞死亡的证据以及肿瘤微环境中病毒介导的“免疫热”增加都表明CAVATAK可能被认为是非肌肉浸润性膀胱癌的新型治疗剂。

A Coxsackie virus strain (CVA21) that causes the common cold is used to treat non-muscle invasive bladder cancer One patient’s disease disappears following such treatment.
This is a phase I clinical trial (CANON) involving 15 patients with non-muscle invasive bladder cancer who had CVA21 virus infection. The patient was directly inoculated with CAVATAK (a purified preparation of CVA21) into the bladder via a catheter one week prior to surgery. In the first phase, 9 patients received only a single dose of CAVATAK; in the second phase, 6 patients also received a concurrent subtherapeutic dose of mitomycin C, which is known to enhance the expression of ICAM-1 (intercellular adhesion molecule) (related to immunity) in bladder cancer cells. The primary endpoints were to determine patient safety and maximum tolerated dose. Secondary endpoints are evidence of viral replication, induction of inflammatory cytokines, anti-tumor activity, and virus-induced changes in excised tissues.
The results showed that the clinical activity of CAVATAK is demonstrated by induction of tumor inflammation and hemorrhage after single or multiple administration of CAVATAK in patients. Whether used alone or in combination with mitomycin C, CAVATAK causes significant inflammatory changes in bladder cancer tissue biopsy by up-regulating interferon-inducible genes and induced cytokines compared to bladder cancer tissues in untreated patients. Moreover, the virus only infects cancer cells, and the patient’s urine sample indicates that the virus continues to replicate and attack more cancer cells. One patient, who was only one week after receiving treatment, did not show any signs of cancer during the procedure.
No significant toxicity was observed in any patient, whether it was a virus or combination therapy.
Conclusions: The safety of CAVATAK, evidence of viral targeting, replication and tumor cell death, as well as increased viral-mediated “immune fever” in the tumor microenvironment suggest that CAVATAK may be considered a novel therapeutic agent for non-muscle invasive bladder cancer.

参考文献 Reference

Annels, NE Clin Can Res 2019; Jule 4. doi: 10.1158/1078-0432.CCR-18-4022

 

肥胖超过吸烟成为导致四种不同类型癌症的主要因素 (7/7/2019)

Obesity overtakes smoking as the leading cause of four types of cancer

英国癌症研究中心的最新数据显示，肥胖者现在的数量超过了英国的吸烟人数，超重导致某些癌症的病例多于吸烟,  虽然吸烟仍然是英国最大的可预防癌症原因，并且比肥胖症患病的风险要高得多，但英国癌症研究中心的分析显示，肥胖超过吸烟成为导致四种不同类型癌症的主要因素。每年，体重过重而不是吸烟,  导致每年约有1,900多例肠癌，。同样的情况发生于肾癌（每年因肥胖引起的病例多于每年吸烟的为1,400例），卵巢（460例）和肝脏（180例）都是如此。

在英国，大约有1340万不吸烟肥胖成年人（体重指数为30+），630万不肥胖的成年吸烟者，以及150万吸烟和肥胖的成年人。根据英国癌症研究中心癌症情报小组的计算，在英国成年人中，肥胖人数超过2：1的人数 。到目前为止，科学家已经确定肥胖导致了13种类型的癌症，但其机制尚未完全了解。因此需要进一步研究，以了解更多关于过多脂肪导致癌症的方法。
减肥并没有灵丹妙药，但多年来吸烟的大幅下降, 部分归功于广告和环境禁令, 表明政府主导的变革有效。该机构希望政府采取行动，例如限制不健康食品和饮料的促销优惠; 在电视上推出晚间9点的垃圾食品广告限制; 在2030年之前将童年肥胖率降低一半。

According to latest data from the Cancer Research UK, the number of obesity people now exceeds that of smokers in the UK. Obesity now leads to more cases than smoking in certainly types of cancer, although smoking remains the leading cause of preventable cancer in the UK and carries higher risk than obesity. The data shows that obesity has overtaken smoking as a major contributor to four different types of cancer. Every year, overweight, not smoking, results in more than 1,900 cases of bowel cancer. The same happens with kidney cancer (1,400 more cases per year associated with obesity than with smoking), as well as ovarian (460 cases) and liver (180 cases) cancers.

In the UK, there are approximately 13.4 million non-smoking obese adults (body mass index 30+), 6.3 million non-obese adult smokers, and 1.5 million adult smokers who are obese. The number of obese people in the UK exceeds smokers by 2:1. So far, scientists have found that obesity causes 13 types of cancer, but the mechanism is not fully understood. Further research is needed to learn more about how extra fat causes cancer.

There is no panacea for weight loss, but the dramatic decline in smoking over the years has been attributed in part to advertising and environmental bans, indicating that government-led change is effective. The agency wants the government to take action, such as introducing a 9 pm watershed for junk food advertisement on TV; restricting promotional offers on unhealthy food and drinks; reducing childhood obesity by half by 2030.

参考文献 Reference

Cancer Research UK 2019; July 3^rd. https://www.cancerresearchuk.org/about-us/cancer-news/press-release/2019-07-03

 

NovoTTF-100L加上化学疗法被FDA批准用于治疗恶性胸膜间皮瘤 (7/6/2019)

NovoTTF-100L plus chemotherapy has been approved by FDA for malignant pleural mesothelioma

NovoTTF（Tumor Treating Field）-100L系统已于今年5月获得FDA批准与培美曲塞（Pemetrexed）和铂类化疗相结合，作为无法切除，局部晚期或转移性恶性胸膜间皮瘤（malignant pleural mesothelioma）患者的第一线治疗。这标志着超过15年来首次为FDA批准的针对这一疾病的治疗方案。

恶性胸膜间皮瘤是一种罕见的恶性肿瘤，与石棉接触密切相关，每年估计有3,000人被诊断患有恶性胸膜间皮瘤。只有10％到20％的患者可以手术切除，在NovoTTF-100L批准之前，培美曲塞加顺铂是FDA批准的无法切除恶性胸膜间皮瘤患者的唯一疗法。 NovoTTF-100L是一种非侵袭性抗有丝分裂癌症疗法，可将TTF传递到肿瘤区域。 TTF疗法使用调整到特定频率的电场来破坏实体肿瘤癌细胞分裂。临床前数据表明人间皮瘤细胞对TTF高度敏感。

FDA的批准是根据前瞻性单臂STELLAR的试验结果，该研究招募了80名从未接受过治疗，局部晚期或转移性恶性胸膜间皮瘤患者，这些患者是培美曲塞和顺铂或卡铂的治疗对像。治疗终了目标为总生存期; 次要终点是无进展生存期, 总体响应率和安全性。

结果显示，上皮样恶性胸膜间患者的中位总生存期为21.2个月（ 53人），非上皮样恶性胸膜间皮瘤患者的中位总生存期为12.1个月（ 21人）。使用NovoTTF-100L加化疗的患者中有62％的患者在1年时仍然存活。此外，至少进行1次随访CT扫描（72人）的患者的疾病控制率为97％。部分响应率为40％，病情稳定率为57％，进展性疾病发生率为3％。

关于安全性，使用NovoTTF-100L和化疗联合治疗后，严重全身不良事件没有增加。最常见的与使用设备相关的不良事件是轻度至中度的皮肤刺激。

The NovoTTF (Tumor Treating Field)-100L system was approved by the FDA in May this year in combination with Pemetrexed and platinum-based chemotherapy as the first line therapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma (MPM). This marks the first FDA-approved treatment for this disease over more than 15 years.MPM is a rare malignant tumor that is closely related to asbestos exposure, with an estimated 3,000 people diagnosed each year. Only 10% to 20% of patients can become a candidate for surgical resection. Prior to the approval of NovoTTF-100L, pemetrexed plus cisplatin was the only treatment approved by FDA for patients with MPM. NovoTTF-100L is a non-invasive anti-mitotic cancer therapy that delivers TTF to the tumor area. TTF therapy uses an electric field that is tuned to a specific frequency to disrupt tumor cell division. Preclinical data indicate that human mesothelioma cells are highly sensitive to TTF.FDA approval is based on a prospective single arm STELLAR trial that enrolled 80 patients who had locally advanced or metastatic MPM and had never received treatment. They were candidates for pemetrexed and cisplatin or platinum treatment. The primary endpoint was the overall survival; secondary endpoints were progression-free survival, overall response rate and safety.The median OS of patients with epithelioid MPM was 21.2 months (53 patients), and the median OS of patients with non-epithelial MPM was 12.1 months (21 patients). 62% of patients who received NovoTTF-100L plus chemotherapy survived at 1 year. In addition, patients with at least one follow-up CT scan (72 patients) had a disease control rate of 97%. The partial response rate was 40%, the disease stability rate was 57%, and the progressive disease rate was 3%.Regarding safety, there was no increase in severe systemic adverse events after treatment with NovoTTF-100L and chemotherapy. The most common adverse event associated with the use of equipment is mild to moderate skin irritation.参考文献 Reference

https://www.fda.gov/medical-devices/recently-approved-devices/novottftm-100l-system-h180002

 

术前厄洛替尼治疗局部晚期非小细胞肺癌的效果 (6/30/2019)

Neoadjuvant erlotinib versus chemotherapy in Stage IIIAN2 NSCLC

一个开放性, 随机对照临床II期试验（EMERGING）显示，对患有局部晚期表皮生长因子受体（EGFR）突变阳性的非小细胞肺癌患者, 术前/后厄洛替尼靶向治疗可能优于标准化疗。
在这项试验中, 72例临床IIIA-N2期 EGFR突变阳性非小细胞肺癌患者。随机接受厄洛替尼（150 毫克/天, 术前治疗42天; 术后治疗，最长12个月），或吉西他滨顺铂化疗（吉西他滨1,250 毫克/平方米加顺铂75毫克/平方米; 术前治疗两个周期; 术后治疗，最多两个周期）。

结果显示，术前厄洛替尼（中位治疗42天）的客观缓解率为54.1％，而术前化疗（大多数患者接受两个周期）的客观缓解率为34.3％。然而，差异并不显著（优势比为2.26; p = .092）。 两组患者均未达到病理完全缓解，但厄洛替尼组有9.7％的患者获得了主要的病理反应（残留活肿瘤细胞低于10％），而化疗组则没有。中位随访时间为14.1个月，厄洛替尼中位无进展生存期为21.5个月，几乎是化疗后11.4个月的两倍（风险比为0.39; p < .001）。总体存活率没有显着差异，但在分析时尚未成熟。

不良事件在很大程度上与每种疗法的预期相同。厄洛替尼治疗3级或4级不良事件的发生率为0％，化疗组为29.4％。

作者认为术前厄洛替尼的最佳持续时间还需要进行额外的调查，以验证围手术期TKI治疗在癌基因驱动非小细胞肺癌的作用。

An open label, randomized controlled phase II trial (EMERGING) showed that neoadjuvant/adjuvant erlotinib targeted therapy may be superior to standard chemotherapy  for NSCLC patients who harbor EGFR mutation.

In this trial, 72 patients with clinical stage IIIA-N2 EGFR mutation-positive NSCLC were randomized to either erlotinib (150 mg/day, treatment for 42 days prior to surgery;  up to 12 months after surgery), or gemcitabine/cisplatin chemotherapy (gemcitabine 1,250 mg/m2 plus cisplatin75mg/m2; two cycles before surgery; up to two cycles after surgery).

The results showed that the objective response rate for preoperative erlotinib (median treatment 42 days) was 54.1%, while the objective response rate for preoperative chemotherapy (most patients received two cycles) was 34.3%. However, the difference was not statistically significant (odds ratio 2.26; p = .092). Pathological complete remission was not achieved in either group, while 9.7% of patients in the erlotinib group achieved major pathologic responses (residual live tumor cells less than 10%), whereas the chemotherapy group did not. The median follow-up time was 14.1 months, and the median progression-free survival of erlotinib was 21.5 months, almost twice that of 11.4 months after chemotherapy (HR 0.39; p < .001). There was no significant difference in overall survival, as the data was not yet mature at the time of analysis.

Adverse events are largely the same as expected for each therapy. The incidence of grade 3 or 4 adverse events was 0% in the erlotinib group, compared with 29.4% in the chemotherapy group.

Authors thought the optimal duration of preoperative erlotinib needs additional investigation to validate the role of perioperative TKI therapy in oncogene-driven NSCLC.

参考文献 Reference

Zhong W-Z et al. J Clin Onc 2019; June 13 2019 https://doi.org/10.1200/JCO.19.00075

 

尿液检测可以提前五年诊断前列腺癌 (6/29/2019)

A simple urine test can diagnose prostate cancer five years earlier

目前的诊断筛选方法，如PSA血液检测, 不够可靠，许多男性需要进一步测试和手术。多达四分之三的病例PSA水平升高后发现活检为阴性，但在其他情况下，检测可能会遗漏癌症，

一项简单的尿液检测可以在需要治疗前五年检测到侵袭性前列腺癌，对患有疑似疾病的男性, 也可能无需进行活检即可获得清晰结论。英国一所大学的研究涉及537名男性，他们确定了35种不同的基因，这些基因是该疾病风险的标志。通过检查尿液样本中167个基因的无细胞表达，该团队发现了35种不同基因的数学组合，可用于产生尿液检测风险特征。这项新测试称为“PUR”（前列腺尿风险）, 预计可以在三年内提供。该测试适用于怀疑患有前列腺癌的男性，但也可用于已被诊断患有低风险癌症的人，以确定他们何时需要在五年内接受治疗。

Current diagnostic or screening tests, such as PSA test, are not accurate enough, and many men require further testing and surgery. Biopsy is found to be negative in as many as three-quarters of cases who have elevated PSA levels, while in other cases, biopsy may miss cancer.
A simple urine test can detect invasive prostate cancer five years before treatment is needed. It may also provide clear conclusion for those who are suspected to have the disease without needing a biopsy. A study in a university in the United Kingdom involved 537 men. The test identified 35 different genes that are markers of the risk of prostate cancer. By examining the cell-free expression of 167 genes in urine samples, the team discovered a mathematical combination of 35 different genes that could be used to generate risk characteristics for the urine test. The new test, called “PUR” (prostate urine risk), is expected to be available within three years. This test is for men who are suspected of having prostate cancer, and can also be used for people who are diagnosed with low-risk cancer to determine when they need treatment within five years.

参考文献 Reference

Connell S et al. BJU Intl 2019; June 2019

 

软海绵素人工合成的突破推动了一种有效的抗癌剂 (6/23/2019)

Break through in total synthesis of halichondrin heralds a novel anti-cancer drug

科学家完全人工合成的软海绵素（halichondrin），是一种天然存在于海绵（sea sponges）中的强效抗癌剂。

1986年, 源自日本海绵的软海绵素首次被发现时，引起了很大的兴趣。 研究人员进行了微量测试，发现它影响细胞分裂所必需的微管的形成, 还可能会影响肿瘤微环境, 和细胞恶性转化。。完整软海绵素分子非常复杂, 人工合成产物（E7130）特别难，因为它具有31个手性中心（chiral center），每个不对称点必须正确定向，大约有40亿种可能会弄错。30年后, 研究人员（日本Eisai 公司和哈佛大学）最终已合成足够数量的E7130，总合成11.5克，纯度为99.81％, 并首次与日本制药公司合作，对其生物活性，药理特性和疗效进行了研究。

在临床前研究中，研究小组不仅将其鉴定为微管动力学抑制剂，还将其作为靶向肿瘤微环境的新型药剂。该科学报告论文描述了动物模型中体外和体内研究的结果，这些研究揭示了分子复杂的作用模式。研究表明，E7130可以增加瘤内CD31阳性内皮细胞，减少α-SMA阳性的癌相关成纤维细胞，这可能是肿瘤微环境中参与恶性转化的成分。

A total synthesis of halichondrin (naturally found in sea sponge) is a potent anticancer agent.

In 1986, when halichondrin from Japanese sponge was first discovered, it arouse great interest. Researchers used tiny amount to conduct experiments and found that it affects the formation of microtubules necessary for cell division, and may also affect the tumor microenvironment, and malignant transformation. The halichondrin molecule is very complex, and the synthesis of its molecule (E7130) is particularly difficult because it has 31 chiral centers, each of which must be correctly oriented, and there are about 4 billion chances that can go wrong. Thirty years later, researchers (announced by Japan Eisai company and Harvard University) finally synthesized a sufficient amount of E7130 of 11.5 grams and a purity of 99.81%. For the first time, they cooperated with Japanese pharmaceutical companies to carry out their biological activities, pharmacological properties and therapeutic effects.

In preclinical studies, the team not only identified it as a microtubule dynamics inhibitor, but also as a novel agent for targeting tumor microenvironment. The scientific report describes the results of in vitro and in vivo studies in animal models that reveal the complex modes of action of molecules. Studies have shown that E7130 can increase intratumoral CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts, which may be involved in malignant transformation in the tumor microenvironment.

参考文献 Reference

Kawano S et al. Scientific Rep 2019; DOI: 10.1038/s41598-019-45001-9

控制烟草措施使加利福尼亚州的肺癌死亡人数减少了28％ (6/22/2019)

Tobacco control reduces lung cancer deaths in California by 28%

加利福尼亚州在20世纪80年代开始采用反吸烟措施, 导致该州肺癌死亡率比美国其他地区低28％。说服年轻人不要开始吸烟是遏制烟草相关疾病和死亡率的最有效方法之一, 因为一旦尼古丁成瘾, 随着时间的推移而逐渐建立，就难以打破。

加州烟草控制计划始于上世纪80年代，并在美国环境保护署发布第一份报告（该报告将二手烟确定为甲类致癌物质）后于1990年加速。该计划强调烟草营销是对青少年吸烟的主要影响，并为当地社区组织者提供资金，制定以烟草有害影响为中心的计划。不久，当地法令开始对允许吸烟的地方实行限制，并限制学校附近的卷烟广告。 1994年，加利福尼亚通过了第一部州法律，规定了无烟工作场所，餐馆和酒吧，远远超过其他州。

疾病控制和预防中心2017年全国健康访谈调查的数据显示, 吸烟的成年人数量已降至约3400万，这是美国有史以来的最低水平。然而，这意味着，在接受调查时，大约14％的成年人在过去30天内吸过香烟。虽然这比2016年下降了15.5％，并自1965年以来下降了67％，但这个数字仍然过高，特别是当吸烟仍然是美国主要可预防的疾病和死亡的原因。
全国健康访谈调查是对美国962,174名居民的代表性抽样调查，其中约10％居住在加利福尼亚州。根据美国国家癌症研究所的监测，流行病学和最终结果计划（1970-2013）中的死亡证明数据，对加利福尼亚州和其他州的肺癌死亡率趋势进行了比较。

1978年，加利福尼亚州18至34岁的吸烟者和其他州的吸烟者的吸烟强度相似（每天18.4支卷烟;  95％置信区间= 17.6-19.1支/天）。然而，在1978年之后2000年，加利福尼亚州的吸烟强度数字与全国其他地区相比下降了45％。 2012年至2014年间，加利福尼亚州18至34岁吸烟者的吸烟强度％（每天6.3支卷烟，95％置信区间 = 5.6-7.0支/天）比美国其他地区（每天9.2支香烟）低30%（95％置信区间 = 9.0-9.5支/天）。此外，大约45.7％的加州吸烟者在35岁时戒烟（95％置信区间 = 41.1％-50.4％），而其他州仅有37.8％的吸烟者戒烟（95％置信区间 = 36.1％-39.4％, p = .0007）。

1985年，加利福尼亚州和该国其他地区的肺癌死亡率相似，但到2013年，加利福尼亚州的死亡率降低了28％（分别为62.6相对于87.5/100,000人口）, 比美国其他地区低33％。

California began anti-smoking initiatives in the 1980s, resulting in a 28% lower lung cancer mortality rate in the state than in other parts of the United States. Convincing young people not to start smoking is one of the most effective ways to curb tobacco-related illness and mortality, as it is more difficult to break a nicotine addiction once it becomes well established.

The California Tobacco Control Program began in the 1980s and accelerated in 1990 after the US Environmental Protection Agency issued its first report, which identified second-hand smoke as a Class A carcinogen. The program emphasizes tobacco marketing as a major influence on youth smoking and funds local community organizers to develop programs that focus on the harmful effects of tobacco. Soon, local law makers began to impose restrictions on places where smoking was allowed, and restricted cigarette advertising near the school. In 1994, California passed the first state law, setting up smoke-free workplaces, restaurants, and bars far ahead other states.

According to data from the 2017 National Health Interview Survey conducted by the Centers for Disease Control and Prevention, the number of adults who smoked has fallen to about 34 million, the lowest level ever in the United States. However, this means that about 14% of adults had smoked cigarettes in the past 30 days when they were surveyed. Although this is 15.5% lower than 2016 and has fallen 67% since 1965, this number is still too high, especially when smoking is still the leading cause for preventable disease and death in the United States.

The National Health Interview Survey is a representative sample survey of 962,174 residents in the United States, of which approximately 10% reside in California. According to the US National Cancer Institute’s monitoring, death evidence data from the Epidemiology and Final Results Program (1970-2013), the trends in lung cancer mortality in California and other states were compared.

In 1978, smokers from 18 to 34 years old in California and smokers in other states had similar smoking intensity (18.4 cigarettes per day; 95% CI = 17.6-19.1 per day). However, after 1978 through 2000, the number of smoking intensity in California fell by 45% compared to the rest of the country. Between 2012 and 2014, the smoking intensity of smokers aged 18 to 34 in California (6.3 cigarettes per day, 95% CI = 5.6-7.0 per day) was 30% lower than in the rest of the United States (9.2 cigarettes per day) ( 95% CI = 9.0-9.5 per day). In addition, approximately 45.7% of California smokers quit smoking by the age of 35 (95% CI = 41.1%-50.4%), while only 37.8% of smokers in other states quit (95% CI = 36.1%-39.4%, p = .0007).

In 1985, California and other parts of the country had similar lung cancer mortality rates. By 2013, California’s mortality rate fell by 28% (62.6 vs. 87.5/100,000, respectively), 33% lower than the rest of the United States.

参考文献 Reference

Filton M. CA: A Cancer J for Clinicians 2019;69:833-5

Erdafitinib为美国食品和药物管理局批准用于局部晚期或转移性尿路上皮癌 (6/16/2019)

Erdafitinib was approved by FDA for locally advanced or metastatic urothelial cell cancer

对具有FGFR3或FGFR2遗传改变的局部晚期或转移性尿路上皮癌的患者，在铂类化疗治疗期间或之后疾病进展，FDA批准了Erdafitinib。

成纤维细胞生长因子受体（FGFR）属于酪氨酸激酶家族（FGFR1-4）, 调节许多关键过程，例如细胞迁移，增殖，分化和存活; FGFR的遗传改变与肿瘤生长，转移，血管生成和存活率降低有关。FGFR基因在20％-60％的尿路上皮癌中发生突变，最常见的是膀胱癌。

在一项多中心，开放标签的单臂试验（BLC2001, NCT02365597）中，有87名患者参加。他们患有局部晚期或转移性尿路上皮癌，而且疾病在至少一次 先前化疗之中或之后进展, 并且具有 某些FGFR3基因突变, 或FGFR2/FGFR3基因融合。Erdafitinib的起始剂量为8毫克，每日一次; 若第14天至第17天血清磷酸盐水平低于5.5毫克 / 毫升，剂量增加至每日9毫克。起始剂量增加至每天9毫克的为41％。患者接受Erdafitinib直至疾病进展或不可接受的毒性。主要疗效结果指标是客观反应率。

客观响应率为32.2％（95％ 置信区间 = 22.4-42.0），完全响应为2.3％，部分响应为29.9％。中位响应持续时间为5.4个月（95％置信区间 = 4.2-6.9）。响应者包括之前对抗PD-L1或PD-1治疗没有响应的患者。

服用Erdafitinib者需要注意眼部症状。中心性浆液性视网膜病变或视网膜色素上皮脱离导致视野缺损影响25％的患者。有至少40％的患者报告最常见的不良反应口腔炎，疲劳，腹泻，口干，指甲剥离; 还有肝转氨酶增加，血清肌酐增加和血清磷酸盐增加。

FDA approved Erdafitinib for patients with locally advanced or metastatic urothelial carcinoma with genetic alterations in FGFR3 or FGFR2, whose disease progressed during or after platinum-containing chemotherapy.

The fibroblast growth factor receptor (FGFR) belongs to the tyrosine kinase family (FGFR1-4) and regulates many key processes such as cell migration, proliferation, differentiation and survival. Genetic mutation of FGFR results in tumor growth, metastasis, angiogenesis and reduced survival. The FGFR gene is mutated in 20%-60% of urothelial carcinomas, the most common being bladder cancer.
In a multicenter, open-label, one-arm trial (BLC2001, NCT02365597), 87 patients participated. They have locally advanced or metastatic urothelial carcinoma, and the disease progressed during or after at least one prior chemotherapy and has certain FGFR3 gene mutations, or FGFR2/FGFR3 fusion. The starting dose of Erdafitinib was 8 mg once daily; if the serum phosphate level was less than 5.5 mg/dL from day 14 to day 17, the dose was increased to 9 mg per day. The initial dose of 9 mg/dL per day accounted for 41% of the patients. Patients received Erdafitinib until disease progression or unacceptable toxicity. The primary efficacy outcome is objective response rate.
The objective response rate was 32.2% (95%CI = 22.4-42.0), the complete response was 2.3%, and the partial response was 29.9%. The median response duration was 5.4 months (95% CI = 4.2-6.9). Responders included patients who had not previously responded to treatment with PD-L1 or PD-1.

People taking Erdafitinib need to pay attention to eye symptoms. Central serous retinopathy or retinal pigment epithelial detachment results in a visual field defect affected 25% of patients. At least 40% of patients reported the most common adverse reactions including stomatitis, fatigue, diarrhea, dry mouth, and nail stripping; as well as increased liver transaminases, serum creatinine, and serum phosphate.

参考文献 Reference

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinom

 

生物标志物预测哪些胰腺囊肿可能变成癌性囊肿 (6/15/2019)

Biomarkers used to predict which pancreatic cysts may become cancerous

50％至70岁的人群中约有2％至4％可能患有胰腺囊肿，80岁以上人群增加到8％至9％。胰腺中的囊肿通常不会发生癌变，但有时会发展为浸润性癌症，这取决于囊肿的类型。切除胰腺囊肿的手术创伤大, 又有很多并发症。

从2010年1月至2017年6月, 研究小组收集了169例手术切除胰腺囊肿的液体（90个导管内乳头状粘液性肿瘤，43个粘液性囊性肿瘤和36个非粘液性囊肿）。高风险胰腺囊肿是那些患有浸润性癌，高度不典型增生或肠型IPMN且中度发育不良的患者。研究人员利用Das-1抗体作为生物标志来分析胰腺囊肿的液体。在先前的研究中，已经发现这种生物标志与会癌变的高风险胰腺囊肿相关联。在这项新研究中，从囊肿中检测 Das-1抗体, 鉴定出高风险胰腺囊肿，其灵敏度为88％，特异性为99％，准确度为95％。目前的临床指南仅有约74％的准确性。

未来的方向是观察生物标志物是否能够在患者接受手术之前识别可能变成癌变的胰腺囊肿

About 2% to 4% of people between 50 and 70 year of age may have pancreatic cysts, and those over 80 years old the chance increases to 8% or 9%. Cysts in the pancreas usually do not become cancerous, but sometimes can become invasive cancer, depending on the type of cyst. Surgical removal of pancreatic cysts is traumatic and can have morbid complications.
From January 2010 to June 2017, a research team collected 169 fluids for surgically removed pancreatic cysts (90 intraductal papillary mucinous tumors, IPMN,  43 mucinous cystic tumors, and 36 non-mucinous cysts). High-risk pancreatic cysts are those with invasive carcinoma, high dysplasia or intestinal IPMN with moderate dysplasia. The researchers used Das-1 monoclonal antibody as a biomarker to analyze the fluids of pancreatic cysts. In previous studies, this biomarker has been found to be associated with high risk pancreatic cysts that turned to be malignant. In this new study, Das-1 antibody was used to correlate with the protein expression in the cyst fluid and high-risk pancreatic cyst, with a sensitivity of 88%, a specificity of 99%, and an accuracy of 95%. The accuracy of current clinical guidelines is only about 74%.

Future direction is to test if this biomarker can identify pancreatic cysts that may become malignant before the patient undergoes surgery.

参考文献 Reference

Das KK et al Gastroenterology 20119: June 5. DOI: https://doi.org/10.1053/j.gastro.2019.05.014

 

生物标志物预测哪些胰腺囊肿可能变成癌性囊肿 (6/15/2019)

Biomarkers used to predict which pancreatic cysts may become cancerous

50％至70岁的人群中约有2％至4％可能患有胰腺囊肿，80岁以上人群增加到8％至9％。胰腺中的囊肿通常不会发生癌变，但有时会发展为浸润性癌症，这取决于囊肿的类型。切除胰腺囊肿的手术创伤大, 又有很多并发症。

从2010年1月至2017年6月, 研究小组收集了169例手术切除胰腺囊肿的液体（90个导管内乳头状粘液性肿瘤，43个粘液性囊性肿瘤和36个非粘液性囊肿）。高风险胰腺囊肿是那些患有浸润性癌，高度不典型增生或肠型IPMN且中度发育不良的患者。研究人员利用Das-1抗体作为生物标志来分析胰腺囊肿的液体。在先前的研究中，已经发现这种生物标志与会癌变的高风险胰腺囊肿相关联。在这项新研究中，从囊肿中检测 Das-1抗体, 鉴定出高风险胰腺囊肿，其灵敏度为88％，特异性为99％，准确度为95％。目前的临床指南仅有约74％的准确性。

未来的方向是观察生物标志物是否能够在患者接受手术之前识别可能变成癌变的胰腺囊肿。

50％至70岁的人群中约有2％至4％可能患有胰腺囊肿，80岁以上人群增加到8％至9％。胰腺中的囊肿通常不会发生癌变，但有时会发展为浸润性癌症，这取决于囊肿的类型。切除胰腺囊肿的手术创伤大, 又有很多并发症。

从2010年1月至2017年6月, 研究小组收集了169例手术切除胰腺囊肿的液体（90个导管内乳头状粘液性肿瘤，43个粘液性囊性肿瘤和36个非粘液性囊肿）。高风险胰腺囊肿是那些患有浸润性癌，高度不典型增生或肠型IPMN且中度发育不良的患者。研究人员利用Das-1抗体作为生物标志来分析胰腺囊肿的液体。在先前的研究中，已经发现这种生物标志与会癌变的高风险胰腺囊肿相关联。在这项新研究中，从囊肿中检测 Das-1抗体, 鉴定出高风险胰腺囊肿，其灵敏度为88％，特异性为99％，准确度为95％。目前的临床指南仅有约74％的准确性。

未来的方向是观察生物标志物是否能够在患者接受手术之前识别可能变成癌变的胰腺囊肿。

About 2% to 4% of people between 50 and 70 year of age may have pancreatic cysts, and those over 80 years old the chance increases to 8% or 9%. Cysts in the pancreas usually do not become cancerous, but sometimes can become invasive cancer, depending on the type of cyst. Surgical removal of pancreatic cysts is traumatic and can have morbid complications.
From January 2010 to June 2017, a research team collected 169 fluids for surgically removed pancreatic cysts (90 intraductal papillary mucinous tumors, IPMN,  43 mucinous cystic tumors, and 36 non-mucinous cysts). High-risk pancreatic cysts are those with invasive carcinoma, high dysplasia or intestinal IPMN with moderate dysplasia. The researchers used Das-1 monoclonal antibody as a biomarker to analyze the fluids of pancreatic cysts. In previous studies, this biomarker has been found to be associated with high risk pancreatic cysts that turned to be malignant. In this new study, Das-1 antibody was used to correlate with the protein expression in the cyst fluid and high-risk pancreatic cyst, with a sensitivity of 88%, a specificity of 99%, and an accuracy of 95%. The accuracy of current clinical guidelines is only about 74%.

Future direction is to test if this biomarker can identify pancreatic cysts that may become malignant before the patient undergoes surgery.

参考文献 Reference

Das KK et al Gastroenterology 20119: June 5. DOI: https://doi.org/10.1053/j.gastro.2019.05.014

AKT抑制剂capivasertib加上fulvestrant有利于芳香酶抑制剂治疗失败后乳腺癌 (6/9/2019)

AKT inhibitor capivasertib plus fulvestrant benefits metastatic breast cancer patients after progression on aromatase inhibitor

Capivasertib加入fulvestrant可显着延长患有转移性，雌激素受体阳性乳腺癌女性的疾病进展时间。

PI3K/AKT/PTEN通路在大约一半的雌激素受体阳性肿瘤中激活。Capivasertib是AKT的一种选择性抑制剂，在之前BEECH试验中 与紫杉醇联合治疗PIK3CA突变型雌激素受体阳性转移性乳腺癌患者无益。
FAKTION是一项II期双盲，安慰剂对照试验，从2015年至2018年间, 英国21个地点的140名绝经后，患转移性或局部晚期乳腺癌的病人, 随机分为fulvestrant加capivasertib（ 69人）或安慰剂（71人）, 两组患者分别为中位数62岁和61岁,  允许之前接受最多一次化疗和三次内分泌治疗。 病人每2星期接受肌肉注射500 毫克fulvestrant, 共3次, 然后每28天一次; 同时口服400 毫克 capivasertib或安慰剂（服4天，休息3天）。治疗进行至疾病进展或不可接受的毒性。

在FAKTION试验中，加入capivasertib至激素治疗后，中位无进展生存期从4.8个月改善至10.3个月（风险比率= 0.57; 95％置信区间= 0.39-0.84，p = .004）。Capivasertib组的客观缓解率显着提高，为41％，而单独使用fulvestrant为12％; capivasertib的临床获益更好，分别为55％相对于36％。

值得注意的是，无论PI3K激活状态如何，都可以看到这种好处，患者在“激活”组（定义为在外显子9或20中有PIK3CA突变）中获得无进展生存期益处（风险比率= 0.59; 95％置信区间=  0.34-1.03，p = .064），相对于未激活组（ 风险比率=  0.56; 95％置信区间= 0.33-0.96，p = .035）。

Capivasertib组≥3级不良事件发生率较高（58％相对于安慰剂组的30％），皮疹（20％），腹泻（14％）和感染（6％）最常见。在capivasertib组中，39％的患者需要至少一次剂量减少，而安慰剂组为4％。由于毒性，capivasertib组中12％的患者停止治疗，而安慰剂组则没有。一名患者由于毒性死于capivasertib。

The addition of Capivasertib to fulvestrant significantly prolonged progression-free survival (PFS) in women with metastatic, estrogen receptor-positive breast cancer.

The PI3K/AKT/PTEN pathway is activated in approximately half of estrogen receptor positive breast cancer. Capivasertib is a selective inhibitor of AKT and was not beneficial in combination with paclitaxel in the previous BEECH trial in patients with PIK3CA mutant estrogen receptor-positive metastatic breast cancer.

FAKTION is a phase II, double-blind, placebo-controlled trial in which 140 postmenopausal patients, from 2015 to 2018, with metastatic or locally advanced breast cancer were randomly assigned to fulvestrant plus capivasertib (69 patients) or placebo (71 patients), with median age of 62 years and 61 years, respectively. They were allowed to receive up to one chemotherapy and three endocrine therapy before. The patient received intramuscular injection of 500 mg of fulvestrant every 2 weeks for 3 times and then every 28 days; at the same time, they received 400 mg of capivasertib or placebo (4 days on, 3 days off). Treatment continues till disease progression or unacceptable toxicity.
In this trial, median PFS improved from 4.8 months (fulvestrant alone) to 10.3 months after addition of capivasertib (hazard ratio = 0.57; 95% CI= 0.39-0.84, p = .004). Objective response rate of the Capivasertib group was significantly higher, at 41%, compared with 12% for fulvestrant alone; the clinical benefit of capivasertib was better, 55% vs. 36%.

It is worth noting that this benefit can be seen regardless of the PI3K activation status. Patients gained PFS benefit in the “activation” group (defined as PIK3CA mutation in exon 9 or 20) (risk ratio = 0.59; 95% CI = 0.34-1.03, p = .064), versus the inactive group (risk ratio = 0.56; 95% CI = 0.33-0.96, p = .035).

The incidence of ≥3 adverse events was higher in the Capivasertib group (58% vs. 30% in the placebo group). Rash (20%), diarrhea (14%), and infection (6%) were the most common. In the capivasertib group, 39% of patients required at least one dose reduction compared to 4% in the placebo group. Due to toxicity, 12% of patients in the capivasertib group discontinued treatment, while there was none in placebo group. One patient died of capivasertib due to toxicity.

参考文献 Reference

Jones RH  et al. J Clin Oncol 2019; 37:  suppl; abstr 1005

 

Pembrolizumab对非肌肉浸润性耐受BCG的高风险膀胱癌有效 (6/8/2019)

Pembrolizumub for high-risk non-muscle invasive bladder cancer refractory to BCG

免疫治疗对非肌肉浸润性耐受BCG的高风险膀胱癌有效。

高风险非肌肉浸润性膀胱癌（NMIBC）定义为任何原位癌，T1肿瘤和/或高级Ta疾病。对BCG耐受的高风险NMIBC定义如下：充分BCG诱导后3个月疾病进展; 尽管有足够的BCG治疗，高风险的NMIBC在6个月时仍然存在; 在充分BCG治疗后12个月内达到无病状态后再次复发。由于疾病进展的高风险，对于BCG无反应的NMIBC患者，根治性膀胱切除术是推荐的标准选择。

KEYNOTE-057为II期临床试验, 是针对BCG耐受的NMIBC患者的单臂2期研究，他们不愿意或不适合接受根治性膀胱切除术。有102名患者符合纳入标准。中位年龄为73岁，63.7％的患者只有原位癌，之前接受BCG滴注的中位治疗数为12（范围6.0-45.0）。他们患有组织学证实的高风险，BCG无反应的原位癌伴或不伴乳头状疾病，并接受了足够的BCG治疗。参加者接受了每3星期pembrolizumab 200 毫克 , 治疗24个月, 或直至复发，疾病进展或不可接受的毒性。该研究的主要终点是完全响应率，次要终点是反应持续时间和安全性。

通过中央评估，3个月的完全响应率为40.2％（95％置信区间 = 30.6％-50.4％）。此外，在3个月达到完全缓解的41名患者中，58.5％在最后一次随访中保持完全缓解，中位数为16.7个月（范围5.9-28.2个月）。75％的患者完全响应持续时间≥ 6个月，53％的患者 ≥ 9个月。在3个月完全缓解的41名患者中，15名患者（36.6％）在完全响应后NMIBC复发，这些患者均未发展为肌肉浸润性或转移性疾病。

治疗相关不良事件发生在66例（64.7％）, 最常见的是瘙痒（10.7％），疲劳（9.7％），腹泻（8.7％），甲状腺功能减退（5.8％）和斑丘疹（5.8％）。只有13名患者（12.7％）患有3/4级治疗相关的不良事件，一名死亡被认为与治疗相关（患有类固醇治疗不充分的结肠炎）。作者报道，免疫介导的不良事件发生率为18.4％。

结果表明，对于有或无乳头状肿瘤的高风险，BCG耐受的原位膀胱癌患者，pembrolizumab十分有效。安全性与先前报导一致。

Immunotherapy is effective for high-risk, non-muscle invasive bladder cancer refractory to BCG.

High-risk non-muscle-invasive bladder cancer (NMIBC) is defined as any carcinoma in situ, T1 tumor and/or advanced Ta disease. High-risk NMIBC refractory to BCG is defined as follows: disease progression 3 months after BCG induction; high-risk NMIBC persists at 6 months despite adequate BCG treatment; disease relapse after disease-free status within 12 months of adequate BCG treatment. Radical cystectomy is usually the recommended standard of choice for patients with NMIBC who are refractory to BCG due to the nature of high risk disease progression.
KEYNOTE-057 is a phase II clinical trial of a single-arm study. Participants had BCG-refractory NMIBC and wre unwilling or unfit for radical cystectomy. 102 patients met the inclusion criteria. The median age was 73 years, and 63.7% of patients had only carcinoma in situ. The median number of previous treatments for BCG infusion was 12 (range 6.0-45.0). They have a high risk of histologically confirmed, BCG-refractory carcinoma in situ with or without papillary disease and received adequate BCG therapy. Participants received 200 mg of pembrolizumab every 3 weeks for 24 months, or until relapse, disease progression or unacceptable toxicity. The primary endpoint of the study was the complete response rate, and the secondary endpoint was response duration and safety.
Through a central assessment, the complete response rate at 3 months was 40.2% (95% CI = 30.6%-50.4%). In addition, of the 41 patients who achieved CR in 3 months, 58.5% remained completely remission during the last follow-up, with a median of 16.7 months (range 5.9-28.2 months). 75% of patients had a CR duration of ≥ 6 months, and 53% of patients had ≥ 9 months. Of the 41 patients who achieved CR in 3 months, 15 patients (36.6%) relapsed after CR, but none of these patients developed a muscle invasive or metastatic disease.
Treatment-related adverse events occurred in 66 patients (64.7%), the most common being pruritus (10.7%), fatigue (9.7%), diarrhea (8.7%), hypothyroidism (5.8%), and maculopapular rash (5.8%). Only 13 patients (12.7%) had grade 3/4 treatment-related adverse events, and one death was considered to be treatment-related (coliitis with inadequate steroid therapy). The authors report that the incidence of immune-mediated adverse events was 18.4%.
The results indicate that pembrolizumab is effective in patients with BCG-refractory bladder cancer in situ with or without papillary tumors. Safety and side-effects profile are consistent with previous reports.

参考文献 Reference

Balar AV et al. ASCO GU Cancer Symposium 2019; #GU 19

 

切除原发病灶改善HER2阳性IV期乳腺癌的生存 (6/2/2019)

Surgery improves survival in HER2-positive metastatic breast cancer women

最近一份报告的结论是, 接受手术的HER2阳性IV期乳腺癌的生存机率比不接受手术的女性要长44％。

该研究小组回顾性研究了2010年至2012年国家癌症数据库中3,231名HER2 阳性IV期乳腺癌女性的数据。他们发现89.4％的患者接受过化疗或靶向治疗，37.7％的患者接受过内分泌治疗，31. 8％的患者接受过放射治疗。 总体而言，1,130名女性（35％）接受了手术治疗。在25％的病例中，转移只见于骨骼。手术患者的平均年龄为56.0岁，而没有手术的患者平均年龄为59.1岁，中位随访时间为21.2个月。接受手术的HER2阳性IV期乳腺癌的生存机率比不接受手术的女性要长44％。

与手术机率增加的相关因素包括私人保险（42.3％），医疗保险(Medicare)/政府保险（30.5％）。其它因素包括接受放射治疗（47.4％），相对于未接受过放疗的28.8％。在接受手术的女性中，36.5％的人接受过化疗或免疫治疗，相对于22％的人未接受过这样的治疗。接受内分泌治疗的患者也更有可能接受手术（41.3%），相对于31.3％。非西班牙系白人女性比非西班牙裔非裔美国女性更有可能接受手术。在学术机构治疗的女性接受手术的可能性低于在社区医院治疗的女性（29.1％对37.1％）。按年龄计，20至39岁的人接受手术的可能性为44.4％，40岁至59岁的女性为36.9％，而60岁以上的女性为30.9％。

A recent report concluded that the survival rate of HER2-positive stage IV breast cancer undergoing surgery was 44% longer than those women who did not undergo surgery.
The report retrospectively reviewed data from 3,231 women with HER2-positive stage IV breast cancer in the National Cancer Database from 2010 to 2012. They found that 89.4% of patients received chemotherapy or targeted therapy, 37.7% received endocrine therapy, and 31.8% received radiation therapy. Overall, 1,130 women (35%) underwent surgery. In 25% of cases, metastases were only seen in bones. The median age of patients who underwent surgery was 56.0 years, while the median age of patients without surgery was 59.1 years, with a median follow-up of 21.2 months. The survival rate of HER2-positive stage IV breast cancer undergoing surgery was 44% longer than thaose who did not undergo surgery.
Factors associated with increased surgical rates include private insurance (42.3%) and Medicare/government insurance (30.5%). Other factors included radiation therapy (47.4%) compared to 28.8% of those who did not receive radiation therapy. Of the women who underwent surgery, 36.5% received chemotherapy or immunotherapy, compared with 22% who did not. Patients who received endocrine therapy were also more likely to undergo surgery (41.3%), compared to 31.3%. Non-Hispanic white women were more likely to undergo surgery than non-Hispanic African American women. Women who were treated in academic institutions were less likely to undergo surgery than women treated in community hospitals (29.1% vs. 37.1%). By age, the probability of surgery was 44.4% for women between 20 and 39 years of age, versus 36.9% for women between 40 and 59 years, and 30.9% for women over 60.

参考文献 Reference

Mudgway R et al. AACR, 2019; abstr 4478

 

十分有希望的胶质母细胞瘤自体疫苗 (6/1/2019)

A promising autologous vaccine against glioblastoma

虽然这仅是一个前瞻性临床Ib试验，但与历史上标准治疗对照已提示生存期的优势。

这项试验共有33例患有胶质母细胞瘤者参加，他们都必须是符合手术切除，并在术后接受辅助治疗的病人。该疫苗（IGV-001）是从原发脑肿瘤患者自身的肿瘤细胞在手术时采样后产生。对这些离休癌细胞，采用针对IGF-R1（insulin-like growth factor）的反义寡核苷酸（anti-sense oligodeoxynucleotide, AS-ODN）处理。IGF-R1是一个驱动肿瘤生长和转移的细胞受体。在将细胞移入扩散皿（diffusion chamber）之前，再加入AS-ODN。这些硬币大小的扩散皿以射线照射后，再植入患者腹部的皮肤下。参加者分成四组，植入的扩散皿从24小时内10个，到最多的为48小时内20个。中位随访时间为13个月（4-39）。

研究人员发现没有疫苗相关的不良事件。

经过反义IGF-1R和辐射处理后，扩散皿内的肿瘤细胞释放抗原，它与免疫调节的AS-ODN一起，扩散到患者的全身并激活免疫系统针对肿瘤细胞。与历史上在相同机构接受标准治疗与护理的35病例比较。接受最高剂量疫苗的患者的总生存期为21.9个月，相对于历史标准的14.6个月。中位无进展生存期分别为最高剂量疫苗的10.4个月，相对于文献上标准治疗的6.9和5.4个月。

预计今年将进行II期临床试验。

Although this is only a clinical Ib trial, it has showed a trend of survival advantage in comparison with historical standard.
A total of 33 patients with glioblastoma were enrolled in this prospective trial. They were all scheduled for surgical resection and receiving adjuvant therapy after surgery. The vaccine (IGV-001) is made from the autologous tumor cells at the time of surgery. These de novo cancer cells were treated with anti-sense oligodeoxynucleotide (AS-ODN) against IGF-R1 (insulin-like growth factor). IGF-R1 is a receptor that drives tumor growth and metastasis. AS-ODN was added before the cells were moved into a diffusion chamber. These coin-sized diffuser chambers were irradiated and implanted under the skin of the patient’s abdomen. Participants were divided into four groups, and the numbers implanted were from 10 diffusion chambers in 24 hours to a maximum of 20 chambers in 48 hours. The median follow-up time was 13 months (4-39).
The researchers found no vaccine-related adverse events.
After antisense IGF-1R and radiation treatment, the tumor cells in the diffusion chambers release antigens, which, together with the immune-regulated AS-ODN, diffuse systematically and activates the immune system against the tumor cells. The comparison was made with 35 cases who received standard treatment and care in the same institution historically. The overall survival of those who received the highest dose of vaccine was 21.9 months, compared to historical data of 14.6 months. The median progression-free survival was 10.4 months for the highest dose vaccine, compared to 6.9 and 5.4 months in published standard care studies.
Phase II clinical trial is expected this year.

参考文献 Reference

Andrews DW. AACR, 2019; abstr CT038

 

抗TIM-3抗体 作为单一疗法和抗PD-L1抗体的组合耐受良好 (5/26/2019)

Anti-TIM-3 antibody was well tolerated as a single agent or in combination with PD-L1 blockade

抗T细胞免疫球蛋白和粘蛋白结构域的分子3（抗TIM-3）抗体，单独或与免疫检查点阻断组合可以抵抗对免疫疗法的内在或获得性抗性, 并且安全性良好。

TIM-3是一种免疫检查点分子，在多种细胞类型上表达，包括T细胞，自然杀伤细胞和巨噬细胞。当激活时，TIM-3导致对T细胞的抑制，是恶性肿瘤和感染中T细胞耗尽的标志。理想的是利用抗TIM-3抗体（LY332）阻断TIM-3以重振T细胞功能，当共同靶向TIM-3和PD-L1时，在临床前期模型中，比单独使用PD-L1疗法的效果更高。还有证据表明临床上对PD-L1或PD-1治疗的耐药性可能部分由TIM-3介导。

这是一项正在进行的，多中心，首次人体Ia /Ib期剂量递增和扩增试验, 该研究的主要目的是确定LY332单独和与抗PD-L1抗体（LY330）组合的安全性，耐受性和II期剂量。晚期实体瘤患者在标准治疗后疾病进展且具有良好的功能状态和足够的器官功能，均符合参加试验的资格。也允许先前接受过抗PD-1或PD-L1疗法。在LY332单药治疗组中，共有6个队列。第一组以每2周3毫克开始，并逐渐升级至最高, 为每周1,200毫克，持续8周，然后是600毫克维持剂量不变。23例患者接受LY332单药治疗。他们患有多种肿瘤类型，最常见的是肺癌，超过50％的患者至少接受过3线治疗，30％的患者接受过PD-1或PD-L1治疗。接受联合治疗的患者同样具有多样性。

关于治疗相关的不良事件，研究者能够提升所有单一疗法和联合疗法的剂量，没有剂量限制性毒性，也没有任何与治疗相关的3或更高级不良事件。 大部分患者在单药治疗和联合治疗时都会产生抗药物抗体（分别约为60％和70％）。然而，这些抗体的滴度在超过50％的病例中是低水平，并且只有1名高滴度的患者具有输注相关反应。此外，即便存在抗药物抗体，也没有干扰药代动力学或毒性。基于总体安全性，药代动力学和功效数据，研究者选择推荐的II期剂量1,200毫克，每2周一次，持续8周，然后600毫克。

对单一疗法，观察到初步抗肿瘤活性。一名患有小细胞肺癌的患者具有确认的部分响应，10名患者疾病稳定，疾病控制率为11/23（47％）。

组合治疗的功效将在稍后的时间与正在进行的推荐的II期剂量组一起报告。

An  antibody against the T cell immunoglobulin and mucin domains molecele 3 (anti-TIM-3), alone or in combination with immune checkpoint blockade, could counter intrinsic or acquired resistance to immunotherapy and it is safe.
TIM-3 is an immune checkpoint molecule that is expressed on a variety of cell types, including T cells, natural killer cells, and macrophages. When activated, TIM-3 leads to inhibition of T cells and is a marker of T cell exhaustion in malignant tumors and infections. The idea is to block TIM-3 by the anti-TIM-3 antibody (LY332) to reinvigorate T cell function. When both TIM-3 and PD-L1 were targeted in preclinical model, outcome was better than PD-L1 therapy alone. There is also evidence that clinical resistance to PD-L1 or PD-1 treatment may be partially mediated by TIM-3.
This is an ongoing, multicenter, first human Ia/Ib dose escalation and amplification trial with the primary objective of determining safety and tolerance of LY332 alone and in combination with anti-PD-L1antibody (LY330) , and the recommended phase II dose. Patients with advanced solid tumors who progressed after standard treatment with good functional status and adequate organ function are eligible to participate in the trial. Those who received anti-PD-1 or PD-L1 therapy were also eligible. In the LY332 monotherapy group, there were 6 cohorts. The first group started with 3 mg every 2 weeks and gradually escalated to a maximum of 1,200 mg per week for 8 weeks, followed by a steady dose of 600 mg. Twenty-three patients received LY332 monotherapy. They included multiple tumor types, the most common being lung cancer, with more than 50% of patients received at least 3 lines of treatment and 30% received PD-1 or PD-L1. Patients receiving combination therapy are similarly had different tumor types.
Regarding treatment-related adverse events, the investigators were able to increase the dose of all monotherapy and combination drugs, without dose-limiting toxicity, and without any treatment-related grade 3 or higher adverse events. Most patients developed anti-drug antibodies (60% and 70%, respectively) in both monotherapy and combination therapy cohorts. However, the titers of these antibodies were low in more than 50% of the cases, and only one patient with high titers had an infusion-related reaction. Furthermore, even if anti-drug antibodies were present, there was no interference with pharmacokinetics or toxicity. Based on overall safety, pharmacokinetics and efficacy data, the investigators selected a recommended phase II dose of 1,200 mg once every 2 weeks for 8 weeks and then a steady dose of 600 mg.
For monotherapy, initial anti-tumor activity was observed. One patient with small cell lung cancer had a confirmed partial response, and 10 patients had stable disease with a disease control rate of 11/23 (47%).
The efficacy of the combination therapy will be reported at a later time along with the ongoing phase II trial.

参考文献 Reference

Harding JJ et al 2019 ASCO-SITC Clin Immuno-Oncol Sym 2019; abstr 12.

 

Tocilizumab用于难治的由阻断PD-1免疫治疗所引起的不良反应 (5/25/2019)

Tocilizumab effective for PD-1 blockade-related adverse effects

IL-6受体拮抗剂Tocilizumab对免疫检查点抑制剂引起，而不为类固醇激素控制的免疫介导的副作用有效。

以下报导的病例都从病历中取得和分析。使用方法是静脉给予Tocilizuma（剂量为4毫克/公斤）。当第一次给予nivolumab时抽取C-反应蛋白;若副作用持续, 继续每两周化验。临床改善的定义为：在7天内症状消退或出院。

在87例接受nivolumab治疗的患者中，34例需要使用tocilizumab（39.1％），所有患者均服用皮质类固醇。大多数（88.2％）是肺癌患者。3/4级副反应为间质性肺炎，占35.3％；血清病占35.3％，脑炎占14.7％，各1例为垂体炎，结肠炎，胰腺炎，肝炎和免疫介导的凝血功能障碍。从第一次接受nivolumab到开始使用tocilizumab的中位时间为76天（范围1-429）。 C反应蛋白有统计意义的显著增加：从基线时的中位数23 毫克/升（范围0.1-238.5）到出现免疫性副作用时的109.3 毫克/升（21.5-350.4）；在使用tocilizumab后，下降到19.2 毫克/升（0.25-149）（p < .00001）。 27/34例患者（79.4％）出现临床改善。一些患者（52.9％）仅需要单剂量，而38.2％需要两剂，8.8％需要三剂，1例需要四剂。其中27剂是在住院患者中给予（49.1％）。出院的中位时间为四天（范围1-27）。 74％的患者出院回家。

结论是，Tocilizumab可能是治疗继发于免疫检查点引起的类固醇难治性副反应的选择。今后的随机临床试验将会更好地阐明这些药物的相对功效和安全性。

Tocilizumab, an IL-6 receptor antagonist, is effective against immune-mediated adverse events secondary to checkpoint inhibitors and refractory to steroids.
The cases reported below were taken and analyzed from medical records. Tocilizumab was administered intravenously (4 mg/kg). The C-reactive protein was taken when the nivolumab is administered for the first time; if the side effects persist, the blood test continued every two weeks. Clinical improvement is defined as resolution of symptoms or hospital discharge within 7 days.
Of the 87 patients who received nivolumab, 34 required tocilizumab (39.1%), and all patients took corticosteroids. Most (88.2%) are lung cancer patients. Grade 3/4 side effects were interstitial pneumonitis, accounting for 35.3%; serum sickness accounted for 35.3%, encephalitis accounted for 14.7%, and one case each was hypophysitis, colitis, pancreatitis, hepatitis and immune-mediated coagulopathy. Median time from the first injection of nivolumab to tocilizumab was 76 days (range 1-429). There was a statistically significant increase in C-reactive protein level: median 23 mg/L from baseline (range 0.1-238.5) to 109.3 mg/L (21.5-350.4) when immune-mediated side effects occurred; then decreased after using tocilizumab to 19.2 mg/l (0.25-149) (p < .00001). Clinical improvement was seen in 27/34 patients (79.4%). Some patients (52.9%) only needed a single dose, while 38.2% required two doses, 8.8% required three doses, and one patient required four doses. Among all, 27 doses were administered in hospitalized patients (49.1%). The median time to discharge was four days (range 1-27), and 74% of patients were discharged home.
In conclusion, Tocilizumab may be the treatment of choice for steroid-refractory immune-mediated side effects secondary to checkpoint blockade. Future randomized clinical trials will better clarify the efficacy and safety of these drugs.

参考文献 Reference

Stroud CR et al. J Pharm Oncol Pract 2019; 25:551-7

 

局部晚期前列腺癌切除术前多药雄激素剥夺疗法提高响应率 （5/19/2019）

Intense neoadjuvant androgen deprivation for locally advanced prostate cancer

前列腺癌患者术前接受四药联用改善根治性前列腺切除术的病理性响应。

在一项开放标签性多中心的临床II期试验中，75名患者以2:1被随机分配为四药联用（50名）和两药联用（25名）。四药为阿比特龙（1,000毫克/天），enzalutamide（160毫克/天），亮丙瑞林（leuprolide）（每12周22.5毫克注射）和强的松（5毫克/天）；两药联用为enzalutamide加亮丙瑞林。一共用药24周，然后进行根治性前列腺切除术。患者的Gleason评分为4 + 3 = 7或更高，前列腺特异性抗原（PSA）> 20 纳克 / 毫升，或前列腺核磁共振成像为T3疾病。淋巴结需要<20 毫米。主要终了目标是病理完全响应或最小残留疾病，定义为中心病理检查审定残留肿瘤≤5毫米。大多数患者（87％）在国家综合癌症网络（NCCN）诊断标准中为高风险疾病。

四药联用组的病理完全响应或最小残留率为15人（30％），其中完全响应率为10％，而两药联用组为4例（16％），病理完全缓解率为8％）（ p = .263）。各组间ypT3病变率（50％相对于56％），阳性边缘率（18％相对于12％）和阳性淋巴结（10％相对于2％）均相似。手术前PSA最低点为0.03 相对于 0.02 纳克 / 毫升。

两组中的残余肿瘤均具有相似水平的ERG，PTEN，雄激素受体PSA和糖皮质激素受体表达。 ERG阳性肿瘤中PTEN丢失率显著升高（65％相对于 29％; p = .017），并且联合肿瘤ERG阳性和PTEN缺失与术后更广泛的残留肿瘤相关。

治疗耐受性良好，与治疗相关的副作用在两组中相似，除了四药联用组中3级高血压，肝转氨酶增加的发生率更高外，并未观察到与治疗相关的4级不良事件。

研究者的结论是，在局部晚期前列腺癌的根治性前列腺切除术前激素治疗在一些患者可以获得有利的病理响应。需要更长时间的随访来评估治疗对复发率的影响。

Patients with locally advanced prostate cancer received neoadjuvant androgen deprivation of four drugs before radical prostatectomy showed improved pathological response.
In an open-label, multicenter phase II trial, 75 patients were randomized to a combination of four drugs (50) and two drugs (25) at a 2:1 ratio. The four drugs are abiraterone (1,000 mg/day), enzalutamide (160 mg/day), leuprolide (22.5 mg injection every 12 weeks) and prednisone (5 mg/day); the two drug regime consists of enzalutamide and leuprolide. Treatment lasted 24 weeks, followed by radical prostatectomy. The patient’s Gleason score was 4 + 3 = 7 or higher, prostate specific antigen (PSA) > 20 ng / ml, or T3 disease by MRI. The lymph nodes need to be <20 mm. The primary end point was pathological complete response or minimal residual disease, defined as residual tumors ≤ 5 mm on central pathology review. Most patients (87%) had high-risk diseases by the National Comprehensive Cancer Network (NCCN) diagnostic criteria.
The pCR or minimum residual rate of the four-drug combination group was 15 patients (30%), of which the complete response rate was 10%, while the two-drug combination group was 4 patients (16%), and the pCR rate was 8%. ) ( p = .263). The rate of ypT3 lesions (50% versus 56%), positive margin (18% vs. 12%) and positive lymph nodes (10% vs. 2%) were similar in the two groups. The lowest PSA before surgery was 0.03 vs. 0.02 ng/mL.
Residual tumors in both groups had similar levels of ERG, PTEN, androgen receptor PSA and glucocorticoid receptor expression. The rate of PTEN loss was significantly elevated in ERG-positive tumors (65% vs. 29%; p = .017), and combined tumor ERG-positive and PTEN-deficient were associated with more postoperative residual tumors.
The treatment was well tolerated, and the side effects associated with treatment were similar in the two groups, except for the grade 3 hypertension and increased liver transaminases in the four-drug group. However there was no treatment-related grade 4 side-effects.
The investigators concluded that hormone deprivation before radical prostatectomy for locally advanced prostate cancer can achieve a favorable pathological response in some patients. Longer follow-up is needed to assess the effect of treatment on recurrence rates.

参考文献 Reference

McKay MC et al. J Clin Onc 2019: https://doi.org/10.1200/JCO.18.01777

 

阻断胰腺星状细胞分泌的蛋白质以治疗胰腺癌 (5/12/2019)

Targeting protein secreted by pancreatic stellete cells to treat pancreatic cancer

胰腺的星状细胞（stellate cell）产生的蛋白质驱动胰腺癌生长并保护其免受化疗杀伤。

胰腺癌通常无症状，仅在转移扩散到全身后才导致晚期诊断。另外，肿瘤细胞被包裹在“保护屏蔽”中，这是造成对许多癌症治疗抗药性的微环境。最近有文章发现胰腺星状细胞，通常在正常组织中处于休眠状态，当激活后，会分泌蛋白质，在肿瘤周围形成一个壳体保护它。活化的星状细胞还分泌称为LIF（leukemic inhibitory factor）的信号蛋白，向肿瘤细胞传递刺激信号以驱动胰腺癌的发展和进展。这表明LIF可能是一种有用的生物标志物，可以更快，更有效地帮助诊断胰腺癌。

为了理解胰腺星状细胞和癌细胞之间的通讯方法，研究人员首先提取细胞培养物来分析从星状细胞中输出的蛋白质。结果发现活化的星状细胞分泌LIF，作用于邻近的癌细胞。LIF通常有助于干细胞在胚胎期保持发育潜力，但在成年期消失。通过观察胰腺癌小鼠模型中阻断或破坏LIF（均使蛋白质无功能）对肿瘤生长的影响，可以研究LIF如何影响肿瘤进展和对治疗的反应。两种途径均独立地显示，没有功能性LIF信号传导，肿瘤进展减慢，并且对用于治疗人类癌症（例如吉西他滨）的化学治疗药物的反应得到改善。以前的研究表明，如果将胰腺星状细胞杀死，胰腺肿瘤会变得更难控制，这表明研究方向不是破坏分泌信号因子的胰腺星状细胞，而是设法阻止它们传递对肿瘤细胞的刺激信号。

研究人员还检查了肿瘤组织和人胰腺癌患者血液中LIF的水平。在患者的肿瘤和血液中发现了高水平的LIF；还发现在LIF水平，肿瘤进展和患者对化疗的反应之间存在显著相关性。这些发现表明LIF有望成为胰腺癌的生物标志物 。目前，唯一获得FDA批准的胰腺癌生物标志物是一种名为CA19-9的碳水化合物。该研究发现LIF是胰腺癌的准确且独立的测量指标，并且是比CA19-9更好的治疗反应指标。

因为抗LIF抗体治疗可能与其他治疗方法联合用于治疗胰腺癌，已有公司开始进行I期临床试验，以测试使用与LIF结合的单克隆抗体治疗的效果。

Proteins produced by the pancreatic stellate cells stimulate pancreatic cancer growth and protect it from chemotherapy.
Pancreatic cancer is usually asymptomatic and diagnosis is usually delated until after metastasis. In addition, tumor cells are encapsulated in a “protective shell,” which forms a microenvironment that renders resistance to many cancer treatments. Recently, it has been found that pancreatic stellate cells, which usually is in a dormant state in normal tissues, secrete proteins when activated, forming a shell around the tumor to protect it. Activated stellate cells secrete a signaling protein called LIF (leukemic inhibitory factor) that transmits stimulation signals to tumor cells to drive the development and progression of pancreatic cancer. This suggests that LIF may be a useful biomarker to make an early diagnosis of pancreatic cancer.
To understand how pancreatic stellate cells communicate with cancer cells, the researchers first extracted cell cultures to analyze proteins exported from stellate cells. It was found that activated stellate cells secrete LIF which acts on adjacent cancer cells. LIF usually helps stem cells maintain their developmental potential during embryonic phase, and disappears in adulthood. By observing the effects of blocking or disrupting LIF (both inactivating the protein) on tumor growth in a mouse model of pancreatic cancer, it is possible to study how LIF affects tumor progression and response to treatment. Both pathways independently show that, without functional LIF signaling, tumor progression is slowed down, and response is improved to chemotherapeutic drugs used to treat human cancers such as gemcitabine. Previous studies have shown that pancreatic tumors become more difficult to control if pancreatic stellate cells are destroyed, suggesting that the research direction is not to destroy pancreatic stellate cells, rather to prevent them from transmitting stimuli to tumor cells.
In addition, the researchers also examined the levels of LIF in tumor tissue and in the blood of pancreatic cancer patients. High levels of LIF were found in tumor specimens and in blood; there was also a significant correlation between tumor progression and patient response to chemotherapy at the LIF level. These findings suggest that LIF can become a biomarker for pancreatic cancer. Currently, the only FDA-approved pancreatic cancer biomarker is a carbohydrate called CA19-9. The study found that LIF is an accurate and independent measure of pancreatic cancer and is a better indicator of therapeutic response than CA19-9.
Because anti-LIF antibody therapy can potentially be used in combination with other drugs to treat pancreatic cancer, companies have begun Phase I clinical trials to test the efficacy of monoclonal antibodies that bind to LIF.

参考文献 Reference

Shi, Y et al. Nature 2019; 569:131-5

 

Savolitinib和osimertinib的组合在EGFR突变的非小细胞肺癌患者 (5/11/2019)

Savolitinib and osimertinib combination may benefit EGFR mutant and MET-amplified NSCLC patients

对EGFR突变的非小细胞肺癌通过MET扩增（amplification）而对先前EGFR靶向治疗产生抗性的患者, savolitinib和osimertinib的组合具有临床活性。

MET扩增是EGFR TKI （酪氨酸激酶抑制剂）获得耐药性, 是EGFR T790M后第二个最常见的驱动因素: 在5-30％的耐药患者中发生。以下是根据TATTON试验的两个扩展队列的中期结果，

使用较老的EGFR抑制剂如吉非替尼和厄洛替尼（Erlotinib），MET扩增仅占获得性耐药患者的5％~10％; 然而，最新的EGFR TKI osimertinib患者中, 耐药性显著增高, 25％的耐药性由MET驱动。TATTON临床试验是第一项在这一特定人群中研究EGFR和MET抑制剂组合。

第一个队列: 这项TATTON试验扩展阶段的最新中期分析, 包括46名NSCLC患者, 中位年龄59岁（41-92）,67％女性,  80％亚洲人, 都有EGFR突变，在先前的第一代或第二代EGFR TKI治疗后疾病进展, MET扩增, 但T790M阴性。大多数患者（67％）接受过一线治疗。 研究人员通过下一代测序或荧光原位杂交（MET基因拷贝5或MET/CEP7比率2）或免疫组织化学（50％肿瘤细胞中+3）。患者每天接受80毫克 osimertinib加600毫克savolitinib。安全性和耐受性是主要终点。次要终点包括抗肿瘤活性的评估。

在2018年2月数据截止时，研究人员报告了客观响应率为52％，其中包括24名患者在4周后确诊的部分响应。中位响应时间为43天（范围40-43），中位响应持续时间为7.1个月。

最常见的所有不良事件包括恶心（37％），腹泻（30％），疲劳（28％），食欲减退（28％），发热（26％）和呕吐（2​​2％）。91％的患者出现了与治疗相关的不良事件，其中43％为3级或更差。37％的患者出现严重不良事件，35％的患者因不良事件而停止研究治疗。两名患者因不良事件死亡，其中一名患者可能患有与savolitinib相关的急性肾损伤，另一名患者肺炎, 但与研究治疗无关。

第二个队列: 研究人员评估了48例NSCLC患者, 中位年龄59岁（28-82）,44％女性,  77％亚洲人, 都有EGFR突变, 在接受osimertinib或其他疗后, 由于MET扩增而获得耐药性。 27％的患者接受过三线治疗，另有27％的患者接受过三线或更多次治疗。由于在TATTON试验开始后，osimertinib获得了FDA批准用于EGFR突变的NSCLC患者的一线治疗，因此只有这一部分患者接受过osimertinib的一线治疗。

在该队列中，客观响应率为25％，有12个部分响应。中位响应时间为46天（43-51），中位响应持续时间为9.7个月。

该队列中最常见的所有原因不良事件是恶心（52％），呕吐（38％），腹泻（27％），疲劳（25％），食欲减退（23％）和发热（21％）。90%的患者经历了与治疗相关的不良事件，其中23％为3级或更差。29%的患者出现严重不良事件; 由于不良事件，21％的患者停用了savolitinib，10％的患者停用了osimertinib。发生了两例死亡，但两者均被认为与研究治疗无关。

研究者认为，尽管添加savolitinib确实会增加毒性，该组合方案似乎是可以忍受的。未来重要的是, 观察这种组合是否从治疗第1天起就阻止关键的耐药机制, 以使第一线治疗更加有效。

The combination of savolitinib and osimertinib is clinically active in patients with EGFR-mutated non-small cell lung cancer who are resistant to previous EGFR-targeted therapy via MET amplification.

MET amplification generates drug resistance to EGFR TKI (tyrosine kinase inhibitor) and is the second most common driver after EGFR T790M: occurring in 5-30% of drug-resistant patients. The following are the interim results of the two extended cohorts according to the TATTON trial.

Using older EGFR inhibitors such as gefitinib and erlotinib, MET amplification accounts for only 5% to 10% of acquired resistance. However, in osimertinib-treated patients, resistance significantly increased. About 25% of drug resistance is driven by MET. The TATTON clinical trial is the first to study a combination of EGFR and MET inhibitors in this particular population.

First cohort: The latest interim analysis of this extended phase of the TATTON trial, included 46 NSCLC patients, with a median age of 59 years (41-92), 67% of women, and 80% of Asians. They all had EGFR mutations and MET amplification. They progressed after first or second generation EGFR TKI treatment. They did not have T790M. Most patients (67%) received first-line treatment. The researchers used next-generation sequencing or fluorescence in situ hybridization (MET gene copy 5 or MET/CEP7 ratio 2) or immunohistochemistry (3+ positive in 50% tumor cells). Patients received 80 mg osimertinib plus 600 mg savolitinib daily. Safety and tolerability are the primary endpoints. Secondary endpoints included an assessment of anti-tumor activity.

At the end of the February 2018 data cutoff, the researchers reported an objective response rate of 52%, including 24% partial response after 4 weeks. The median response time was 43 days (range 40-43) and the median response duration was 7.1 months.

The most common all-cause adverse events included nausea (37%), diarrhea (30%), fatigue (28%), loss of appetite (28%), fever (26%), and vomiting (22%). Treatment-related adverse events occurred in 91% of patients, with 43% being grade 3 or worse. Severe adverse events occurred in 37% of patients, and 35% of patients discontinued study due to adverse events. Two patients died of adverse events, one of whom may have acute kidney injury associated with savolitinib and another patient with pneumonia, but was not thought due to study drug.

The second cohort: The researchers evaluated 48 patients with NSCLC, with a median age of 59 years (28-82), 44% of women, and 77% of Asians with EGFR mutations. They acauired resistance after receiving osimertinib or other treatments. Among them, 27% of patients received third-line therapy, and another 27% received three or more treatments. Since osimertinib received FDA approval for first-line treatment for EGFR mutated NSCLC after the start of the TATTON trial, only this portion of patients received first-line treatment with osimertinib.

In this analyses, the objective response rate was 25% and there were 12 partial responses. The median response time was 46 days (43-51) and the median response duration was 9.7 months.

The most common adverse events in this cohort were nausea (52%), vomiting (38%), diarrhea (27%), fatigue (25%), loss of appetite (23%), and fever (21%). 90% of patients experienced treatment-related adverse events, 23% of which were grade 3 or worse. Severe adverse events occurred in 29% of patients; savolitinib was discontinued in 21% of patients and osimertinib was discontinued in 10% of patients due to adverse events. Two deaths occurred, but both were considered unrelated to the study drug.

The researchers believe that the combination seems to be tolerable in spite of increased toxicity when savolitinib was added. It is important in the future to see if this combination blocks key resistance mechanisms from day 1 of treatment to make first-line treatment more effective.

参考文献 Reference
Sequist LV et al. 2019 AACR abstr CT033
Yu H et al. 2019 AACR abstr CT032

 

如何处理乳腺癌局部复发的问题：Memorial Sloane-Kettering 癌症中心乳腺癌外科主任Morrow医生 (5/5/2019)

How to manage local recurrence in breast cancer: a talk from Dr. Morrow, chief of breast cancer service in MSKCC

首先是必须排除同时存在的全身转移性，包括正电子发射断层扫描。在近一半的局部复发患者中，远处转移是在同一时间或3个月内诊断出来的。

1）单纯性腋窝复发并不常见，在前哨淋巴结阴性患者中仅佔不到0.6％，在前哨淋巴结阳性但未接受腋窝淋巴结清扫的妇女中约佔1.1％。 腋下局部复发可能是由于前哨淋巴结活检的假阴性率有关，它与腋窝淋巴结清扫后的复发预后不同，腋窝复发是一个早期事件，绝大多数病例发生在手术后5年。在没有远处转移的情况下，腋窝淋巴结清扫是治疗前哨淋巴结活检后淋巴结复发的确当方法。

2）孤立性锁骨上淋巴结复发，非常罕见，很难确定最合适的局部治疗方法。 通常为局部和全身治疗的结合。

是否需要再次前哨淋巴结活检

这个问题多出现在乳房内或胸壁复发的情况下。根据一项对692名患者（都保留了乳房，接受或并未接受放疗）的调查发现，在这些局部复发的病人中，若起先手术是哨前淋巴结活检时，成功定位的可能性为81％，相比于起先手术为腋窝淋巴结清扫术的52％。 在成功定位的患者中，25％的初次腋窝手术为前哨淋巴结活检者其淋巴引流异常，占所有接受前哨淋巴结活检的14％。相比之下，75％的初次手术为腋窝淋巴结清扫的患者其淋巴引流到腋窝外，约占所有腋窝淋巴结清扫患者的33％。最常见的异常引流部位是内乳淋巴结，这些患者中约有三分之一引流至对侧腋窝。由于再次前哨淋巴结检出频率较低，联合应用放射性胶体和蓝色染料是必要的。如果在皮内或乳晕下注射放射性同位素，很少见腋外前哨淋巴结。因此，应在肿瘤周围区域内注射同位素。

一项MSK研究调查了1997年至2000年期间接受治疗的1,527例患者，这些患者有任何大小的原发肿瘤和阴性前哨淋巴结。在83例局部复发的患者中，79例有乳房内复发，4例复发胸壁复发 。虽然再次活检前哨淋巴结是可行的，但对于局部复发为浸润性的，都应接受前身治疗，那篇文章的结论是再次前哨淋巴结活检并无必要。

在本次谈话中，她提到淋巴结的肿瘤状态不是全身治疗的决定因素，在CALOR试验的长期随访显示，局部复发的妇女随机分布为接受或不接受化疗，只有雌激素受体阴性妇女，在接受化疗后，无病生存率，无乳腺癌间隔和总体生存率均有所提高，而雌激素受体阳性患者则没有。淋巴结状态并没有改变这种情况。

但当保留的乳房发生第二次原发肿瘤的患者，发现淋巴结可能会改变治疗，就像在原发乳腺癌的主要治疗中淋巴结状态会改变治疗方法。

3) 对侧转移

美国癌症联合委员会TNM分期系统将对侧淋巴结疾病分类为IV期， 需要进行转移性检查，需要确保在对侧乳房中排除新的原发肿瘤，乳房X光检查和磁共振是有必要的。由于有限的报道，对此无法作明确的建议，但手术对某些病例有良好的结果。这些患者特别适合术前全身治疗，对某些疾病快速发展的患者，术前全身治疗可能会避免手术。

4) 乳房保留治疗后患侧乳腺肿瘤复发

在乳房保留术后同侧乳腺肿瘤复发的研究中，在中位随访6至244个月（20年）时，其他局部复发的发生率很高，从7％到29％。

重行乳房肿瘤切除术而不予放疗并不是标准治疗方法。 例外的是患者在初次手术后符合无放射治疗的标准：即她们年龄超过70岁，为T1N0期，雌激素受体阳性，HER2阴性乳腺癌；或为中低级的原位癌（≤1.5cm）；或两次肿瘤之间有很久的无疾病间隔，是在一个不同的象限，或患者有严重的合并症。长期局部控制肿瘤并不成为一个问题。

关于保留乳头的乳房切除术（应参加者要求回答）

与传统的乳房切除术相比，保留乳头的乳房切除术在技术上更难以做好；局部复发的风险增加不仅仅发生在乳头-乳晕复合体中，部分乳房组织可能会被留下以保持乳头-乳晕复合体的血液供应，复发风险可能遍布胸壁。这种手术适用于乳房周围的肿瘤且较小，距离乳头-乳晕复合体至少1或2厘米。

(本报告由在线报告翻译缩短)

The first step is to rule out systemic metastasis, including a PET scan. In nearly half of patients with local recurrence, distant metastases were diagnosed at the same time or within 3 months.
1) Isolated axillary recurrence is uncommon, accounting for less than 0.6% of sentinel node-negative patients and 1.1% of women with sentinel lymph node-positive but not undergoing axillary lymph node dissection. Local recurrence of the armpit may be due to the false-negativity of sentinel lymph node biopsy, which is different from the prognosis of axillary lymph node dissection. Axillary recurrence is an early event, and the vast majority of cases occur 5 years after surgery. In the absence of distant metastases, axillary lymph node dissection is a definitive method for the treatment of lymph node recurrence after sentinel lymph node biopsy.
2) Isolated supraclavicular lymph node recurrence is very rare and it is difficult to be dogmatic about the most appropriate local treatment. Usually a combination of local and systemic treatments.
Reoperative sentinel lymph node biopsy
This problem occurs mostly in the breast or in the case of chest wall recurrence. According to a survey of 692 patients (had breast conservation, with or without radiation), with locally recurrent disease, if the initial surgery was a sentinel lymph node biopsy, the probability of successful mapping was 81%., compared with 52% if the initial surgery was axillary lymph node dissection. Among those who were successfully mapped, 25% of those whose initial axillary surgery was a sentinel biopsy had abnormal lymphatic drainage, accounting for 14% of all sentinel lymph node biopsies. In contrast, 75% who had prior axillary dissection drained to basins outside the axilla or in addition to the axilla, representing about 33% of patients with axillary dissection. The most common abnormal drainage site is the internal mammary lymph node, and about one-third of these patients are drained to the contralateral axilla. Due to the lower frequency of reoperative, a combined application of radioactive colloids and blue dyes is necessary. If a radioisotope is injected under the skin or the areola, it is rare to see an extra-axillary lymph node. Therefore, isotope should be injected in the area surrounding the tumor.
An MSK study investigated 1,527 patients who underwent treatment between 1997 and 2000 with primary tumors of any size and negative sentinel lymph nodes. Of the 83 patients with local recurrence, 79 had intramammary recurrence and 4 had recurrence of chest wall recurrence. Although it is feasible to perform reoperative sentinel lymph node biopsy, the article in reference concluded that it may not be necessary.
In this conversation, she mentioned that the tumor status of lymph nodes is not a determinant of systemic therapy. Long-term follow-up of the CALOR trial showed that when women with local recurrence were randomly assigned to receive or not receive chemotherapy, only estrogen receptor-negative women, disease-free survival, no breast cancer interval and overall survival were improved after chemotherapy; while estrogen receptor-positive patients did not benefit. The state of the lymph nodes did not change this.
However, when a patient had a second primary tumor in the remaining breast, it is found that the lymph node status may change the treatment, just as the lymph node status changes the treatment in the setting of primary treatment of primary breast cancer.
3) contralateral metastases
The American Joint Committee on Cancer TNM staging system classifies contralateral lymph node disease as stage IV. These women require a metastatic work-up. One needs to make sure a new primary is excluded from the contralateral breast. Mammography and magnetic resonance are necessary. Due to limited data, no definite recommendations can be made for this, but surgery has good results for some cases. These patients are particularly suitable for preoperative systemic therapy. For patients with rapid disease development, preoperative systemic therapy may avoid surgery.
4) Ipsilateral breast tumor recurrence after breast conserving therapy
In the study of ipsilateral breast tumor recurrence after breast preservation, the incidence of local recurrences was high at 7% to 29% at a median follow-up of 6 to 244 months (20 years). Resection of the breast with lumpectomy without radiotherapy is not the standard treatment. Exceptions are those patients who meet the criteria for no radiation therapy after initial surgery: that is, they are over 70 years old, are T1N0, estrogen receptor-positive, HER2-negative breast cancer; or low-grade carcinoma in situ (≤1.5cm) ; or a long periods of no disease interval, in a separate quadrant, or patients with severe comorbidities. Long-term local control of the tumor does not become a problem.
(This report was translated by an online report, without verification by a spokesperson)

About nipple-sparing mastectomy (in response to questions from the participants)
Nipple-sparing mammectomy is technically more difficult than conventional mastectomy. An increased risk of local recurrence does not only occur in the nipple-areola complex, where part of the breast tissue may be left to keep the blood supply to the areola complex, it also spreads over the chest wall. This procedure is suitable for tumors in the periphery of the breast and is small, at least 1 or 2 cm from the nipple-areola complex.

(abbreviated and adapted from Dr. Morrow’s talk reported online)

参考文献 Reference

Morrow M. ASCO Post 2019; Jan

Maaskant-Braat AJ et al. Breast Cancer Res Treat 2013; 138:13-20

Maaskant-Braat AJ et al. Ann Surg Oncol 2013; 20:620-6

Wapnir IL et al. J Clin Oncol 2018; 36:1073-9

 

Darolutamide延长非转移性前列腺癌患者的无转移生存期 (5/4/2019)

Darolutamide prolonged metastasis-free survival in castration-resistant prostate cancer

Darolutamide是一种结构独特的雄激素受体拮抗剂，在非转移性前列腺癌患者中延长无转移生存期。

一项随机，安慰剂对照的3期双盲临床试验（ARAMIS）中，1509名参加者患有非转移性，激素耐受性前列腺癌，但前列腺特异性抗原倍增时间为10个月或更短。患者以2：1（955名相对于554名）的比例随机分配接受darolutamide（每日两次300毫克）或安慰剂，同时继续进行雄激素剥夺治疗。主要终点是无转移生存，每16周进行一次放射检查，这些检查由独立中心来审查确定是否存在转移。

在437个主要终点事件发生后进行的分析中，使用darolutamide的中位无转移生存为40.4个月，而安慰剂组为18.4个月（风险比为0.41; 95％置信区间 = 0.34-0.50; p < .001）。 Darolutamide还与所有次要终点的益处相关，包括总生存期，疼痛加重开始时间，化疗开始时间和症状性骨骼事件开始时间。治疗期间不良事件发生率，包括3级或更高的事件，在两组中相似。由于不良事件而中止指定方案治疗的患者在darolutamide组中为8.9％，在安慰剂组中为8.7％。Darolutamide与癫痫发作，跌倒，骨折，认知障碍或高血压的发生率无关。

结论: 在具有非转移性，激素耐受性的前列腺癌患者中，darolutamide延长无转移生存期，而且安全。

Darolutamide is a structurally unique androgen receptor antagonist that is effective in delaying metastasis and death in patients with non-metastatic prostate cancer.
In a randomized, placebo-controlled, phase 3 double-blind clinical trial (ARAMIS), 1,509 patients had non-metastatic, castration-resistant prostate cancer, whose PSA doubling time was 10 months or less. Patients were randomized to receive darolutamide (300 mg twice daily) or placebo in a ratio of 2:1 (955 vs. 554) while continuing androgen deprivation therapy. The primary endpoint was metastasis-free survival. Radiological examinations were performed every 16 weeks, and they were subject to independent central review to determine the presence of metastases.
In the analysis performed after 437 primary endpoint events, median metastasis-free survival with darolutamide was 40.4 months, compared with 18.4 months in the placebo group (HR= 0.41; 95% CI = 0.34 – 0.50; p < .001). Darolutamide is also associated with the benefit of all secondary endpoints, including overall survival, time to onset of pain progression, time to start chemotherapy, and time to onset of symptomatic skeletal events. The incidence of adverse events during treatment, including grade 3 or higher events, was similar in the two groups. Patients who discontinued the assigned rtreatment due to adverse events were 8.9% in the darolutamide group and 8.7% in the placebo group. Compared with placebo, Darolutamide was not associated with seizures, falls, fractures, cognitive impairment or hypertension.
Conclusion: In non-metastatic, castration-resistant prostate cancer patients, darolutamide demonstrated a significantly longer metastasis-free survival than placebo and is safe.

参考文献 Reference

Fizazi K, et al. Abstract 140. GU Cancers Sympo 2019; abstr 140

 

逆转黑色素瘤对免疫疗法的抵抗力 (4/28/2019)

Entinostat, a histone deacetylase inhibitor, may reverse melanoma resistance to immunotherapy

一项临床试验显示，对PD-1 / L1抗体治疗产生耐药的转移性黑色素瘤患者，在接受组蛋白去乙酰化酶（histone deacetylase . HDAC）抑制剂entinostat后能剂获得持久反应。

临床前模型的研究显示了HDAC与抗PD-1药物协同作用的证据，在单剂量的entinostat以后14天内髓源抑制细胞显著下降, 证明该药物有助于肿瘤微环境中免疫抑制细胞的下调。

一项II期开放性研究评估了53例复发或转移性黑色素瘤患者在接受pembrolizumab期间或之后疾病进展，他们然后接受entinostat和pembrolizumab联合治疗。治疗史包括联合使用易普利姆玛和PD-1抑制剂（37名），和BRAF/MEK抑制剂组合（12名）。Entinostat和pembrolizumab联用在19％（10/53）的患者中产生了客观响应，包括一名完全响应; 36％的患者获得了临床效果。 大多数患者有一定程度的肿瘤缩小。 中位随访10.6个月后，研究人群的中位无进展生存期为4.2个月。 10名患者的随访时间超过一年，其中包括一名早期响应患者，由于不耐受而停止治疗，但在随访期间保持了90周以上的反应。

所有等级的常见治疗副作用为恶心（47.2％），疲劳（37.7％），腹泻（20.8％），中性粒细胞计数减少（18.9％），血小板减少（17％），瘙痒（ 17％），贫血（15.1％），关节痛（15.1％）和呕吐（15.1％）。 3/4级副作用包括中性粒细胞减少症（7.5％），低钠血症（5.7％）和疲劳症（5.7％）。

In a phase II clinical trial, patients with metastatic melanoma who developed resistance to PD-1 / L1 antibody demonstrated a durable response after receiving a histone deacetylase (HDAC) inhibitor entinostat, in addition to a PD-1/L1 inhibitor.
Preclinical studies have shown evidence of a synergistic effect of HDAC with anti-PD-1 drugs, with a significant decrease in myeloid-derived suppressor cells within 14 days after a single dose of entinostat. The results demonstrated that the drug contributes to down-regulation of immunosuppressive cells in the tumor microenvironment.
A phase II open-label study evaluated 53 patients with relapsed or metastatic melanoma who had disease progression during or after pembrolizumab treatment. They were then treated with entinostat and pembrolizumab. Their prior treatment history included a combination of ipilimum and PD-1 inhibitors (37 patients) and a BRAF/MEK inhibitor combination (12 patients). The combination of Entinostat and pembrolizumab produced an objective response in 19% (10/53) of patients, including one complete response; 36% of patients demonstrated clinical benefit. Most patients had certain degree of tumor shrinkage. After a median follow-up of 10.6 months, the median progression-free survival of the study population was 4.2 months. Ten patients were followed for more than one year, including an early-responding patient who discontinued treatment due to intolerance but maintained a response of more than 90 weeks during follow-up.
Common treatment-related side-effects of all grades were nausea (47.2%), fatigue (37.7%), diarrhea (20.8%), neutropenia (18.9%), thrombocytopenia (17%), itching (17%), anemia (15.1%), joint pain (15.1%) and vomiting (15.1%). Grade 3/4 side effects included neutropenia (7.5%), hyponatremia (5.7%), and fatigue (5.7%).

参考文献 Reference

Sulivan RJ. Am Asso Cancer Res 2019

 

更多数据显示延长内分泌治疗的益处 (4/27/2019)

More data regarding the benefit of extended endocrine therapy

数据来自两项研究:

早期乳腺癌试验协作组（EBCTCG）进行24.912患者的荟萃分析。这项分析包括了7,500名仅接受5年他莫西芬，4,800名仅接受芳香酶抑制剂，12,600名在接受了5-10年的他莫西芬后再服用芳香酶抑制剂。分析发现，延长内分泌治疗使任何形式的复发㓕少24%（9.5% 相对于7.0%; p < .00001）；远处转移减少15%（6.1% 相对于5.1%;  p =.004）。死亡率的减少没有达到统计上有意义的区别（3.1% 相对于2.8%;   p = .09）。

延长芳香化酶抑制剂治疗对复发减少的程度与之前服用什么药物有关：若在延长治疗开始之前是服用他莫西芬者，复发风险减少为33%（p < .00001）；若之前服用的为芳香酶抑制剂，风险减少则为19%（p < .0010）。另外，当转移的淋巴结数目增多时，风险减少的绝对值也增高。

日本进行的AERAS试验。 它报道了使用相同的芳香酶抑制剂10年相对于5年，5年无病生存率分别为91.9％和84.4（风险比率＝0.548; p =.0004），远处无转移生存率分别是97.2% 相对于94.3%（风险比率＝0.514; p = .0077）。总生存率没有什么不同，双臂均为99％。

3级或以上的副作用很少见。延长的芳香化酶抑制和5年芳香化酶抑制治疗的副作用包括骨折（2.8%相对于1.1%），骨质疏松（33%相对于28%），关节痛（19.2%相对于11.7%），和潮热（6.7%相对于3.1%）。

以上结果与以前的研究如MA.17不同,  它为选择可能受益于延长内分泌治疗的女性提供针对性指导。

The data comes from two studies:
The Early Breast Cancer Trial Collaborative Group (EBCTCG) conducted a meta-analysis of 24.912 patients. The analysis included 7,500 patients who received only 5 years of tamoxifen, 4,800 patients who only received aromatase inhibitors, and 12,600 patients who received aromatase inhibitors after 5-10 years of tamoxifen. The analysis found that prolonged endocrine therapy reduced 24% any recurrence (9.5% vs. 7.0%; p < .00001); decreased distant metastasis by 15% (6.1% vs. 5.1%; p = .004). The reduction in mortality did not reach a statistically significant difference (3.1% vs. 2.8%; p = .09).
The extent of benefit from extended aromatase inhibitor treatment is related to what medication was taken before AI: if tamoxifen was taken before AI, the risk of recurrence was reduced by 33% (p < .00001); if it was preceded by an AI, the risk reduction was 19% (p < .0010). In addition, the absolute benefit of risk reduction increases when there is an increased number of metastatic lymph nodes.
The AERAS test conducted in Japan. It reported that using the same aromatase inhibitor for 10 years versus 5 years, the 5-year disease-free survival rates were 91.9% vs 84.4% respectively (HR = 0.548; p = .0004), and the distant metastasis-free survival rate was 97.2. % vs. 94.3% (HR = 0.514; p = .0077). There is no difference in overall survival as both arms are 99%.
Grade 3 or higher side effects  are rare. Side effects from prolonged aromatase inhibitor use and 5-year AI treatment included fractures (2.8% vs. 1.1%), osteoporosis (33% vs. 28%), and joint pain (19.2% vs. 11.7%). And hot flashes (6.7% vs. 3.1%).
The above results are somewhat different from previous studies such as MA.17. The data will provide more relevant guidance for women who may benefit from extended endocrine therapy.

参考文献 Reference

Gray R. 2018 San Antonio Breast Cancer Symp abstr GS3-03 

Ohtani S et al. 2018 San Antonio Breast Cancer Symp abstr GS3-04 

 

放射性配体疗法对转移性前列腺癌的疗效 (4/21/2019)

Radioligand has activity in metastatic prostate cancer

在最近报道的一项试验中，采用对前列腺膜抗原（PSMA）的特异性放射性配体（radioligand）疗法（lutetium-177 PSMA-617 -[LuPSMA]）, 对大多数患有转移性耐激素前列腺癌有疗效。

LuPSMA是一种小分子靶向配体，选择性地结合前列腺（细胞）膜抗原（PSMA）。PSMA通常在前列腺癌细胞上表达，将l -177，一种放射性有效载荷，搭载在PSMA上，为前列腺转移瘤提供高剂量的放射，同时避免对正常细胞的辐射损害。 该化合物的半衰期为7天。 LuPSMA发射的β粒子功能距离大约1毫米，可导致肿瘤死亡，还有低水平的伽马射线可以通过核成像显示，以确定疾病是否正在消退。

这是LuPSMA的第一项前瞻性II期单臂研究，共报道了50名耐激素的转移性前列腺癌患者参加，所有病人在之前的治疗中都有疾病进展，参加该试验前的PSA倍增时间中位数为2.6个月。大多数患者（90％）接受过泰索帝（doctaxel）（84％）或阿比特龙（abiraterone）加强的松（prednisone）或enzalutamide（90％）。有48％的病人接受过二线卡巴他赛（cabazitaxel）的治疗。参加者每6周静脉内接受LuPSMA治疗（最多4次）。他们定时测试PSA水平并接受CT或PET以评估反应。主要终点是PSA反应和毒性。

50例患者中有32例（64％）PSA下降≥50％，其中22例（44％）PSA下降≥80％。在27名基线软组织转移患者中，56％有部分或完全反应。但患者随后经历了疾病进展，PSA进展的中位时间为6.9个月。 PSA下降≥50％的患者的总生存期为18个月。在疾病进展后用LuPSMA再次治疗的男性中也发现了高反应率。有14名接受过LuPSMA而疾病进展的患者接受了中位数2次以上LuPSMA的注射; 在9名患者（64％）中观察到PSA下降≥50％。该组的中位生存期为33个月。虽然由于缺乏对照组和参加人数的限制，该研究无法观察生存情况，但接受LuPSMA治疗的男性在治疗后的中位存活为13.3个月，超过了9个月的预期存活率。

不良事件与早先报道的30例患者相似。大约10％的患者出现3至4级血小板减少和贫血。研究人员认为这是一种有效无毒的疗法。

In a recently reported trial, a radioligand therapy (lutetium-177 PSMA-617 -[LuPSMA]) specific for prostate membrane antigen (PSMA) was effective in metastatic castration-resistant prostate cancer.
LuPSMA is a small target ligand that selectively binds to prostate (cell) membrane antigen (PSMA). PSMA is usually expressed on prostate cancer cells, and l-177, a radioactive payload, is attached to LuPSMA to provide high doses of radiation to metastatic prostate cancer while avoiding radiation damage to normal cells. The compound has a half-life of 7 days. LuPSMA emits beta particles that travels approximately 1 mm and cause tumor death. Low levels of gamma rays can be visualized with nuclear imaging to determine if the disease is regressing.
This is the first LuPSMA phase II single-arm study. A total of 50 patients with castration-resistant metastatic prostate cancer was reported. All patients had disease progression from previous treatments. The median PSA doubling time before participating the trial was 2.6 months. Most patients (90%) received doctaxel (84%) or abiraterone plus prednisone or enzalutamide (90%). 48% of patients have been treated with second-line cabazitaxel. Participants received LuPSMA intravenously every 6 weeks (up to 4 times). They regularly were tested for PSA levels and received CT or PET to assess their response. The primary endpoint is response to PSA and drug toxicity.
Of the 50 patients, 32 (64%) had a PSA decrease of ≥ 50%, of which 22 (44%) had a PSA decrease of ≥ 80%. Of the 27 patients with baseline soft tissue metastases, 56% had partial or complete responses. However, those patient subsequently experienced disease progression and the median time to PSA progression was 6.9 months. Patients with a PSA reduction of ≥50% had a total survival of 18 months. High response rates were also found in men who were retreated with LuPSMA after disease progression. Fourteen patients whose disease progressed on LuPSMA received more than 2 (median) injections of LuPSMA; a decrease in PSA of ≥50% was observed in 9 patients (64%). The median survival of this group was 33 months. Although survival could not be concluded on the study due to lack of control and small number of participants, the median survival among men treated with LuPSMA was 13.3 months after treatment, exceeding the expected survival rate of 9 months.
Adverse events were similar to the 30 patients previously reported. About 10% of patients develop grade 3 to 4 thrombocytopenia and anemia. Researchers believe this is an effective and safe treatment.

参考文献 Reference

Hofman M et al. 2019 Genitourinary Cancers Symp  abstr 228  

 

Denosumab辅助治疗有利于激素受体阳性的绝经后乳腺癌患者 (4/20/2019)

Advantage of adjuvant denosumab for estrogen-receptor positive postmenopausal breast cancer

使用denosumab作为芳香酶抑制剂的辅助治疗可显著减少临床骨折。 并延长无病生存期。

患有早期，激素受体阳性的绝经后乳腺癌患者，在完成手术，放疗或/和化疗并接受辅助芳香酶抑制剂，参加这项前瞻性，双盲对照的3期试验（ABCSG-18）。患者以1:1分配, 每6个月接受皮下denosumab（60 毫克）或每6个月 安慰剂注射。主要终点是随机化后首次临床骨折的时间。此处报告的次要终点是意向治疗人群的无病生存期（定义为从随机化到局部或远处转移，对侧乳腺癌，继发性癌或任何原因的死亡）。

在2006年12月18日至2013年7月22日期间，共有3,425名符合条件的患者入选并随机分配: 1,711名为denosumab组，1,709名为安慰剂组。中位随访为73个月。denosumab中患者240例（14.0％），安慰剂组中287例（16.8％）患者发生无疾病生存事件。 denosumab组与安慰剂组相比，无病生存率显著提高（风险比率 = 0.82; 95％置信区间 = 0.69–0.98，Cox p = .0260）。在denosumab组中，5年无病生存率为89.2％, 相对于安慰剂组的87.3％（85.7-89.0）（95％置信区间 = 87.6–90.8），8年随访时为80·6％（78.1-83.1）, 相对于安慰剂组的77.5％（74.8–80.2）。

没有独立的颌骨坏死或确诊的非典型股骨骨折病例。 Denosumab组和安慰剂组的不良事件总数相似。最常见的严重不良事件是骨关节炎（denosumab组为62件（3.6%）; 安慰剂组为58件（3.4％）。半月板损伤为 1.3％相对于 1.4％。 白内障为0.9％相对于1.7％。 denosumab组发生一例（<0.1％）治疗相关死亡（由于肺炎，脓毒性肾 衰竭和心脏代偿失调）。

结论是, denosumab对接受芳香酶抑制剂治疗的绝经后激素受体阳性乳腺癌患者为有效且安全的辅助治疗。

The use of adjuvant denosumab for aromatase inhibitors can significantly reduce fractures and prolong disease-free survival.
Postmenopausal women with early-stage, hormone receptor-positive breast cancer who underwent surgery, radiation and/or chemotherapy and received adjuvant aromatase inhibitors participated in this prospective, double-blind, placebo-controlled phase 3 trial (ABCSG-18) . Patients were assigned 1:1 to receive either subcutaneous denosumab (60 mg) every 6 months or placebo injection every 6 months. The primary endpoint was the time to first clinical fracture after randomization. The secondary endpoint reported in this report is disease-free survival in the intention-to-treat population (defined as local or distant metastases, contralateral breast cancer, secondary cancer, or death from any cause from randomization).
During the period from December 18, 2006 to July 22, 2013, a total of 3,425 eligible patients were enrolled and randomly assigned to: 1,711 for the denosumab group and 1,709 for the placebo group. The median follow-up was 73 months. There were 240 patients (14.0%) in denosumab and 287 (16.8%) patients in the placebo group had disease-free survival events. Disease-free survival was significantly higher in the denosumab group compared with the placebo group (HR = 0.82; 95% CI = 0.69 – 0.98, Cox p = .0260). In the denosumab group, the 5-year disease-free survival rate was 89.2%, compared with 87.3% (85.7-89.0) in the placebo group (95% CI = 87.6 – 90.8). In the 8-year follow-up. DFS was 80.6% (78.1 – 83.1), vs 77.5% (74.8 – 80.2).
There were no officially determined cases of the jaw necrosis or a diagnosis of atypical femoral fractures. The total number of adverse events was similar in the denosumab group and the placebo group. The most common serious adverse events were osteoarthritis: 62 in the denosumab group (3.6%); 58 in the placebo group (3.4%). The meniscus injury was 1.3% vs. 1.4%. Cataract was 0.9% vs. 1.7%. One case (<0.1%) of treatment-related deaths (due to pneumonia, septic renal failure, and cardiac decompensation) occurred in the denosumab group.
In conclusion, Denosumab is an effective and safe adjuvant therapy for postmenopausal hormone receptor-positive breast cancer patients receiving aromatase inhibitors.

参考文献 Reference

Gnant M et al. Lancet Onc 2019;20:339-51

 

粪便移植可以帮助黑色素瘤患者响应免疫治疗 (4/14/2019)

Fecal transplant may help melanoma patients on immunotherapy

美国癌症研究协会（AACR）年会上报导，最初未从免疫治疗药物中获益的患者，在接受其他获益患者的粪便样本后，其肿瘤停止生长甚至缩小。虽然这两项研究迄今为止只有少数患者, 而且只服用了几个月，但他们的初步结果令人鼓舞。

一组试验收集了两名患有转移性黑色素瘤患者的粪便样本，这些患者已经扩散，但他们的肿瘤在获得PD-1药物后消失。然后，研究小组通过结肠镜, 将他们的粪便转移到三名患有同样癌症的患者身上，这些患者的肿瘤之前对抗PD-1药物无甚反应, 接受者还口服含有供体者干粪的药丸。所有三名患者的肠道微生物组改变为更接近供体者肠道微生物组的基因组成。在两位接受者中，供体者的微生物似乎可以增强他们对PD-1药物的反应: 一名患者的肿瘤变小，但移植后2个月却出现了新的肿瘤; 另一名患者的肿瘤最终萎缩，7个月后该男子仍然良好。肠道和肿瘤组织的活组织检查显示，移植后，患者的肠道中含有更多的免疫细胞，这些细胞也与T细胞一起渗入肿瘤。

尚未解决的问题是, 究竟哪种微生物有助于提高所需的免疫活性。在之前发表的研究显示，来自四个城市的病人中对这些药物有反应的患者肠道微生物组的变化很大。另外，那些服用益生菌 （probiotics）药片的患者，比不用的患者对PD-1药物的效果更差。

参考文献 Reference

Harper DM et al. Gyn Onc 2019: https://doi.org/10.1016/j.ygyno.2019.03.250

At the 2019 annual meeting of the American Association for Cancer Research (AACR), melanoma patients, who did not initially benefit from immunotherapy, witnessed their tumors stopped growing or even shrinking after receiving a stool sample from other patients in whom immunotherapy was effective. Although the studies have so far only had a few patients and they have only taken for a few months, the initial results are encouraging.
One trial collected fecal samples from two patients with metastatic melanoma, but their tumors disappeared after receiving PD-1. The team then transferred their stools to three patients with the same cancer through a colonoscopy. The tumors of these patients did not respond to PD-1 drugs initially, and the recipients also took pills containing donors’ dry stool. The gut microbiome of all three patients changed to a genetic makeup closer to the donor’s gut microbiome. Among the two recipients, the donor’s microbes appeared to enhance their response to PD-1 drugs: one patient’s tumor became smaller, but new tumors appeared two months after transplantation; another patient’s tumor eventually shrank and the man is still doing well after 7 months. Biopsy of the gut and tumor tissue revealed that after transplantation, the patient’s intestine contained a type of immune cells, which also infiltrated the tumor with T cells.
The unresolved question is which microbes help to increase the required immune activity. Previous studies in four cities have shown that patients who respond to immunotherapy display a large variation in the gut microbiomes. In addition, patients who take probiotics do worse on anti-PD-1 drugs than those who do not.

参考文献 Reference

Baruch EN et 2019 AACR, presented March 31.

 

人乳头瘤病毒（HPV）治疗性疫苗Tipapkinogen Sovacivec对宫颈上皮内瘤变的有效性和安全性 (4/13/2019)

Safety and efficacy of therapeutic HPV vaccine Tipapkinogen sovacivec in treating cervical intraepithelial neoplasia

Tipapkinogen sovacivec比安慰剂更能完全消除CIN 3级病变。

已接种了人乳头瘤病毒（HPV）疫苗的女性, 仍能产生2或3级宫颈上皮内瘤变（CIN）。该试验的主要目的是评估tipapkinogen sovacivec（TS）疫苗在对高风险HPV类型相关的CIN2/3级的疗效。

TS是重组疫苗，当皮下注射后，它感染附近的细胞，后者表达了HPV E6和E7蛋白。病毒激活的树突状细胞加工了这些蛋白质，然后迁移至引流的淋巴结，并将E6和E7多肽呈现给未激活的T细胞，从而引起一连串的细胞免疫反应。

已患有CIN2/3级的18岁及以上女性参加了随机，双盲性的II期试验，并以2：1的比例分配给药物（疫苗或安慰剂）。终点结果在第6个月进行切除治疗时分析。细胞学和高风险 HPV分型的测定是在第3个月，第6个月，然后每6个月,至第30个月进行。安全性的测定包括接受至少一剂研究药物的所有患者。

在随机接种疫苗的129名女性和安慰剂组的63名女性中，无论所测定的13种高风险 HPV类型如何，疫苗组的CIN 2/3级完全消退率均显著高于安慰剂组（24％对10％，p < .05）。同样，无论高风险HPV类型如何，疫苗组CIN 3的完全消退率为21％对0％，（p < .01）。与安慰剂相比，疫苗组的病毒DNA清除率更高（p < .01）。疫苗耐受性良好，最常见的不良事件是注射部位局部反应。

结论是，TS疫苗能清除三分之一受试者的CIN 2/3级，与高风险 HPV类型无关，并且在30个月内是安全的。

 

Women who have been vaccinated with HPV vaccine are still able to develop grade 2 or 3 cervical intraepithelial neoplasia (CIN). The primary objective of the trial was to evaluate the efficacy of the Tipapkinogen sovacivec (TS) vaccine in the CIN 2 / 3 class associated with high-risk HPV types.
TS is a recombinant vaccine that, when injected subcutaneously, infects nearby cells that express HPVE6 and E7 proteins. Viral-activated dendritic cells process these proteins, then migrate to draining lymph nodes, and present E6 and E7 polypeptides to unactivated T cells, causing a cascade of cellular immune responses.
Women 18 years of age and older who had CIN 2 / 3 participated in a randomized, double-blind, phase II trial and were assigned in a 2:1 ratio (vaccine or placebo). Study end point was analyzed at 6th month when CIN was resected. Cytology and HR HPV typing is performed at month 3, month 6, and then every 6 months to 30 months. Safety measures include all patients receiving at least one dose of study drug.
Among the 129 women randomized to vaccination and 63 women in the placebo group, the complete resolution rate of  CIN2/3 in the vaccine group was significantly higher than that of the placebo group regardless of the 13 HR HPV types measured ( 24% vs. 10%, p < .05). Similarly, regardless of the high-risk HPV type, the complete resolution rate of CIN 3 for the vaccine group was 21% vs. 0%, (p < .01). The viral DNA clearance rate was also higher in the vaccine group compared to placebo (p < .01). The vaccine is well tolerated and the most common adverse event is local reaction at the injection site.
In conclusion, the TS vaccine cleared CIN 2/3 in one-third of the participants regardless high-risk HPV types, and was safe for 30 months during the trial.

参考文献 Reference

Harper DM Gyn Onc 2019; April 4^th. https://doi.org/10.1016/j.ygyno.2019.03.250

 

抑制外来体的PD-L1会诱导抗肿瘤免疫 (4/7/2019)

Inhibition  of exosomal PD-L1 leads to tumor suppression

一项研究发现癌症用以逃避免疫治疗的另一个机制，并提供解决的线索。这项研究专注于结直肠癌和前列腺癌，至今，这些癌症对免疫治疗药物不敏感。

肿瘤逃逸和抑制免疫细胞的一个机制是通过肿瘤的PD-L1 和T细胞的PD-1相互作用。PD-L1存在于肿瘤细胞表面上，它结合效应T细胞上的受体PD-1，从而抑制它的活性。 抗PD-L1的抗体阻断了这种结合，因而激活了抗肿瘤的免疫应答，而使部分癌症患者能持久缓解。

在这项报导中，研究者描述了另一个PD-L1活性的作用机制: PD-L1来自肿瘤的外泌体（exosome）。主要的发现是:

• 将外泌体PD-L1除去后 即使在耐受PD-L1抗体的肿瘤模型中，肿瘤生长也能被抑制。
• 来自肿瘤的外泌体PD-L1能抑制引流淋巴结中的T细胞的激活。
• 外来体PD-L1缺陷的肿瘤机体，会抑制在远处注射的野生型肿瘤细胞的生长，这种抑制在注射一开始就开始或有好几个月。
• 对不能自身分泌PD-L1的肿瘤，若在体内引入外泌体PD-L1，结果能使使肿瘤再生长。

研究者认为, 外泌体PD-L1阻断增强了抗PD-L1抗体对抑肿瘤生长的作用，它不是一种多余的机制。总之，这些发现表明，外来体PD-L1代表了一种未开发的治疗靶点，可能克服对目前免疫抗体方法的耐受。

One recent study found another mechanism for cancer cells to evade immunosurveillance and therapy.  It provide clues to future therapy. The study focuses on colorectal cancer and prostate cancer, and to date, these cancers are not sensitive to immunotherapy.
One mechanism by which tumors escape and suppress immune cells is through the interactions between tumor PD-L1 and PD-1 on T cells. PD-L1 is present on the surface of tumor cells and binds to the PD-1 receptor on effector T cells, thereby inhibiting its activity. Antibodies against PD-L1 block this binding, thereby activating an anti-tumor immune response that allows some cancer patients to achieve remission.

In this report, the investigator described the mechanism of another PD-L1 activity: PD-L1 derived from the exosome of the tumor. The major findings are:

• Upon removal of exosomal PD-L1, tumor growth can be inhibited even in tumor models that are resistant to PD-L1 antibodies.
• Tumor-derived exosomal PD-L1 inhibit the activation of T cells in draining lymph nodes.
• Exsome PD-L1 deficient tumors can inhibit the growth of wild-type tumor cells injected at a remote site immediately and for several months after the injection.
• For tumors that cannot secrete PD-L1 by themselves, systemic introduction of exosomal PD-L1 can make tumor cell regrow.

Researchers believe that exosomal PD-L1 blockade is additive to the tumor inhibition by anti-PD-L1 antibody, and it is not an redundant  mechanism. Taken together, these findings indicate that exosomal PD-L1 represents an undeveloped therapeutic target that may overcome tolerance to current immunotherapeutic agents.

参考文献 Reference

Poggio M et al. Cell 2019; April 4  DOI:https://doi.org/10.1016/j.cell.2019.02.016

 

BRAF和MEK靶向治疗胆管癌 (4/6/2019)

Target therapy with BRAF and MEK inhibitors may benefit biliary tract cancer

BRAF和MEK靶向治疗对具有BRAF V600E突变胆管癌患者有临床益处，这项研究代表了首次用这种抑制剂联合治疗这样患者的前瞻性分析。

大多数胆道癌患者患有晚期疾病，5年生存率约为15％。约5％的胆管肿瘤中发现了BRAF基因的突变，肝内形式的胆道癌症可以富含这种突变。

ROAR研究是一项”篮子性”II期试验，共涉及178名罕见恶性肿瘤患者的9个不同队列，所有患者均携带BRAF V600E突变。胆道癌队列包括35名接受BRAF抑制剂dabrafenib和MEK抑制剂trametinib联合治疗的患者。该队列包括74％的胆道腺癌，17％的肝胆管癌和9％的胆管癌。大多数患者（74％）在入组时患有IV期疾病，所有35名患者接受过既往化疗; 80％的病人至少接过过2次。接受治疗的中位持续时间为6个月，86％的患者接受治疗超过3个月。中位随访时间为8个月。

试验研究者评估的部分反应为42%，稳定疾病达到45％。中位无进展生存期为9.2个月，中位总生存期为11.7个月。在6个月时，66％的患者仍然维持治疗响应。16名患者的遗传分析显示所有不同个体的异质性和低肿瘤突变负荷，这一发现与先前关于胆道癌遗传观察一致。与患有稳定疾病的患者相比，MAP激酶途径的基因表达水平，在两名以进行性疾病作为其最佳反应的患者中更高。

57％的人有3/4级的副作用。最常见的治疗相关不良事件是发热（40％），皮疹（29％）和恶心（23％）。

Combination of BRAF and MEK targeted therapy has clinical benefit in biliary tract cancer patients with BRAF V600E mutation. This study represents the first prospectively analyzed cohort of such patients treated with the combination of BRAF and MEK inhibitors.
Most patients with biliary tract cancer have advanced disease with a 5-year survival rate of approximately 15%. Mutations in the BRAF gene are found in about 5% of biliary tract tumors, and such mutation is enriched in intrahepatic forms of biliary cancer.
The ROAR study was a “basket” phase II trial involving 9 different cohorts of 178 patients with rare malignancies, all carrying the BRAF V600E mutation. The biliary cancer cohort included 35 patients who received the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. The cohort included 74% of biliary adenocarcinomas, 17% of hepatobiliary carcinomas, and 9% of cholangiocarcinomas. Most patients (74%) had stage IV disease at enrollment, and all 35 patients received prior chemotherapy; 80% of patients had received at least 2 lines. The median duration of treatment was 6 months, and 86% of patients received treatment for more than 3 months. The median follow-up time was 8 months.
Partial response as evaluated by the investigators was 42% and stable disease reached 45%. The median progression-free survival was 9.2 months, with a median overall survival of 11.7 months. At 6 months, 66% of patients still remained in response. Genetic analysis of 16 patients showed heterogeneity and low tumor mutation burden, a finding consistent with previous genetic observations of biliary tract cancer. The gene expression level of the MAP kinase pathway is higher in two patients with progressive disease as their best response compared to patients with stable disease.

About 57% patients had grade 3/4 side effects. The most common treatment-related adverse events were fever (40%), rash (29%), and nausea (23%).

参考文献 Reference

Wainberg ZA ET AL. 2019 GI Cancer Symposium abstr 187

 

免疫治疗用于晚期难治性结直肠癌 (3/31/2019)

Combination of Durvalumab and tremelimumab for refractory colorectal cancer

Durvalumab和tremelimumab显着延长了难治性结直肠癌患者的总体生存率并保持了生活质量

Durvalumab是一种程序性细胞死亡配体1（PD-L1）抑制剂: tremelimumab是一种抗细胞毒性T淋巴细胞相关蛋白4（CTLA-4）抗体。在一项II期临床试验（CCTGCO.26）中, 从2016年8月至2017年6月期间共有179名患者参加, 参加者必须接受过氟嘧啶，伊立替康和奥沙利铂（如果他们的疾病是RAS野生型，还必须接受过EGFR抑制剂）而疾病进展。他们可以2: 1被随机分配接受durvalumab 和tremelimumab的组合加上最佳支持治疗（联合组）或单独的最佳支持治疗（支持组）。联合组中的患者在每周期的第1天接受75毫克的tremelimumab，和1,500毫克的durvalumab, 每4星期为一个周期。 约85％的患者接受了至少90％的计划剂量的联合治疗。主要终点是总生存期 。

中位随访时间为15.2个月。联合组的中位总生存期为6.6个月，支持组为4.1个月（风险比 = 0.72; 90％可信区间 = 0.54-0.97; p = .07）。

无进展生存期的差异分别为1.8和1.9个月（风险比 = 1.01;  90％ 可信区间 = 0.76-1.34; p = .97）。联合组的疾病控制率为22.7％，支持组为6.6％％（p = .006）。

治疗引起的副作用更多见于联合组（包括3/4级腹痛，疲劳，淋巴细胞增多症和嗜酸性粒细胞增多症）; 但联合治疗组的身体功能恶化程度较轻。虽然具有缺陷性错配修复肿瘤的患者不能参加该研究，但重新确认错配修复状态正在进行中。

研究者的结论是：durvalumab和tremelimumab显著延长了难治性结直肠癌患者的总体生存率并保持了生活质量。 但durvalumab和tremelimumab的不良事件更为频繁。这是第一项研究表明PD-L1和CTLA-4联合抑制可延长晚期难治性结直肠癌患者的生存期，而且这些患者并无缺陷性错配修复。

Durvalumab and tremelimumab significantly prolonged overall survival and maintain quality of life in patients with refractory colorectal cancer
Durvalumab is a programmed cell death ligand 1 (PD-L1) inhibitor: tremelimumab is an anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) antibody. In a Phase II clinical trial (CCTGCO.26), a total of 179 patients participated between August 2016 and June 2017. Participants must receive fluoropyrimidine, irinotecan and oxaliplatin (if their disease harbors wild type RAS, they must also have been treated with an EGFR inhibitor). They were randomly assigned to receive a combination of durvalumab and tremelimumab plus best supportive care (treatment group) or best supportive care alone (support group). Patients in the treatment group received 75 mg of tremelimumab and 1,500 mg of durvalumab on the first day of each cycle, which consists of 4 weeks. Approximately 85% of patients received at least 90% of the planned dose. The primary endpoint is overall survival.
The median follow-up time was 15.2 months. The median overall survival was 6.6 months in the treatment group and 4.1 months in the support group (HR = 0.72; 90% CI = 0.54-0.97; p = .07). The difference in progression-free survival was 1.8 and 1.9 months, respectively (HR = 1.01; 90% CI = 0.76-1.34; p = .97). The disease control rate was 22.7% in the treatment group and 6.6% in the support group (p = .006).
The side effects caused by treatment were more common in the treatment group (including grade 3/4 abdominal pain, fatigue, lymphocytosis, and eosinophilia). However, the treatment group had a milder deterioration in physical function. Although patients with defective mismatch repair tumors were not allowed to participate in the study, reconfirmation of mismatch repair status is ongoing.
The investigators concluded that durvalumab and tremelimumab significantly prolonged overall survival and maintained quality of life in patients with refractory colorectal cancer. However, the adverse events of durvalumab and tremelimumab are more frequent. This is the first study to demonstrate that combined inhibition of PD-L1 and CTLA-4 prolongs the survival of patients with advanced refractory colorectal cancer, and these patients have no defective mismatch repair.

参考文献 Reference

Chen et al. Gastrointestinal Cancer Symposium 2019; abstr 481

 

肿瘤相关免疫细胞如何阻碍治疗胰腺癌的化疗药物吉西他滨 (3/30/2019)

How tumor-associated immune cells hinder gemcitabine in Pancreatic Cancer

据报道，肿瘤相关巨噬细胞（tumor-associated macrophages, TAM）可以引起对吉西他滨的抗药性。

胰腺导管腺癌的特征在于有大量肿瘤相关巨噬细胞的浸润, 而吉西他滨是胰腺癌的重要化疗药物。通过分析代谢物交换，研究者发现, 胰腺癌细胞编程的巨噬细胞释放一系列嘧啶物, 包括脱氧胞苷，其通过药物摄取和代谢水平的分子竞争来抑制吉西他滨。因此，胰腺癌的鼠模型中, 研究者通过遗传或药理学的方法消除肿瘤相关巨噬细胞, 因而使这些肿瘤对吉西他滨敏感。与此一致，具有低巨噬细胞负荷的患者表现出对吉西他滨治疗的好反应。总之，这些发现提供了巨噬细胞在胰腺癌治疗中可能的作用，并有可能为未来治疗的设计提供信息。此外，从嘧啶释放在交替激活巨噬细胞中的功能，可发现它在免疫细胞中的新作用。

Tumor-associated macrophages (TAM) have been reported to induce resistance to gemcitabine.
Pancreatic ductal adenocarcinoma is characterized by infiltration of a large number of tumor-associated macrophages (TAM). Gemcitabine is an important chemotherapeutic drug for pancreatic cancer. By analyzing metabolite exchange, researchers found that pancreatic cancer cell-programmed macrophages release a series of pyrimidines, including deoxycytidine, which inhibits gemcitabine by molecular competition in drug uptake and metabolic levels. In a murine model of pancreatic cancer, researchers were able to make pancreatic cells sensitive to gemcitabine by genetic or pharmacological method to deplete TAM. Consistent with this, patients with a low macrophage load show a good response to gemcitabine treatment. Together, these findings provide a possible role of macrophages in the treatment of pancreatic cancer and may help design future treatments. Furthermore, the release of pyrimidine from alternately activated macrophages reveals some new roles in immune cells.

参考文献 Reference

Halbrook CJ et al. Cell Metab 2019: Feb 21. 

 

药物海绵可以减少癌症治疗的副作用 (3/24/2019)

Drug sponge may decrease side effects of cancer therapy

治疗肝癌时，药物能通过肝动脉中的导管直接输送到肿瘤，但剩余的药物可以逃逸并影响身体其他部位的健康器官。新设计使用药物海绵吸收残留的药物，以减少副作用; 甚至还可以增加药物剂量来提高疗效。

药物海绵是一种吸收性聚合物，涂有3D打印的圆柱体，通过导线将海绵带入血液并放入支架中，可以精确地贴合在静脉中，然后放置一段时间进行化疗，可能需要几个小时。该静脉携带流出目标器官（例如肝脏的血液。在那里，它会吸收未被肿瘤吸收的药物，防止其到达并可能使其他器官中毒。

在动物实验中，3D打印装置植入猪的静脉中，以测量在上游注射多柔比星（化疗药）后保留在吸收器下游的程度。在健康的猪中，大约64％的药物被清除。

药物海绵可以应用于不同类型的肿瘤和化疗药物，并可能应用于其他毒性高的药物，例如对肾脏有毒但能杀死病原体的高效抗生素。

When treating liver cancer, the drug can be delivered directly to the tumor through a catheter in the hepatic artery. However, the remaining drug can escape and affect healthy organs in other parts of the body. The new design uses a drug sponge to absorb residual drugs to reduce side effects. Using this method, drug dose may also be increased to improve efficacy.
The drug sponge is an absorbent polymer coated with a 3D printed cylinder. The sponge is brought into the blood stream through a wire and placed in a stent. It can be accurately attached to the vein and then placed for a period of time, for example several hours, when chemotherapy is delivered. The vein carries blood that flows out of the target organ (such as the liver), where it absorbs drugs that are not retained by the tumor, preventing it from reaching and possibly poisoning other organs. In animal experiments, a 3D printing device was implanted into the veins of pigs to measure the extent of retention downstream of the absorber after injection of doxorubicin (chemotherapeutic drug) upstream. In healthy pigs, approximately 64% of the drugs are cleared.
Drug sponges can be applied to different types of tumors and chemotherapeutic drugs, and may be applied to other highly toxic drugs, such as high-potency antibiotics that are toxic to the kidneys.

参考文献 Reference

Oh HJ et al ACS Central Science, 2019; DOI: 10.1021/acscentsci.8b00700

 

病理性完全缓解的乳腺癌患者可以在手术后避免化疗? 芸萃分析的结果 (3/23/2019)

Breast cancer patients who achieved pathological complete response may not need post-operative chemo

病理性完全缓解的定义为: 在化疗后,手术中切除的乳房组织和淋巴结中所有侵袭性癌症均消失。

经手术前化疗后, 取得病理性完全缓解的乳腺癌患者, 与没有取得病理完全缓解的患者相比，发生疾病复发的可能性降低69％。对三阴性或HER2阳性乳腺癌患者，取得病理完全缓解后复发可能性降低分别为82％和68％。对雌激素受体阳性的病人取得病理性完全缓解，与没有病理完全缓解的患者相比，具有复发风险降低的趋势，但差别没有达到统计学意义。与没有取得病理完全缓解的患者相比，病理完全缓解的患者死亡风险也降低了78％。

在取得病理完全缓解后, 再接受术后化疗的患者,复发的可能性减少66％, 相对于未接受术后化疗的患者, 复发的可能性减少64％, 两者之间具有可比性。

这一研究结果可能反映了肿瘤的生物特性: 若乳腺和淋巴结中的肿瘤对术前化疗敏感, 通常其他微转移部位对治疗也很敏感, 这就可能最大限度地减少术后辅助治疗带来的额外好处。因此，一些达到病理完全反应的患者可以在手术后避免化疗。

该芸萃分析，选择了1999年至2016年符合条件的临床试验。在所审查的3,209篇摘要中，来自52项研究的27,895名患者符合纳入标准。由于这些研究中使用了各种治疗方法, 为了解释统计学方法中的治疗差异，研究者使用随机效应模型，该模型比其他方法更保守，并且还进行了许多敏感性分析以确认结果。

该研究的主要局限是该分析受到各研究中使用的可变报告和研究特定结果定义的影响。  但是，研究结果基于术前化疗本身的效果，而不是特定的治疗方案。

Pathological complete remission is defined as: after pre-operative chemotherapy, all invasive cancers in the breast tissue and lymph nodes specimen removed during surgery are no longer found.
After preoperative chemotherapy, breast cancer patients who achieved pathological complete remission (pCR) had a 69% reduction in the likelihood of recurrence compared with those who did not achieve complete pCR. For patients with triple-negative or HER2-positive breast cancer, the likelihood of recurrence after pCR was reduced by 82% and 68%, respectively. PCR was obtained in estrogen receptor-positive patients, and there was a tendency to have reduced risk of recurrence compared with patients without pCR, but the difference did not reach statistical significance. The risk of death was also reduced by 78% in patients with pCR compared with patients who did not.
Following pCR, patients who received postoperative chemotherapy had a 66% reduction in recurrence, compared with 64% in patients who did not receive postoperative chemotherapy. The results from the two conditions were comparable.
The results of this study may reflect biological characteristics of the tumor: If tumors in the breast and lymph nodes are sensitive to neoadjuvant chemotherapy, other micrometastases are often sensitive to treatment, which may minimize the benefit of postoperative adjuvant therapy. Therefore, some patients who achieve pCR may avoid chemotherapy after surgery.
The meta-analysis selected eligible clinical trials from 1999 to 2016. Of the 3,209 abstracts reviewed, 27,895 patients from 52 studies met the inclusion criteria. Since various treatments were used in these studies, in order to account for the treatment differences in their statistical approach, the researchers used a random effects model that is more conservative than other methods. THey also performed a number of sensitivity analyses to confirm the results.
The main limitation of the study was that the analysis is subject to various reporting and study-specific outcome definitions in each study. However, the results of the study are based on the effects of preoperative chemotherapy itself, rather than specific treatment regimes.

参考文献 Reference

Spring L et al. San Antonio Breast Cancer Symposium 2018; abstr GS2-03

 

Pembrolizumab / Axitinib联合治疗相比于舒尼替尼可改善肾癌患者的治疗效果 (3/17/2019) 

Pembrolizumab / Axitinib combination therapy may improve survival in patients with renal cell carcinoma compared with sunitinib

作为第一线治疗转移性透明细胞肾癌，检查点抑制剂pembrolizumab加血管内皮生长因子酪氨酸激酶抑制剂（TKI）阿西替尼（Axitinib）与舒尼替尼相比，显著改善了总体存活率，无进展生存期和客观缓解率。

舒尼替尼一直是转移性肾细胞癌第一线的标准治疗方法。Ib期研究的结果显示，pembrolizumab和axitinib的组合, 与治疗初期转移性肾细胞癌中的任一种药物相比具有更高的抗肿瘤活性。之后，开放标签III期KEYNOTE-426试验招募了861名患有透明细胞转移性肾细胞癌的病人, 并且之前没有转移性疾病全身治疗。患者随机分配1：1接受1）pembrolizumab ，200 毫克静脉注射，每3周一次，最多35个周期，同时口服阿西替尼，5 毫克，每日两次；2）口服舒尼替尼，每日50  mg，连续服用4周，然后休息2周，再开始下一周期。 。治疗一直进行到患者疾病进展，或产生不可接受的毒性或由研究者决定。根据国际转移性肾细胞癌数据库联盟（International Metastatic Renal Carcinoma Database Consortium）将患者按风险组分为有利，中度或高风险的疾病，并根据地理区域进行分层。大约31％的人为有利风险，56％为中度风险，13％为高风险疾病。共有82％的患者进行过肾切除术，75％的患者在2个或更多器官中有转移。

在中位随访12.8个月时，pembrolizumab联合阿西替尼的组合显示总生存率（风险比= 0.53），无进展生存期和客观缓解率显著改善。联合用药组12个月总生存率为89.9％，舒尼替尼组为78.3％（p = 0.0001）; 18个月的总生存率分别为82.3％和72.1％。无论PD-L1表达水平如何，在所有风险组和亚组中均观察到pembrolizumab与阿西替尼联合应用的益处。

联合治疗组12个月无进展生存率为59.6％，相对于41.1％。中位无进展生存期分别为15.1个月相对于11.1个月（p = .0001），客观缓解率分别为59.3％相对于35.7％（p <.0001）。

联合治疗组3至5级不良事件发生率高于舒尼替尼: 分别为62.9％相对于58.1％。导致死亡的治疗相关不良事件分别为0.9％相对于1.6％。停药率为8.2％相对于10.1%。

值得注意的是，在类似的实验中，阿西替尼加稍微不同的检查点抑制剂avelumab（而不是pembrolizumab），尚未显示出比舒尼替尼更高的生存益处，而KEYNOTE-426已显示存活益处达47％。
As a first-line treatment for metastatic clear cell renal cell carcinoma, the checkpoint inhibitor pembrolizumab plus vascular endothelial growth factor tyrosine kinase inhibitor (TKI) axitinib significantly improved overall survival rate, progression-free survival and objective response rate, compared with sunitinib.

Sunitinib has been the standard of care for the first line treatment of metastatic renal cell carcinoma. The results of a phase Ib study showed that the combination of pembrolizumab and axitinib had higher antitumor activity than any of the drugs in the treatment of metastatic renal cell carcinoma. Later, the Open Label Phase III KEYNOTE-426 trial enrolled 861 patients with clear cell metastatic renal cell carcinoma and had no prior systemic treatment for metastatic disease. Patients were randomly assigned 1:1 to receive 1) pembrolizumab, 200 mg intravenously, once every 3 weeks, up to 35 cycles, with concurrent oral axitinib, 5 mg twice daily; 2) oral sunitinib 50 mg daily for 4 weeks, then rest for 2 weeks before starting a new cycle. . Treatment continues until patients progress, or unacceptable toxicity or investigator’s choice. According to the International Metastatic Renal Carcinoma Database Consortium, patients are classified as favorable, intermediate or poor-risk diseases, and stratified according to geographic regions. About 31% had favorable risk, 56% intermediate, and 13% poor risk. A total of 82% of patients underwent nephrectomy, and 75% of patients had metastases in 2 or more organs.
At a median follow-up of 12.8 months, the combination of pembrolizumab plus axitinib showed an overall survival benefit (hazard ratio = 0.53), improvement in progression-free survival and objective response. The 12-month overall survival rate was 89.9% in the combination group and 78.3% in the sunitinib group (p = 0.0001); the overall survival rate at 18 months was 82.3% and 72.1%, respectively. Regardless of the PD-L1 expression level, the benefit of the combined use of pembrolizumab with axitinib was observed in all risk groups and subgroups. The 12-month progression-free survival rate was 59.6% in the combination treatment group, compared with 41.1%. The median progression-free survival was 15.1 months vs. 11.1 months (p = .0001), and the objective response rate was 59.3% vs. 35.7% (p < .0001).
The incidence of grade 3 to 5 adverse events was higher in the combination group than in sunitinib: 62.9% vs. 58.1%. The treatment-related adverse events leading to death were 0.9% vs. 1.6%, respectively. The withdrawal rate was 8.2% vs. 10.1%.
Of note, in a similarly-designed trial, axitinib plus a slightly different checkpoint inhibitor avelumab (instead of pembrolizumab), has not yet yielded data to demonstrate survival benefit over sunitinib, while KEYNOTE-426 has shown a survival benefit by 47%.

 参考文献 Referenes

Powles T et al. 2019 GU Cancers Symposium 2019: abstr 543

Motzer RJ et al. ESMO 2018 Congress abstr LBA6  

 

PET扫描识别可避免化疗的乳腺癌患者 (3/16/219)

PET scan may detect those women who may avoid chemotherapy

一项研究利用正电子发射断层扫描（PET）来确定哪些HER2阳性乳腺癌的患者可能免除化疗。

这项2期临床试验有88名患II期或III期雌激素受体阴性，HER2阳性的乳腺癌女性参加，83位可评价。她们在手术前接受4个周期的帕妥珠单抗和曲妥珠单抗（不包括化疗）。在治疗开始前和治疗后15天，她们接受PET扫描以检测癌细胞中的糖摄取（校正瘦体重后的最大标准摄取值, tumor maximum standardized uptake values corrected for lean body mass, SULmax）。75个（85%）患者完成所有4个周期，完全病理反应率为34%。

在取得病理性完全反应和未取得完全反应的病人间，SULmax的减少存在统计学上有意义的区别（63.8% 相对于33.5%，p < .001）。SULmax减少大于40%者为86%相对于46%（p <.001，阴性预测值为88%；阳性预测值为49%）。

虽然PET扫描生物标志物可以在大范围内使用，但完成其可靠性之前尚需要进一步的研究。但这项研究的结果有可能推动乳腺癌精准治疗的选择。

One study used positron emission tomography (PET) to determine which patients with HER2-positive breast cancer may be exempt from chemotherapy.
In this phase 2 clinical trial, 88 women with stage II or III estrogen receptor-negative, HER2-positive breast cancer were enrolled, and 83 were evaluable. They received 4 cycles of pertuzumab and trastuzumab (excluding chemotherapy) prior to surgery. Before the start of treatment and 15 days after treatment, they underwent a PET scan to detect glucose uptake in cancer cells (tumpr maximum standardized uptake values ​​corrected for lean body mass, or SULmax). Seventy-five (85%) patients completed all four cycles with a complete pathologic response rate of 34%.
There was a statistically significant difference in the reduction in SULmax in patients who achieved a pathologic complete response compared with those who did not achieve a complete response (63.8% vs. 33.5%, p < .001). A decrease in SULmax greater than 40% was 86% vs. 46% (p < .001, a negative predictive value of 88%; a positive predictive value of 49%).
Although PET scan biomarkers can be used on a large scale, further research is needed before their reliability is determined. But the results of this study have the potential to further the choice of precision therapy for breast cancer.

参考文献 Referenes

Connolly RM et al J Clin Oncol 2019; Feb. 5.

 

如何改变对免疫治疗缺乏反应的肿瘤 (3/10/2019)

How to increase response to immunotherapy in otherwise “cold” cancer

有人将对免疫治疗无甚反应的肿瘤称为冷性; 反之，反应强烈的为热性。免疫性冷肿瘤是由于各种原因而仅含有少量浸润性T细胞，并且肿瘤未被识别，也不会引起免疫系统强烈反应，目前的免疫疗法难以治疗。典型免疫性冷肿瘤包括胶质母细胞瘤，卵巢癌，前列腺癌，胰腺癌和大多数乳腺癌。相反，免疫性热肿瘤含有較多的浸润性T细胞和更多的抗原，因而更容易被免疫系统识别，更有可能引发强烈的免疫反应。具有免疫学热肿瘤包括膀胱癌，头颈癌，肾癌，黑素瘤和非小细胞肺癌。然而，即使在这些免疫性热肿瘤中，也只有少数患者似乎能从免疫疗法中受益。有研究将免疫疗法与改良的传统癌症疗法（包括放射疗法和化学疗法）相结合，可能有助于刺激炎症反应，使免疫系统发挥作用，引发更有效的治疗反应，并使多种肿瘤类型的患者获得更持久的缓解。

有人认为免疫检查点抗体，如抗程序性细胞死亡蛋白1（抗PD-1）和抗程序性细胞死亡配体1（抗PD-L1），主要通过激活已经作出反应的T细胞起作用，从而控制肿瘤。在免疫性热肿瘤中，往往癌症对T细胞产生分子制动作用。若使用检查点抗体来抑制这些分子的功能，那么T细胞可以再次起作用并开始破坏肿瘤。在许多肿瘤中已见证过这种活动，尤其是黑色素瘤和肺癌。

在胰腺癌中，检查点抑制剂很少有效（除非是微卫星不稳定性高的肿瘤, 约1%）。通过对小鼠的研究，免疫性冷胰腺肿瘤细胞产生一种称为CXCL1的信号蛋白，它可以募集另一种称为骨髓细胞（myeloid cells）的免疫细胞。 髓样细胞具有免疫抑制作用，可防止T细胞攻击肿瘤。 在这些肿瘤中去除CXCL1基因可增强T细胞浸润和对免疫疗法的敏感性。

从放射治疗方面来看，常规辐射使用小量单剂量的外部束辐射，在数天和数周内递送。 有研究提示，最具免疫原性的放射治疗量是相当高剂量的外部束辐射，只需发送几次。将免疫疗法与化学疗法结合起来仅限于几个肿瘤类型，如非小细胞肺癌，似乎给予标准剂量的化学疗法以及检查点抑制剂可能是刺激免疫T细胞起作用的最佳方式。

Those tumors that respond poorly to immunotherapy are considered “cold”; on the contrary, these with intense response are considered “hot”. Cold tumors contain only a small amount of infiltrative T cells for various reasons, and the tumors are not recognized by the host, and do not generate a strong reaction by the immune system. They do not typically respond to current immunotherapy. Typical cold tumors include glioblastoma, ovarian, prostate, pancreatic, and most breast cancers. In contrast, hot tumors contain more invasive T cells and more antigens, and are therefore more susceptible to recognition by the immune system and are more likely to display a strong immune response. They include bladder, head and neck, kidney, non-small cell lung cancers and melanoma. However, even among these hot tumors, only a small percentage of patients seem to benefit from immunotherapy. Combining immunotherapy with modified traditional cancer therapies (including radiation and chemotherapy) may help stimulate the inflammatory response, trigger more effective and durable therapeutic responses.
It is believed that immunological checkpoint antibodies, such as anti-PD-1and anti-PD-L1, act primarily by activating T cells that have responded while cancer cells often produce molecules that block effective T cells. If checkpoint antibodies are used to inhibit the function of these molecules, the T cells can become aetive again and begin to destroy the tumor such a in hot tumors. This activity has been seen in many tumors, especially melanoma and lung cancer.
In pancreatic cancer, checkpoint inhibitors are rarely effective (unless rarely about 1% of tumors with high microsatellite instability). Through studies in mice, cold pancreatic tumor cells produce a signaling protein called CXCL1 that recruits myeloid cells. Which have an immunosuppressive effect and prevent T cells from attacking tumors. Removal of the CXCL1 in these tumors enhances T cell infiltration and sensitivity to immunotherapy.
From the perspective of radiation therapy, conventional radiation is delivered over days or weeks using a small dose of external beam radiation. Studies have suggested that the most immunogenic radiotherapy is a fairly high dose of external beam radiation that is delivered only a few times. Combining immunotherapy with chemotherapy is limited to several tumor types, such as non-small cell lung cancer, and it seems that the administration of standard doses of chemotherapy and checkpoint inhibitors may be the best way to stimulate immune T cells to function.

参考文献 References

Li J et al Immunity 2018; 49:178-93

Maity A et al Br J Cancer 2018; 119:1200-7

ASCO Post 2019; Feb. 10, 48-9

 

Capivasertib对AKT突变的癌症有效 (3/9/2019)

Capivasertib is effective in ALK-mutated tumors

研究AKT抑制剂capivasertib（AZD5363）显示它对具有AKT突变癌症患者有临床活性。该研究是较大的NCI-MATCH试验的一部分, 判断对肿瘤基因进行定制治疗的有效性。 此前，研究人员发现，在NCI-MATCH试验中，在1.3％的患者中存在AKT突变。

临床II期试验（EAY 131-Y; NCT02465060）招募了35名患有转移性AKT突变肿瘤的患者，这些患者之前接受过3线或以上的治疗。每天两次口服Capivasertib，每周服4天，休息3天。在治疗之前和之后通过CT测量肿瘤。结果显示，8名患者（23％）观察到肿瘤减少; 16名患者（46％）患有稳定的疾病。研究人员估计，在治疗后6个月内，52％的患者存活并且病情稳定。研究者事先确定，如果有16％的患者从治疗中得到阳性反应，那么将药物转移到更大的试验。

关于安全性，最常报告的不良事件是高血糖，疲劳，腹泻，恶心，呕吐和皮疹。

NCI-MATCH（NCT02465060）是一项研究根据肿瘤分子异常来治疗是否会有效，并能够随着时间的推移添加或删除新的治疗方法。每种治疗都用于一个独特的病人组。 NCI-MATCH于2015年8月启动，拥有近40个治疗组，每个治疗组的目标是招募至少35名肿瘤具有特定分子异常的患者。它将帮助走向更个性化的癌症治疗。这种试验方法对于那些患有罕见癌症的患者尤为重要。

The study of an AKT inhibitor capivasertib (AZD5363) showed that it is clinically active in patients with AKT mutant cancer. This study is part of a larger NCI-MATCH trial to determine the effectiveness of tailoring treatments for specific tumor genes. Previously, the researchers found that in the NCI-MATCH trial, AKT mutations were present in 1.3% of patients.
EAY 131-Y (NCT02465060) is a phase II clinical trial that recruited 35 patients with metastatic AKT mutations. All patients had previously received 3 or more lines of treatment. Capivasertib was taken orally twice a day for 4 days a week, with 3 days off. Tumors were measured by CT before and after treatment. The results showed that tumor reduction was observed in 8 patients (23%); 16 patients (46%) had stable disease. The researchers estimated that 52% of patients would survive and be stable within 6 months of treatment. The investigators pre-determined that if 16% of patients had a positive response from treatment, the drug would be transferred to a larger trial.
Regarding safety, the most frequently reported adverse events include hyperglycemia, fatigue, diarrhea, nausea, vomiting and rash.
NCI-MATCH (NCT02465060) is a study to determine whether treatment is effective based on tumor molecular abnormalities.  New treatments can be added or removed over time. Each treatment is used in a unique patient arm. Launched in August 2015, NCI-MATCH has nearly 40 treatment groups, each of which aims to recruit at least 35 patients with specific molecular abnormalities. It will help to direct towards more personalized cancer treatments. This method is especially important for patients with rare cancers.

参考文献 Reference

Kalinsky K. 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; 2018; abstr 001。

 

狄诺塞麦（Denosumab）加上芳香酶抑制剂可以改善雌激素受体阳性乳腺癌的预后 (3/3/2019)

Denosumab plus aromatase inhibitors improves prognosis in estrogen receptor-positive breast cancer

在一项III期临床试验（ABCSG-18）中，激素受体阳性绝经后早期乳腺癌女性，在接受芳香酶抑制剂时加入狄诺塞麦（保骼丽），无病生存率相对于安慰剂组有所提高，而且治疗耐受性良好。

该研究有随机接受狄诺塞麦的1,711名患者和1,709名接受安慰剂治疗的患者。试验中几乎所有患者均为白人，约四分之三的患者年龄超过60岁。绝大多数患者HER2为阴性（两组均为93.2％）。两组中超过75％的患者在随机化前未接受过化疗。结果显示，每年两次皮下注射狄诺塞麦显著延迟了首次临床骨折的时间，并且使用芳香酶抑制剂激素受体阳性的早期乳腺癌患者的骨矿物质密度增加。中位随访为73个月后无疾病生存率的结果。

狄诺塞麦组共有240例复发事件（14.0％），安慰剂组有287例此类事件（16.8％）。风险比有利于狄诺塞麦（0.82，95％置信区间= 0.69-0.98; p = .0260）。5年时，狄诺塞麦的无疾病生存率为89.2％，安慰剂的无疾病生存率为87.3％。 8年时，无疾病生存率分别为80.6％和77.5％。局部或对侧复发，原位导管癌和经证实的远处转移的发生率相似。

两组间治疗后出现的不良事件发生率相似，狄诺塞麦组有1,367例（521例严重事件），安慰剂组有1,339例（515例严重事件）。 7.8％的狄诺塞麦患者和7.2％的安慰剂患者发生严重的肌肉骨骼和结缔组织疾病。试验中没有颌骨坏死的病例。

作者认为，术后狄诺塞麦为接受芳香酶抑制剂治疗的激素受体阳性乳腺癌绝经后患者提供了有效和安全的治疗选择。但迄今为止，对狄诺塞麦如何减少复发，特别是骨骼以外部位的复发仍然缺乏了解。

In a phase III clinical trial (ABCSG-18), hormone-receptor-positive postmenopausal women with early-stage breast cancer received denosumab together with an aromatase inhibitor (AI), disease-free survival was improved compared to placebo. The treatment is well tolerated.
The study included 1,711 patients randomized to AI plus Denosumab and 1,709 patients treated with AI plus placebo. Almost all patients in the trial were white, and about three-quarters of patients were over 60 years old. The vast majority of patients were HER2-negative (93.2% in both groups). More than 75% of the patients in the two groups did not receive chemotherapy before randomization. The results showed that twice-daily subcutaneous injection of denosumab significantly delayed the onset of first clinical fracture and increased bone mineral density in patients with early-stage breast cancer who received AI. The median follow-up for DFS was the result 73 months.
There were 240 recurrent events (14.0%) in the denosumab group and 287 (16.8%) in the placebo group. The risk ratio favored Denosumab (0.82, 95% CI = 0.69-0.98; p = .0260). At 5 years, the DFS of denosumab was 89.2%, and that of placebo was 87.3%. At 8 years, DFS were 80.6% and 77.5%, respectively. Local or contralateral recurrence, the incidence of ductal carcinoma in situ and proven distant metastases were similar.
The incidence of adverse events after treatment was similar between the two groups. There were 1,367 (521 serious events) in the denosumab group and 1,339 (515 serious events) in the placebo group. 7.8% of patients with denosumab and 7.2% of placebo patients developed severe musculoskeletal and connective tissue disease. There were no cases of osteonecrosis of the jaw in the trial.
The authors believe that postoperative denosumab provides an effective and safe treatment option for postmenopausal patients receiving aromatase inhibitors. But so far, there lacks un understanding of how Denosumab reduces recurrence, especially in extraosseous tissues.

参考文献 Reference

Gnant M et al Lancet Onc 2019; 20: 339-51

 

术前单剂抗PD-1治疗可预测黑色素瘤的预后 (3/2/2019)

Single dose of pre-operative pembrolizumab can predict outcome in melanoma patients

术前给予单剂量抗细胞凋亡1（PD-1）抗体pembrolizumab (Keytruda)，在一些IIIB / C期和IV期黑色素瘤患者中有效。

2015年开始的单中心试验中的最后一组包括27名可切除的黑色素瘤患者，平均年龄为62岁（28-85岁），其中59％为男性。 59％的患者患有IIIC期或IV期黑素瘤，其余为IIIB期疾病。超过四分之一病人的基线肿瘤标志乳酸脱氢酶增加，一名患者接受了BRAF定向免疫治疗。在切除前21天（17-42天）, 参加试验者接受了单剂量pembrolizumab。手术后，所有患者均接受了辅助治疗。8例患者显示了完全或主要的病理反应，术后肿瘤标本中仅有<10％的癌细胞。在25个月的中位随访期间，均没有疾病复发。但术前免疫治疗后，肿瘤表现出较差病理反应的患者，尽管接受术后辅助治疗，复发风险仍超过50%。

PD-1阻断后外周血中的免疫反应非常迅速，T细胞的激活在治疗后7天达到顶峰。约30％患者的完全或主要的病理反应，都在3周内发生。研究人员认为，大约三分之一的患者可能在三周内治愈，显示了免疫治疗的快速性。但需要进行额外的测试来证明。

A single dose of anti-programmed cell death 1 (PD-1) antibody pembrolizumab (Keytruda) was administered preoperatively and was effective in some patients with stage IIIB/C and stage IV melanoma.
The final cohort in the single-center trial that began in 2015 included 27 resectable melanoma patients with a median age of 62 years (28-85 years), 59% of whom were men. 59% of patients had stage IIIC or IV Melanoma, the rest is stage IIIB disease. More than one-quarter of patients had an increase in baseline tumor marker LDH, and one patient received BRAF-directed immunotherapy. Twenty-one days before the resection (17-42 days), participants received a single dose of pembrolizumab. After surgery, all patients received adjuvant therapy. Eight patients showed complete or major pathological response, and only <10% of cancer cells were found in tumor specimens. There remained disease-free during the median follow-up of 25 months. However, in those whose tumor specimen showed a poor pathological response, the risk of recurrence was more than 50% despite postoperative adjuvant therapy.
The immune response in the peripheral blood was very rapid after PD-1 blockade, and the re-inauguration of T cells peaked 7 days after treatment. A complete or major pathological response in approximately 30% of patients occurred within 3 weeks. Researchers believed that about one-third of patients may be cured within three weeks, demonstrating the rapidity of immunotherapy. However, additional tests are needed to prove it.

参考文献 Reference

Huang AC et al. Nature Med 25 Feb. 2019

 

Avapritinib有可能改变胃肠道间质瘤治疗的常规 (2/8/2019)

Potential practice change for Avapritinib in the treatment of gastrointestinal stromal tumor (GIST)

格列卫（Gleevec）是治疗晚期胃肠道间质瘤患者的第一线治疗方法，但大多数患者不可避免地复发或进展。他们的KIT和PDGF会产生突变。舒尼替尼和Stivarga是经批准的第二线和三线药物，但它们的活性或耐受性有限。Avapritinib是一种高效的选择性口服激酶抑制剂，可以靶向KIT和PDGFRA的突变形式。

根据2018年CTOS年会上提出的I期NAVIGATOR（NCT02508532）临床试验结果，Avapritinib在胃肠道间质瘤和有KIT和PDGFRA突变患者（主要包括具有D842V突变）中显示出显著的临床活性。

这项临床试验评估了avapritinib在231名患者中的有效性和安全性，这些患者在I期临床试验的剂量递增和扩增部分期间以8个剂量水平（每天一次30至600毫克）进行了使用avapritinib治疗。该参加群包括167名患有KIT驱动的胃肠道间质瘤的患者，和56名患有PDGFRA D842V驱动的胃肠道间质瘤，以及8名具有其他PDGFRA突变的患者。临床试验主要目标包括根据治疗和突变状态确定最大耐受剂量，推荐的II期剂量，安全性，药代动力学和临床活性。

到数据截止日期，接受评估的有56例患有PDGFRA D842V驱动的胃肠道间质瘤，109例接受avapritinib作为第四线或更晚治疗；23例接受avapritinib作为第三线或四线治疗，并且从未接受过regorafenib，也没有PDGFRA D842V突变；20名没有PDGFRA D842V突变，接受Avapritinib作为二线治疗。这些患者肿瘤的扫描，由中心根据胃肠道间质瘤的mRECIST标准审查。临床受益率的评估是在≥2次扫描后决定的。

Avapritinib在所有剂量水平的PDGFRA驱动的胃肠道间质瘤患者中均表现出临床活性。这些患者的客观响应率为84％（95％置信区间=71.7％ – 92.47％）; 9％有完全反应，75％有部分反应，而4个部分反应等待确认。 16％的患者达到稳定疾病，4个月的临床受益率为96％（95％置信区间= 87.7％-89.6％）。中心放射学的最佳反应显示，98％的患者肿瘤减少。 12个月的反应持续时间为76％，12个月的无进展生存期为81.2％。

在第4线或以上接受300或400 毫克 avapritinib的患者中，客观响应率为20％（95％置信区间=13.1-29.0）; 1例（1％）患者达到完全反应，19％有部分反应，1例部分反应正在等待确认; 40％的患者显示稳定疾病, 为40％的临床受益率（95％置信区间=31.1％-50.2％）。中位反应持续时间为7.3个月，该组合群中78％的患者表现出肿瘤减少。中位无进展生存期由中心审查和由调查人员审查各为3.7个月和5.4个月。接受300或400毫克avapritinib作为三线或四线治疗, 并且未接受过regorafenib治疗的患者队列的反应为26％（95％置信区间= 10.0-48.4）。没有患者取得完全反应，57％的患者显示稳定疾病, 临床受益率为70％。中位反应持续时间为10.2个月。 78％的患者表现出肿瘤减少。中位无进展生存期为8.6个月 。

Avapritinib耐受性良好。3级或4级治疗相关的不良反应发生在 ≥2 ％的患者, 包括贫血，疲劳，低磷血症，胆红素增加，白细胞计数减少/中性粒细胞减少和腹泻。20名患者（8.7％）由于治疗相关的副作用而停用了Avapritinib治疗。
Gleevec is the first line treatment for patients with advanced GIST, but most patients inevitably relapse or progress. They may harbor KIT and PDGF mutations. Sunitinib and Stivarga are approved as second- and third-line drugs, but their activity or tolerance is limited. Avapritinib is a highly potent, selective oral kinase inhibitor that targets both KIT and PDGFRA mutants.
According to the results of the Phase I NAVIGATOR (NCT02508532) clinical trial presented at the 2018 CTOS Annual Meeting, Avapritinib showed significant clinical activity in GIST and patients with KIT and PDGFRA (mainly D842V) mutations.
This clinical trial evaluated the efficacy and safety of aphapritinib in 231 patients who were given 8 dose levels (from 30 to 600 mg once daily) during the dose escalation and amplification phases of Phase I clinical trials. The participants included 167 patients with KIT-driven GIST, and 56 patients with PDGFRA D842V-driven GIST, and 8 patients with other PDGFRA mutations. The primary objectives of clinical trials include determining the maximum tolerated dose recommended for phase II, safety, pharmacokinetics, and clinical efficacy.
As of the data cut-off date, these patients evaluated included 56 patients with PDGFRA D842V-driven GIST, 109 patients who received avarritinib as fourth-line or later treatment, and 23 patients who received avaritritinib as third- or fourth-line treatment, and regorafenib-naive and no PDGFRA D842V mutation; 20 had no PDGFRA D842V mutation and received Avapritinib as second-line therapy. Radiographic scanning of these patients was centrally reviewed according to the mRECIST criteria for GIST. The assessment of clinical benefit was determined after ≥ 2 scans.
Avapritinib showed clinical activity in all dose levels of PDGFRA-driven GIST. The objective response rate of these patients was 84% ​​(95% confidence interval = 71.7 – 92.47); 9% had a complete response, 75% had a partial response, and 4 partial responses were awaiting confirmation. 16% of patients achieved stable disease, and the clinical benefit rate for 4 months was 96% (95% confidence interval = 87.7-89.6). The best response evaluated by central radiology showed a reduction in tumors in 98% of patients. The 12-month response duration was 76% and the 12-month progression-free survival was 81.2%.
In patients who received 300 or 400 mg of avaritritinib for 4^th line higher, the objective response rate was 20% (95% CI = 13.1 – 29.0); 1 patient (1%) achieved complete response and 19% had partial response. One partial response was awaiting confirmation; 40% of patients showed stable disease. The median response duration was 7.3 months, and 78% of patients in this cohort showed tumor reduction. The median progression-free survival reviewed by the central board or by investigators was 3.7 months and 5.4 months respectively. The response rate for those who received 300 or 400 mg of avaritritinib as a third- or fourth-line treatment and who were regorafenib-naïve, was 26% (95% confidence interval = 10.0-48.4). No patients achieved complete response, 57% of patients showed stable disease, and the clinical benefit rate was 70%. The median response duration was 10.2 months. 78% of patients showed a reduction in tumors. The median progression-free survival was 8.6 months.
Avapritinib is well tolerated. Grade 3 or 4 treatment-related adverse events occurred in ≥ 2% (original article) of patients, including anemia, fatigue, hypophosphatemia, increased bilirubin, decreased white blood cell count/neutropenia, and diarrhea. Twenty patients (8.7%) discontinued Avapritinib treatment due to treatment-related side effects.

参考文献 Reference

Heinrich M et al. 2018 CTOS Annual Meeting 2018; Rome, Italy. Paper 012

 

Brigatinib与克里唑蒂尼在ALK阳性非小细胞肺癌中的应用 (2/3/2019)

Comparison of brigatinib and crizotinib in ALK-positive non-small cell lung cancer

Brigatinib是一种下一代ALK抑制剂，对克唑替尼难以治疗的ALK阳性非小细胞肺癌患者具有很强的疗效。

在一项开放性的3期临床试验中，共有275名ALK阳性患者接受了1:1随机分组: 137例患者接受brigatinib治疗（180 毫克/天; 开始7天先服用的剂量为90 毫克），138例接受克里唑蒂尼治疗（250毫克,每日两次）。治疗主要终点是通过独立中心来评估无进展生存期。次要终点包括客观响应率和颅内响应。

在第一次中期分析（99次事件）中，brigatinib组的中位随访时间为11.0个月，克里唑蒂尼组为9.3个月。 Brigatinib的估计12个月无进展生存率（67％; 95％置信区间 = 56-75）高于克里唑蒂尼（43％; 95％置信区间 =32 – 53）。相对于疾病进展或死亡的风险比为0.49 （95％置信区间 = 0.33-0.74; p < .001）。确诊的客观响应率分别为71%（brigatinib, 95％置信区间 = 62-78），和60％（克里唑蒂尼, 95％置信区间 = 51-68）。确诊的颅内响应发生率分别为78％（95％置信区间 = 52-94）和29％（95％置信区间 = 11-52）。没有发现新的安全问题。

研究者的结论是，在既往未接受过ALK抑制剂的ALK阳性非小细胞肺癌患者中，接受brigatinib治疗的患者无进展生存期明显长于接受克里唑蒂尼治疗的患者。但与克里唑蒂尼相比，布立替尼治疗对先前尚未接受过ALK抑制剂的晚期ALK阳性非小细胞肺癌患者的疗效尚不清楚。

Brigatinib is a next-generation ALK inhibitor that is highly potent in patients with ALK-positive non-small cell lung cancer who are refractory to crizotinib.
In an open-label phase 3 clinical trial, a total of 275 ALK-positive patients underwent a 1:1 randomization: 137 patients received brigitinib (180 mg/day, with a 7-day lead-in period at 90 mg). 138 patients were treated with crizotinib (250 mg twice daily). The primary endpoint of treatment was progression-free survival as assessed by blinded independent central review. Secondary endpoints included objective response rate and intracranial response.
In the first interim analysis (99 events), the median follow-up was 11.0 months in the brigitinib group and 9.3 months in the crizotinib group. For patients who received brigatinib, the estimated 12-month progression-free survival rate (67%; 95% confidence interval = 56-75) was higher than crizotinib (43%; 95% confidence interval = 32-53). The hazard ratio relative to disease progression or death was 0.49 (95% confidence interval = 0.33-0.74; p < .001). The confirmed objective response rate was 71% (brigatinib, 95% confidence interval = 62-78), versus 60% (crizotinib, 95% confidence interval = 51-68). The incidence of confirmed intracranial responses was 78% (95% confidence interval = 52-94) versus 29% (95% confidence interval = 11-52). No new security issues were found.
The investigators concluded that in patients with ALK-positive non-small cell lung cancer who had not previously received ALK inhibitors, progression-free survival was significantly longer in those who received brigatinib than those who received crizotinib. However, in patients with advanced ALK-positive NSCLC patients who have not previously received ALK inhibitors, the efficacy of Brigatinib is unclear compared with crizotinib.

参考文献 Reference

Ambridge DR et al. N Engl J Med 2018;379:2027-39

 

身体如何保护播散的乳腺癌细胞及动物试验如何预防它 (2/2/2019)

How body protects breast cancer cells and animal studies how to prevent it

已经脱离原始肿瘤的细胞（播散的肿瘤细胞）可能会隐藏在身体的其他部位，譬如骨髓，避开可以消除它们的治疗方法, 而成长为转移性肿瘤。在乳腺癌患者身体的任何部位都可以发现播散性肿瘤细胞，但估计70％的转移性乳腺癌女性骨骼中有肿瘤，据认为这些肿瘤来自骨髓中的播散的肿瘤细胞，海绵状的血管周围有潜伏的乳腺癌细胞。研究者发现播散的肿瘤细胞被一种称为整合素（integrin）的蛋白质有效地粘附在血管上，整合素延伸到细胞表面，允许它们与外部环境交流。以前人们认为播散的肿瘤细胞逃避化疗，是因为它们没有分裂，但新的研究表明，情况可能更复杂，播散的肿瘤细胞和整合素之间的相互作用更为重要。 研究者发现血管可以保护细胞免于化疗攻击。只要播散的肿瘤细胞在脉管系统周围，它们就对化疗没有反应。
研究者给乳腺癌小鼠模型一种针对特定整合素β-1的抗体与化疗结合一起时，大约94％的休眠细胞死亡。 癌症转移的发生率从单用化疗的70％下降到联合治疗的22％。他们发现，通过抑制整合素β-1，可以在不唤醒肿瘤细胞并使它们分裂的情况下,使它们对化疗敏感。 整合素是在体内每个细胞上发现的蛋白质，其作用是使细胞与周围的环境相通，一个自然的问题是，用治疗靶向是否可能会引起很大毒性。然而，该研究发现，虽然小鼠使用的化学疗法对其健康的血细胞有明显的影响,  但当加入整合素抑制剂时，情况并没有更糟。

下一步是创建一个人的整合素抗体并进入临床试验阶段。 目前还没有一种药物选择性地靶向播散的休眠的肿瘤细胞。

Cells that have detached from the primary tumor (disseminated tumor cells) may be hidden in other parts of the body, such as the bone marrow, and may eventually grow as a metastatic tumor, avoiding treatments that can eliminate them. Disseminated tumor cells can be found in any part of the body in breast cancer patients, but an estimated 70% of women with metastatic breast cancer have tumors in their bones. These tumors are thought to be derived initially from disseminated tumor cells in the bone marrow, around spongy-like blood vessels. Researchers have found that disseminated tumor cells are attached to blood vessels by a protein called integrin, which extends to the cell surface and allows them to communicate with the surrounding environment. Previously, it was thought that the disseminated tumor cells evaded chemotherapy because they did not divide, but new research suggests that the situation may be more complicated, and the interaction between disseminated tumor cells and integrins is more important. Researchers have found that blood vessels protect cells from chemotherapy attacks. As long as disseminated tumor cells are around the vasculature, they do not respond to chemotherapy.

When the researchers combined a specific integrin β-1 antibody with chemotherapy in a breast cancer mouse model, approximately 94% of dormant cells died. The incidence of cancer metastasis decreased from 70% in chemotherapy alone to 22% in combination therapy. They found that by inhibiting integrin β-1, they can make mouse sensitive to chemotherapy without awakening tumor cells or stimulating them to divide. Integrins are proteins found on every cell in the body, and their role is to connect cells to the surrounding environment. A natural question is whether targeting integrin with an inhibitor may cause grave toxicity. However, the study found that although chemotherapy used in the mouse model had a significant effect on healthy blood cells, the situation was not made worse when integrin inhibitors were added.
The next step is to create a human integrin antibody and use it in clinical trials. There is currently no drug that selectively targets disseminated dormant tumor cells.

参考文献 Reference

Ghajar C et al. Nature Cell Biol 2019; Jan 21, 2019

 

术前化疗与首先减瘤手术用于卵巢/输卵管癌的比较 (1/26/2019)

Comparison of neoadjuvant chemotherapy and upfront debulking surgery in advanced tubo-ovarian cancer

对III期临床试验（EORTC 55971和CHORUS）的长期随访数据分析表明，术前治疗与晚期输卵管首先减瘤手术的总体生存率相似。但对IV期肿瘤，术前化疗的效果更好。

该研究包括来自EORTC试验的670名女性和来自CHORUS试验的550名病人。其中，612名女性被随机分配接受首先减瘤手术，随后接受至少6个疗程的铂类化疗；608位被随机分配接受3个疗程的术前铂类化疗，然后进行减瘤手术，再接受至少3个铂类化疗疗程。

在EORTC试验中，病人都患有国际妇产科联合会（FIGO）IIIC期或IV期侵袭性上皮性输卵管卵巢癌;  CHORUS试验中的入选标准相似。

中位随访时间为7.6年，包括EORTC试验的9.2年和CHORUS试验的5.9年。在整个人群中，术前化疗组的中位总生存期为27.6个月，而首先减瘤手术组为26.9个月（风险比 = 0.97，p = .586）。中位无进展生存期为11.6个月，相对于11.1个月（风险比 = 0.98，p = .688）。

EORTC试验中所有患者的中位总生存期为30.2个月，而CHORUS试验中所有患者的中位总生存期为23.6个月（风险比 = 1.20，p = .004），但异质性（hetrogeneity）检验不显著（p = .17）。两项试验的中位无进展生存率相似（11.5 相对于 10.9个月，风险比 = 0.96，P = .531）。在患有IV期疾病的女性中，术前化疗组的中位总生存率较高（24.3 相对于21.2个月，风险比 = 0.76，p = .048）和无进展生存期（10.6 相对于 9.7个月，风险比 = 0.77，p = .049）。

结论是：长期随访数据证实了先前的结果，术前化疗和首先减瘤手术对晚期输卵管卵巢癌的总体存活率相似，而在IV期疾病患者中, 术前化疗的存活率更高。术前化疗对于IIIC-IV期输卵管/卵巢癌患者是一种有价值的选择，特别是对于肿瘤负荷高或功能状态不佳的患者。

 

 

 

Long-term follow-up data from phase III clinical trials (EORTC 55971 and CHORUS) showed that neoadjuvant chemotherapy and up-front debulking surgery had similar overall survival rate in advanced tubo-ovarian cancer. However, for stage IV tumors, neo-adjuvant chemotherapy is more effective.
The study included 670 women from the EORTC trial and 550 patients from the CHORUS trial. Of these, 612 women were randomly assigned to undergo cytoreductive surgery first, followed by at least 6 courses of platinum-based chemotherapy; 608 were randomly assigned to receive 3 courses of preoperative platinum-based chemotherapy, followed by cytoreductive surgery, and then at least 3 platinum chemotherapy sessions.
In EORTC trial, patients had FIGO stage IIIC or stage IV invasive epithelial fallopian tube-ovarian cancer; the inclusion criteria in the CHORUS trial were similar.
The median follow-up was 7.6 years, including 9.2 years for EORTC trial and 5.9 years for CHORUS trial. The median overall survival of the neoadjuvant chemotherapy group was 27.6 months in the entire population, compared with 26.9 months in the upfront cytoreductive group (hazard ratio = 0.97, p = .586). The median progression-free survival was 11.6 months vs. 11.1 months (hazard ratio = 0.98, p = .688). The median overall survival of all patients in the EORTC trial was 30.2 months, whereas the median overall survival of all patients in the CHORUS trial was 23.6 months (hazard ratio = 1.20, p = .004), but heterogeneity test was not significant (p = .17). The median progression-free survival rates were similar in the two trials (11.5 versus 10.9 months, hazard ratio = 0.96, P = .531). Among women with stage IV disease, the median overall survival rate was higher in the neoadjuvant chemotherapy group (24.3 vs. 21.2 months, hazard ratio = 0.76, p = .048) and progression-free survival (10.6 vs. 9.7) month, hazard ratio = 0.77, p = .049).
CONCLUSIONS: Long-term follow-up data confirmed previous results. Neoadjuvant chemotherapy and upfront cytoreductive surgery had similar overall survival rates for advanced fallopian tube-ovarian cancer, whereas in patients with stage IV disease, preoperative chemotherapy had a higher survival rate. Neoadjuvant chemotherapy is a valuable option for patients with stage IIIC-IV fallopian tube-ovarian cancer, especially in patients with high tumor burden or poor performance status.

 

参考文献 Reference

Vergote I et al. Lnacet Onc. 2018: 19:1680-7

 

Margetuximab加Pembrolizumab对晚期HER2 阳性胃癌的抗肿瘤活性 (1/20/2019) Combination of Margetuximab and Pembrolizumab showed activity in advanced HER2-positive gastric cancer

这项开放性, 剂量递增临床试验评估了margetuximab（一种Fc优化[optimized] 的抗HER2单克隆抗体）与pembrolizumab（一种抗PD-1抗体）的组合，用于治疗胃食管癌患者。试验目的是研究该组合的安全性，最大耐受剂量和抗肿瘤活性。参加患者都有复发或难治性HER2 阳性的晚期胃癌或胃食管交接处癌，而且在曲妥珠单抗加化疗后疾病进展或耐药。患者的免疫组织化学HER2均为3+；但无论其PD-L1表达如何，都可以参加。

95名患者显示治疗安全，推荐的2期临床试验剂量为15毫克/公斤margetuximab和200毫克pembrolizumab，两者均为每三周一次治疗。 17.9％的患者发生3级或更高的治疗相关不良事件，其中最常见的是输药时的反应（3.2％）。

在2019年1月8日数据截止日期时，可评估的胃癌患者中观察到客观反应率（18/55）为32.7％，疾病控制率（包括部分反应和稳定疾病）为69.1％。中位无进展生存期为4.7个月。在PD-L1阳性的亚组患者中，客观反应率（12/23）为52.2％，疾病控制率为82.6％，中位无进展生存期为4.14个月。截至数据截止日期，该研究正在进行中，13名胃癌患者仍在接受治疗。这些组中的任何一组均未达到中位总生存率。

This is a open-label, dose-escalating clinical trial, that evaluated the combination of margetuximab (an Fc-optimized anti-HER2 monoclonal antibody), and pembrolizumab (an anti-PD-1 antibody) for the treatment of patients with gastroesophageal cancer. The aim of the trial was to study the safety, maximum tolerated dose and anti-tumor activity of the combination. All patients had recurrent or refractory advanced HER2-positive gastric or gastroesophageal junction cancer. They were treated with trastuzumab plus chemotherapy in the past and were considered refractory or resistent. The immunohistochemical staining of HER2 was 3+; however, regardless of their PD-L1 status, they were eligible for the trial.
The combination was safe and tolerated in 95 patients. The recommended dose for phase 2 clinical trial is margetuximab (15 mg/kg) and pembrolizumab (200 mg), both of which were given every three weeks. Grade 3 or higher treatment-related adverse events were seen in 17.9%, the most common of which was infusion-associated reaction (3.2%).
At the data cut-off date of January 8, 2019, the objective response rate (18/55) was 32.7% in evaluable gastric cancer patients, and the disease control rate (including partial response and stable disease) was 69.1%. The median progression-free survival was 4.7 months. In the PD-L1-positive subgroup, the objective response rate (12/23) was 52.2%, the disease control rate was 82.6%, and the median progression-free survival was 4.14 months. As of the data cut-off date, the study is still ongoing and 13 patients with gastric cancer are still receiving treatment. None of these groups have reached median overall survival.

参考文献 Reference

Daniel VT et al. 2019 ASCO GI Cancer Symposium Abstr 65

 

BRAF突变的结直肠癌对治疗的挑战 (1/19/2019)

Challenges from BRAF-mutated colorectal cancer

大约10％的转移性结直肠癌患者有BRAF突变, 其中，约4/5的人携带BRAF V600E突变。 BRAF V600E突变的转移性肠癌具有独特的临床特征，这些患者在一线治疗失败后预后不良，中位无进展生存期约为2个月，总生存期低于6个月。这种亚型在老年人和女性中更常见。 它们与右侧结肠，高级别肿瘤，容易产生腹膜和广泛的淋巴结转移有关。 分子研究显示它们与错配修复缺陷有关。

在多中心III期临床试验（TRIBE）中，508名患者随机（1：1）地分为接受FOLFIRI（5-氟尿嘧啶，伊立替康和亚叶酸）加阿瓦斯汀，或FOLFOXIRI（FOLFIRI加奥沙利铂）和阿瓦斯汀。 在更新的分析中，RAS和BRAF野生型亚组的总生存期（次要终点）为37.1个月（95％置信区间 = 29.7-42.7），而RAS-突变亚组为25.6个月（95％ 置信区间 = 22.4-28.6）相对于BRAF突变亚组的13.4个月份（95％置信区间 = 8.2-24.1；p <.0001）。

然而，并非所有BRAF突变体都表现相同。 在一项回顾性队列研究中，非V600E BRAF突变IV期结直肠癌患者的中位总生存期（60.7个月）明显长于BRAF V600E突变体（11.4个月）, 相比于BRAF野生型患者（43.0个月）。

在二线治疗中, 免疫疗法似乎对于BRAF突变的IV期结直肠癌患者患者有益。 在II期临床试验（CheckMate 142）中，12名患BRAF突变但有错配修复缺陷的患者，接受nivolumab（25％）获得客观反应。 它高于历史上化疗的响应率（<10％）。此外，nivolumab加ipilimumab在先前治疗的有错配修复缺陷的患者中显示出55％的响应率，并且疾病控制率为79％。

单用BRAF抑制剂的效果并不好，人们发现当BRAF受到抑制时，EGFR的表达增加。 使用vemurafenib（BRAF抑制剂）加西妥昔单抗（EGFR途径抑制剂）和伊立替康（化疗）的临床试验（SWOG 1406）与没有西妥昔单抗的联合用药相比具有更好的反应，尽管受益的幅度很小，中位无进展生存期为4.4个月相比于 2.0个月。
About 10% of patients with metastatic colorectal cancer have BRAF mutations, of which about 4/5th carry the BRAF V600E mutation. The BRAF V600E mutant metastatic colorectal cancer has unique clinical features. These patients have a poor prognosis after first-line treatment failure. The median progression-free survival is about 2 months, and the overall survival is less than 6 months. This subtype is more common in the elderly and women. They are associated with the right-side colon, high-grade tumors, and propensity to peritoneal and extensive lymph node metastases. Molecular studies have shown that they are associated with mismatch repair deficiency.
In a multicenter phase III clinical trial (TRIBE), 508 patients were randomized (1:1) to receive FOLFIRI (5-fluorouracil, irinotecan and folinic acid) plus Avastin, or FOLFOXIRI (FOLFIRI plus Oxaliplatin) and Avastin. In the updated analysis, the overall survival (secondary endpoint) of the RAS and BRAF wild-type subgroups was 37.1 months (95% confidence interval = 29.7-42.7), while the RAS-mutant subgroup was 25.6 months (95% confidence interval = 22.4-28.6) vs. 13.4 months for the BRAF mutation subgroup (95% confidence interval = 8.2-24.1; p < .0001). However, not all BRAF mutants behaved the same way. In a retrospective cohort study, the median overall survival in patients with stage IV colorectal cancer who were not V600E BRAF mutants (60.7 months) was significantly longer than the BRAF V600E mutant (11.4 months) compared with BRAF wild-type patients (43.0 months).
In second-line therapy, immunotherapy appeared to be beneficial for patients with stage IV colorectal cancer with BRAF mutation. In the Phase II clinical trial (CheckMate 142), 12 patients with BRAF mutations and mismatch repair defeciency received nivolumab and had objective response (25%). It is higher than the historical response rate of chemotherapy (<10%). In addition, nivolumab plus ipilimumab showed a 55% response rate in patients with previously treated patients who had mismatched repair deficiency. A disease control rate was 79%.
BRAF inhibitor itself did not generate response rate.  It was found that when BRAF was inhibited, the expression of EGFR and reactivation of its pathway were increased. Clinical trials using vemurafenib (BRAF inhibitor) plus cetuximab (EGFR pathway inhibitor) and irinotecan (chemotherapy) (SWOG 1406) showed a better response than the combination without cetuximab, Although the margin of benefit is small, with a median progression-free survival of 4.4 months compared to 2.0 months.

参考文献 Reference

Cremolini C et al. Lancet Onc 2015; 16: 1306-5.

Jones JC et al. J Clin Onc 2017: 35:  2624-30

Overman  MJ et al  J Clin Onc 2018; 36: 773-9

 

大剂量高精度放射治疗提高一些”无法治愈”患者的生存率 (1/13/2019)

High dose of radiation improved survival in cancer patient with oilgomets

在第一个这样类型的随机II期开放性研临床试验（SABR-COMET）中，研究人员发现，大剂量高精度放射治疗可以增加孤独转移灶患者的生存期。

在这项试验中，病人来自四个国家/地区（加拿大，苏格兰，荷兰和澳大利亚）的99名患者。每位患者都接受了癌症治疗，但癌症已复发。患者有多种癌症类型，最常见的是乳腺癌（18人），肺癌（18人），结肠癌或直肠癌（18人）和前列腺癌（16人）。在大多数患者（92人）中，癌症已蔓延至一至三个新部位。所有患者功能状态良好（ECOG 0-1），预期寿命超过6个月。

在2012年2月至2016年8月期间，患者以1:2的比例随机分为两个治疗组：标准姑息放射治疗组, 和立体定向放射治疗所有转移性病变。患者年龄中位数为68岁（范围= 43-89），59％的患者为男性。两个治疗组之间没有基线患者特征显著不同。中位随访时间为27个月。立体定向放射治疗为立体定向消融放疗（stereotactic ablative radiotherapy , SABR）治疗，也称为立体定向放射治疗（stereotactic body radiation therapy, SBRT），这是一种高精度癌症治疗方法，仅在一个或几个肿瘤部位提供更高剂量的放射治疗。

接受立体定向放射治疗治疗的患者的中位总生存期为41个月（95％置信区间= 26个月-未达到上限），而姑息放射治疗组为28个月（95％置信区间 = 19 – 33个月）（p = .09）。立体定向放射也使患者在没有癌症生长的情况下生存的时间增加了一倍。立体定向放射治疗组的无进展生存期为12个月（95％ = 6.9 – 30个月），而接受姑息放射治疗的患者为6个月（95％置信区间= 3.4 -7.1个月）（p =  .001）。接受立体定向放射治疗的患者中近一半（46％）在五年后仍然存活，而对照组为24％。

但用立体定向辐射治疗导致比姑息放射治疗有更多的副作用。接受姑息治疗的患者中仅有9％出现严重不良事件（2级或更高），而立体定向辐射治疗组有30％（p =  .022）。最常见的副作用是疲劳（10人），呼吸困难（ 9人），肌肉和关节疼痛（7人），骨痛（ 6人）或其他疼痛（7人）。实验组的3名患者因不良事件死亡: 一名由于肺脓肿，一名由于硬膜外出血，和一名由于放射性肺炎。虽然这种事件可能由于标准放射疗法发生，但它们很少见 。

立体定向放射治疗有严重的副作用和死亡的小风险, 需要由经验丰富的团队操作。但总体而言，对于癌症已经扩散且预计不会存活很长的患者，立体定向放射治疗的整体生存获益超过了这些风险。 而且，两种治疗组在生活质量测量方面没有差异,治疗后6个月的癌症治疗功能评估相似。

 

In the first randomized phase II open-label clinical trial (SABR-COMET) of this kind, researchers have found that large-dose high-precision radiation therapy can increase the survival of patients with isolated metastases.
In this trial, patients were from 99 patients in four countries/districts (Canada, Scotland, the Netherlands, and Australia). Every patient received cancer treatment, but the cancer has recurred. Patients have multiple cancer types, the most common being breast cancer (18), lung cancer (18), colon or rectal cancer (18) and prostate cancer (16). In most patients (92), cancer has spread to one to three new sites. All patients were in good performance status (ECOG 0-1) with an expected life expectancy of more than 6 months.
Between February 2012 and August 2016, patients were randomized to two treatment groups at a 1:2 ratio: standard palliative radiotherapy, or stereotactic radiotherapy for all metastatic lesions. The median age of the patients was 68 years (range = 43-89) and 59% of the patients were male. There were no significant differences in baseline patient characteristics between the two treatment groups. The median follow-up time was 27 months. Stereotactic radiotherapy is a stereotactic ablative radiotherapy (SABR) treatment, also known as stereotactic body radiation therapy (SBRT), which is a high-precision cancer treatment, to only one or several tumor sites. It provides a higher dose of radiation therapy.
The median overall survival was 41 months in patients receiving stereotactic radiotherapy (95% confidence interval = 26 months – no upper limit), compared with 28 months in the palliative radiotherapy group (95% confidence interval = 19 – 33 months) (p = .09). Stereotactic radiation also doubles the time to survive without cancer. The progression-free survival was 12 months (95% = 6.9 – 30 months) in the stereotactic radiotherapy group and 6 months in patients receiving palliative radiotherapy (95% confidence interval = 3.4 – 7.1 months) (p = .001). Nearly half (46%) of patients receiving stereotactic radiotherapy survived after five years, compared with 24% in the control group.
However, treatment with stereotactic radiation has more side effects than palliative radiotherapy. Only 9% of patients who received palliative care had serious adverse events (Grade 2 or higher), compared with 30% in the stereotactic radiation therapy group (p = .022). The most common side effects were fatigue (n=10), difficulty breathing (n=9), muscle and joint pain (n=7), bone pain (n=6) or other pain (n=7). Three patients in the experimental group died of adverse events: one drom lung abscess, one due to epidural hemorrhage, and one due to radiation pneumonitis. Although such events may occur due to standard radiation therapy, they are rare.
Stereotactic radiotherapy has serious side effects and a small risk of death. It needs to be operated by an experienced team. But overall, the overall survival benefit of stereotactic radiotherapy outweighs the risks for patients who have relapsed cancer and are not expected to survive very long. Moreover, there was no difference in quality of life measurements between the two treatment groups, and the assessment of cancer treatment function was similar at 6 months after treatment.

参考文献 Reference

Palma DA et al. Int J Radia Onc 2018; 102: S3-4

 

HDAC抑制剂可克服晚期乳腺癌对内分泌治疗的耐药性 (1/12/2019)

HDAC inhibitors may overcome resistance to endocrine therapy in advanced breast cancer

表观变化 (epigenetic changes)与癌症的发展有关，表观遗传疗法是针对肿瘤微环境的策略。针对表观遗传变化的一种方法是使用组蛋白脱乙酰酶（HDAC）抑制剂，它具有抗肿瘤作用，包括生长停滞，细胞凋亡和诱导细胞分化。

一项III期临床试验 (ACE)中, chidamide（一种口服选择性HDAC抑制剂）加上依西美坦（exemestane），对内分泌治疗有耐药性的晚期乳腺癌患者有效果。这是第一项III期临床试验，证明HDAC抑制剂加内分泌治疗可改善无进展生存期。

在中国开发的chidamide具有比较好的耐受性。它在中国被用于治疗外周T细胞淋巴瘤。ACE试验招募了365名在中国22个中心激素受体阳性/HER2阴性晚期乳腺癌的绝经后妇女。所有女性在之前都接受过内分泌治疗（包括他莫昔芬和/或芳香酶抑制剂）, 最多接受过四线先前治疗, 而且疾病进展。

患者以2:1的比例随机分配接受每周两次30 毫克的chidamide加上依西美坦（25毫克/天）（244名）; 或安慰剂加依西美坦（121名）。治疗继续至疾病进展或毒性不可接受。

使用chidamide加依西美坦治疗的中位持续时间为24周，而单用依西美坦治疗中位持续时间为16周。剂量需要减少的患者分别为33.2％和2.5％，剂量中断的患者分别为为48.4％和4.1％。治疗中止率分别为10.2％对2.5％ 。

根据研究者评估，使用chidamide加依西美坦的中位无进展生存期为7.4个月，而单用依西美坦的为3.8个月（p = .0336）。在意向治疗分析中，中位无进展生存期分别为9.2个月和3.8个月（p = .024）。

不良事件在治疗组中更常见。最常见的不良事件是血液学毒性。

Epigenetic changes are associated with development of cancer, and epigenetic therapy is a strategy for tumor microenvironment. One approach to epigenetic changes is the use of histone deacetylase (HDAC) inhibitors, which have anti-tumor effects, including growth arrest, apoptosis, and induction of cell differentiation.

In a Phase III clinical trial (ACE), chidamide (an oral selective HDAC inhibitor) plus exemestane is effective in advanced breast cancer patients who developed resistance to endocrine therapy. This is the first phase III clinical trial to demonstrate that HDAC inhibitor plus endocrine therapy improves progression-free survival.

Chidamide developed in China appears to have better tolerance. It is used in China to treat peripheral T-cell lymphoma. The ACE trial enrolled 365 postmenopausal women in 22 centers in China. They have hormone receptor-positive/HER2-negative advanced breast cancers. All women have previously received up to four line of prior endocrine therapy (including tamoxifen and/or aromatase inhibitors), have received up to four prev and disease progressed.

Patients were randomized in a 2:1 ratio to receive either twice a week 30 mg of chidamide plus exemestane (25 mg/day) (n = 244) , or placebo plus exemestane (n = 121). Treatment continues until disease progression or unacceptable toxicity.

The median duration of treatment exposure with chidamide plus exemestane was 24 weeks, while the median duration of treatment exposure with exemestane alone was 16 weeks. The patients required to dose reduction were 33.2% versus 2.5%, respectively, and the patients with dose discontinuation were 48.4% versus 4.1%, respectively. The treatment discontinuation rates were 10.2% versus 2.5%, respectively.

According to investigator’s assessment, the median progression-free survival of chidamide plus exemestane was 7.4 months, compared with 3.8 months for exemestane alone (p = .0336). In the intention-to-treat analysis, median progression-free survival was 9.2 months and 3.8 months, respectively (p = .024).

Adverse events were more common in the treatment group. The most common adverse event is hematological toxicity.

参考文献 Reference

Jiang Z et al: ESMO 2018 Congress. Abstract 283O_PR.

 

索拉非尼和拓扑替康对耐铂类卵巢癌有效 (1/6/2019)

Sorafenib and topotecan effective in platinum-resistant ovarian cancer

这是一个在德国的进行的多中心，双盲2期试验（TRIAS）。 参加者为曾接受过 < 2线化疗，且对铂类耐药的卵巢癌复发患者（≥18岁）。病人随机分配（1：1） 为拓扑替康（第1 – 5天为1.25 毫克/平方米）加上口服索拉非尼400 毫克或安慰剂，每日2次，每次6-15天，每21天重复6次，然后每日维持索拉非尼或安慰剂治疗 ，没有进展的患者持续口服1年。 索拉非尼或安慰剂是双盲; 拓扑替康是开放标签。 治疗的终了目标为研究者评估的无进展生存期。

在2010年1月18日和2013年9月19日之间，共招募了185名患者，其中174名被随机分配：索拉非尼85名（两名患者在治疗前出现严重不良事件，被排除在分析之外），安慰剂89名。索拉非尼组83例患者和安慰剂组89例相比，无进展生存期显著改善（风险比 = 0.60; 95％置信区间 = 0.43-0.83; p = .0018）。索拉非尼的中位无进展生存期为6.7个月（95％置信区间 = 5.8-7.6），安慰剂为4.4个月（3.7-5.0）。最常见的3/4级不良事件是白细胞减少症, 为57例 (69％)（索拉非尼组相）相对于47例 (53％)（安慰剂组）。中性粒细胞减少症为46例 (55％) 相对于48例 (54％）和血小板减少症23 例 (28％) 相对于 20例 (22％）。 索拉非尼组（呼吸困难和一般情况较差，败血性休克，腹水和呼吸困难，腸穿孔）的4例患者（5％）发生致命事件，安慰剂组有7例（8％）（两例肺栓塞）患者，两名患者的疾病进展，以及各一例败血症，胸腔积液和肿瘤恶病质。

索拉非尼与拓扑替康联合口服并作为维持治疗，在铂类耐药卵巢癌患者中显示出无进展生存的显著改善。这些结果支持抗血管生成与化疗相结合的效应。
This is a multi-center, double-blind phase 2 trial (TRIAS) conducted in Germany. Participants were patients with ovarian cancer who had undergone < 2-lines of  chemotherapy and were resistant to platinum (≥18 years). Patients were randomized (1:1) to topotecan (1.25 mg/m2 on days 1-5) plus oral sorafenib 400 mg or placebo twice daily for 6-15 days. The treatment repeats 6 times every 21 days, then patients continue to take sorafenib or placebo daily, and the maintenance lasts for one year in those who have not progressed. Sorafenib or placebo is double-blind; topotecan is open label. The primary end point is progression-free survival assessed by the investigators.
Between January 18, 2010 and September 19, 2013, a total of 185 patients were enrolled, of whom 174 were randomly assigned: 85 patients with sorafenib (two patients had serious adverse events before treatment, and are excluded from the analysis), placebo 89. There was a significant improvement in progression-free survival in 83 patients in the sorafenib group compared with 89 patients in the placebo group (hazard ratio = 0.60; 95% confidence interval = 0.43-0.83; p = .0018). The median progression-free survival of sorafenib was 6.7 months (95% confidence interval = 5.8-7.6) and placebo was 4.4 months (3.7-5.0). The most common grade 3/4 adverse events were leukopenia, 57 (69%) (sorafenib group) versus 47 (53%) (placebo). Neutropenia were 46 (55%) vs. 48 (54%) and thrombocytopenia in 23 (28%) vs. 20 (22%). Four patients (5%) in the sorafenib group (dyspnea and poor general condition, septic shock, ascites and dyspnea, intestinal perforation) developed fatal events, and 7 patients (8%) in the placebo group (two patients with pulmonary embolism, disease progression in two patients, and one case of each in sepsis, pleural effusion and cachexia.
Treatment with oral sorafenib combined with topotecan and as a maintenance therapy showed a significant improvement in progression-free survival in patients with platinum-resistant ovarian cancer. These results support the combined efficacy of anti-angiogenesis and chemotherapy.

参考文献 Reference

Chekerov R et al. Lancet Onc 2018; 19: 1247-58

 

第一个术前免疫疗法用于结肠癌的试验 (1/5/2019)

First clinical trial about preoperative immunotherapy in colon cancer

在一项早期结肠癌患者的小型研究中，术前使用易普利姆玛（ipilimumab）加nivolumab，100％有错配修复（MMR）缺陷的肿瘤患者有主要的病理反应，但错配修复正常患者却没有一个有病理反应。

这是一项II期非比较性的NICHE试验, 是第一个给错配修复缺陷和错配修复正常的早期结肠癌病人术前易普利姆玛加nivolumab的试验。该研究有19例可切除的早期结肠癌患者参加，在第1天用1 毫克/公斤的易普利姆玛治疗1天，在第1天和第15天用3 毫克/公斤的nivolumab治疗。从结肠镜检查到手术的时间为6周或更短。共有14个可评估的病例，包括7个错配修复缺陷肿瘤和8个错配修复正常的肿瘤（1个患者具有2个肿瘤）。

在7个错配修复缺陷肿瘤（100％）中观察到主要的病理反应（<10％残留肿瘤），4个完全反应（57％）。 在错配修复正常的肿瘤中没有观察到主要的病理反应。

在患有错配修复缺陷的肿瘤患者中，治疗效应不能根据治疗前CD3细胞浸润或免疫基因特征来预测。与研究者预期的相反，在错配修复缺陷肿瘤中，治疗前CD3细胞浸润并不高。但治疗后，错配修复缺陷肿瘤中CD3细胞浸润显着增加（p = 0.031），错配修复正常肿瘤略有增加（p = .461）。错配修复缺陷肿瘤在基线时具有显著（p = .027）的CD8阳性细胞数量，并且术后CD8阳性T细胞增加4.8倍（p = .0009）。 CD8阳性T细胞的显著增加2.4倍（p = .018），但在错配修复正常患者中，并没有见到临床反应。

在错配修复缺陷肿瘤中, 治疗干扰素-γ特征显着增加（p = .036）; 但在错配修复正常肿瘤中没有显着增加（P = .08），这会帮助区分应答者与无应答者。

免疫疗法耐受性良好，所有患者均接受切除术，手术无延迟。 3名患者术后发生腹部感染，吻合口漏和肺炎各1例，均未归因于免疫治疗。

今后的方向是大型试验, 以独立验证术前免疫治疗对错配修复缺陷肿瘤的作用。

 In a small study of patients with early colon cancer, preoperative ipilimumab plus nivolumab has major pathological responses in 100% of patients with mismatched repair (MMR) deficient, but none of the MMR-proficient patients had a pathological response.
This is a phase II non-comparative NICHE trial and is the first trial of preoperative ipilimumab plus nivolumab in patients with early colon cancer who are MMR-deficient or MMR-proficient. The study involved 19 patients with resectable early colon cancer who were treated with 1 mg/kg of ipilimumab for 1 day on day 1 and 3 mg/kg of nivolumab on days 1 and 15. The time from colonoscopy to surgery is 6 weeks or less. There were 14 evaluable cases, including 7 MMR-deficient tumors and 8 MMR-proficient tumors (1 patient had 2 tumors).
The primary pathological response (residual vital tumor <10%) was 100% in 7  MMR-deficient tumors and 4 complete responses (57%) . No major pathological response were observed in tumors which are MMR-proficient.
In patients with MMR-deficient tumors, the therapeutic effect cannot be predicted based on pre-treatment CD3 infiltration or immune gene signatures. Contrary to what the researchers expected, CD3 infiltration was not high before treatment in MMR-deficient tumors. However, after treatment, CD3 infiltration was significantly increased in MMR-deficient tumors (p =  .031), and that in MMR-proficient tumors was slightly increased (p = .461). MMR-deficient tumors had a significant (p = .027) number of CD8 positive cells at baseline and a 4.8-fold increase in median postoperative CD8 positive T cells (p = .0009). Significant increases in CD8-positive T cells were 2.4-fold (p = .018) in MMR-proficient tumors, but no clinical response was seen.
In the MMR-deficient tumors, there was a significant increase in interferon-gamma signatures (p = .036) but no significant increase in MMR-proficient tumors (P = .08). This may help to distinguish between responders and non-responders. .

参考文献  Reference

Chalabi M et al. 2018 ESMO Congress. Abstract LBA37_PR