CT 检查与儿童和年轻人的脑癌 (12/31/2022)
Brain cancer after radiation exposure from CT examinations of children and young adults
一项欧洲队列研究（EPI-CT）旨在评估儿童和年轻人 CT 检查的脑癌风险。这项队列研究汇集了来自九个欧洲国家的数据。符合条件的参与者在 1977 年至 2014 年期间记录在 22 岁之前至少接受过一次 CT 检查，之前没有诊断出癌症或良性脑肿瘤，并且在第一次 CT 后至少 5 年还活着并且没有癌症。 通过 276 家医院的放射科信息系统确定了参与者。 参与者与国家或地区癌症和生命状况登记处相关联，符合条件的病例是根据世界卫生组织国际肿瘤学疾病分类的脑癌患者。 神经胶质瘤与所有脑癌分别进行了分析。 使用历史机器设置和大量 CT 图像样本重建器官剂量。 使用线性剂量反应模型计算每 100 mGy 脑部累积剂量的脑癌超额相对风险 (ERR)。 结果是在第一次 CT 检查后 5 年的排除期后首次报告的脑癌诊断。
研究者确定了 948 174 人，其中 658 752 (69%) 人符合研究条件。 658 752 名参与者中有 368 721 名 (56%) 为男性，290 031 名 (44%) 为女性。 在中位随访 5.6 年 (IQR 2.4–10.1) 期间，发生了 165 例脑癌，包括 121 例 (73%) 神经胶质瘤。 滞后 5 年的平均累积脑剂量在所有个体中为 47.4 mGy (SD 60.9)，在脑癌患者中为 76.0 mGy (100.1)。 所有脑癌（ERR 每 100 mGy 1.27 [95% CI 0.51–2.69]）和神经胶质瘤（ERR 每 100 mGy 1.11 [0.36]）均观察到显著的线性剂量反应关系 –2.59])。 当随访开始延迟超过 5 年并且排除可能患有先前未报告的癌症的参与者时，结果是稳健的。
在这项具有个体剂量评估的大型多中心研究中，观察到 CT 相关辐射暴露与脑癌之间存在显著的剂量反应关系，强调了对儿科 CT 的仔细论证和使用尽可能低的剂量。
An European cohort study (EPI-CT) aimed to assess brain cancer risk in children and young adults after CT scans. This cohort study pooled data from nine European countries. Eligible participants, with no previous diagnosis of cancer or benign brain tumors, had at least one CT scan before age 22 between 1977 and 2014. They were alive and cancer-free for at least 5 years after their first CT. Participants were identified through the radiology information systems of 276 hospitals. Participants were linked to national or regional cancer and vital status registries, and eligible cases were patients with brain cancer according to the World Health Organization International Classification of Diseases in Oncology. Gliomas were analyzed separately from all brain cancers. Reconstruct organ doses using historical machine settings and a large number of CT image samples. Excess relative risk (ERR) of brain cancer per cumulative brain dose of 100 mGy was calculated using a linear dose-response model. The results were the first reported brain cancer diagnoses after a 5-year exclusion period following the first CT scan.
The investigators identified 948 174 individuals, of whom 658 752 (69%) were eligible for the study. Of the 658 752 participants, 368 721 (56%) were men and 290 031 (44%) were women. During a median follow-up of 5.6 years (IQR 2.4–10.1), 165 brain cancers occurred, including 121 (73%) gliomas. The mean cumulative brain dose at a lag of 5 years was 47.4 mGy (SD 60.9) in all individuals and 76.0 mGy (100.1) in brain cancer patients. Significant linear dose-response relationships were observed for all brain cancers (ERR 1.27 [95% CI 0.51–2.69] per 100 mGy) and gliomas (ERR 1.11 [0.36] per 100 mGy –2.59]). Results were robust when start of follow-up was delayed more than 5 years and participants who may have had previously unreported cancer were excluded.
In this large multicenter study with individual dose assessments, a significant dose-response relationship between CT-related radiation exposure and brain cancer was observed, emphasizing careful justification for pediatric CTs and the use of the lowest possible doses.
参考文献 Reference
Hauptmann M et al. Lancet Onc 2022; DOI:https://doi.org/10.1016/S1470-2045(22)00655-6
Lifileucel 治疗免疫检查点抑制剂疾病进展后的晚期黑色素瘤 (12/25/2022)
Lifileucel therapy in advanced melanoma after progression from check-point inhibitor
肿瘤浸润淋巴细胞 (TIL) 细胞疗法可能会提供免疫检查点抑制剂疾病进展后的黑色素瘤患者的治疗需求。
Lifileucel 是一种使用冷冻保存的自体 TIL 的研究性过继细胞疗法，C-144-01是一项针对晚期黑色素瘤的多中心 II 期研究。 这是免疫检查点抑制剂后晚期黑色素瘤中最大的细胞治疗研究。 队列 2 招募了 66 名患者，注册队列 4 招募了 87 名患者。 两个队列的资格标准相同，对先前治疗的数量没有限制。 所有患者都接受了非清髓性淋巴细胞清除、单次 lifileucel 输注和最多六剂静脉推注白介素，没有进一步治疗计划。 主要终点是客观响应率。 患者接受过多线的预先治疗，治疗线的中位数为三线。 大多数患者对先前的 PD-1 治疗有原发性耐药。
客观响应率为 31.4%，包括 9 个完全响应和 39 个部分反应。在所有分析的亚组中观察到对 lifileucel 的响应，包括 BRAF 突变状态和 PD-L1 评分。 在 48 名响应者中有 39 人在 6 周的第一次疾病评估时获得了响应，但许多响应随着时间的推移而加深:最初有部分反应的 7 名患者改善为完全响应，10 名患者从疾病稳定改善为部分反应。尚未达到中位响应持续时间，中位随访时间为 36 个月，41.7% 的响应至少维持 24 个月。该组的中位总生存期为 13.9 个月，12 个月总生存率为 54%。
治疗中出现的不良事件评估从第 0 天开始（淋巴细胞耗尽后）。 最常见的非血液学治疗相关的不良事件是寒战、发热（包括发热性中性粒细胞减少症）、低磷血症、低血压、疲劳和腹泻。 所有患者都经历了实验室评估的 3 级或 4 级中性细胞减少症, 淋巴细胞减少症。大多数不良事件是短暂可控的，在输注 lifileucel 后的 2 周内，新不良事件的发生率迅速下降。
Tumor-infiltrating lymphocyte (TIL) cell therapy may provide the treatment needs of melanoma patients after disease progression on immune checkpoint inhibitors.
Lifileucel is an investigational adoptive cell therapy using cryopreserved autologous TIL C-144-01 is a multicenter phase II study in advanced stage melanoma. This is the largest study of cell therapy in advanced melanoma after progression an immune checkpoint inhibitors. Cohort 2 enrolled 66 patients and cohort 4 enrolled 87 patients. Eligibility criteria were the same for both cohorts, with no restrictions on the number of prior treatments. All patients received nonmyeloablative lymphodepletion, a single infusion of lifileucel, and up to six doses of intravenous bolus interleukin, with no further treatment planned. The primary endpoint was objective response rate. Patients received multiple lines of prior treatment, with a median of three lines of treatment. Most patients had primary resistance to previous PD-1 therapy.
The objective response rate was 31.4%, including 9 complete responses and 39 partial responses. Responses to lifileucel were observed in all subgroups analyzed, including BRAF mutation status and PD-L1 score. Thirty-nine of 48 responders achieved a response at the first disease assessment at 6 weeks, but many responses deepened over time: seven patients who initially had partial responses improved to complete responses, and 10 patients improved from stable disease to partial response. The median duration of response had not yet reached, with a median follow-up of 36 months, and 41.7% of responses were maintained for at least 24 months. Median overall survival in this group was 13.9 months, with a 12-month overall survival rate of 54%.
Evaluation of treatment-emergent adverse events began on day 0 (after lymphocyte depletion). The most common nonhematologic treatment-related adverse events were chills, pyrexia (including febrile neutropenia), hypophosphatemia, hypotension, fatigue, and diarrhea. All patients experienced laboratory-assessed grade 3 or 4 neutropenia, and lymphopenia. Most adverse events were transient and manageable, and the rate of new adverse events decreased rapidly within 2 weeks after lifileucel infusion.
参考文献 Reference
Sarnaik A et al. 2022 SITC Annual Meeting. Abstr 789.
抗 TIGIT 抗体增强了IV 期高水平PD-L1的非小细胞肺癌的免疫治疗活性 (12/24/2022)
Anti-TIGIT antibody increased activity of immunotherapy in ST IV NSCLC with high PD-L1 level
Domvanalimab (D) 是一种 Fc 沉默（Fc-silent）人源化 IgG1 单克隆抗体，可阻断 T 细胞免疫球蛋白和 ITIM 结构域 (TIGIT)，从而减少 T/NK 细胞的免疫抑制并促进抗肿瘤活性。 Etrumadenant (E) 是在免疫细胞上表达的 A2a 和 A2b 受体的选择性双重拮抗剂，从而减少细胞外腺苷的免疫抑制。
ARC-7 (NCT04262856) 是一项随机、开放标签的 2 期临床试验，评估了抑制 TIGIT 和腺苷通路是否会增强 zimberelimab (抗 PD-1 抗体）在PD-L1高表达 的非小细胞肺癌患者中的活性。该试验招募了未经治疗的 IV 期鳞状或非鳞状PD-L1高表达（TPS ≥ 50%）的非小细胞肺癌患者，无 EGFR 或 ALK 突变。 患者被随机分配 (1:1:1) 至： 第 1 组 (Z)：zimberelimab 360 mg 静脉注射, 每 3 周一次； 第 2 组 (DZ)：Domvanalimab 15 mg/kg 静脉注射, 每 3 周一次 + zimberelimab； 第 3 组 (EDZ)：每天一次口服 Etrumadenant 150 mg + DZ。 第 1 组中确认疾病进展的患者可以选择交叉到 EDZ。共同主要终点是总响应率和无进展生存期。 结果： 截至 2022 年 8 月 31 日，149 名患者至少接受了一剂研究治疗。 该中期分析的有效性包括在数据截止前至少 13 周随机分组的 133 名患者，允许进行 ≥ 2 次基线后扫描。 中位随访 11.8 个月，与 Z 组相比，含Domvanalimab组显示总响应率和无进展生存期有所改善。客观响应率在Z 组中为 27%，在 DZ 组中为 41%，在 EDZ 组中为 40%。 中位无进展生存期分别为 5.4 个月、12.0 个月和 10.9 个月，与单一疗法相比，相对风险分别降低了 45% 和 35%。 在 6 个月时，无进展患者的百分比在 Z 组中为 43%，在 DZ 组中为 65%，在 EZD 组中为 63%。
发生 ≥ 3 级治疗紧急不良事件发生在58% (Z)、47% ( DZ) 和 52% (EDZ)。 所有皮疹病均为 1-2 级，可通过局部皮质类固醇进行控制，并且在 EDZ 更为常见。
结论： 在首次发表的评估 Fc 沉默 TIGIT 抗体 的随机数据集中，与 Z 相比，两个含 D 的臂在总响应率和无进展生存期方面均表现出具有临床意义的改善。用 Z, DZ 和 EDZ 治疗耐受性良好。正在进行的 3 期试验正在评估 DZ 与转移性非小细胞肺癌护理标准的比较。
Domvanalimab (D) is an Fc-silent humanized IgG1 monoclonal antibody that blocks T cell immunoglobulin and ITIM domains (TIGIT), thereby reducing T/NK cell immunosuppression and promoting anti- tumor activity. Etrumadenant (E) is a selective dual antagonist of A2a and A2b receptors expressed on immune cells, thereby reducing immunosuppression by extracellular adenosine.
ARC-7 (NCT04262856) was a randomized, open-label, phase 2 clinical trial evaluating whether inhibition of the TIGIT and adenosine pathways enhances zimberelimab (anti-PD-1 antibody) in NSCLC patients with high PD-L1 expression. The trial enrolled untreated patients with stage IV squamous or nonsquamous PD-L1-high expression (TPS ≥ 50%) NSCLC without EGFR or ALK mutations. Patients were randomly assigned (1:1:1) to: Arm 1 (Z): zimberelimab 360 mg IV every 3 weeks; Arm 2 (DZ): Domvanalimab 15 mg/kg IV every 3 weeks + zimberelimab; Group 3 (EDZ): Etrumadenant 150 mg orally once daily + DZ. Patients in cohort 1 with confirmed disease progression had the option to cross over to the EDZ. Co-primary endpoints were overall response rate and progression-free survival. Results: As of August 31, 2022, 149 patients had received at least one dose of study treatment. Efficacy at this interim analysis included 133 patients randomized at least 13 weeks before data cutoff, allowing ≥ 2 post-baseline scans. At a median follow-up of 11.8 months, the domvanalimab-containing arm showed an improvement in overall response rate and progression-free survival compared with the Z arm. Objective response rates were 27% in the Z arm, 41% in the DZ arm, and 40% in the EDZ arm. Median progression-free survival was 5.4 months, 12.0 months, and 10.9 months respectively, representing relative risk reductions of 45% and 35%, respectively, compared with monotherapy. At 6 months, the percentages of progression-free patients were 43% in the Z arm, 65% in the DZ arm, and 63% in the EZD arm.
Grade ≥ 3 treatment-emergent adverse events occurred in 58% (Z), 47% (DZ), and 52% (EDZ). All rashes were grade 1-2, manageable with topical corticosteroids, and were more common in the EDZ.
Conclusions: In the first published randomized dataset evaluating an Fc-silencing TIGIT antibody, both D-containing arms demonstrated clinically meaningful improvements in overall response rate and progression-free survival compared with Z alone. Treatment with Z, DZ and EDZ was well tolerated. An ongoing phase 3 trial is evaluating DZ compared to standard care in metastatic NSCLC.
参考文献 Reference
Johnson ML et al. ASCO Plenary Series: Dec 2022; abstr 397600
Modakafusp Alfa 治疗多发性骨髓瘤 (12/18/22)
Modakafusp Alfa treating multiple myeloma
Modakafusp alfa 是第一种免疫靶向减毒细胞因子。 它由 2 个减毒干扰素α2b 分子组成，该分子与抗 CD38 IgG4 单克隆抗体的 Fc 部分基因融合，允许将 干扰素α靶向递送至免疫细胞以及骨髓瘤细胞。 研究者之前报告了在 1/2 期研究 (NCT03215030) 中每 4 周接受1.5 mg/kg 的一组 30 名患者的初步结果。 现在报告研究的最终安全性和有效性结果。
患者既往接受过 ≥ 3 线治疗，并且对 ≥ 1 种蛋白酶体抑制剂和 ≥ 1 种免疫调节药物耐药或不耐受。 在数据截止时（2022 年 4 月），100 名患者接受了 modakafusp 治疗； 56 名剂量递增患者和 44 名扩展队列患者。 在剂量递增期间，每周和每 2 周给药方案报告了剂量限制性毒性。 在每 4 周给药方案中，modakafusp 的最大耐受剂量超过 6 mg/kg，因此，MTD 被确定为每 4 周 3 mg/kg。 在剂量递增期间，部分响应见于每周 0.1 mg/kg 和 0.4 mg/kg（各1），每3周0.4 mg/kg 未观察到 VGPR (very good partial response），部分响应（n=3）和 完全响应（n= 1) 见于每4周 1.5–6 mg/kg。 在扩展期间，在每3周接受 modakafusp 0.4 mg/kg 的 8 名患者中，5 名出现稳定疾病，3 名出现疾病进展。 在每3周接受 0.4 mg/kg + 地塞米松的 3 名患者中，2 名出现稳定疾病，1 名出现疾病进展。
在每4周接受 modakafusp 1.5 mg/kg的 30 名患者中（5 名剂量递增，25 名剂量扩大），总客观响应率 为 43%，中位开始响应时间为 1.2 个月，未达到中位反应持续时间（范围 1.0 –18.9 个月）。 中位无进展生存期为 5.7 个月（95% 置信区间 1.2–15.9）。初步分析显示外周血免疫细胞上CD38受体密度与临床反应无相关性。 在每4周接受 1.5 mg/kg时，26 名 (87%) 患者发生了 ≥ 3级 的治疗紧急不良事件，包括中性粒细胞减少症 (n=19, 63% [4级 n=9, 30%])、血小板减少症 (n =14, 47% [4级 n=6, 20%]）和淋巴细胞减少症（n=11, 37% [4级 n=7, 23%]）； 3 名 (10%) 患者发生3级感染，1 名 (3%) 患者发生3级出血事件。 除1例4级高尿酸血症报告外，无4级非血液学治疗紧急不良事件。
结论: Modakafusp alfa 具有新颖的作用机制、可管理的安全性，并在每4周接受 1.5 mg/kg时具有抗骨髓瘤活性，与外周血免疫细胞 CD38 表达无关。
Modakafusp alfa is the first immune-targeted attenuated cytokine. It consists of 2 attenuated interferon alpha 2b molecules genetically fused to the Fc portion of an anti-CD38 IgG4 monoclonal antibody, allowing targeted delivery of interferon alpha to immune cells as well as myeloma cells. The investigators previously reported preliminary results from a cohort of 30 patients who received 1.5 mg/kg every 4 weeks in a Phase 1/2 study (NCT03215030). Now they reported final safety and efficacy results from the study.
Patients had received ≥ 3 prior lines of therapy and were resistant or intolerant to ≥ 1 proteasome inhibitor and ≥ 1 immunomodulatory drug. At data cutoff (April 2022), 100 patients had been treated with modakafusp; 56 dose-escalation patients and 44 expansion cohort patients. Dose-limiting toxicities were reported with weekly and every 2-week dosing regimens during dose escalation. In the every 4-week dosing regimen, the maximum tolerated dose of modakafusp exceeded 6 mg/kg, therefore, the MTD was determined to be 3 mg/kg every 4 weeks. During dose escalation, partial responses were seen at weekly 0.1 mg/kg and 0.4 mg/kg (1 each). At 0.4 mg/kg every 3 weeks no VGPR (very good partial response) was observed. Partial response (n=3) and complete response (n=1) were seen at 1.5–6 mg/kg every 4 weeks. During the expansion period, of the 8 patients receiving modakafusp 0.4 mg/kg every 3 weeks, 5 had stable disease and 3 had progressive disease. Of the 3 patients receiving 0.4 mg/kg + dexamethasone every 3 weeks, 2 had stable disease and 1 had progressive disease.
Among 30 patients receiving modakafusp 1.5 mg/kg every 4 weeks (5 dose escalation, 25 dose expansion), the overall objective response rate was 43%, with a median time to response was 1.2 months and a median duration of response not reached (range 1.0–18.9 months). Median progression-free survival was 5.7 months (95% confidence interval 1.2–15.9). Preliminary analysis showed no correlation between CD38 receptor density on peripheral blood immune cells and clinical response. At 1.5 mg/kg every 4 weeks, 26 (87%) patients experienced grade ≥ 3 treatment-emergent adverse events, including neutropenia (n=19, 63% [grade 4 n=9, 30%]), thrombocytopenia (n=14, 47% [Grade 4 n=6, 20%]), and lymphopenia (n=11, 37% [Grade 4 n=7, 23%]); Grade 3 infection occurred in 3 (10%) patients and grade 3 bleeding event occurred in 1 (3%) patient. There were no grade 4 non-hematologic treatment-emergent adverse events except for one report of grade 4 hyperuricemia.
Conclusions: Modakafusp alfa has a novel mechanism of action, manageable safety profile, and antimyeloma activity independent of peripheral blood immune cell CD38 expression when administered at 1.5 mg/kg every 4 weeks.
参考文献 Reference
Vogl DT et al. 2022 ASH abst 565
在氟维司群中加入 Capivasertib 治疗晚期激素受体阳性乳腺癌 (12/17/2022)
Adding capivasertib to fulvestrant for advanced ER-positive breast cancer
这是一项III期临床试验（CAPItello-291），以确定将 AKT 抑制剂 capivasertib 添加到氟维司群后是否会改善激素受体阳性, HER2 阴性乳腺癌患者的预后, 招募共有708名患者参加, 这些患者对芳香酶抑制剂产生了耐药性。 研究人员随机分配 355 名患者接受 capivasertib 加氟维司群治疗（联合治疗），353 名患者接受安慰剂加氟维司群治疗。 接受联合治疗患者的中位无进展生存期为 7.2 个月，而接受安慰剂加氟维司群治疗的为 3.6 个月。 联合治疗患者的疾病进展的风险降低了 40%。 接受联合治疗治疗的患者的客观响应率为 22.9%，而接受安慰剂加氟维司群治疗的患者的客观响应率为 12.2%。 总体而言，分配接受治疗的患者中有 41% 患有带有 AKT 通路突变的肿瘤。 在接受联合治疗的 AKT 通路突变患者中，中位无进展生存期为 7.3 个月，客观缓解率为 28.8%。 在接受安慰剂加氟维司群治疗的 AKT 通路突变患者中，中位无进展生存期为 3.1 个月，客观缓解率为 9.7%。
在接受联合治疗的患者中，最常见的 3 级或更高级别不良事件是皮疹 (12.1%)、腹泻 (9.3%) 和高血糖 (2.3%)。 因不良事件停药的比例为 13%，而接受安慰剂联合氟维司群治疗的患者为 2.3%。
This is a phase III trial (CAPItello-291) to evaluate whether adding the AKT inhibitor capivasertib to fulvestrant improves outcomes in patients with hormone receptor-positive, HER2-negative breast cancer. It enrolled a total of 708 patients. These patients developed resistance to aromatase inhibitors. Researchers randomly assigned 355 patients to receive capivasertib plus fulvestrant (combination group) and 353 patients to receive placebo plus fulvestrant. Median progression-free survival was 7.2 months for patients in the combination group compared vs. 3.6 months for those who received placebo plus fulvestrant. The risk of disease progression was reduced by 40% in patients treated in the combination group. The objective response rate was 22.9% for those in the combination group compared with 12.2% in those treated with placebo plus fulvestrant. Overall, 41 percent of patients assigned to treatment had tumors with mutations in the AKT pathway. Among patients with AKT pathway mutations who received combination therapy, the median progression-free survival was 7.3 months and the objective response rate was 28.8%. Among patients with AKT pathway mutations who received placebo plus fulvestrant, the median progression-free survival was 3.1 months and the objective response rate was 9.7%.
Among patients receiving combination therapy, the most common grade 3 or higher adverse events were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Discontinuation due to adverse events was 13% compared with 2.3% of patients receiving placebo plus fulvestrant.
参考文献 Reference
Turner N et al. 2022 San Antonio Breast Cancer Symp abstr GS3-04
Camizestrant用于激素受体阳性/HER2 阴性乳腺癌 (12/11/2022)
Camizestrantfor ER+/HER2- breast cancer
氟维司群（fulvestrant）是是唯一获得 FDA 批准用于治疗乳腺癌的雌激素受体降解剂 (SERD), 但必须接受肌肉注射。 Camizestrant是下一代口服SERD。 这是一项II期临床试验（SERENA-2）, 以评估雌激素受体阳性乳腺癌患者是否会从camizestrant或氟维司群治疗中获益更多。 既往接受过不超过一种内分泌治疗方案和不超过一种既往化疗方案的患者被随机分配接受氟维司群或每日camizestrant三种剂量水平之一：75 毫克, 150 毫克 或 300 毫克。 由于策略管理上并非毒性问题的原因，300 毫克组提前停用。 75 毫克 camizestrant 组, 150 毫克 camizestrant 组和氟维司群组分别包括 74、73 和 73 名患者。
在总体人群中，与氟维司群相比，在 75 毫克和 150 毫克组中, camizestrant显著降低了 42% 和 33% 的疾病进展或死亡风险。中位无进展生存期分别为 7.2 个月和 7.7 个月，而接受氟维司群治疗的患者为 3.7 个月。 在有 ESR1 突变的患者中，camizestrant 在 75 毫克剂量下将疾病进展或死亡的风险降低了 67%（中位无进展生存期为 6.3 相对于氟维司群的 2.2 个月），在 150毫克剂量下降低了 45%（中位无进展生存期为 9.2 相对于 2.2 个月）。 在未检测到 ESR1 突变的患者中也观察到疾病进展或死亡风险降低，75 毫克剂量组风险降低 22%，150 毫克剂量组风险降低 24%。 在其他高危患者亚组中，与氟维司群相比，camizestrant 的疗效也有所提高； 与氟维司群相比，患有肺和/或肝转移的患者在 75 毫克剂量组和 150 毫克剂量组的疾病进展或死亡风险分别降低了 57% 和 45%。 先前接受过细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 抑制剂治疗的患者在 75 毫克剂量下疾病进展或死亡风险降低了 51%，在 150 毫克剂量下降低了 32%。
在 75 毫克/天,150 毫克/天camizestrant 和氟维司群组中，3 级或更高级别的不良事件分别发生在 12.2%、21.9% 和 13.7% 的患者中。
Fulvestrant is the only estrogen receptor degrader (SERD) approved by the FDA for the treatment of breast cancer. It must be administered intramuscularly. Camizestrant is a next-generation oral SERD. This is a phase II clinical trial (SERENA-2) to evaluate whether patients with estrogen receptor positive breast cancer will benefit more from camizestrant or fulvestrant. Patients who had received no more than one prior endocrine therapy regimen and no more than one prior chemotherapy regimen were randomly assigned to receive fulvestrant or one of three daily dose levels of camizestrant: 75 mg, 150 mg, or 300 mg. The 300 mg group was discontinued early for strategic reason, not due to toxicity concerns. The 75 mg camizestrant, 150 mg camizestrant, and fulvestrant groups included 74, 73, and 73 patients, respectively.
In the overall population, camizestrant significantly reduced the risk of disease progression or death by 42% and 33% in the 75 mg and 150 mg groups compared with fulvestrant. Median progression-free survival was 7.2 months and 7.7 months, respectively, compared with 3.7 months for patients treated with fulvestrant. In patients with ESR1 mutations, camizestrant reduced the risk of disease progression or death by 67% at the 75 mg dose (median progression-free survival of 6.3 months versus 2.2 months for fulvestrant) and at the 150 mg dose decreased by 45% (median progression-free survival of 9.2 versus 2.2 months). A reduced risk of disease progression or death was also observed in patients without detected ESR1 mutations, with a 22% risk reduction in the 75 mg dose group and a 24% risk reduction in the 150 mg dose group. The efficacy of camizestrant was also improved compared to fulvestrant in other subgroups of high-risk patients; patients with lung and/or liver metastases in the 75 mg and 150 mg doses compared to fulvestrant. The risk of disease progression or death was reduced by 57% and 45%, respectively, in the two groups. Patients who had previously received a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor had a 51% reduction in the risk of disease progression or death at the 75 mg dose and a 32% reduction at the 150 mg dose.
Grade 3 or higher adverse events occurred in 12.2%, 21.9%, and 13.7% of patients on 75 mg/day, 150 mg/day camizestrant, and fulvestrant, respectively.
参考文献 Reference
Oliveira M e al. 2022 San Antonio Breast Cancer Symp abstr GS3-02
T-DXd作为 HER2 阳性转移性乳腺癌患者的二线治疗优于 T-DM1 (12/10/2022)
T-DXd is better than T-DM1 in second line therapy for metastatic HER-2 positive breast cancer
Fam-trastuzumab deruxtecan-nxki (T-DXd)和ado-trastuzumab emtansine (T-DM1) 都是抗体-药物偶联物并被批准作为HER2 阳性转移性乳腺癌的二线治疗。根据III 期临床试验DESTINY-Breast03的最新结果， 与T-DM1 相比，使用T-DXd进行二线治疗可延长该患者群的总生存期。
在参加试验的 524 名患者中，261 名接受了 T-DXd，263 名接受了 T-DM1。 T-DXd 组的中位研究随访时间为 28.4 个月，T-DM1 组为 26.5 个月。 新数据显示，接受 T-DXd 治疗的患者死亡风险比接受 T-DM1 治疗的患者低 36%，具有统计学意义的改善。 此外，接受 T-DXd 治疗的患者的总生存率更高：12 个月后，T-DXd 组 94.1% 的患者存活，而 T-DM1 组为 86%。 24 个月后，接受 T-DXd 和 T-DM1 治疗的患者的总生存率分别为 77.4% 和 69.9%。接受 T-DXd 治疗的患者的中位无进展生存期为 28.8 个月相比于 6.8 个月。 客观响应分别为 78.5% 相比于 35%; 完全响应分别为 21.1% 相比于 9.5%。
在 T-DXd 和 T-DM1 组分别有 56.4% 和 51.7% 的患者观察到 3 级或更高级别的治疗相关不良事件。 与药物相关的间质性肺病/肺炎分别有 15.2% 和 3.1%。
结论：在二线治疗 HER2 阳性转移性乳腺癌患者中，使用 T-DXd 可获得显着的总生存期和持续的无进展生存期获益。
Fam-trastuzumab deruxtecan-nxki (T-DXd) and ado-trastuzumab emtansine (T-DM1) are both antibody-drug conjugates approved as second-line treatment for HER-2-positive metastatic breast cancer.
According to the latest results from the phase III clinical trial DESTINY-Breast03, second-line treatment with T-DXd prolonged overall survival compared with T-DM1. Of the 524 patients enrolled in the trial, 261 received T-DXd and 263 received T-DM1. Median follow-up was 28.4 months in the T-DXd arm and 26.5 months in the T-DM1 arm. The new data showed that patients treated with T-DXd had a 36 percent lower risk of death than those treated with T-DM1, a statistically significant improvement. In addition, patients treated with T-DXd had better overall survival: After 12 months, 94.1 percent of patients in the T-DXd group were alive, compared with 86 percent in the T-DM1 group. After 24 months, overall survival was 77.4% and 69.9% for patients treated with T-DXd and T-DM1, respectively. Patients treated with T-DXd had a median progression-free survival of 28.8 months versus 6.8 months. Objective responses were 78.5% vs 35%; complete responses were 21.1% vs 9.5%, respectively.
Grade 3 or higher treatment-related adverse events were observed in 56.4% and 51.7% of patients in the T-DXd and T-DM1 arms, respectively. Drug-related interstitial lung disease/pneumonia occurred in 15.2% and 3.1%, respectively.
Conclusions: Significant overall survival and sustained progression-free survival benefits were obtained with T-DXd in second-line treatment for patients with HER2-positive metastatic breast cancer.
参考文献 Reference
Hurvitz S et al. 2022 San Antonio Breast Cancer Symp Abstr GS2-02
FDA给于Sapanisertib快速通道用于NRF2突变的鳞状非小细胞肺癌 (12/4/2022)
FDA has granted fast track status to Sapanisertib for pretreated NRF@-mutated squamous NSCLC
鳞状肺癌患者的治疗方法有限, 患有 NRF2/KEAP1 通路突变的肺癌患者通常比那些肿瘤没有这些突变的患者预后更差。FDA 已授予 sapanisertib 快速通道资格，作为未切除或转移性鳞状非小细胞肺癌患者具有 NRF2 突变的治疗选择，并且之前接受过铂类化疗和免疫检查点抑制。
首次人体 1 期研究 (NCT01058707)探索了该药物在晚期实体瘤患者中以多种给药方案给药的安全性和有效性。确定药物的最大耐受剂量为每天 6 毫克, 每周 50 毫克; 每天 9 毫克，每周 3 天; 以及每天 7 毫克，每周 5 天。
该药物最常见的剂量限制性毒性是高血糖、斑丘疹、乏力和口腔炎。 在研究的扩展阶段，研究人员选择每天 5 毫克和每周 30 毫克作为进一步检查的给药方案。 数据显示，1 名肾细胞癌患者对治疗达到完全反应。 在 7 名肾细胞癌患者,1 名类癌患者和 1 名子宫内膜癌患者中观察到部分反应。
研究者发起的 2 期试验 (NCT02417701) 的数据显示，在 11 名经过大量以往治疗的 NRF2 突变鳞状非小细胞肺癌患者中，sapanisertib 的客观缓解率为 27%。 在这些患者中，中位无进展生存期为 8.9 个月（95% CI，7个月-未达到）。
Treatment options for patients with squamous NSCLC are limited, and those with mutations in the NRF2/KEAP1 pathway usually have a worse prognosis than those whose tumors do not have such mutations. The FDA has granted fast track designation to sapanisertib as a treatment option for patients with unresectable or metastatic squamous NSCLC with an NRF2 mutation and who have previously received platinum-based chemotherapy and immune checkpoint inhibition.
The first human phase 1 study (NCT01058707) explored the safety and efficacy of the drug at various dosing regimens in patients with advanced solid tumors. The maximum tolerated dose of the drug was found to be 6 mg per day, 50 mg per week; 9 mg per day, 3 days per week; and 7 mg per day, 5 days per week. The most common dose-limiting toxicities of the drug were hyperglycemia, maculopapular rash, fatigue, and stomatitis. In the extension phase of the study, researchers chose 5 mg daily and 30 mg weekly as dosing regimens for further examination. The data showed that one patient with renal cell carcinoma achieved a complete response to treatment. Partial responses were observed in 7 patients with renal cell carcinoma, 1 with carcinoid and 1 with endometrial carcinoma.
Data from an investigator-initiated phase 2 trial (NCT02417701) showed sapanisertib had an objective response rate of 27% in 11 patients with heavily previously treated NRF2-mutated squamous NSCLC. Among these patients, median progression-free survival was 8.9 months (95% CI, 7 months-not reached).
参考文献 Reference
https://www.globenewswire.com/news-release/2022/10/03/2526655/0/en/Calithera-Receives-FDA-Fast-Track-Designation-for-Sapanisertib-for-the-Treatment-of-NRF2-mutated-Squamous-Lung-Cancer.htmlhttps://clinicaltrials.gov/ct2/show/NCT05275673
https://clinicaltrials.gov/ct2/show/NCT05275673
Sacituzumab govitecan治疗雌激素受体阳性（ER+）/HER2 阴性 晚期乳腺癌患者 (12/3/2022)
Sacituzumab govitecan treating ER+/HER2- advanced breast cancer
Sacituzumab govitecan (SG)是一种抗Trop-2抗体-药物偶联物，已获FDA批准用于转移性三阴性乳腺癌。TROPiCS-02是一项 3期随机研究 (NCT03901339)，旨在确认SG对ER+/HER2-晚期乳腺癌的治疗效果。
方法：具有ER+/HER2-不可切除的局部晚期或转移的乳腺癌患者,既往接受过 2-4种转移的乳腺癌 化疗方案的成人符合条件；如果在（新）辅助治疗后疾病进展 ≤ 12个月，则允许进行 1次转移的乳腺癌既往治疗。患者必须在任何情况下接受过≥1种既往紫杉烷、CDK4/6抑制剂和内分泌治疗。患者以 1:1的比例随机接受 SG（第 1天和第 8天，每 21天静脉注射 10mg/kg）或医生选择的治疗（卡培他滨、艾日布林、长春瑞滨或吉西他滨），直至疾病进展/出现不可接受的毒性。主要终点是无进展生存期，关键次要终点是总生存期（第一次计划中期分析）。
结果：在 2022年 1月 3日数据截止时，分别有 272名和 271名患者随机接受 SG和医生选择的治疗。SG（与医生选择的治疗相比）改善了中位无进展生存期（5.5与 4.0个月；HR，0.66；95%CI，0.53-0.83；P= 0.0003）； 6个月和 12个月的无进展生存率分别为 46%对 30%和 21%对 7%。SG与医生选择的治疗相比在总生存期上显示出数值上但不显著的差异（13.9与 12.3个月；HR，0.84；P= 0.143）；总响应率为21%对 14%和临床获益率为34%对 22%，中位反应持续时间分别为 7.4个月和 5.6个月。
总体而言，发生 ≥3级治疗中出现的不良事件,SG与与医生选择的治疗相比分别为74%与 60%；中性粒细胞减少症（51%对 39%）和腹泻（10%对 1%）最为常见。SG组有 1例治疗相关死亡；医生选择的治疗臂中没有。
结论：与单药化疗相比，SG具有无进展生存期益处，并且在接受过大量治疗的ER+/HER2-的局部晚期或转移性乳腺癌患者患者中具有可控的安全性。
Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate that has been approved by FDA for metastatic triple-negative breast cancer.TROPiCS-02 is a phase 3 randomized study (NCT03901339) to evaluate the efficacy of SG in ER+/HER2- advanced breast cancer.
Methods: Adults with ER+/HER2- unresectable locally advanced or metastatic breast cancer who have received 2-4 prior chemotherapeutic regimens for metastatic breast cancer were eligible. If disease progressed after (neo)adjuvant therapy ≤ 12months, one prior treatment for metastatic breast cancer was allowed.Patients must have received ≥ 1 prior taxane, CDK4/6 inhibitor, and endocrine therapy in any event.Patients were randomized 1:1 to receive SG (10 mg/kg IV every 21 days on days 1 and 8) or physician’s choice of treatment (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity.The primary endpoint was progression-free survival, and the key secondary endpoint was overall survival (first planned interim analysis).
Results: At data cutoff on January 3, 2022, 272 and 271 patients were randomized to SG and physician’s choice of treatment, respectively.SG (compared to physician’s choice of treatment) improved median progression-free survival (5.5 vs. 4.0 months; HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003); 6- and 12-monthprogression-free survival was 46% vs 30% and 21% vs 7%, respectively.SG showed a numerical but non-significant difference in overall survival compared to physician’s choice of therapy (13.9 vs 12.3 months; HR, 0.84; P = 0.143); overall response rate 21% vs 14% and clinical benefit was 34% vs 22%, with a median duration of response of 7.4 months and 5.6 months, respectively. Overall, ≥ grade 3 treatment-relaed adverse events occurred in 74% in SG arm vs. 60% of physician’s choice of therapy: neutropenia (51% vs. 39%) and diarrhea (10%to 1%) were most common.There was 1 treatment-related death in the SG arm; none in the physician’s choice treatment arm.
Conclusions: Compared with single-agent chemotherapy, SG demonstrated progression-free survival benefit and a manageable safety profile in heavily treated ER+/HER2- patients with locally advanced or metastatic breast cancer.
参考文献 Reference Rugo HS et al. J Clin Onc 2022; 40:17_suppl.LBA1001辅助阿特珠单抗有益于 PD-L1 表达 ≥ 50% 的非小细胞肺癌生存 (11/27/2022)
Early data suggested survival benefit for adjuvant Atezolizumab in NSCLC with PD-L1 expression ≥ 50%
在III期临床试验（IMpower010）中，II-IIIA期非小细胞肺癌患者完成了手术切除后进行了辅助化疗,随后随机分配接受阿替珠单抗免疫治疗或不接受进一步治疗。 先前对无病生存期的分析显示，在接受铂类化疗后切除的非小细胞肺癌患者中，辅助阿特珠单抗与最佳支持治疗相比具有显著益处。
在 2022年世界肺癌大会期间提供的数据评估了总生存期和安全性，中位随访 46个月后，中期分析表明PD-L1阳性（肿瘤表达至少 1%）,II-IIIA期非小细胞肺癌（风险比 [HR] = 0.71）。 5年时，阿特珠单抗组 76.8%的患者存活，而对照组为 67.5%。 然而，对于意向治疗人群或所有随机化的II-IIIA期人群，未观察到曲线分离 (HR = 0.95)。PD-L1表达至少为 50%患者的风险比为0.43;PD-L1表达介于 1%和 49%之间的患者的风险比为 0.95，而PD-L1阴性肿瘤患者的风险比为 1.36。
接受辅助免疫治疗的患者的总体安全性与之前的分析一致，没有观察到新的安全信号。
In a phase III clinical trial (IMpower010), patients with stage II-IIIA NSCLC who underwent surgical resection followed by adjuvant chemotherapy were randomly assigned to receive atezolizumab immunotherapy or no further treatment. A previous analysis of disease-free survival showed a significant benefit of adjuvant atezolizumab compared with best supportive care in patients with resected NSCLC after platinum-based chemotherapy.
Data presented during the World Congress on Lung Cancer 2022 assessed overall survival and safety after a median follow-up of 46 months. Interim analysis showed PD-L1 positive, stage II-IIIA NSCLC (at least 1% tumor expression) had a hazard ratio [HR] = 0.71. At 5 years, 76.8% of patients in the atezolizumab group were alive compared with 67.5% in the control group. However, no separation of curves was observed for the intention-to-treat population or all randomized stage II-IIIA populations (HR = 0.95). Patients with at least 50% PD-L1 expression had a hazard ratio of 0.43; those with PD-L1 expression between 1% and 49% had a hazard ratio of 0.95, and those with PD-L1-negative tumors had a hazard ratio of 1.36.
The overall safety profile of patients receiving adjuvant immunotherapy was consistent with previous analyses, and no new safety signals were observed.
参考文献 Reference Wakelee H et al. World Conf on lung cancer 2022: abstr PL 03.09局部晚期错配修复缺陷（dMMR）型结肠癌的新辅助免疫检查点抑制治疗 (11/26/2022)
Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer
方法: 在一项临床试验（NICHE-2）中，非转移性dMMR结肠癌患者接受一剂易普利姆玛 (1mg/kg)和两剂纳武单抗 (3mg/kg)治疗，并在注册后 6周内接受手术。共同主要终点是安全性和 3年无进展生存。次要终点包括主要病理响应和完全响应率。病理响应定义为 ≤50%的残留活肿瘤，主要病理反应定义为 ≤10%的残留活肿瘤。
结果: 总共治疗了 112名患者。在 3名 (3%)患者中观察到 3-4级免疫相关不良事件，只有 3名患者经历了手术延迟，达到了安全性主要终点。在疗效评价人群 (n=107)中，基线放射学评估显示 89%III期, 77%高风险III期（T4 和/或 N2）和 64%T4肿瘤。从第一次给药到手术的中位时间为 5周，在 106/107 (99%)例患者中观察到病理响应，其中 102/107 (95%)例取得主要病理反应和 4例 (4%)取得部分响应。在 72/107 (67%)患者中观察到完全响应。中位随访 13个月（范围 1-57）时，所有患者均未出现疾病复发。
结论: 在NICHE-2试验证实了先前报道的局部晚期错配修复缺陷型结肠癌的大型患者队列对短期新辅助纳武单抗加易普利姆玛的病理响应，主要病理响应率率为 95%，包括 67%完全响应。
Methods: In a clinical trial (NICHE-2), patients with non-metastatic dMMR colon cancer received one dose of ipilimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg). Surgery was performed within 6 weeks of registration. Co-primary endpoints were safety and 3-year progression-free survival. Secondary endpoints included primary pathological response and complete response rate. Pathological response was defined as ≤ 50% residual viable tumor, and major pathological response was defined as ≤ 10% residual viable tumor.
Results: A total of 112 patients were treated. Grade 3-4 immune-related adverse events were observed in 3 (3%) patients, and only 3 patients experienced a delay in surgery, meeting the primary safety endpoint. In the population evaluated for efficacy (n=107), baseline radiographic assessment revealed 89% stage III, 77% high-risk stage III (T4 and/or N2) and 64% T4 tumors. The median time from first dose to surgery was 5 weeks, and pathological responses were observed in 106/107 (99%) patients, with 102/107 (95%) achieving major pathological responses and 4 (4 %) got a partial response. Complete responses were observed in 72/107 (67%) patients. At a median follow-up of 13 months (range, 1-57), none of the patients had experienced disease recurrence.
Conclusions: The previously reported pathologic response to short-term neoadjuvant nivolumab plus ipilimumab in a large cohort of patients with locally advanced mismatch repair-deficient colon cancer was confirmed in the NICHE-2 trial, with a primary pathologic response rate of 95%, including 67% complete responses.
参考文献 Reference Chalabi M et al. Ann Onc 2022; 33 (suppl 7); s808PRAME×CD3 MC-F106C 在黑色素瘤中显示出作为 T 细胞受体驱动疗法的潜力 (11/20/2022)
PRAME×CD3 MC-F106C showed potential as T-cell receptor-driven therapy in melanoma
首次人体临床 I 期试验 (ImmTAC, NCT04262466) 评估了 PRAME*×CD3 IMC-F106C 在 PRAME 阳性, 转移或不可切除肿瘤患者中的疗效和安全性，
安全: 35% 的患者 (n = 19/55) 经历了至少 1 次 3 级或更高级别的不良反应，77% 的患者在最初的 3 次给药期间经历了细胞因子释放综合征 (n = 55) 。
在 2022 年 ESMO 大会期间公布的研究结果表明，接受 IMC-F106C 治疗的 31 名恶性肿瘤患者中有 7 名产生了持续长达 9 个月的部分响应，而 90% 的患者 (n = 18) 经历了减少多种肿瘤类型的 循环肿瘤DNA （ctDNA）。 13 名患者 (65%) 的 ctDNA 减少了 50%。在从未接受过 tebentafusp治疗的葡萄膜黑色素瘤患者中观察到 3 例部分响应，在皮肤黑色素瘤患者中观察到 2 例部分响应。也有卵巢癌患者在接受 PD-1, PARP 抑制剂、VEGF 抑制剂和铂的治疗后获得了部分响应。
*PRAME （Preferentially expressed antigen in melanoma） 是一种睾丸选择性癌症睾丸抗原，在体细胞组织中表达受限，在各种癌症中重新表达，与转移的结果和风险相关。
A first-in-human phase I trial (ImmTAC, NCT04262466) evaluated the efficacy and safety of PRAME×CD3 IMC-F106C in patients with PRAME-positive, metastatic/unresectable tumors,
Safety: 35% of patients (n = 19/55) experienced at least 1 adverse reaction of grade 3 or higher, and 77% of patients experienced cytokine release syndrome (n = 55).
Results presented at 2022 ESMO Congress showed that 7 of 31 malignancies treated with IMC-F106C produced partial responses lasting up to 9 months, while 90% of patients (n = 18) experienced reduced circulating tumor DNA (ctDNA) in multiple tumor types. Thirteen patients (65%) had a 50% reduction in ctDNA. Three partial responses were observed in uveal melanoma patients who were naive to tebentafusp and two partial responses were observed in cutaneous melanoma patients. There were also ovarian cancer patients who had achieved partial responses after treatment with PD-1, PARP inhibitors, VEGF inhibitors, and platinum-based chemotherapy.
*PRAME (preferentially expressed antigen in melanoma is a testis-selective cancer testis antigen with restricted expression in somatic tissues and re-expression in various cancers. It has been associated with the outcome and risk of metastasis.
参考文献 Reference Hamid O et al. Ann Oncol. 2022;33(suppl 7):S875.FDA 批准 Mirvetuximab Soravtansine-gynx 用于治疗叶酸受体（FR）α 阳性耐铂类药的卵巢癌 (11/19/2022)
FDA approved Mirvetuximab Soravtansine-gynx for patients with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer
Mirvetuximab soravtansine 是一种 FRα 定向抗体和微管抑制剂偶联物。这是一项针对 106 名 FRα 阳性,耐铂类药上皮性卵巢癌、输卵管癌或原发性腹膜癌患者的单臂试验。允许患者接受最多三线的全身治疗；所有患者都必须接受过贝伐珠单抗治疗。如果患者患有角膜疾病、需要持续治疗的眼部疾病, > 1 级周围神经病变或非感染性间质性肺病的患者被排除在外。 患者每 3 周接受 6 mg/kg（根据调整后的理想体重）静脉输注 mirvetuximab soravtansine，直至疾病进展或出现不可接受的毒性。前 36 周每 6 周进行一次肿瘤反应评估，此后每 12 周进行一次。 主要疗效结果指标是研究者评估的总体响应率和响应持续时间。
在可评估人群中（n = 104），确认的总体响应率为 31.7%（95% 置信区间 [CI] = 22.9%– 41.6%），中位响应持续时间为 6.9 个月（95% CI = 5.6–9.7 个月）。 最常见（≥ 20%）的不良反应，包括视力障碍, 疲劳, 天冬氨酸转氨酶升高, 恶心, 谷丙转氨酶升高, 角膜病变, 腹痛, 淋巴细胞减少, 周围神经病变, 腹泻, 白蛋白减少, 便秘, 碱性磷酸酶升高, 干眼症, 镁减少, 白细胞减少, 中性粒细胞减少和血红蛋白减少。产品标签包括针对眼部毒性的黑框警告。
推荐的 mirvetuximab soravtansine 剂量为 6 mg/kg （调整后的理想体重），每 3 周（21 天周期）静脉输注一次，直至疾病进展或出现不可接受的毒性。
Mirvetuximab soravtansine is a folate receptor (FR) α-directed antibody and microtubule inhibitor conjugate. This was a single-arm trial in 106 patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. Patients were allowed to receive up to three lines of systemic therapy; all patients needed to have received prior bevacizumab. Patients were excluded if they had corneal disease, ocular disease requiring ongoing treatment, > grade 1 peripheral neuropathy, or noninfectious interstitial lung disease. Patients received mirvetuximab soravtansine by intravenous infusion at 6 mg/kg (based on adjusted ideal body weight) every 3 weeks until disease progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks for the first 36 weeks and every 12 weeks thereafter. The primary efficacy outcome measures were investigator-assessed overall response rate and duration of response.
In the evaluable population (n = 104), the confirmed overall response rate was 31.7% (95% confidence interval [CI] = 22.9%–41.6%), with a median duration of response of 6.9 months (95% CI = 5.6 –9.7 months). Most common (≥ 20%) adverse reactions included visual disturbance, fatigue, elevated aspartate aminotransferase, nausea, elevated alanine aminotransferase, keratopathy, abdominal pain, lymphopenia, peripheral neuropathy, diarrhea, decreased albumin level, constipation, elevated alkaline phosphatase, dry eye, decreased magnesium, leukopenia, neutropenia and anemia. Product labeling includes a boxed warning for ocular toxicity.
The recommended dose of mirvetuximab soravtansine is 6 mg/kg (adjusted ideal body weight) intravenously every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-mirvetuximab-soravtansine-gynx-fra-positive-platinum-resistant摄入超加工的食品与结直肠癌风险的关联 (11/13/2022)
Consumption of ultra-processed food linked to risk for colorectal cancer
从三个大型前瞻性队列研究超加工食品消费与结直肠癌风险之间的关系。 使用食物频率问卷每四年评估一次膳食摄入量。
参与者来自”卫生专业人员随访研究” (1986-2014) 的男性 (n = 46,341) 和女性 (n=159,907), 她们来自”护士健康研究” (1986-2014; n = 67,425) 和”护士健康研究 II”的 (1991-2015; n = 92,482) , 提供有效的膳食摄入量测量，并且在基线时没有被诊断癌症。 主要结果为测量 超加工食品消费与结直肠癌风险之间的关联，使用针对潜在混杂因素调整的时变 Cox 比例风险回归模型进行估计。
结果: 在 24-28 年的随访中记录了 3216 例结直肠癌（男性，n = 1294；女性，n = 1922）。与超加工食品消费量最低的五分之一相比，消费量最高的五分之一的男性患结直肠癌的风险高出 29%（最高与最低五分之一的风险比为 1.29，95% 置信区间为 1.08 至 1.53；P趋势 = 0.01），正相关仅限于远端结肠癌（风险增加 72%；风险比 1.72、1.24 至 2.37；趋势 P < 0.001）。在进一步调整体重指数或饮食营养质量指标（即西方饮食模式或饮食质量评分）后，这些关联仍然显著。未观察到整体超加工食品消费与女性患结直肠癌的风险之间存在关联。
在超加工食品亚组中，与男性结直肠癌风险增加相关为消费较高的肉类/家禽/海鲜类即食产品(ready-to-eat food) （最高与最低五分之一的风险比为 1.44，1.20 至 1.73；趋势 P < 0.001）和含糖饮料（1.21， 1.01 至 1.44；趋势 P = 0.013）以及女性消费较高的即食/加热混合菜肴（1.17, 1.01 至 1.36；趋势 P = 0.02）；酸奶和乳制品甜点与女性患结直肠癌的风险呈负相关（风险比为 0.83、0.71 至 0.97；趋势 P = 0.002）。
结论: 在三个大型前瞻性队列中，男性高摄入超加工食品, 男性和女性高摄入某些亚组的超加工食品与结直肠癌风险增加有关。需要进一步研究了解导致结直肠癌发生的超加工食品的潜在属性。
Study of the association between ultra-processed food consumption and colorectal cancer risk from three large prospective cohorts. Dietary intake was assessed every four years using food frequency questionnaires.
Participants were men (n = 46,341) from the “Health Professionals Follow-up Study” (1986-2014) and women (n=159,907) from the Nurse Health Study (1986-2014; n = 67,425) and the Nurse Health Study II (1991-2015; n = 92,482), with valid dietary intake measuremen, and no cancer diagnoses at baseline. The primary outcome was to measure the association between ultra-processed food consumption and colorectal cancer risk, estimated using time-varying Cox proportional hazards regression models adjusted for potential confounding factors.
Results: 3216 cases of colorectal cancer were recorded during 24-28 years of follow-up (men, n = 1294; women, n = 1922). Men in the highest quintile of ultra-processed food consumption had a 29% higher risk of developing colorectal cancer compared with those in the lowest quintile of ultra-processed food consumption (hazard ratio for highest to lowest quintile, 1.29, 95 % confidence interval 1.08 to 1.53; P for trend = 0.01), the positive association was limited to distal colon cancer (72% increased risk; hazard ratios 1.72, 1.24 to 2.37; P for trend < 0.001). These associations remained significant after further adjustment for body mass index or indicators of nutritional quality of the diet (ie, Western dietary patterns or diet quality scores). No association was observed between overall ultra-processed food consumption and the risk of colorectal cancer in women.
In the ultra-processed food subgroup, higher consumption of meat/poultry/seafood ready-to-eat food products (highest-to-lowest one-fifth hazard ratio 1.44, 1.20 to 1.73; trend P < 0.001) and sugar-sweetened beverages (1.21, 1.01 to 1.44; trend P = 0.013) was associated with an increased risk of colorectal cancer in men and ready-to-eat/heat mixed dishes among women (1.17, 1.01 to 1.36; trend P = 0.02) ; Yogurt and dairy desserts were inversely associated with the risk of colorectal cancer in women (hazard ratios 0.83, 0.71 to 0.97; P for trend = 0.002).
Conclusions: In three large prospective cohorts, high consumption of total ultra-processed foods in men and certain subgroups of ultra-processed foods in men and women was associated with an increased risk of colorectal cancer. Further research is needed to understand the potential properties of ultra-processed foods that contribute to the development of colorectal cancer.
参考文献 Reference Wang L et al. Br Med J 2022; 378:e068921一种 B 细胞成熟抗原 × CD3 双特异性 T 细胞抗体首次用于复发/难治性多发性骨髓瘤人体I 期研究 (11/12/2022)
A phase I first-in-human Study of a B-cell maturation antigen × CD3 bispecific T-cell Antibody, in relapsed/refractory multiple myeloma
ABBV-383 是一种 B 细胞成熟抗原 × CD3 T 细胞结合双特异性抗体，在复发/难治性多发性骨髓瘤患者的一项正在进行的首次人体 I 期研究（NCT03933735）中显示出有希望的结果。
方法: 对患有复发/难治性多发性骨髓瘤 的患者（≥三线先前治疗，包括蛋白酶体抑制剂, 免疫调节药物和抗 CD38 单克隆抗体）, ABBV-383 每 3 周在 1-2 小时内静脉内给药一次，无需任何分步给药。使用 3 + 3 设计，回填用于剂量递增（患者内递增至允许的最高安全剂量），然后开始剂量扩展。
结果: 截至 2022 年 1 月 8 日，124 名患者（剂量递增 [0.025-120 毫克]，n = 73；剂量扩大 [60 毫克]，n = 51）接受了 ABBV-383；中位年龄为 68 岁（范围 35-92 岁）。
最常见的血液治疗相关不良事件是中性粒细胞减少症（所有级别：37%）和贫血（29%）。最常见的非血液学治疗相关不良事件是细胞因子释放综合征 (57%) 和疲劳 (30%)。研究人员报告了 7 例治疗相关不良事件死亡，所有这些都被认为与研究药物无关。
对于所有可评估疗效的患者（n = 122；所有剂量），客观缓解率为 57%，非常好的部分缓解（VGPR）或更好（≥ VGPR）率为 43%。在 60 毫克剂量扩展队列（n = 49）中，客观缓解率和≥ VGPR 率分别为 59% 和 39%；在≥ 40 毫克剂量递增加剂量扩展组（n = 79）中，分别为 68% 和 54%。
结论: 在复发/难治性多发性骨髓瘤患者中的 ABBV-383 耐受性良好，剂量 ≥ 40 毫克时的客观缓解率为 68%。这种新疗法在经过大量预处理的患者中具有良好的初步抗肿瘤活性，值得进一步临床评估。
ABBV-383, a B cell maturation antigen × CD3 T cell binding bispecific antibody, showed promising results in an ongoing first-in-human phase I study (NCT03933735) in patients with relapsed/refractory multiple myeloma.
Methods: In patients with relapsed/refractory multiple myeloma (≥3 lines of prior therapy including proteasome inhibitors, immunomodulatory drugs and anti-CD38 monoclonal antibodies), ABBV-383 was administered every 3 weeks as 1-2 hours intravenous infusion, without any step dosing. Using a 3 + 3 design, with backfilling for dose escalation was used (intra-patient escalation to the highest safe dose allowed) and followed by dose expansion.
Results: As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose escalation [60 mg], n = 51) received ABBV-383; median age was 68 years (Range 35-92 years). The most common hematologic treatment-related adverse events were neutropenia (all grades: 37%) and anemia (29%). The most common non-hematologic treatment-related adverse events were cytokine release syndrome (57%) and fatigue (30%). The investigators reported seven treatment-related adverse event deaths, all of which were not considered to be related to the study drug.
For all patients evaluable for response (n = 122; all doses), the objective response rate was 57%, and the very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), objective response and ≥ VGPR rates were 59% and 39%, respectively; in the ≥ 40 mg escalating dose expansion cohort (n = 79), 68% and 54%.
Conclusions: ABBV-383 was well tolerated in patients with relapsed/refractory multiple myeloma, with an objective response rate of 68% at doses ≥ 40 mg. This new therapy has good preliminary antitumor activity in heavily pretreated patients and warrants further clinical evaluation.
参考文献 Reference D’ Souza A et al. J Clin Onc 2022; 40: 3576结肠镜筛查对结直肠癌和相关死亡风险的影响 (11/6/2022)
Effect of colonoscopy screening in relation to colorectal cancer incidence and related death
NordICC 试验作为第一个发表的结肠镜检查效果的随机临床试验。
方法: 在 2009 年至 2014 年期间从波兰、挪威、瑞典和荷兰的人口登记处进行了一项实用的随机试验，涉及 55 至 64 岁的假定健康男性和女性。参与者以 1:2 的比例随机分配接受接受单一筛查结肠镜检查的邀请（受邀组）或不接受邀请或筛查（常规护理组）。主要终点是结直肠癌和相关死亡的风险，次要终点是全因死亡。
结果: 波兰、挪威和瑞典的 84,585 名参与者获得了随访数据——邀请组中有 28,220 人，其中 11,843 人（42.0%）接受了筛查，常规护理组有 56,365 人。共有 15 名参与者在切除息肉后出现大出血。结肠镜检查后 30 天内未发生穿孔或筛查相关的死亡。在 10 年的中位随访期间，邀请组诊断出 259 例结直肠癌，而常规治疗组诊断出 622 例。在意向筛查分析中，受邀组和常规治疗组 10 年结直肠癌的风险分别为 0.98% 和 1.20%，风险降低了 18%（风险比，0.82；95% 置信区间 [ CI]，0.70 至 0.93)。受邀组的结直肠癌死亡风险为 0.28%，常规治疗组为 0.31%（风险比，0.90；95% CI，0.64 至 1.16）。以预防 1 例结直肠癌病例而需要邀请接受筛查的人数为 455（95% CI，270 至 1429）。受邀组的全因死亡风险为 11.03%，常规治疗组为 11.04%（风险比，0.99；95% CI，0.96 至 1.04）。
结论: 在这项随机试验中，被邀请接受结肠镜检查的参与者在 10 年时患结肠直肠癌的风险低于未接受筛查的参与者。
The NordICC trial was the first published randomized clinical trial testing the efficacy of colonoscopy.
Methods: A pragmatic randomized trial involving presumably healthy men and women aged 55 to 64 years was conducted from population registries in Poland, Norway, Sweden and the Netherlands between 2009 and 2014. Participants were randomly assigned in a 1:2 ratio to receive an invitation to a single screening colonoscopy (invited group) or no invitation or screening (usual care group). The primary endpoint was the risk of colorectal cancer and related death, and the secondary endpoint was death from any cause.
Results: Follow-up data were available for 84,585 participants in Poland, Norway, and Sweden, with 28,220 in the invitation group, of whom 11,843 (42.0%) were screened and 56,365 in the usual care group. A total of 15 participants experienced major bleeding after polyp removal. There were no perforation or screening-related deaths within 30 days of colonoscopy. During a median follow-up of 10 years, 259 colorectal cancers were diagnosed in the invitation group compared with 622 in the usual care group. In the intent-to-screen analysis, the 10-year risk of colorectal cancer was 0.98% in the invited group and 1.20% in the usual care group, representing an 18% risk reduction (hazard ratio, 0.82; 95% confidence interval [CI], 0.70 to 0.93). The risk of death from colorectal cancer was 0.28% in the invited group and 0.31% in the usual care group (hazard ratio, 0.90; 95% CI, 0.64 to 1.16). The number of people required to be invited to screening to prevent 1 case of colorectal cancer was 455 (95% CI, 270 to 1429). The risk of death from any cause was 11.03% in the invited group and 11.04% in the usual care group (hazard ratio, 0.99; 95% CI, 0.96 to 1.04).
Conclusions: In this randomized trial, participants who were invited to undergo colonoscopy had a lower risk of colorectal cancer at 10 years than those who were not screened.
参考文献 Reference Bretthauer M et al. N Engl J Med 2022; 387: 1547奥希替尼辅助治疗EGFR 突变 IB至 IIIA 期非小细胞肺癌的长期随访 (11/5/2022)
Long-term follow-up in adjuvant Osimertinib therapy in EGFR-mutated stage IB-IIIA NSCLC
临床III 期ADAURA 试验招募了 682 名确诊为原发性非鳞状 NSCLC 和 EGFR 外显子 19 缺失或 L858R 突变的患者，这些患者在完全切除后手术切缘阴性。关键分层因素是疾病分期（IB vs II vs IIIA）, EGFR 突变状态（外显子 19 缺失 vs L858R ）和种族（亚洲与非亚洲）。患者的中位年龄约为 63 岁，约 70% 为女性。两组中的大多数患者从不吸烟（分别为 68% 和 75%）、亚洲人（两组分别为 64%）。几乎所有患者都患有腺癌（> 95%），约 60% 接受了辅助化疗。患者以 1:1 的比例随机分配接受 80 毫克/天的奥希替尼或每天一次的安慰剂。计划治疗时间为 3 年，治疗持续至疾病复发或出现不可接受的毒性。 主要终点是研究者评估的 II/IIIA 期疾病患者的无病生存期。次要终点包括总体人群的无病生存期； 2、3、4 和 5 年无病生存；总生存期；安全;和健康相关的生活质量。数据截止日期为 2020 年 1 月 17 日。
分析显示，在 II/IIIA 期疾病患者人群中，奥希替尼和安慰剂组的 24 个月无病生存率分别为 90% 和 46%；在 36 个月时，这些比率分别为 84% 和 34%；在 48 个月时，分别为 70% 和 39%。在整个研究人群中，奥希替尼组和安慰剂组的 24、36 和 48 个月无病率分别为 90% 和 55%；85% 和 44%； 73% 和 38%。
共有 63 名患者经历了中枢神经系统无病生存事件；奥希替尼组 22 例，安慰剂组 41 例。任一组均未达到中位 CNS 无病生存期。奥希替尼组和安慰剂组的 24 个月中枢神经系统无病生存率分别为 98% 和 81%；在 36 个月时，这些比率分别为 97% 和 77%；在 48 个月时，这些比率分别为 90% 和 75%。 奥希替尼组 36 个月时中枢神经系统复发的估计概率为 2%，而安慰剂组为 13%。
不良事件: 随着 ADAURA 的长期随访，没有出现新的安全问题。 3 级或更高级别的不良事件分别发生在 23% 奥希替尼组和 14% 的安慰剂组患者中。导致治疗中断的不良事件发生在研究组的 13% 和对照组的 3%。分别有 12% 和 1% 的患者因不良事件而减少剂量，分别有 27% 和 13% 的患者因不良事件导致剂量中断。据报道，奥希替尼组的一名患者和安慰剂组的两名患者因不良事件而死亡。
The phase III ADAURA trial enrolled 682 patients with confirmed primary non-squamous NSCLC and EGFR exon 19 deletion or L858R mutation and they had negative surgical margins after complete resection. Key stratification factors were disease stage (IB vs II vs IIIA), EGFR mutation status (exon 19 deletion vs L858R), and ethnicity (Asian vs non-Asian). The median age of the patients was about 63 years, and approximately 70% were female. The majority of patients in both groups were never smokers (68% and 75%, respectively), and Asian (64% in both groups). Almost all patients had adenocarcinoma (>95%), and about 60% received adjuvant chemotherapy. Patients were randomized 1:1 to receive 80 mg/day of osimertinib or once-daily placebo. The planned duration of treatment was 3 years. Treatment continued until disease recurrence or unacceptable toxicity. The primary endpoint was disease-free survival in patients with investigator-assessed stage II/IIIA disease. Secondary endpoints included disease-free survival in the overall population; disease-free survival at 2, 3, 4, and 5 years; overall survival; safety; and health-related quality of life. Data cutoff date was January 17, 2020.
The analysis showed that in the stage II/IIIA disease patient population, the 24-month disease-free survival rates were 90% and 46% in the osimertinib and placebo groups, respectively; at 36 months, these rates were 84% and 34%, respectively; at 48 months, 70% and 39%, respectively. In the overall study population, disease-free rates at 24, 36, and 48 months were 90% and 55%; 85% and 44%; and 73% and 38% respectively.
A total of 63 patients experienced CNS disease-free survival events; 22 in the osimertinib group and 41 in the placebo group. Median CNS disease-free survival was not reached in either group. The 24-month CNS disease-free survival rates were 98% and 81% in the osimertinib and placebo groups, respectively; at 36 months, these rates were 97% and 77%, respectively; at 48 months, these ratios were 90% and 75%, respectively. The estimated probability of CNS relapse at 36 months was 2% in the osimertinib group and 13% in the placebo group.
Adverse events: With the long-term follow-up of ADAURA, no new safety concerns emerged. Adverse events of grade 3 or higher occurred in 23% of patients in the osimertinib group and 14% of patients in the placebo group. Adverse events leading to treatment discontinuation occurred in 13% of the study group and 3% of the control group. Adverse events led to dose reductions in 12% and 1% of patients, respectively, and dose interruptions due to adverse events in 27% and 13% of patients, respectively. One patient in the osimertinib group and two in the placebo group died due to adverse events.
参考文献 Reference Tsuboi M et al. 2022 ESMO Congress. Abstract LBA47肠肝分流驱动的胆汁血症易患肝癌 (10/30/2022)
Entero-hepatic shunt-driven cholemia predisposes to liver cancer
给小鼠喂食可发酵的富含纤维*的饮食容易患上肝细胞癌。
方法: 当C57BL/6 小鼠喂食可发酵的富含纤维的饮食, 容易患上肝细胞癌。这些标志物用于分型和寻找 肝细胞癌的发展阶段。并使用从肝细胞癌病例对照队列中前瞻性收集的血清测试了它们与人类的相关性。
结果: 小鼠的肝细胞癌易感性取决于先天性门体分流 (portosystemic shunt , PSS) 的存在，这导致血清胆汁酸显著升高。来自不同来源的大约 10% 的小鼠表现出 PSS/胆血症，但在喂食标准食物时缺乏明显的表型。然而，饲喂成分明确的饮食的 PSS/胆血小鼠出现胆汁酸和环氧合酶依赖性肝损伤，当饮食中富含可发酵的菊粉纤维时，这种损伤会加剧并均匀地发展为肝细胞癌。这种进展为胆汁淤积的肝细胞癌与恶化的胆汁血症和免疫抑制环境相关，这两者都是通过阻碍胆汁酸生物合成或中和白细胞介素 10 或程序性死亡蛋白 1 来预防肝细胞癌所必需的。对人类血清的分析显示，升高的胆汁酸与肝癌的未来发展相关。
结论: PSS 在 C57BL/6 小鼠中相对常见，会导致无症状胆汁血症，这会导致肝损伤和肝细胞癌，尤其是在喂食可发酵的富含纤维的饮食时。人类无症状 PSS/胆血症的发病率有待调查。无论如何，测量血清胆汁酸可能有助于肝细胞癌风险评估，可能会提醒选定的个体考虑饮食或胆汁酸干预措施。
*可发酵纤维是指肠道细菌可以发酵和分解的纤维类型。有时会在加工食品中添加高度精制的可发酵纤维。含有高度精制的可发酵纤维的加工食品的例子包括方便食品，如零食和强化纤维的谷物。
Mice fed with a fermentable fiber-enriched diet are at risk of developing hepatocellular carcinoma.
Methods: C57BL/6 mice were prone to developing hepatocellular carcinoma (HCC) when fed a fermentable fiber-enriched diet. These markers were used to phenotype and interrogate the stage of development of HCC. The human relevance was tested using serum collected prospectively from a case-control cohort of HCC.
Results: HCC susceptibility in mice was dependent on the presence of a congenital portosystemic shunt (PSS), which resulted in significantly elevated serum bile acids. Approximately 10% of mice from various sources exhibited PSS/choleremia but lacked a distinct phenotype when fed standard chow. However, PSS/ cholemic mice fed a compositionally defined diets developed bile acid and cyclooxygenase-dependent liver damage, which was exacerbated and progressed uniformly to HCC when the diet was enriched with fermentable fiber inulin. This progression to HCC to cholestasis associated with worsening cholemia and an immunosuppressive milieu, both of which were required in HCC, was prevented by impeding bile acid biosynthesis or neutralizing interleukin 10 or programmed death protein 1. Analysis of human sera showed that elevated bile acids were associated with future development of HCC.
Conclusions: PSS is relatively common in C57BL/6 mice and causes asymptomatic bileemia, which can lead to liver damage and hepatocellular carcinoma, especially when fed a fermentable fiber-enriched diet. The incidence of asymptomatic PSS/choleremia in humans remains to be investigated. Regardless, measurement of serum bile acids may aid in HCC risk assessment and may prompt selected individuals to consider dietary or bile acid interventions.
*Fermentable fiber refers to the type of fiber that gut bacteria can ferment and break down. Highly refined fermentable fibers are sometimes added to processed foods. Examples of processed foods that contain highly refined fermentable fiber include convenience foods such as snacks and fiber-fortified cereals.
参考文献 Reference Yeoh BS et al. Gastroenterology 2022; DOI:https://doi.org/10.1053/j.gastro.2022.08.033在复发性非肌肉浸润性膀胱癌中使用短期, 强化丝裂霉素 (10/29/2022)
Shor-term, intensive chemoresection with mitomycin in recurrent nonmuscle invasive bladder cancer
方法: 从2018 年 1 月至 2021 年 8 月在丹麦的两个泌尿科进行了一项随机对照试验（DaBlaCa-13）。共有 120 名有 Ta 低或高级别非肌肉浸润性膀胱癌病史的患者在复发时被纳入研究。试验组每周接受 3 次膀胱内丝裂霉素 (40 mg/40 mL)，持续 2 周，仅在反应不完全时接受经尿道膀胱肿瘤切除术或办公室活检。对照组接受经尿道膀胱肿瘤切除术或办公室活检和每周一次共6周丝裂霉素滴注。主要结果是纳入后 2 年内接受手术患者的数量，使用卡方检验在组间进行比较。使用 Kaplan-Meier 方法分析无复发生存率。
结果: 试验组需要手术的患者明显少于对照组：71%（95% CI，57 至 81）和 100%（95% CI，94 至 100），P < .001。试验组和对照组的 12 个月无复发生存率分别为 36%（95% CI，24 至 50）和 43%（95% CI，30 至 56）（P = .5）。
结论: 短期强化化疗后切除是复发性非肌肉浸润性膀胱癌的有效治疗策略，可减少所需手术的数量，而不影响长期肿瘤学安全性。
Methods: A randomized controlled trial (DaBlaCa-13) was conducted in two urology departments in Denmark from January 2018 to August 2021. A total of 120 patients with a history of Ta low or high-grade nonmuscle-invasive bladder cancer were included at the time of recurrence. The experimental arm received intravesical mitomycin (40 mg/40 mL) 3 times a week for 2 weeks, and underwent transurethral resection of bladder tumor, （TURBT） or in-office biopsy only if the response was incomplete. The control arm received TURBTor in-office biopsy and mitomycin instillation once a week for 6 weeks. The primary outcome was the number of patients undergoing surgery within 2 years of inclusion, which was compared between groups using the chi-square test. Relapse-free survival was analyzed using the Kaplan-Meier method.
Results: Significantly fewer patients in the experimental group required surgery than in the control group: 71% (95% CI, 57 to 81) and 100% (95% CI, 94 to 100), P < .001. The 12-month recurrence-free survival rates were 36% (95% CI, 24 to 50) and 43% (95% CI, 30 to 56) in the experimental and control groups, respectively (P = .5).
Conclusions: Short-term intensive chemoresection is an effective treatment strategy for recurrent nonmuscle-invasive bladder cancer, reducing the number of required procedures without compromising long-term oncological safety.
参考文献 Reference
Lindgren MS et al. J Clin Onc Published online October 12, 2022 DOI: 10.1200/JCO.22.00470头发矫直剂和其他美发产品的使用与子宫癌的发生 (10/23/2022)
Hair straighteners and other hair products in relation to incidental uterine cancer
方法: 在 33, 947 名年龄在 35-74 岁的姐妹研究参与者中检查了美发产品使用与子宫癌发生之间的关联，这些参与者在入组时（2003-2009 年）都有子宫。在基线调查问卷中，这个大型, 种族和民族多样化的前瞻性队列的参与者自我报告了她们在过去 12 个月内使用的护发产品，包括染发剂；矫直机、松弛剂或压制产品；和永久性头发或头发波浪剂。研究者使用 Cox 比例风险模型估计了调整后的风险比 (HR) 和 95% 置信区间 (CI)，以确诊定美发产品使用与子宫癌之间的数量关联。所有统计测试都是双面的。
结果: 在平均 10.9 年的随访中，发现了 378 例子宫癌病例。在过去的 12 个月中，曾经与从不使用矫直产 品与较高的子宫癌发病率相关（HR = 1.80，95% CI = 1.12 至 2.88）。在比较频繁使用（过去 12 个月中 > 4 次）与从不使用（HR = 2.55, 95% CI = 1.46 至 4.45；Ptrend = .002）时，相关性更强。使用其他头发产品，包括染料和永久性头发或头发波浪，与发生子宫癌无关。
结论: 这些发现是使用头发矫直剂与子宫癌之间关联的第一个流行病学证据。但有必要进行更多的研究，以在其他环境中复制这个发现。
Methods: The association between use of hair products and uterine cancer development was examined in 33,947 Sister Study participants aged 35-74 who had a uterus at enrollment (2003-2009). In a baseline questionnaire, participants in this large, racially and ethnically diverse prospective cohort self-reported their use of hair care products in the past 12 months, including hair dye; straighteners, relaxers, or compression products ; and permanents or body waves. The researchers estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models to determine the quantitative association between hair product use and uterine cancer. All statistical tests were two-sided.
Results: Over an average follow-up of 10.9 years, 378 cases of uterine cancer were identified. In the previous 12 months, ever vs never use of straightening products was associated with a higher incidence of uterine cancer (HR = = 1.80, 95% CI = 1.12 to 2.88). The association was stronger when comparing frequent use (>4 times in the previous 12 months) with never use (HR = 2.55, 95% CI = 1.46 to 4.45; Ptrend = .002). The use of other hair products, including dyes and permanents or body waves, was not associated with developing uterine cancer.
Conclusions: These findings are the first epidemiologic evidence of an association between hair straightener products and uterine cancer. More research is warranted to replicate this finding in other settings.
参考文献 Reference Chang CJ et al. J Natl Cancer Inst 2022; published Oct 17来曲唑和 Abemaciclib 用于雌激素受体阳性的复发性子宫内膜癌 (10/22/2022)
Letrozole and abemaciclib in ER-positive recurrent endometrial cancer
方法 研究者在复发性 ER 阳性子宫内膜癌中进行了来曲唑/abemaciclib 的 II 期两阶段研究。对参加者先前治疗没有限制（允许之前的激素治疗）。主要终点是 RECIST 1.1 的客观响应率和 6 个月时的无进展生存率。
结果 在数据截止日期（2021 年 12 月 3 日），30 名患者（28 名患有子宫内膜样子宫内膜癌）开始了方案治疗； 15 名 (50%) 患者之前接受过激素治疗。共有 9 例响应（8 例已确认），客观响应率为 30%（95% CI，14.7 至 49.4），均为子宫内膜样腺癌。中位无进展生存期 为 9.1 个月，6 个月时无进展生存期为 55.6%（95% CI，35.1 至 72），中位响应持续时间为 7.4 个月。无论肿瘤等级、先前的激素治疗、错配修复和孕酮受体状态如何，都可以观察到响应。探索性肿瘤分析揭示了几种机制相关的候选反应预测因子（CTNNB1、KRAS 和 CDKN2A 突变）或无响应（TP53 突变），但这需要独立验证。
最常见的≥3级治疗相关不良事件是中性粒细胞减少症（20%）和贫血（17%）。
结论 来曲唑/abemaciclib 在复发性 ER 阳性子宫内膜样子宫内膜癌中表现出持久的活性。
Methods: Researchers conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive endometrial cancer. There was no restriction on the participant’s prior therapy (previous hormone therapy was allowed). The primary endpoints were RECIST 1.1 objective response rate and progression-free survival at 6 months.
Results: At the data cutoff date (December 3, 2021), 30 patients (28 with endometrioid endometrial carcinoma) initiated protocol therapy; 15 (50%) patients had received prior hormone therapy. A total of 9 responses (8 confirmed), with an objective response rate of 30% (95% CI, 14.7 to 49.4), were all endometrioid adenocarcinomas. The median progression-free survival was 9.1 months, progression-free survival at 6 months was 55.6% (95% CI, 35.1 to 72), and the median duration of response was 7.4 months. Responses were observed regardless of tumor grade, previous hormone therapy, mismatch repair, and progesterone receptor status. Exploratory tumor analysis revealed several mechanistically relevant candidate predictors of response (CTNNB1, KRAS, and CDKN2A mutations) or no response (TP53 mutations), but this requires independent validation.
The most common grade ≥3 treatment-related adverse events were neutropenia (20%) and anemia (17%).
Conclusions: Letrozole/abemaciclib showed durable activity in recurrent ER-positive endometrioid endometrial carcinoma.
参考文献 Reference Konstantinopoulos PA et al. J Clin Onc 2022; Sept 29 DOI: 10.1200/JCO.22.00628实际生活中Brigatinib 用于既往ALK-TKI 治疗过的非小细胞肺癌患者的数据 (10/16/2022)
Brigatinib use in real life in NSCLC patients who received prior ALK-TKI
方法：数据来自 IQVIA 药房索赔数据库中 2017 年 4 月 1 日至 2020 年 9 月 30 日期间（索引日期）≥1 次Brigatinib索赔的成人进行随访，直至剂量减少、停药或随访结束。患者进行了 ≥12 个月的指数前观察和 ≥1 个月的指数后观察。
结果：共分析了 413 名接受Brigatinib治疗的患者。超过 80% 接受过 ≥1 个既往 ALK-TKI；艾乐替尼（alectinib） 和克唑替尼（crizotinib）是最常见的（分别为 58.8% 和 51.3% 的患者）。中位随访时间为 8.4 个月。Brigatinib的中位治疗终止时间为 10.3 个月 (95% CI, 8.2-15.0), 45% 的患者在 12 个月时仍在治疗中。同时接受克唑替尼和艾乐替尼的患者的中位治疗终止时间最短（约 8 个月），而在Brigatinib之前仅接受艾乐替尼的患者的中位治疗终止时间最长（11.8 个月）。依从性（坚持服药）很高，92.7% 的患者的药物持有率 > 80%。中位剂量依从性（dose compliance score）评分为 1.0。大多数患者的Brigatinib剂量达到 180 mg/天（77%）； 13.2% 的患者减少了剂量，分别有 89.3% 和 84.6% 的患者在第 3 个月和第 6 个月继续接受 180 mg/天的治疗。
作者认为, Brigatinib似乎在美国真实世界的 ALK+ NSCLC 人群中有效且耐受性良好，在下一代 ALK-TKI 的患者中显示出益处。值得注意的是，实际生活中剂量减少率明显低于临床试验中所观察到的, 后者多数因此为无症状的异常实验室结果。
Methods: Adults with ≥1 brigatinib claim (index date) between April 1, 2017, and September 30, 2020 in the longitudinal IQVIA pharmacy claims database were followed until dose reduction, discontinuation, or end of follow-up. Patients had ≥12 months of pre-index observation and ≥1 month of post-index observation.
Results: A total of 413 patients treated with Brigatinib were analyzed. More than 80% had received ≥1 prior ALK-TKI; alectinib and crizotinib were the most common (58.8% and 51.3% of patients, respectively). The median follow-up time was 8.4 months. The median time to treatment discontinuation for brigatinib was 10.3 months (95% CI, 8.2-15.0), with 45% of patients still on treatment at 12 months. Patients who received both crizotinib and alectinib had the shortest median time to treatment discontinuation (about 8 months), while those who received alectinib only before Brigatinib had the longest median time to treatment discontinuation (11.8 months). Adherence was high, with 92.7% of patients having >80% medication possession. The median dose compliance score was 1.0. Most patients received brigatinib doses of 180 mg/day (77%); 13.2% of patients had dose reductions, with 89.3% and 84.6% continuing to receive 180 mg/day at months 3 and 6, respectively.
According to the authors, brigatinib appears to be efficative and well tolerated in the real-world ALK+ NSCLC population in the United States, showing benefit in patients after a next-generation ALK-TKIs. Notably, dose reduction rates appeared markedly less than those seen in trials when most trial-related dose reductions were for asymptomatic laboratory abnormalities.
参考文献 Reference Jahanzeb M et al Oncologist 2022; 27: 790GPRC5D 靶向 CAR T 细胞用于骨髓瘤 (10/15/2022)
GPRC5D targeted CAR T cell in heavily-treated multiple myeloma
B 细胞成熟抗原 (BCMA) 导向的嵌合抗原受体 (CAR) T 细胞疗法已在晚期骨髓瘤患者中产生响应，但复发很常见。 G 蛋白偶联受体，C 类，第 5 组，成员 D (GPRC5D) 已被确定为多发性骨髓瘤的免疫治疗靶点。临床前研究显示了 GPRC5D 靶向 CAR T 细胞的功效，包括在 BCMA 抗原逃逸模型中的活性。
方法: 在这项 1 期（MCARH109）剂量递增研究中，以四个剂量水平对经过多线治疗的多发性骨髓瘤患者（包括 BCMA CAR T 细胞治疗后复发的患者）进行了 GPRC5D 靶向 CAR T 细胞疗法。
结果 共有 17 名患者入组并接受了 MCARH109 治疗。在 150×106 个 CAR T 细胞中确定了最大耐受剂量。在 450×106 CAR T 细胞剂量下，1 名患者出现 4 级细胞因子释放综合征和免疫效应细胞相关神经毒性综合征（ICANS），2 名患者出现原因不明的 3 级小脑疾病。接受 25×106 至 150×106 细胞剂量的 12 名患者未发生小脑疾病, 任何级别的 ICANS 或 3 级或更高级别的细胞因子释放综合征。整个队列中 71% 的患者和接受 25×106至 150×106 细胞剂量的患者中有 58% 报告了响应。有响应的患者包括以前接受过 BCMA 治疗的患者；在整个队列中 10 名此类患者中的 7 名和接受 25×106 至 150×106 细胞的 6 名此类患者中的 3 名观察到响应。
结论: 这项针对 GPRC5D 的 CAR T 细胞疗法的研究结果证实 GPRC5D 是多发性骨髓瘤的主动免疫治疗靶点。
B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has generated response in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D targeting CAR T cells, including activity in the BCMA antigen escape model.
Methods: In this phase 1 (MCARH109) dose-escalation study, GPRC5D-targeted CAR T was administered at four dose levels in multiple myeloma patients who had been heavily, including those who relapsed after BCMA CAR T-cell therapy.
Results A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150 × 106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient developed grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients developed unexplained grade 3 cerebellar disease. Twelve patients who received doses of 25 × 106 to 150 × 106 cells did not develop cerebellar disease, any grade of ICANS, or grade 3 or higher cytokine release syndrome. Responses were reported in 71% of patients in the entire cohort and in 58% of patients who received doses ranging from 25× 106 to 150×106 cells. Responding patients included patients previously treated with BCMA; responses were observed in 7 of 10 such patients and 3 of 6 such patients who received 25 × 106 to 150 × 106 cells in the entire cohort.
Conclusions: The results of this study of GPRC5D-targeted CAR T-cell therapy confirm that GPRC5D is an active immunotherapy target for multiple myeloma.
参考文献 Reference Mailankody, S et al. N Engl J Med 2022; 387; 1196Elacestrant（口服选择性雌激素受体降解剂）治疗雌激素受体阳性, HER2 阴性晚期乳腺癌 (10/9/2022)
Elacestrant (oral selective estrogen receptor degrader)in ER-positive, HER2-negative advanced breast cancer
这是一项开放标签, 随机III 期临床试验（EMERALD）,招募了 ER 阳性/HER2 阴性晚期乳腺癌患者，这些患者接受了 1-2 线内分泌治疗（包括细胞周期蛋白依赖性激酶 4/6 抑制剂），以及≤1 次化疗, 患者被随机分配接受每日一次口服 400 mg 的 elacestrant 或标准护理内分泌单药治疗。主要终点是通过盲法独立中央审查对所有患者和可检测到 ESR1 突变的患者进行的无进展生存期。
结果: 患者被随机分配到 elacestrant (n = 239) 或标准护理 (n = 238)。 有47.8% 的患者检测到 ESR1 突变，43.4% 的患者既往接受过两次内分泌治疗。所有患者（风险比 = 0.70；95% CI，0.55 至 0.88；P = 0.002）和 ESR1 突变患者（风险比 = 0.55；95% CI，0.39 至 0.77；P = .0005）均延长了无进展生存期。
接受 elacestrant 的 7.2% 和接受标准护理 的 3.1% 发生与治疗相关的 3/4 级不良事件。接受 elacestrant 的 2.5% 和接受 标准护理的 0.9% 发生3/4级的恶心。导致治疗中止的治疗相关不良事件在 elacestrant 组中为 3.4%，而在标准护理组中为 0.9%。
结论 Elacestrant 是第一个口服选择性 ER 降解剂，在针对 ER 阳性/HER2 阴性晚期乳腺癌患者的 III 期试验中，在总体人群和 ESR1 突变患者中与标准护理相比具有显著的无进展生存期改善，且安全性可控。
This is an open-label, randomized phase III clinical trial (EMERALD) enrolling patients with ER-positive/HER2-negative advanced breast cancer who had received 1-2 lines of endocrine therapy (including cyclin-dependent kinase 4/6 inhibitor), and ≤ 1 chemotherapy. Patients were randomly assigned to receive 400 mg of elacestrant orally once daily or standard-of-care endocrine monotherapy. The primary endpoint was progression-free survival in all patients and in those with detectable ESR1 mutations by blinded independent central review.
Results: Patients were randomly assigned to elacestrant (n = 239) or standard of care (n = 238). ESR1 mutations were detected in 47.8% of patients, and 43.4% had received two prior endocrine therapies. Progression-free survival was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = 0.002) and in patients with ESR1 mutations (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005).
Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving standard of care. Grade 3/4 nausea occurred in 2.5% receiving elacestrant and 0.9% receiving standard care. Treatment-related adverse events leading to treatment discontinuation were 3.4% in the elacestrant group and 0.9% in the standard-of-care group.
Conclusions: Elacestrant, the first oral selective ER degrader in a phase III trial in patients with ER-positive/HER2-negative advanced breast cancer, improved progression-free survival compared to standard of care in the general population and in patients with ESR1 mutations, and the safety is controllable.
参考文献 Reference Francois-Clement B et a. J Clin Onc 2022; 40: 3246Avelumab 加axitinib治疗晚期 B3 型胸腺瘤和胸腺癌 (10/8/2022)
Avelumab plus axitinib in treating advanced type B3 thymoma and thymic carcinoma
这是一项II期临床试验（CAVEATT），来自意大利两个中心的 32 名患者在 2019 年 4 月至 2021 年 6 月期间接受了每 2 周 10 mg/kg 的 avelumab 和每天两次 5 mg 的axitinib，直至疾病进展或不可接受毒性。 在32例患者中，胸腺癌27例，B3型胸腺瘤3例，B3胸腺瘤与胸腺癌混合型2例； 29人患有IVB期疾病； 13 人 (41%) 曾接受过抗血管生成剂治疗。主要终点是集中评估的总体反应率。
在 11 名患者（34%）中观察到客观响应（都为部分响应）（90% 置信区间 [CI] = 21%–50%）。另有 18 名患者（56%）病情稳定；疾病控制率为91%。中位响应持续时间为 5.5 个月（90% CI = 3.9-9.2 个月）。中位随访 22.4 个月后，中位无进展生存期为 7.5 个月（90% CI = 3.7-10.0 个月），6 个月和 12 个月的生存率分别为 61.3% 和 29.0%。在数据截止时，中位总生存期为 26.6 个月（90% CI = 17.0-30.0 个月），12 个月和 24 个月的生存率分别为 82.7% 和 52.2%。
在 19 名既往未接受过抗血管生成治疗的患者中，客观响应率为 47%，而 13 名既往接受过治疗的患者的客观响应率为 15%。中位无进展生存期为 10.0 个月 vs 4.5 个月，中位总生存期为 26.6 个月相对于 17.0 个月。仅 27 例胸腺癌患者的客观响应率为 33%，其余 5 例患者有 2 例缓解。
不良事件:最常见的与治疗相关的 3 级或 4 级不良事件是高血压（19%）和肌酸激酶升高（9%）。 4 名患者 (12%) 发生了严重的新发免疫相关不良事件，包括 1 名 3 级间质性肺炎、2 名 3 级多发性肌炎和 1 名 4 级多发性肌炎。没有发生与治疗相关的死亡。
结论: Avelumab 联合axitinib对晚期 B3 型胸腺瘤和化疗后进展的胸腺癌患者具有良好的抗肿瘤活性和可接受的毒性，并可能成为这种情况下的新标准治疗选择。
This is a phase II clinical trial (CAVEATT) in which 32 patients from two Italian centers received avelumab 10 mg/kg every 2 weeks and xitinib 5 mg twice daily between April 2019 and June 2021 a until disease progression or unacceptable toxicity. Of the 32 patients, 27 had thymic carcinoma, 3 had B3 thymoma, and 2 had mixed B3 thymoma and thymic carcinoma; 29 had stage IVB disease; 13 (41%) had previously received antiangiogenic agents treat. The primary endpoint was the centrally assessed overall response rate.
Objective responses (all partial responses) were observed in 11 patients (34%) (90% confidence interval [CI] = 21%–50%). An additional 18 patients (56%) had stable disease; the disease control rate was 91%. The median duration of response was 5.5 months (90% CI = 3.9-9.2 months). After a median follow-up of 22.4 months, the median progression-free survival was 7.5 months (90% CI = 3.7-10.0 months), and the 6-month and 12-month survival rates were 61.3% and 29.0%, respectively. At the time of data cutoff, the median overall survival was 26.6 months (90% CI = 17.0-30.0 months), and the 12- and 24-month survival rates were 82.7% and 52.2%, respectively. Among the 19 patients who had not received prior antiangiogenic therapy, the objective response rate was 47%, compared with 15% in the 13 patients who had received prior such therapy. Median progression-free survival was 10.0 months vs 4.5 months, and median overall survival was 26.6 months vs 17.0 months. Only 27 patients with thymic carcinoma had an objective response rate of 33%, and the remaining 5 patients had 2 responses.
Adverse Events: The most common treatment-related grade 3 or 4 adverse events were hypertension (19%) and increased creatine kinase (9%). Serious immune-related adverse events occurred in 4 patients (12%), including 1 grade 3 interstitial pneumonitis, 2 grade 3 polymyositis, and 1 grade 4 polymyositis. No treatment-related deaths occurred.
Conclusions: Avelumab combined with axitinib had favorable antitumor activity and acceptable toxicity in patients with advanced B3 thymoma and thymic carcinoma that has progressed after chemotherapy, and may become a new standard of care option in this setting.
参考文献 Reference Conforti F et al. Lancet Onc 2022; 23: 1233Teclistamab 治疗复发或难治性多发性骨髓瘤 (10/2/2022)
Teclistamab used in relapsed or refractory multiple myeloma
Teclistamab 是一种双特异性抗体，可靶向 T 细胞表面表达的 CD3 和骨髓瘤细胞表面表达的 B 细胞成熟抗原。在一项临床试验中，teclistamab 在复发或难治性多发性骨髓瘤患者中显示出疗效。
方法: 在这项I-II 期研究中，参加者接受过至少三线治疗（包括免疫调节药物、蛋白酶体抑制剂和抗 CD38 抗体三类药物）后复发或难治性骨髓瘤的患者。在接受 0.06 mg 和 0.3 mg/kg 的递增剂量后，患者每周接受一次 teclistamab 皮下注射（剂量为 1.5 mg/kg）。主要终点是总体响应（部分响应或更好）。
结果: 在接受 teclistamab 治疗的 165 名患者中，77.6% 患有对三类药物难治性疾病（中位数，5 线既往治疗）。中位随访时间为 14.1 个月，总体响应率为 63.0%，其中 65 名患者 (39.4%) 获得完全响应或更好的。共有 44 名患者 (26.7%) 未发现微小残留病 (MRD)；完全缓解或更好的患者的MRD阴性率为46%。中位缓解持续时间为 18.4 个月（95% 置信区间 [CI]，14.9 至不可估计）。中位无进展生存期为 11.3 个月（95% CI，8.8 至 17.1）。
常见的不良事件包括细胞因子释放综合征（72.1% 的患者；3 级，0.6%；无 4 级）、中性粒细胞减少症（70.9%；3 或 4 级，64.2%）、贫血（52.1%；3 级或4, 37.0%) 和血小板减少症 (40.0%; 3 或 4 级, 21.2%)。感染很常见（76.4%；3 级或 4 级，44.8%）。 24 名患者（14.5%）发生神经毒性事件，包括 5 名患者（3.0%；均为 1 级或 2 级）的免疫效应细胞相关神经毒性综合征。
结论 Teclistamab 在三类药物复发性或难治性多发性骨髓瘤患者中产生了深度和持久反应。
Teclistamab is a bispecific antibody that targets CD3 expressed on the surface of T cells and B cell maturation antigen expressed on the surface of myeloma cells. In a clinical trial, teclistamab showed efficacy in patients with relapsed or refractory multiple myeloma.
Methods: In this phase I-II study, participants had relapsed or refractory myeloma after at least three lines of therapy, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies. After receiving escalating doses of 0.06 mg and 0.3 mg/kg, patients received weekly subcutaneous injections of teclistamab (at a dose of 1.5 mg/kg). The primary endpoint was overall response (partial response or better).
Results: Of the 165 patients treated with teclistamab, 77.6% had disease refractory to three classes of drugs (median, 5 lines of prior therapy). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) achieving a complete response or better. A total of 44 patients (26.7%) were free of minimal residual disease (MRD); 46% of patients with a complete response or better had an MRD-negative rate. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median progression-free survival was 11.3 months (95% CI, 8.8 to 17.1).
Common adverse events included cytokine release syndrome (72.1% of patients; grade 3, 0.6%; no grade 4), neutropenia (70.9%; grade 3 or 4, 64.2%), anemia (52.1%) ; grade 3 or 4, 37.0%) and thrombocytopenia (40.0%; grade 3 or 4, 21.2%). Infections were common (76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-related neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).
Conclusion: Teclistamab produced deep and durable responses in patients with relapsed or refractory multiple myeloma progressed after triple-class drugs.
参考文献 Reference Moreau P et al. New Engl J Med 2022; 387: 495新型免疫治疗组合用于微卫星稳定结直肠癌(10/1/2022)
Novel combination of immunotherapy in microsatellite-stable metastatic colorectal cancer
这是一项开放标签、多中心、首次人体I期临床试验（C-800），评估了 botensilimab 作为单药以及 botensilimab 和 balstilimab 组合的安全性、耐受性、药代动力学和药效学特征。Botensilimab 是一种新型可结晶工程化免疫球蛋白 G1 抗细胞毒性 T 淋巴细胞抗原 4（抗 CTLA-4）人单克隆抗体，balstilimab 是一种抗 PD-1 抗体。 Botensilimab 具有增强的 Fc 区，可增加与抗原呈递细胞和自然杀伤细胞上 Fc γ 受体的结合，并产生相对于第一代 CTLA-4 抗体的若干独特特性。
在这个经过大量预处理的 IV 期人群中，患者每 6 周接受 1 mg/kg (n = 7) 或 2 mg/kg 的 botensilimab 联合每 2 周 3 mg/kg (n = 34) 的 balstilimab。该队列仍在招募中。患者必须在 6 周时进行至少一次重新分期扫描。
研究结果显示，在 5.8 个月的中位随访中, 响应率为 24%，疾病控制率为 73%。 在没有活动性肝转移的患者中响应丰富。 80% 的客观响应在数据截止时正在进行，30% 的客观响应超过 1 年。一项探索性回顾性分析显示，无活动性肝转移患者（该组包括无肝转移病史的患者和肝转移灶消融或切除后无复发的患者）的响应率为42%，疾病控制率为96%。 所有响应者的肿瘤突变负荷低至 10；两名应答者对先前的免疫疗法（包括 PD-1/酪氨酸激酶抑制剂组合）无效。
安全概况: 3 级治疗相关不良事件为24%, 没有 4 级或 5 级毒性。最常见的与治疗相关的 3 级毒性包括腹泻或结肠炎 (10%)、疲劳 (2%)、发热 (2%)、天冬氨酸氨基转移酶水平升高 (2%) 和关节痛 (2%)。未报告垂体炎，肺炎罕见。共有 10% 的患者因治疗相关的不良事件而停用了 botensilima，另外 10% 的患者停用了两种药物。
This is an open-label, multicenter, first-in-human phase I clinical trial (C-800) evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of botensilimab as a single agent and the combination of botensilimab and balstilimab . Botensilimab is a novel crystallizable-engineered immunoglobulin G1 anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA-4) human monoclonal antibody, and balstilimab is an anti-PD-1 antibody. Botensilimab has an enhanced Fc region that increases binding to Fc gamma receptors on antigen-presenting cells and natural killer cells and yields several unique properties relative to first-generation CTLA-4 antibodies.
In this heavily pretreated stage IV population, patients received botensilimab at 1 mg/kg every 6 weeks (n = 7) or 2 mg/kg in combination with balstilimab at 3 mg/kg every 2 weeks (n = 34). The cohort is still recruiting. Patients must have at least one restaging scan every 6 weeks. The results showed that at a median follow-up of 5.8 months, the response rate was 24% and the disease control rate was 73%. Responses were abundant in patients without active liver metastases. Eighty percent of objective responses were ongoing at the time of data cutoff and 30% were more than 1 year old. An exploratory retrospective analysis showed a response rate of 42% and a disease control rate of 96% in patients without active liver metastases (a group that included patients with no history of liver metastases and those with no recurrence after ablation or resection of liver metastases). All responders had tumor mutational burdens as low as 10; two responders were refractory to prior immunotherapy, including the PD-1/tyrosine kinase inhibitor combination.
Safety profile: Grade 3 treatment-related adverse events were reported in 24%, with no grade 4 or 5 toxicities. The most common treatment-related grade 3 toxicities included diarrhea or colitis (10%), fatigue (2%), pyrexia (2%), elevated aspartate aminotransferase levels (2%), and arthralgia ( 2%). Hypophysitis was not reported, and pneumonitis was rare. A total of 10% of patients discontinued botensilima due to treatment-related adverse events, and an additional 10% discontinued both drugs.
参考文献 Reference Bullock AJ et al. World Congress on Gastrointestinal Cancer 2022. Abstr LBA-09早期直肠癌的新辅助化疗, 切除和观察 (9/25/2022)
Neoadjuvant chemotherapy, excision and observation for early-stage rectal cancer
这项 II 期试验的目的是确定接受新辅助化疗和经肛门切除手术治疗的早期直肠癌患者的结果和器官保留率。
方法: 这项试验纳入了临床 T1-T3abN0 低位或中位直肠腺癌患者，符合内镜切除术的条件，他们接受了 3 个月的化疗（改良FOLFOX 6 或CAPOX）。那些有响应证据的人在 2-6 周后进行经肛门内窥镜手术。主要终点是方案规定的器官保存率，定义为肿瘤降期至 ypT0/T1N0/X 且避免根治性手术的患者比例。
结果 在入组的 58 名患者中，全部开始化疗，56 名进行手术。共有 33/58 名患者的手术标本肿瘤降期至 ypT0/1N0/X，导致意向治疗方案指定的器官保存率为 57%（90% CI，45 至 68）。在根据方案要求推荐进行全直肠系膜切除术 （TME） 手术的 23 名剩余患者中，13 名拒绝并选择直接进行观察，导致 79%（90% CI，69 至 88）实现器官保存。其余 10/23 名患者进行推荐的 TME，其中 7 名没有组织病理学残留疾病。 1年和2年局部无复发生存率分别为98%（95% CI，86～100）和90%（95% CI，58～98），无远处复发或死亡。观察到生活质量和直肠功能变化很小。
结论: 三个月的诱导化疗可能会成功降低大部分早期直肠癌患者的分期，从而实现器官保留手术。
The purpose of this phase II trial was to determine outcomes and organ preservation rates in patients with early-stage rectal cancer treated with neoadjuvant chemotherapy and transanal resection surgery.
Methods: This trial enrolled patients with clinically T1-T3abN0 low- or mid-rectal adenocarcinoma, eligible for endoscopic resection, and received 3 months of chemotherapy (modified FOLFOX 6 or CAPOX). Those with evidence of response underwent transanal endoscopic surgery 2-6 weeks later. The primary endpoint was the protocol-specified organ preservation rate, defined as the proportion of patients with tumors downstaging to ypT0/T1N0/X and who avoided radical surgery.
Results Of the 58 patients enrolled, all started chemotherapy and 56 underwent surgery. A total of 33/58 patients had tumor downstaging in surgical specimens to ypT0/1N0/X, resulting in an intent-to-treat protocol-designated organ preservation rate of 57% (90% CI, 45 to 68). Of the 23 remaining patients recommended for total mesorectal excision (TME) surgery according to protocol requirements, 13 declined and opted for direct observation, resulting in organ preservation in 79% (90% CI, 69 to 88). The remaining 10/23 patients underwent the recommended TME, 7 of whom had no histopathological residual disease. The 1- and 2-year local recurrence-free survival rates were 98% (95% CI, 86 to 100) and 90% (95% CI, 58 to 98), respectively, without distant recurrence or death. Minimal change in quality of life and rectal function score was observed.
Conclusions: Three months of induction chemotherapy may successfully downgrade the majority of patients with early-stage rectal cancer, allowing organ-preserving surgery.
参考文献 Reference Kennecke HF et al. J Clin Onc Published online August 18, 2022. DOI: 10.1200/JCO.22.00184PD-L1 表达和其他变量与晚期胃食管癌免疫检查点抑制获益的关联(9/24/2022)
Association of PD-L1 expression and other variables with benefits from immune checkpoint inhibition in advanced gastroesophageal cancer
这项荟萃分析包含 11,166 名患者的 17 项 3 期随机临床试验, 发现基于组织的 PD-L1 表达是免疫检查点抑制 （ICI ）总体生存获益的最强预测因子，超过其他变量（在微卫星不稳定性之后）。在 PD-L1 缺失或低表达（相对于高）PD-L1 的患者中，ICI 的益处普遍减少。
数据来源 MEDLINE、Embase、Scopus、Web of Science、Cochrane Central Register (2000-2022)。研究筛选、数据提取和偏倚评估由 2 位评审员独立完成。在筛选的 5,752 条记录中，有 26 条被评估为合格；分析中包括了 17 项试验。 预先设定的主要终点是总生存期。计算了 ICI 与护理标准（SOC, standard of care）的平均风险比 (HR)（随机效应模型）。通过计算每个变量的 2 个水平之间的平均 HR 比率来量化预测值。
结果 共纳入低偏倚风险的 17 项随机临床试验（9 项一线，8 项一线后）和 14 个预测变量，共 11,166 名参与者（鳞状细胞癌5,067 名，腺癌 6,099 名；77.6% 为男性，22.4% 为女性; 59.5% 的患者年龄小于 65 岁，40.5% 的患者年龄在 65 岁或以上）。在鳞状细胞癌患者中，PD-L1 肿瘤比例评分 (TPS) 是 ICI 获益的最强预测因子（高 TPS 的 HR，0.60 [95% CI，0.53-0.68]；相对于低 TPS，HR，0.84 [95% CI，0.75-0.95] ）, 预测值为41.0%, 有利于高 TPS（其他变量≤16.0%）。在腺癌患者中，PD-L1 联合阳性评分 (CPS) 是 ICI 获益的最强预测因子（在微卫星不稳定性高状态后）（高 CPS 的 HR，0.73 [95% CI，0.66-0.81]；相对于低 TPS , HR，0.95 [ 95% CI, 0.84-1.07] ，预测值为29.4%, 有利于高 CPS（相对于 ≤12.9% 对于其他变量）。
结论和相关性: 基于组织的 PD-L1 表达，比任何变量（除微卫星不稳定性高以外）都更能确定 17 项随机试验中晚期胃食管癌患者对 ICI 治疗的益处。
This meta-analysis of 17 phase 3 randomized clinical trials in 11,166 patients found that tissue-based PD-L1 expression was the strongest predictor of overall survival benefit from immune checkpoint inhibition (ICI) over other variables (after microsatellites instability). The benefit of ICI was generally diminished in patients with PD-L1 deletion or low (vs. high) PD-L1.
Data sources MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022). Study screening, data extraction, and bias assessment were performed independently by 2 reviewers. Of the 5,752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis. The prespecified primary endpoint was overall survival. Mean hazard ratios (HR) for ICI and standard of care (SOC) were calculated (random-effects model). Predicted values were quantified by calculating the average HR ratio between the 2 levels of each variable.
Results: A total of 17 randomized clinical trials (9 first-line, 8 post-first-line) and 14 predictors at low risk of bias were included, with a total of 11,166 participants (5,067 for squamous cell carcinoma and 6,099 for adenocarcinoma; 77.6% were male), 22.4% were female; 59.5% of patients were younger than 65 years, and 40.5% were 65 years or older. In patients with squamous cell carcinoma, the PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR for high TPS, 0.60 [95% CI, 0.53-0.68]; HR for low TPS, 0.60 [95% CI, 0.53-0.68] 0.84 [95% CI, 0.75-0.95] ), yielding a predictive value of 41.0%, favoring high TPS (≤16.0% for other variables). In adenocarcinoma patients, the PD-L1 combined positive score (CPS) was the strongest predictor of ICI benefit (after microsatellite instability high status) (HR for high CPS, 0.73 [95% CI, 0.66-0.81] ]; HR for low TPS, 0.95 [95% CI, 0.84-1.07], yielding a predictive value of 29.4% in favor of high CPS (relative to ≤12.9% for other variables).
Conclusions and relevance: Tissue-based PD-L1 expression, more than any variable (except high microsatellite instability), determined the benefit of ICI therapy in patients with advanced gastroesophageal cancer in 17 randomized trials.
参考文献 Reference Yoon HH et al. JAMA Onc published online August 25, 2022. doi:10.1001/jamaoncol.2022.3707MRI 引导聚焦超声局部治疗中危性前列腺癌 (9/17/2022)
MRI-guided ultrasound focal therapy for patients with intermediate-risk prostate cancer
这项研究旨在调查 MRI 引导的聚焦超声局部治疗是否可以安全地减轻局部中危性前列腺癌患者的治疗负担。
方法: 这项在美国 8 个医疗保健中心进行的单臂, 多中心, 2b 期研究中（NCT01657942），招募了 50 岁及以上患有单侧, MRI 可见, 原发性, 中度风险, 先前未治疗的前列腺腺癌的男性（PSA ≤20 ng/mL，2 级或 3 级；肿瘤分类 ≤T2). 经联合活检（结合 MRI 靶向活检和系统活检）证实。 MRI 引导的聚焦超声能量，依次滴定到足以进行组织消融的温度（约 60-70°C），使用实时磁共振测温法将其传递到索引病变和 5 mm 或更多正常组织的计划边缘用于术中监测。主要结局是肿瘤学结局（在 6 个月和 24 个月的联合活检中，治疗区域没有 2 级或更高级别的癌症；当 24 个月的活检数据不可用且 2 级或更高级别的癌症发生在6 个月时的治疗区域，6 个月的活检结果包括在最终分析中）和安全性（不良事件长达 24 个月）
结果: 在 2017 年 5 月 4 日至 2018 年 12 月 21 日期间，评估了 194 名患者的资格，并使用 MRI 引导的聚焦超声治疗了 101 名患者。中位年龄为 63 岁，前列腺特异性抗原的中位浓度为 5.7 ng/mL (IQR 4.2–7.5)。大多数癌症为 2 级（101 例中的 79 例 [78%]）。在 24 个月时，89 名男性中有 78 名（88% [95% CI 79-94]）在治疗区域没有 2 级或更高级别前列腺癌的证据。
不良事件: 未报告 4 级或 5 级治疗相关不良事件，仅报告 1 例 3 级不良事件（尿路感染）。没有与治疗相关的死亡。
结论: 24 个月的活检结果表明，MRI 引导的聚焦超声局部治疗是安全的，并且可以有效地治疗 2 级或 3 级前列腺癌。
This study was conducted to investigate whether MRI-guided focused ultrasound local therapy can safely reduce the treatment burden in patients with localized intermediate-risk prostate cancer.
Methods: This single-arm, multicenter, phase 2b study (NCT01657942) at 8 U.S. health care centers enrolled patients 50 years of age and older with unilateral, MRI-visible, primary, intermediate-risk, untreated prostate adenocarcinoma (PSA ≤20 ng/mL, grade 2 or 3; tumor classification ≤T2). Diagnosis was confirmed by combined biopsy (combined MRI-targeted biopsy and systematic biopsy). MRI-guided focused ultrasound energy, sequentially titrated to a temperature sufficient for tissue ablation (approximately 60-70°C), was delivered to the planned margins of index lesions and 5 mm or more of normal tissue using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcome was oncological outcome and safety (adverse events up to 24 months). Oncological outcome was absence of grade 2 or higher cancer in the treated area at combined biopsies at 6 and 24 months; when biopsy data at 24 months were not available and grade 2 or higher cancer had occurred in the treated area at 6 months, 6-month biopsy results were included in the final analysis.
Results: Between May 4, 2017, and December 21, 2018, 194 patients were assessed for eligibility and 101 were treated with MRI-guided focused ultrasound. The median age was 63 years, and the median prostate-specific antigen concentration was 5.7 ng/mL (IQR 4.2–7.5). Most cancers were grade 2 (79 of 101 [78%]). At 24 months, 78 of 89 men (88% [95% CI 79-94]) had no evidence of grade 2 or higher prostate cancer in the treated area.
Adverse Events: No grade 4 or 5 treatment-related adverse events were reported, only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths.
Conclusions: Biopsy results at 24 months demonstrated that MRI-guided focused ultrasound local therapy is safe and effective in the treatment of grade 2 or 3 prostate cancer.
参考文献 Reference Ehdaie B et al. Lancet 2022; 23: 910巨细胞病毒疫苗治疗复发性胶质母细胞瘤 (9/11/2022)
CMV vaccine in recurrent GBM
超过 90% 的胶质母细胞瘤 （GBM） 存在巨细胞病毒 (CMV) 抗原。基于 CMV 的 GBM 免疫治疗剂中的免疫原性靶标为gB 和 pp65 抗原。
方法：共有 20 名首次复发的 GBM 患者入组，在 IIa 期临床试验（NCT03382977）扩展阶段的 2 个臂中接受 VBI-1901（一种 gB/pp65 包膜病毒样颗粒) 辅以 GM-CSF（皮内给药）或 AS01B（肌肉内给药）。患者每 4 周接种一次 VBI-1901，每次接种后 2 周进行血清学免疫监测，每 6 周监测一次脑部 MRI 扫描。
结果：中位年龄为 58 岁（33-67 岁）的 10 名患者（6 名女性，4 名男性）被纳入 GM-CSF 组，10 名患者（3 名女性，7 名男性）中位年龄为 65 岁（40- 67) 加入 AS01B 组。 GM-CSF 和 AS01B 臂的 12 个月 总生存率分别为 60% 和 70%； GM-CSF 臂的 18 个月总生存率为 30%，AS01B 臂预计为 30%-40%（数据尚未成熟）。在 GM-CSF 组中观察到两个持久的部分缓解，其中一名患者无进展，并且在 2 年后仍在接受治疗，相对于治疗开始，肿瘤大小减少了 93%。免疫学分析表明，长期每月接受 VBI-1901 不会导致免疫耐受。用 GM-CSF 配制的 VBI-1901 治疗后 CMV 特异性 CD4 Tem 细胞在外周血中的动态增强和丢失可能与肿瘤反应相关。
结论：美国 FDA 授予 VBI-1901在首次复发性 GBM 患者中辅以 GM-CSF 的快速通道指定。
Cytomegalovirus (CMV) antigen is present in more than 90% of glioblastomas (GBM). The immunogenic targets in CMV-based GBM immunotherapeutics are the gB and pp65 antigens.
Methods: A total of 20 GBM patients at first relapse were enrolled and received VBI-1901 (a gB/pp65 enveloped virus-like particle) supplemented with GM-CSF ( intradermal administration) or AS01B (intramuscular administration). Patients were vaccinated with VBI-1901 every 4 weeks, followed by serological immunomonitoring 2 weeks after each vaccination, and brain MRI scans every 6 weeks.
Results: Ten patients (6 women, 4 men) with a median age of 58 years (33-67 years) were enrolled in the GM-CSF group, and 10 patients (3 women, 7 men) had a median age of Age 65 (40-67) joined AS01B group. The 12-month OS rates were 60% and 70% in the GM-CSF and AS01B arms, respectively; 18-month OS rates were 30% in the GM-CSF arm and 30%-40% in the AS01B arm (data immature). Two durable partial responses were observed in the GM-CSF group, with one patient being progression-free and still receiving treatment 2 years later, with a 93% reduction in tumor size relative to treatment initiation. Immunological analysis indicated that long-term monthly administration of VBI-1901 did not result in immune tolerance. The dynamic boosting and loss in the peripheral blood of CMV-specific CD4 Tem cells after treatment with VBI-1901 formulated with GM-CSF may correlate with tumor response.
Conclusions: The U.S. FDA granted Fast Track designation to VBI-1901 supplemented with GM-CSF in patients with first relapsed GBM.
参考文献 Reference Wen PY et al. J Clin Onc 2022; 40 (16, suppl ): 2014可切除非小细胞肺癌的新辅助化疗加免疫治疗 (9/10/2022)
Neoadjuvant chemotherapy plus immunotherapy for resectable nonsmall cell lung cancer
这是一项开放标签、多中心、单臂II期临床试验（NADIM, NCT03081689），可手术切除的 IIIA 期非小细胞肺癌患者接受了新辅助（neoadjuvant）紫杉醇（200毫克/平方米）和卡铂（AUC = 6）加 nivolumab（360 毫克），在每个周期（21 天,）的第 1 天一次，共 3 个周期，然后辅助 nivolumab 单药治疗 1 年（240 毫克 每 2 周一次，持续 4 个月，然后是 480 毫克，每4 周一次共 8 个月）。 3 年总生存期和 循环肿瘤DNA （ctDNA） 分析分别是该试验的主/次要目标。
结果: 在意向治疗人群中，36 个月时的总生存率为 81.9%（95% CI，66.8 至 90.6）。肿瘤突变负荷和程序性细胞死亡配体 1 染色都不能预测存活。相反，治疗前低水平的 ctDNA与无进展生存期和总生存率的改善显著相关（风险比0.20；95% CI，0.06 至 0.63，HR，0.07；95% CI，0.01 至 0.39）。根据临床响应结果不能预测生存。然而，新辅助治疗后检测不到ctDNA 水平与无进展生存期和总生存率显著相关（HR，0.26；95% CI，0.07 至 0.93，HR，0.04；95% CI，0.00 至 0.55）。
结论 新辅助化疗加nivolumab治疗可切除非小细胞肺癌的疗效得到 3 年总生存率的支持。 ctDNA 水平与总生存率显著相关，并且在预测生存率方面优于放射学评估。
This is an open-label, multicenter, single-arm phase II clinical trial (NADIM, NCT03081689) in patients with operable stage IIIA non-small cell lung cancer who received neoadjuvant paclitaxel (200 mg/ m²) and carboplatinum (AUC = 6) plus nivolumab (360 mg) once on day 1 of each cycle (21 days,) for 3 cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg every 2 weeks for 4 months, then 480 mg every 4 weeks for 8 months). Three-year overall survival and circulating tumor DNA (ctDNA) analysis were primary and secondary objectives of the trial.
Results: In the intention-to-treat population, the overall survival rate at 36 months was 81.9% (95% CI, 66.8 to 90.6). Neither tumor mutational burden nor programmed cell death ligand 1 staining predicted survival. Conversely, low levels of ctDNA before treatment were significantly associated with improved progression-free survival and overall survival (hazard ratio, 0.20; 95% CI, 0.06 to 0.63, HR, 0.07; 95% CI, 0.01 to 0.39). Survival cannot be predicted based on clinical response outcomes. However, undetectable ctDNA levels after neoadjuvant therapy were significantly associated with progression-free survival and overall survival (HR, 0.26; 95% CI, 0.07 to 0.93, HR, 0.04; 95% CI, 0.00 to 0.55).
Conclusions The efficacy of neoadjuvant chemotherapy plus nivolumab in the treatment of resectable non-small cell lung cancer is supported by the 3-year overall survival rate. ctDNA levels were significantly associated with overall survival and were superior to radiographic assessment in predicting survival.
参考文献 Reference Provencio M et al. J Clin Onc 2022; 40: 2924交替两种化疗可提高转移性胰腺癌的总体生存率 (9/4/2022)
Sequencing therapy may improve survival in metastatic pancreatic cancer patients
与标准化疗相比，白蛋白结合型（Nab-）紫杉醇/吉西他滨和改良的 FOLFOX交替给药导致 12 个月总生存期, 客观缓解率, 疾病进展时间, 无进展生存期和中位总生存期的改善。
该研究随机分配了 157 名未接受过转移性胰腺癌治疗的患者, 超过一半的人口至少有三个转移部位。标准治疗为每 4 周的第 1, 8 和 15 天给予Nab-紫杉醇加吉西他滨的标准治疗，直至疾病进展。试验组在第 1, 8 和 15 天给予 Nab-紫杉醇/吉西他滨，在第 29 天使用改良的 FOLFOX，每 6 周一次，直到疾病进展。主要终点是 12 个月的总生存期。
在 12 个月时，试验组的总生存率为 55.3%，标准组的总生存率为 35.4% (P = .016)。中位总生存期分别为 13.2 个月和 9.7 个月（风险比 [HR] = 0.676；P = .023）, 达到了主要终点，实验组的治疗时间显著延长（8.3 个月对 4.0 个月；P < .001），但该组的剂量延迟也明显更多（64% 对 43%；P = .010），剂量减少（ 71% 对 52%；P = .021）和短暂中断（82% 对 65%；P = .019）。标准组更多患者接受了后续治疗（55% 对 40%；P = .08）。
两组之间的安全性相当，在试验组中，更多的≥3级中性粒细胞减少症（46% 对 24%；P = .004）和 ≥ 3级血小板减少症（24% 对8%；P = .007）。该组的两名患者 (2.6%) 死于不良事件（蜂窝组织炎和败血症）。 研究人员在基线和 12, 24, 36 和 48 周时进行了生活质量评估。在身体, 情绪或社会功能方面没有显著差异。
Alternate administration of nab-paclitaxel/gemcitabine and modified FOLFOX improved 12-month overall survival, objective response rate, time to disease progression, progression-free survival, and median overall survival compared with standard chemotherapy.
The study randomly assigned 157 treatment-naïve patients with metastatic pancreatic cancer. More than half of the population had at least three metastatic sites. Standard of care was Nab-paclitaxel plus gemcitabine on days 1, 8, and 15 every 4 weeks until disease progression. The experimental group involved Nab-paclitaxel/gemcitabine on days 1, 8, and 15, and modified FOLFOX on day 29, every 6 weeks until disease progression. The primary endpoint was 12-month overall survival.
At 12 months, overall survival was 55.3% in the experimental arm vs 35.4% in the standard arm (P = .016). Median overall survival was 13.2 months vs 9.7 months, respectively (hazard ratio [HR] = 0.676; P = .023), and the primary endpoint was met. There was significantly longer duration of treatment in the experimental group (8.3 months vs. 4.0 months; P < .001), but that group also had significantly more dose delays (64% vs. 43%; P = .010), dose reductions (71% vs. 52%; P = .021) and brief interruptions (82% vs. 65%; P = .019). More patients in the standard group received subsequent treatment (55% vs 40%; P = .08).
Safety profile was comparable between the two groups, with more grade ≥3 neutropenia (46% vs 24%; P = .004) and ≥ grade 3 thrombocytopenia (24% vs 8% in the trial arm; P = .007). Two patients (2.6%) in the experiment group died of adverse events (cellulitis and sepsis). Quality of life assessments were performed at baseline and at 12, 24, 36 and 48 weeks. There were no significant differences in physical, emotional or social functioning.
参考文献 Reference Carrato A et al. 2022 ASCO Ann Meeting. Abstr 4022Epcoritamab 用于难以治疗的大 B 细胞淋巴瘤 (9/3/2022)
Epcoritamab for refractory large B-cell lymphoma
Epcoritamab 是一种皮下注射的双特异性抗体，同时与 T 细胞上的 CD3 和 B 细胞上的 CD20 结合。
这是一项II期临床试验（EPCORE™ NHL-1）, 该试验招募了157名复发或难治性 CD20 阳性大 B 细胞淋巴瘤患者，包括弥漫性大 B 细胞淋巴瘤, 高级别 B 细胞淋巴瘤、原发性纵隔大 B 细胞淋巴瘤和 3B 级滤泡性淋巴瘤。 他们之前接受过中位三线治疗。根据基线特征，61% 的患者对初级治疗无效，20% 的患者既往接受过自体干细胞移植，39% 的患者接受了 CAR T 细胞治疗（其中 75% 的患者对 CAR T 细胞治疗无效）。患者每 28 天接受 1 mL 皮下注射 epcoritamab, 直至疾病进展或出现不可接受的毒性。根据方案，仅第一次全剂量需要 24 小时住院，以确保密切观察减轻细胞因子释放综合征。研究的主要终点是独立审查委员会的总体响应率。关键的次要终点包括响应持续时间, 响应时间, 无进展生存期, 总生存期, 完全响应率, 安全性和耐受性。
中位随访时间为 10.7 个月，结果显示，总体响应率为 63%，完全响应率为 39%。首次接受 CAR T 细胞治疗的患者获得了 69% 的总体响应率和 42% 的完全响应率，而接受过 CAR T 细胞治疗的患者获得了 54% 的总体响应率和 34% 的完全响应率。 响应的中位持续时间约为 12 个月。然而，尚未达到完全响应患者的中位响应持续时间，89% 的患者在 9 个月时仍处于完全响应状态。
安全性是可控的，并且与之前的研究结果一致，大多数治疗中出现的不良事件在治疗的前 12 周内得到解决。最常见的 3 级或 4 级治疗出现的不良事件 (≥ 5%) 包括中性粒细胞减少 (14.6%), 贫血 (10.2%), 中性粒细胞计数减少 (6.4%) 和血小板减少 (5.7%)。观察到的 3 级细胞因子释放综合征较低（2.5%）。未观察到 4 级或 5 级细胞因子释放综合征。
正在进行一项 III 期, 开放标签, 随机试验，评估 epcoritamab 作为复发或难治性弥漫性大 B 细胞淋巴瘤患者的单一疗法。还在探索 epcoritamab 联合治疗各种血液系统恶性肿瘤。
Epcoritamab is a subcutaneously administered bispecific antibody that binds simultaneously to CD3 on T cells and CD20 on B cells. This is a phase II clinical trial (EPCORE™ NHL-1) which enrolled 157 patients with relapsed or refractory CD20-positive large B-cell lymphoma, including diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and grade 3B follicular lymphoma. They had previously received a median of third-lines of therapy. Based on baseline characteristics, 61% of patients were refractory to primary therapy, 20% had prior autologous stem cell transplantation, and 39% had received CAR T-cell therapy (75% of whom were refractory to CAR T-cell therapy). Patients received 1 mL of epcoritamab subcutaneously every 28 days until disease progression or unacceptable toxicity. According to the protocol, only the first full dose required a 24-hour hospital stay to ensure close observation of cytokine release syndrome. The primary endpoint of the study was the overall response rate by the independent review committee. Key secondary endpoints included duration of response, time to response, progression-free survival, overall survival, complete response rate, safety and tolerability.
With a median follow-up of 10.7 months, the results showed an overall response rate of 63% and a complete response rate of 39%. CAR T-cell-naïve patients achieved an overall response rate of 69% and a complete response rate of 42%, while those who had received CAR T-cell therapy achieved an overall response rate of 54% and a complete response rate of 34%. The median duration of response was approximately 12 months. However, the median duration of response for patients in complete response has not been reached, with 89% of patients still in a state of complete response at 9 months.
Safety was manageable and consistent with previous findings, with most treatment-emergent adverse events resolved within the first 12 weeks of treatment. The most common grade 3 or 4 treatment-emergent adverse events (≥ 5%) included neutropenia (14.6%), anemia (10.2%), neutropenia (6.4%) and thrombocytopenia (5.7%) %). The observed grade 3 cytokine release syndrome was low (2.5%). No grade 4 or 5 cytokine release syndrome was observed.
A Phase III, open-label, randomized trial is underway evaluating epcoritamab as monotherapy in patients with relapsed or refractory diffuse large B-cell lymphoma. Combination therapy with epcoritamab is also being explored for various hematological malignancies.
参考文献 Reference Thieblemont C et al. Eur Hemat Asso 2022 Congress abstr LB2364 Hutchings M et al. Lancet 2021; 398:1157Elotuzumab 加泊马度胺和地塞米松治疗复发/难治性多发性骨髓瘤 (8/27/2022)
Elotuzumab Plus pomalidomide and dexamethasone for relapsed/refractory multiple myeloma
这是一项II期临床试验（ELOQUENT-3, NCT02654132），与泊马度胺/地塞米松相比，elotuzumab* 联合泊马度胺/地塞米松显著改善复发/难治性多发性骨髓瘤患者的生存期。
方法: 既往接受过≥ 2线治疗的复发/难治性多发性骨髓瘤患者，被随机分配 (1:1)接受elotuzumab联合泊马度胺/地塞米松或联合泊马度胺/地塞米松。治疗以 28天为一个周期，在第 1和第 2周期的第 1, 8, 15和 22天以 10毫克/公斤一次给药，在每个后续周期的第 1天以 20毫克/公斤 一次给药。所有患者在每个周期的第 1天至第 21天每天一次接受 4毫克 泊马度胺，每周一次口服 40毫克 地塞米松（> 75岁的患者为 20毫克）；在elotuzumab给药日，elotuzumab联合泊马度胺/地塞米松组患者接受口服（28毫克；年龄>75岁的患者为 8毫克）和静脉内（8毫克）地塞米松。主要终点是研究者评估的无进展生存期。总客观响应率和总生存期是次要终点。
结果: 共有 117名患者被随机分配到elotuzumab联合泊马度胺/地塞米松 (n = 60)和泊马度胺/地塞米松 (n = 57)。在接受治疗的患者中，elotuzumab联合泊马度胺/地塞米松组有 37例（61.7%）死亡，泊马度胺/地塞米松组有 41例（74.5%）死亡，最常见的原因是疾病进展（41.7%相比于49.1%）。中位总生存期（95% CI）在elotuzumab联合泊马度胺/地塞米松组显著改善（29.8 [22.9至 45.7]个月）相比于泊马度胺/地塞米松组17.4 [13.8至 27.7]个月），风险比为 0.59（95%CI，0.37至 0.93；P = .0217)。在大多数患者亚组中观察到elotuzumab联合泊马度胺/地塞米松带来的总生存期益处。
Elotuzumab联合泊马度胺/地塞米松的安全概况与之前的报告一致，没有检测到新的安全信号。
结论: 在先前接受来那度胺治疗和蛋白酶体抑制剂而复发/难治性多发性骨髓瘤患者中，Elotuzumab联合泊马度胺/地塞米松与泊马度胺/地塞米松相比，总生存期有统计学意义的改善。
*Elotuzumab 是一种人源化 IgG1 单克隆抗体，靶向信号淋巴细胞激活分子家族成员 7 (SLAMF7)
This is a phase II clinical trial (ELOQUENT-3, NCT02654132) that compared elotuzumab* in combination with pomalidomide/dexamethasone, with pomalidomide/dexamethasone. The triple combination significantly improved overall survival in patients with relapsed/refractory multiple myeloma.
Methods: Patients with relapsed/refractory multiple myeloma who had received ≥ 2 lines of prior therapy (including proteasome inhibitor) were randomly assigned (1:1) to receive elotuzumab plus pomalidomide/dexamethasone or pomalidomide/dexamethasone. Treatment in a 28-day cycles with 10 mg/kg on days 1, 8, 15 and 22 of cycles 1 and 2, and 20 mg/kg on day 1 of each subsequent cycle. All patients received pomalidomide 4 mg once daily and dexamethasone 40 mg orally once weekly (20 mg for patients > 75 years) on days 1 to 21 of each cycle; on elotuzumab dosing days, patients in the elotuzumab plus pomalidomide/dexamethasone group received oral (28 mg or 8 mg if >75 years) and intravenous (8 mg) dexamethasone. The primary endpoint was investigator-assessed progression-free survival. Overall objective response rate and overall survival were secondary endpoints.
Results: A total of 117 patients were randomly assigned to elotuzumab plus pomalidomide/dexamethasone (n = 60) and pomalidomide/dexamethasone (n = 57). Among treated patients, 37 (61.7%) in the elotuzumab plus pomalidomide/dexamethasone group and 41 (74.5%) in the pomalidomide/dexamethasone group died, the most common cause being Disease progression (41.7% vs 49.1%). Median overall survival (95% CI) was significantly improved (29.8 [22.9 to 45.7] months) in the elotuzumab plus pomalidomide/dexamethasone group compared with 17.4 [13.8 to 13.8 to 27.7] months), the hazard ratio was 0.59 (95% CI, 0.37 to 0.93; P = .0217). The overall survival benefit of elotuzumab in combination with pomalidomide/dexamethasone was observed in most subgroups of patients.
The safety profile of elotuzumab in combination with pomalidomide/dexamethasone was consistent with previous reports, with no new safety signals detected.
Conclusion: Elotuzumab combined with pomalidomide/dexamethasone compared with pomalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with lenalidomide and a proteasome inhibitor. There was a statistically significant improvement in survival.
*Elotuzumab is a humanized IgG1 monoclonal antibody that targets the signaling lymphocytic activation molecule family member 7 (SLAMF7)
参考文献 Reference Dimopopulos MA et al. J Clin Onc 2022; Aug 12 DOI: 10.1200/JCO.21.02815FOLFOXIRI + 贝伐单抗相比于 FOLFOX或FOLFIRI + 贝伐单抗在肝转移和右侧和/或 RAS/BRAFV600E 突变原发性结直肠组中的比较 (8/26/2022)
FOLFOXIRI + bevacizumab versus FOLFOX/FOLFIRI + bevacizumab in patients with initially unresectable liver metastases and right-sided and/or RAS/BRAFV600E-mutated colorectal cancer
这是一项荷兰结直肠癌III期临床试验（CAIRO5），旨在寻找最佳诱导方案。患者在 FOLFOX 或 FOLFIRI + 贝伐单抗（A 组）和 FOLFOXIRI-贝伐单抗（B 组）之间随机分配，两组均长达 12 个周期，随后进行 5-氟嘧啶/亚叶酸/贝伐单抗 维持治疗。每 2 个月根据小组多数投票评估可切除性。主要终点是无进展生存期。次要终点是 R0/1 切除, 总生存期, 总响应率, 毒性, 病理缓解, 以及术后发病率。
结果：从 2014 年 12 月开始直到 2021 年 3 月，在 43 个荷兰和 1 个比利时地点，294 名患者被随机分组，A 组 148 人，B 组 146 人。中位随访时间为 40 个月。患者在 A 组与 B 组中接受中位数为 10 对 9 个诱导周期。主要特征为（A/B 组）：中位年龄 61/65 岁，男性 63.9/60.4%，右侧原发肿瘤 39.5/41.7%，RAS突变体 85.7/86.1%，BRAFV600E 突变体 6.8/8.3%，同步病 86.4/89.6%，既往辅助化疗 4.8/4.9%。对于 259 次事件，A 组与 B 组的中位无进展生存期为 9.0 相比于 10.6 个月（分层 HR 0.74，95% CI 0.57-0.96，p=0.02）。 总响应率分别为 32.0% 相比于52.1% (p < 0.001)， R0/1 切除 ± 消融率为 37.4% 相比于51.4% (p = 0.02)，二期手术分别为 16.4% 相比于32.4% (p = 0.04)，
术后并发症发生率为 38.2% 相比于51.2% (p=0.14)， 任何≥3 级不良事件发生率为 58.5% 相比于 75.0% (p = 0.003) 。最常见的是中性粒细胞减少症12.9 相比于38.2%, （p < 0.001）; 高血压14.3相比于13.9% 和腹泻 3.4相比于9.4% （p < 0.001)。
结论：FOLFOXIRI-B 与 FOLFOX/FOLFIRI-B 相比，显著增加了无进展生存期, 总响应率 和 R0/1 切除率，但代价是增加了患者的毒性。
This is a Dutch phase III clinical trial in colorectal cancer (CAIRO5). The goal was to find the best induction regimen. Patients were randomized between FOLFOX or FOLFIRI + bevacizumab (arm A) and FOLFOXIRI-bevacizumab (arm B), both for up to 12 cycles, followed by 5-fluoropyrimidine/leucovorin/bevacizumab maintenance therapy. Resectability was assessed every 2 months based on panel votes. The primary endpoint was progression-free survival. Secondary endpoints were R0/1 resection, overall survival, overall response rate, toxicity, pathological response, and postoperative morbidity.
Results: From December 2014 to March 2021, at 43 Dutch and 1 Belgian sites, 294 patients were randomized, 148 in arm A and 146 in arm B. The median follow-up was 40 months. Patients received a median of 10 versus 9 induction cycles in Arms A and B. The main characteristics were (group A/B): median age 61/65 years, male 63.9/60.4%, right primary tumor 39.5/41.7%, RAS mutant 85.7/86.1%, BRAFV600E mutant 6.8/8.3%, synchronous disease in 86.4/89.6%, previous adjuvant chemotherapy 4.8/4.9%. For 259 events, the median progression-free survival was 9.0 vs 10.6 months in arms A vs. B (stratified HR 0.74, 95% CI 0.57-0.96, p=0.02). Overall response rates were 32.0% vs. 52.1% (p < 0.001), R0/1 resection ± ablation rates were 37.4% vs. 51.4% (p = 0.02), and secondary surgery was 16.4% vs. 32.4 % (p = 0.04)
Postoperative complication rates were 38.2% vs 51.2% (p=0.14), and any grade ≥ 3 adverse events were 58.5% vs 75.0% (p=0.003). The most common were neutropenia 12.9 vs 38.2%, (p < 0.001); hypertension 14.3 vs 13.9% and diarrhea 3.4 vs 9.4% (p < 0.001).
Conclusions: FOLFOXIRI-B significantly increased progression-free survival, overall response rate, and R0/1 resection rate compared with FOLFOX/FOLFIRI-B, but at the expense of increased patient toxicity.
参考文献 Reference Punt CJA et al. J Clin Onc 2022; 40 (17): suppl LBA 3506贝伐单抗加内分泌维持治疗晚期或转移性激素受体阳性乳腺癌 (8/21/2022)
Bevacizumab plus endocrine therapy as maintenance in advanced or metastatic ER-positive breast cancer
BOOSTER （NCT01989780）是一项前瞻性, 开放标签, 多中心, 随机,对照, II 期研究，在2014 年 1 月 1 日至 2015 年 12 月 31 日期间，从日本 53 家医院招募了 160 名ER 阳性, HER2 阴性晚期或转移性乳腺癌患者, 从未接受过化疗。所有患者均接受 4 至 6 个周期（4 周治疗为一个周期）每周紫杉醇加贝伐单抗诱导治疗（每周紫杉醇 90 毫克/平方米，在每个周期的第 1, 8 和 15 天静脉内给药，加贝伐单抗 10 毫克/公斤 在每个周期的第 1 天和第 15 天静脉内给药）。诱导治疗后完全缓解、部分缓解或疾病稳定的患者（响应者, n = 125, 78%）被随机分配（1:1）继续每周紫杉醇加贝伐单抗（n = 63）或改用维持性内分泌治疗（芳香酶抑制剂或氟维司群伴）加贝伐单抗（n = 61）。如果患者在维持内分泌治疗加贝伐单抗后出现疾病进展，则可以每周接受紫杉醇加贝伐单抗再诱导治疗。主要终点是策略失败时间（time to failure of strategy, TFS）。
结果: 在内分泌治疗加贝伐单抗维持组的 61 名患者中，32 名（52%）患者重新开始每周接受紫杉醇加贝伐单抗治疗。在中位随访 21.3 个月（IQR 13.0–28.2）时，内分泌治疗加贝伐单抗组的 TFS 显著长于每周紫杉醇加贝伐单抗组（中位数 16.8 个月 [95% CI 12.9–19.0] 相比于 8.9 个月 [5.7–13.8]；风险比 0.51 [0.34–0.75]；p = 0.0006)。
随机分组后最常见的 3-4 级非血液学不良事件是蛋白尿（内分泌治疗加贝伐单抗维持组 61 名患者中的 10 名 [16%] 相比于紫杉醇加贝伐单抗组 63 名患者中的 8 名 [13%]） 、高血压（6 [10%] 相比于6 [10%]）和周围神经病变（1 [2%] 相比于 6 [10%]）。紫杉醇加贝伐单抗组（十二指肠溃疡穿孔）报告了 1 例与治疗相关的死亡。
在 ER 阳性,HER2 阴性晚期或转移性乳腺癌患者中，可在响应者中将紫杉醇加贝伐单抗转为维持内分泌治疗加贝伐单抗，是一种有效的替代方案，并有更好的安全性。
BOOSTER (NCT01989780) is a prospective, open-label, multicenter, randomized, controlled, phase 2 study. It recruited 160 ER-positive, HER-2-negative advanced or metastatic breast cancer patients from 53 hospitals in Japan from January 1, 2014 to December 31, 2015. Patients had never received prior chemotherapy. All patients received 4 to 6 cycles (4-week treatment was one cycle) of weekly paclitaxel plus bevacizumab induction therapy (weekly paclitaxel at 90 mg/m² intravenously on days 1, 8 and 15 of each cycle) , plus bevacizumab 10 mg/kg intravenously on days 1 and 15 of each cycle). Patients with complete response, partial response, or stable disease after induction therapy (responders, n = 125, 78%) were randomly assigned (1:1) to continue weekly paclitaxel plus bevacizumab (n = 63) or switch to maintenance endocrine therapy (with an aromatase inhibitor or fulvestrant) plus bevacizumab (n = 61). Weekly reinduction therapy with paclitaxel plus bevacizumab could be given if patients develop disease progression after maintenance endocrine therapy plus bevacizumab. The primary endpoint was time to failure of strategy (TFS).
Results: Of the 61 patients in the endocrine therapy plus bevacizumab maintenance group, 32 (52%) restarted weekly paclitaxel plus bevacizumab. At a median follow-up of 21.3 months (IQR 13.0–28.2), TFS was significantly longer in the endocrine therapy plus bevacizumab group than in the weekly paclitaxel plus bevacizumab group (median 16.8 months [95% CI 12.9–19.0] ] versus 8.9 months [5.7–13.8]; hazard ratio 0.51 [0.34–0.75]; p = 0.0006).
The most common grade 3-4 nonhematologic adverse event after randomization was proteinuria (10 [16%] of 61 patients in the endocrine therapy plus bevacizumab maintenance group vs. paclitaxel plus bevacizumab 63). 8 [13%] of patients), hypertension (6 [10%] vs 6 [10%]), and peripheral neuropathy (1 [2%] vs 6 [10%]). One treatment-related death was reported in the paclitaxel plus bevacizumab group (perforated duodenal ulcer).
Conclusion: In patients with ER-positive, HER2-negative advanced or metastatic breast cancer, switching paclitaxel plus bevacizumab to maintenance endocrine therapy plus bevacizumab in responders is an effective alternative with better tolerability.
参考文献 Reference Saji S et al. Lancet Onc 2022;23:636Pralsetinib 治疗RET 融合阳性癌症患者 (8/20/2022)
Pralsetinib in RET fusion positive cancer
高选择性 RET 抑制剂 pralsetinib 具有良好的耐受性，并对 RET 融合阳性癌症患者（无论肿瘤类型如何）有持久的响应。当含有 RET 基因的染色体与另一条染色体重新连接时，就会发生 RET 融合。 RET 改变在甲状腺髓样癌、甲状腺乳头状癌和非小细胞肺癌中最常见，在其他组织类型中很少发生。
根据国际 I/II 期 ARROW临床试验的早期结果，FDA于 2020 年 9 月批准 pralsetinib 作为 RET 融合阳性的非小细胞肺癌 的治疗方法，并于 2020 年 12 月批准用于晚期 RET 改变的甲状腺癌。 为了确定该疗法是否提供了超越这两个肿瘤的益处，这项研究还招募了患有多种 RET 融合阳性实体瘤的患者, 包括胰腺癌、胆管癌、神经内分泌肿瘤和肉瘤。 该研究招募了 29 名患有 12 种不同癌症类型的患者。其中，23 名患者能够进行疗效评估。这些患者的中位年龄为 53 岁； 14 人（61%）是女性。大多数患者患有转移性疾病（87%）并接受过先前的癌症治疗（87%）。 在这 23 名患者中，3 名患者（13%）确认完全响应，10 名（43%）确认部分响应。中位响应持续时间为 11.7 个月，中位无进展生存期为 7.4 个月，中位总生存期为 13.6 个月。
在 25 名患者 (86%) 中观察到与治疗相关的副作用，20 名患者 (69%) 出现了 3 级或更高级别的不良事件。 最常见的副作用是天冬氨酸转氨酶和丙氨酸转氨酶水平升高以及中性粒细胞减少。共有 17 名患者 (59%) 有短期剂量中断，13 名患者 (45%) 由于副作用而永久减少剂量。
这些发现证明了 RET 抑制剂pralsetinib有可能使各种肿瘤类型的患者受益。
The highly selective RET inhibitor pralsetinib was well tolerated and demonstrated durable responses in patients with RET fusion-positive cancers regardless of tissue types. RET fusions occur when the chromosome containing the RET gene rejoins with another chromosome. RET alterations are most common in medullary thyroid carcinoma, papillary thyroid carcinoma, and non-small cell lung cancer, and rarely occur in other tissue types.
Based on early results from the international phase I/II ARROW trial, FDA approved pralsetinib in September 2020 as a treatment for RET fusion-positive non-small cell lung cancer and in December 2020 for advanced RET-altered thyroid cancer. To determine whether the therapy provided benefits beyond these two tumors, the study also enrolled patients with multiple RET fusion-positive solid tumors, including pancreatic cancer, cholangiocarcinoma, neuroendocrine tumors, and sarcomas. The study enrolled 29 patients with 12 different cancer types. Of these, 23 patients were able to be evaluated for efficacy. The median age of these patients was 53 years; 14 (61%) were women. Most patients had metastatic disease (87%) and received prior cancer therapy (87%). Of these 23 patients, 3 patients (13%) achieved a complete response and 10 (43%) had a partial response. The median duration of response was 11.7 months, median progression-free survival was 7.4 months, and median overall survival was 13.6 months.
Treatment-related side effects were observed in 25 patients (86%), and 20 patients (69%) experienced adverse events of grade 3 or higher. The most common side effects were increased levels of aspartate aminotransferase and alanine aminotransferase and neutropenia. A total of 17 patients (59%) had short-term dose interruptions and 13 patients (45%) had permanent dose reductions due to side effects.
These findings demonstrate the potential of the RET inhibitor pralsetinib to benefit patients across a variety of tumor types.
参考文献 Reference Subbiah V et al. Nature Med 2022;28:1640FDA批准 fam-trastuzumab deruxtecan-nxki (Enhertu) 用于不可切除或转移性 HER2低表达的乳腺癌患者 (8/14/2022)
FDA approves Enhertu for unresectable or metastatic HER2-low breast cancer
2022 年 8 月 FDA批准 fam-trastuzumab deruxtecan-nxki (Enhertu) 用于治疗不可切除或转移性 HER2低表达的乳腺癌患者, 他们在转移性环境中接受过先前化疗或在完成辅助化疗期间或六个月内出现疾病复发。这是对HER2低表达（以前称为 HER2 阴性）的乳腺癌的首个此类批准。
疗效基于 DESTINY-Breast04 临床试验(NCT03734029)，这是一项随机、多中心、开放标签的试验，招募了 557 名不可切除或转移性 HER2低表达的乳腺癌患者。该试验包括两个队列：494 名激素受体阳性患者和 63 名激素受体阴性患者。HER2低表达的定义为免疫组化IHC 1+ 或 IHC 2+/原位杂交ISH-。患者随机 (2:1) 接受 Enhertu 5.4 毫克/公斤 (N=373) 每 3 周静脉输注, 或医生选择的化疗方案（N=184，包括艾日布林、卡培他滨、吉西他滨、白蛋白结合型紫杉醇或紫杉醇）。主要疗效指标是激素受体阳性患者的无进展生存期，通过独立中央审查进行评估。次要疗效指标是总体人群（所有随机激素受体阳性和阴性患者）的无进展生存期, 激素受体阳性患者的总生存期和总体人群的总生存期。 患者的中位年龄为 57 岁（范围：28 至 81 岁），24% 为 65 岁或以上。
激素受体阳性队列的中位无进展生存期在 Enhertu 组为 10.1 个月（95% CI：9.5, 11.5），在化疗组为 5.4 个月（95% CI：4.4, 7.1）（风险比 [HR] 0.51；95% CI： 0.40，0.64；p < 0.0001)。总体人群中, Enhertu 组中位无进展生存期为 9.9 个月 (95% CI: 9.0, 11.3)，接受化疗组为 5.1 个月 (95% CI: 4.2, 6.8) (HR 0.50; 95% CI: 0.40, 0.63; p < 0.0001)。 在激素受体阳性队列中，Enhertu 和化疗组的中位总生存期分别为 23.9 个月（95% CI：20.8、24.8）和 17.5 个月（95% CI：15.2、22.4）（HR 0.64；95% CI：0.48、0.86 ;p = 0.0028)。在总体人群中，Enhertu 组的中位总生存期为 23.4 个月 (95% CI: 20.0, 24.8)，而化疗组为 16.8 个月 (95% CI: 14.5, 20.0) (HR 0.64; 95% CI: 0.49, 0.84) ; p = 0.001)。
接受 Enhertu 患者最常见的不良反应（发生率 ≥20%）是恶心、疲劳、脱发、呕吐、贫血、便秘、食欲下降、腹泻和肌肉骨骼疼痛。处方信息包括一个黑框警告，间质性肺病和胚胎-胎儿毒性的风险。
乳腺癌的推荐 Enhertu 剂量为 5.4毫克/公斤，每 3 周静脉输注一次，直至疾病进展或出现不可接受的毒性。
In August 2022, FDA approves fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. This is the first such approval for breast cancer with HER2 low expression (previously known as HER2 negative).
Efficacy was based on the DESTINY-Breast04 clinical trial (NCT03734029), a randomized, multicenter, open-label trial that enrolled 557 patients with unresectable or metastatic HER2-low breast cancer. The trial included two cohorts: 494 hormone receptor-positive patients and 63 hormone receptor-negative patients. Low expression of HER2 was defined as immunohistochemical IHC 1+ or IHC 2+/in situ hybridization ISH-. Patients were randomized (2:1) to receive Enhertu 5.4 mg/kg (N=373) intravenously every 3 weeks, or physician’s choice of chemotherapy (N=184, including eribulin, capecitabine, gemcitabine, albumin-bound paclitaxel or paclitaxel). The primary efficacy measure was progression-free survival in hormone receptor-positive patients, as assessed by independent central review. Secondary efficacy measures were progression-free survival in the overall population (all randomized hormone receptor-positive and negative patients), overall survival in hormone receptor-positive patients, and overall survival in the overall population. The median age of patients was 57 years (range: 28 to 81 years), and 24% were 65 years or older.
Median progression-free survival in the hormone receptor-positive cohort was 10.1 months (95% CI: 9.5, 11.5) in the Enhertu group and 5.4 months (95% CI: 4.4, 7.1) in the chemotherapy group (hazard ratio [HR] ] 0.51; 95% CI: 0.40, 0.64; p < 0.0001). In the overall population, median progression-free survival was 9.9 months (95% CI: 9.0, 11.3) in the Enhertu group and 5.1 months (95% CI: 4.2, 6.8) in the chemotherapy group (HR 0.50; 95% CI: 0.40, 0.63; p < 0.0001). In the hormone receptor-positive cohort, median overall survival was 23.9 months (95% CI: 20.8, 24.8) and 17.5 months (95% CI: 15.2, 22.4) in the chemotherapy groups, respectively (HR 0.64; 95 %CI: 0.48, 0.86; p = 0.0028). In the overall population, median overall survival was 23.4 months (95% CI: 20.0, 24.8) in the Enhertu arm versus 16.8 months (95% CI: 14.5, 20.0) in the chemotherapy arm (HR 0.64; 95% CI : 0.49, 0.84) ; p = 0.001).
The most common adverse reactions (incidence ≥20%) in patients receiving Enhertu were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain. The package inserts includes a Boxed Warning: the risk of interstitial lung disease and embryo-fetal toxicity.
The recommended dose of Enhertu for breast cancer is 5.4 mg/kg as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-enhertu-fam-trastuzumab-deruxtecan-nxki-adult-patientsFDA 批准capmatinib治疗转移性非小细胞肺癌 (8/13/2022)
FDA approves capmatinib for metastatic NSCLC with MET mutation
2022年8月FDA 常规批准capmatinib用于具有MET外显子 14 跳跃突变的转移性非小细胞肺癌患者。
这是一项多中心、非随机、开放标签、多队列研究（GEOMETRY mono-1, NCT02414139）, 参加者为160 名转移性非小细胞肺癌患者并具有导致 MET 外显子 14 跳跃性突变。患者每天两次口服capmatinib 400 毫克，直至疾病进展或出现不可接受的毒性。 主要疗效指标是由盲法独立审查委员会确定的总响应率和响应持续时间。
在 60 名初治患者中，总响应率为 68% (95% CI: 55, 80)，响应持续时间为 16.6 个月 (95% CI: 8.4, 22.1)。在 100 名先前接受过治疗的患者中，总响应率为 44%（95% CI：34、54），响应持续时间为 9.7 个月（95% CI：5.6、13）。 患者的中位年龄为 71 岁（48 至 90 岁）。选定的人口统计数据报告如下：61% 女性，77% 白人，61% 从不吸烟，83% 患有腺癌，16% 患有中枢神经系统转移。在既往接受过治疗的患者中，81% 接受过一次全身治疗，16% 接受过两次全身治疗，3% 接受过三次全身治疗。在既往接受过治疗的患者中，86% 接受过基于铂的化疗。
患者最常见的不良反应（≥20%）是水肿、恶心、肌肉骨骼疼痛、疲劳、呕吐、呼吸困难、咳嗽和食欲下降。 推荐的capmatinib剂量为每天两次口服 400 毫克。
In August 2022, FDA granted regular approval to capmatinib for patients with metastatic non-small cell lung cancer that harbors MET exon 14 skip mutation.
This is a multicenter, nonrandomized, open label, multicohort study (GEOMETRY mono-1, NCT02414139) in which 160 patients with metastatic non-small cell lung cancer that harmors a MET exon 14 skip mutation. Patients received capmatinib 400 mg orally twice daily until disease progression or unacceptable toxicity. The primary efficacy measures were overall response rate and duration of response as determined by a blinded independent review committee.
Among 60 treatment-naïve patients, the overall response rate was 68% (95% CI: 55, 80), and the duration of response was 16.6 months (95% CI: 8.4, 22.1). Among 100 previously treated patients, the overall response rate was 44% (95% CI: 34, 54), and the duration of response was 9.7 months (95% CI: 5.6, 13). The median age of the patients was 71 years (48 to 90 years). Selected demographics were reported as follows: 61% female, 77% white, 61% never smoked, 83% with adenocarcinoma, and 16% with CNS metastases. Among previously treated patients, 81% received one systemic therapy, 16% received two systemic therapies, and 3% received three systemic therapies. Among previously treated patients, 86% had received platinum-based chemotherapy.
The most common adverse reactions (≥20%) were edema, nausea, musculoskeletal pain, fatigue, vomiting, dyspnea, cough, and decreased appetite. The recommended dose of capmatinib is 400 mg orally twice daily.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capmatinib-metastatic-non-small-cell-lung-cancerAdgrasib在 KRASG12C 突变非小细胞肺癌和脑转移患者中的活性(8/7/2022)
Adgrasib used in KRASG12C-mutated NSCLC with brain metastases
携带 KRASG12C 突变的非小细胞肺癌患者中有27-42%发生脑转移。 Adgrasib是一种 KRASG12C 抑制剂，选择性结合 KRASG12C，将其锁定在其非活性状态，并对药代动力学特性进行了优化，包括长半衰期, 剂量依赖性的中枢神经系统渗透和颅内肿瘤消退。
这是一项多队列临床I/II期试验（KRYSTAL-1, NCT03785249），评估 Adgrasib作为单一疗法或与选定药物联合用于携带 KRASG12C 突变的晚期实体瘤患者。在 1b 期队列中，患有 KRASG12C 突变的非小细胞肺癌和未治疗的脑转移患者接受了 Adgrasib 600 毫克, 每天两次。这个 1b 期队列的目标是评估安全性和临床活动，包括反应持续时间, 无进展生存期和总生存期。可行时收集脑脊液，并用于测量 Adgrasib 浓度。
结果：截至 2021 年 12 月 31 日，共有 25 名非小细胞肺癌患者入组并接受治疗。截止日期的中位随访时间为 6.6 个月。中位年龄为 66 岁，52% 为女性，先前全身治疗的中位线为 1（范围 0-4+）。总客观响应率为 31.6%（6/19；3 名完全响应，2 名部分响应，1 名未确认部分响应）； 疾病控制率为 84.2%（16/19，包括 10 个稳定疾病）。中位疾病控制率未达到 (95% CI 4.1–未达到)；中位无进展生存期 为 4.2 个月（95% CI 3.8–未达到）。收集了两名患者的脑脊液样本，观察到Adgrasib 脑脊液浓度超过了目标颅内50，证明中枢神经系统渗透和抗肿瘤活性。对于所有入组的患者，总生存期不成熟，在分析时尚未达到中位数。
Adgrasib的安全性与之前报道一致； 有36% 的患者发生 3 级治疗相关的副作用，没有 4/5 级。
结论：Adgrasib 具有良好的耐受性，在携带 KRASG12C 突变的非小细胞肺癌患者中，能渗透中枢神经系统和具有颅内活性。这是第一个证明 KRASG12C 抑制剂对该人群中先前未接受过治疗的脑转移有特异性活性。
Brain metastases occur in 27-42% of NSCLC patients with KRASG12C mutations. Adgrasib is a KRASG12C inhibitor that selectively binds KRASG12C, locking it in its inactive state, with optimized pharmacokinetic properties including long half-life, dose-dependent CNS penetration and intracranial tumor regression .
This is a multi-cohort phase I/II clinical trial (KRYSTAL-1, NCT03785249) evaluating Adgrasib as monotherapy or in combination with selected agents in patients with advanced solid tumors harboring a KRASG12C mutation. In the Phase 1b cohort, patients with KRASG12C -mutated non-small cell lung cancer and untreated brain metastases received Adgrasib 600 mg twice daily. The objectives of this phase 1b cohort were safety and clinical activity, including duration of response, progression-free survival, and overall survival. Cerebrospinal fluid was collected when feasible and used to measure Adgrasib concentrations.
Results: As of December 31, 2021, a total of 25 patients with non-small cell lung cancer were enrolled and treated. The median follow-up at the cutoff date was 6.6 months. The median age was 66 years, 52% were female, and the median line for prior systemic therapy was 1 (range 0-4+). The overall objective response rate was 31.6% (6/19; 3 complete responses, 2 partial responses, and 1 unconfirmed partial response); the disease control rate was 84.2% (16/19, including 10 stable disease). The median disease control rate was not reached (95% CI 4.1 – not reached); median progression-free survival was 4.2 months (95% CI 3.8 – not reached). CSF samples were collected from two patients, and Adgrasib CSF concentrations were found to exceed target intracranial 50, demonstrating CNS penetration and antitumor activity. For all enrolled patients, overall survival was immature and had not yet reached the median at the time of analysis.
The safety profile of adgrasib was consistent with previous reports; grade 3 treatment-related side effects occurred in 36% of patients, with no grades 4/5.
Conclusions: Adgrasib was well tolerated, penetrated the central nervous system and exhibited intracranial activity in patients with KRASG12C -mutated non-small cell lung cancer. This is the first report to demonstrate that a KRASG12C inhibitor has specific activity for untreated brain metastases in this population.
参考文献 Reference Sabari JK et al. J Clin Onc 2022;40:17 suppl LBA 9009减肥手术与肥胖成人癌症风险和死亡率的关系 (8/6/2022)
Association of bariatric surgery and risk of cancer and mortality in obese adults
在这项包含 30,318名患者（包括 5053名接受减肥手术的患者和 25265名非手术对照组的匹配患者）的回顾性队列研究中，减肥手术与肥胖相关癌症的风险降低显着相关（风险比，0.68）和癌症相关死亡率（风险比，0.52）。
在外科手术和肿瘤疾病发病率和死亡的长期疗效（SPLENDID）匹配队列研究中，体重指数为 35或更高的成年人,从2004年到2017年在美国卫生系统接受减肥手术的患者被包括在内。接受减肥手术的患者与因肥胖未接受手术的患者以 1:5的比例匹配，总共有 30,318名患者:减肥手术 (n = 5053)包括 Roux-en-Y胃旁路术和袖状胃切除术，与非手术治疗 (n = 25265)。随访于2021年2月结束。
结果: 该研究包括 30318名患者（中位年龄，46岁；中位体重指数，45；77%为女性；73%为白人），中位随访时间为 6.1年（3.8-8.9年）。减肥手术组 10年时体重的平均组间差异为 24.8公斤 (95% CI, 24.6-25.1公斤)或 19.2% (95% CI, 19.1%-19.4%)。在随访期间，减肥手术组的 96名患者和非手术对照组的 780名患者发生了肥胖相关癌症（每 1000人年的发病率分别为 3.0事件和 4.6事件）。减重手术组 10年主要终点的累积发生率为 2.9%（95% CI，2.2%-3.6%），非手术对照组为 4.9%（95% CI，4.5%-5.3%）。绝对风险差异，2.0% [95% CI，1.2%-2.7%]；调整后的风险比，0.68 [95% CI，0.53-0.87]，P = .002）。减肥手术组 21例患者和非手术对照组 205例患者发生癌症相关死亡率（发生率分别为每 1000人年 0.6次事件和 1.2次事件）。减肥手术组 10年癌症相关死亡率的累积发生率为 0.8%（95% CI，0.4%-1.2%），非手术对照组为 1.4%（95% CI，1.1%-1.6%）。绝对风险差，0.6% [95% CI，0.1%-1.0%]；调整后的风险比，0.52 [95% CI，0.31-0.88]，P = .01）。
结论:在肥胖的成年人中，与不进行手术相比，减肥手术与肥胖相关癌症的发生率和癌症相关死亡率显著降低相关。
In this retrospective cohort study of 30,318 patients (including 5,053 patients who underwent bariatric surgery and 25,265 matched patients in a non-surgical control group), bariatric surgery was significantly associated with a reduced risk of obesity-related cancers (hazard ratio, 0.68) and cancer-related mortality (hazard ratio, 0.52).
In the Surgical and Oncological Disease Incidence and Mortality Long-Term Efficacy (SPLENDID) matched cohort study, adults with a BMI of 35 or higher who underwent bariatric surgery in the U.S. health system from 2004 to 2017 were included. Patients who underwent bariatric surgery were matched 1:5 with those who did not due to obesity, for a total of 30,318 patients: bariatric surgery (n = 5.053) included Roux-en-Y gastric bypass and sleeve gastrectomy , and non-surgical treatment (n = 25265). Follow-up ended in February 2021.
Results: The study included 30,318 patients (median age, 46 years; median body mass index, 45; 77% female; 73% white) with a median follow-up of 6.1 years (3.8-8.9 years). The mean between group difference in weight at 10 years in the bariatric surgery group was 24.8 kg (95% CI, 24.6-25.1 kg) or 19.2% (95% CI, 19.1%-19.4%). During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group developed obesity-related cancers (incidence rate of 3.0 events and 4.6 events per 1000 person-years, respectively). The 10-year cumulative incidence of the primary end point was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group. Absolute risk difference was 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio was 0.68 (95% CI, 0.53-0.87, P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and in 205 patients in the nonsurgical control group (0.6 events per 1000 person-years and 1.2 events, respectively). The 10-year cumulative incidence of cancer-related mortality was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group. Absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 (95% CI, 0.31-0.88, P = .01).
Conclusions: Among obese adults, bariatric surgery compared with no surgery was associated with significantly lower rates of obesity-related cancer and cancer-related mortality.
参考文献 Reference Aminian A et al. JAMA 2022; 327: 2423全氟和多氟烷基物质在癌症发展和医疗保健成本中的作用 (7/31/2022)
The role of per- and polyfluoroalkyl substances in cancer development and healthcare costs
每天接触用于生产许多家居用品的一类化学品可能会导致癌症、甲状腺疾病和儿童肥胖。
全氟烷基物质和多氟烷基物质 (PFAS)是4,700多种人造化学物质中的一组，在数百万人的血液中检测到这些化学物质。这些化学物质用于生产防水防油服装、电子产品和不粘炊具，在食物接触到包装后会摄入这些化学物质。这些物质被认为会破坏激素的功能。 这项针对大约 5,000名美国人的新研究确定了 13种可能由 PFAS暴露引起的疾病，例如不孕症、糖尿病和子宫内膜异位症。 在这项调查中，研究人员使用从参加美国国家健康和营养检查调查的成人和儿童获得的血液样本，确定了 2018年有多少美国人可能接触了 PFAS化学物质。接下来，研究小组分析了过去十年中数十项研究的数据，这些研究探索了与这些物质有关的疾病。该团队使用早期调查的模型来估计与 PFAS接触最密切相关的前五种医疗条件导致的医疗费用和工人生产力损失的国家经济成本。这些包括低出生体重、儿童肥胖、肾癌和睾丸癌以及甲状腺功能减退。研究人员还扩大了他们的经济估计范围，包括与 PFAS暴露有初步联系的其他八种疾病，包括子宫内膜异位症、成人肥胖和儿童肺炎。考虑到这些疾病，总成本高达 630亿美元。
结果强烈支持环境保护署最近决定降低水中这些物质的安全允许水平。 尽管对 PFAS的健康风险进行了大量研究，但随着时间的推移，很少有研究探讨这种暴露的影响。研究小组接下来计划检查 PFAS的长期风险，
Daily exposure to a class of chemicals used in the production of many household items may contribute to cancer, thyroid disease and childhood obesity.
Per- and polyfluoroalkyl substances (PFAS) are a group of more than 4,700 man-made chemicals that have been detected in the blood of millions of people. These chemicals are used to make waterproof and oil-resistant clothing, electronics and non-stick cookware, and are ingested after food comes into contact with packaging. These substances are thought to disrupt hormone function. The new study of about 5,000 Americans identified 13 conditions that could be caused by PFAS exposure, such as infertility, diabetes and endometriosis. For the survey, researchers used blood samples obtained from adults and children who participated in the National Health and Nutrition Examination Survey to determine how many Americans were likely exposed to PFAS chemicals in 2018. Next, the team analyzed data from dozens of studies over the past decade that have explored diseases associated with these substances. The team used models from earlier investigations to estimate the national economic cost of medical bills and lost worker productivity from the top five medical conditions most closely associated with PFAS exposure. These include low birth weight, childhood obesity, kidney and testicular cancer, and hypothyroidism. The researchers also expanded their economic estimates to include eight other diseases initially linked to PFAS exposure, including endometriosis, obesity in adults and pneumonia in children. Taking these diseases into account, the total cost is as high as $63 billion.
The results strongly support the Environmental Protection Agency’s recent decision to lower the safe allowable levels of these substances in water. Although there has been a lot of research on the health risks of PFAS, few studies have explored the effects of this exposure over time. The research team next plans to examine the long-term risks of PFAS,
参考文献 Reference Obsekov V et al. Springer Link 2022; July 26.Ramucirumab加派姆单抗与标准护理相比治疗先前接受过免疫疗法的晚期非小细胞肺癌 (7/30/22)
Ramucirumab plus pembrolizumab versus standard of care in advanced NSCLC patients previously treated with immunotherapy
在这项随机 II期临床试验（Lung-MAP） 非匹配亚组(S1800A)中，晚期非小细胞肺癌患者在接受过免疫检查点抑制（至少 84天后）和铂类化疗且疾病进展，被随机分配接受Ramucirumab加上派姆单抗或研究者选择的标准护理（多西他赛/Ramucirumab,多西他赛,吉西他滨或培美曲塞）。主要目标是比较总生存期（使用单边 10%水平，标准对数秩和加权对数秩)。次要终点包括客观响应,响应持续时间、研究者评估的无进展生存期和毒性。
结果:在入组的 166名患者中，136名符合条件（69名接受Ramucirumab加派姆单抗；67名接受标准护理）。Ramucirumab加派姆单抗显著改善了总生存期（风险比80%,CI：0.69 [0.51至 0.92]；标准对数秩单侧P = .05；标准对数秩单侧P= .15）。Ramucirumab加派姆单抗组的中位（80% CI）生存期为 14.5（13.9至 16.1）个月，标准护理组为 11.6（9.9至 13.0）个月。在大多数亚组中都可以看到Ramucirumab加派姆单抗的总生存期益处。研究者评估的无进展生存期（风险比 [80%CI]：0.86 [0.66至 1.14]。响应率在两组之间相似。Ramucirumab加派姆单抗组中42%的患者和标准护理组中60%的患者发生≥ 3级治疗相关不良事件。
结论: 这项随机II期试验表明，与标准护理相比，Ramucirumab加派姆单抗组改善了接受过免疫检查点抑制和铂类化疗且疾病进展治疗的晚期非小细胞肺癌患患者的总生存期。
In this randomized phase II (Lung-MAP) unmatched substudy (S1800A), patients with advanced non-small cell lung cancer who had progressed after immune checkpoint inhibitors (after at least 84 days) and platinum-based chemotherapy were randomized. They were assigned to receive ramucirumab plus pembrolizumab or investigator’s choice of standard of care (docetaxel/ramucirumab, docetaxel, gemcitabine, or pemetrexed). The primary objective was to compare overall survival (using a one-sided 10% level usingthe better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary endpoints included objective response, duration of response, investigator-assessed progression-free survival, and toxicity.
Results: Of the 166 patients enrolled, 136 were eligible (69 received ramucirumab plus pembrolizumab; 67 received standard of care). Ramucirumab plus pembrolizumab significantly improved overall survival (hazard ratio 80%, CI: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). Median (80% CI) survival was 14.5 (13.9 to 16.1) months in the ramucirumab plus pembrolizumab group and 11.6 (9.9 to 13.0) months in the standard-of-care group. The overall survival benefit of ramucirumab plus pembrolizumab was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]). Response rates were similar between the two groups. Overall, 42% of patients in the ramucirumab plus pembrolizumab group and 60% in the standard-of-care group had grade ≥ 3 treatment-related adverse events.
Conclusions This randomized phase II trial demonstrated that ramucirumab plus pembrolizumab improved overall survival compared with standard care in patients with advanced non-small cell lung cancer who had received immune checkpoint inhibitors and platinum-based chemotherapy and whose disease had progressed.
参考文献 Reference Reckamp K et al. J Clin Onc 2022;40: 2295化疗加上帕尼单抗或贝伐单抗用于RAS 野生型转移性结直肠癌 (7/24/2022)
Panitumumab versus bevacizumab plus chemotherapy in RAS wild-type colorectal cancer
PARADIGM是一项在日本进行的开放标签、多中心 试验 (NCT02394795)。从未接受过化疗的RAS野生型转移性结直肠癌患者接受帕尼单抗（panitumumab）加上mFOLFOX6或贝伐单抗加上mFOLFOX6。主要终点为总生存率,在左侧肿瘤患者中进行了分层测试，其次是在全分析组人群中的患者。关键次要终点包括无进展生存,响应率和治愈性切除 (R0)率。
结果： 从 2015年 5月到 2017年 6月，823名患者被随机分组； 12人未接受方案治疗，9人因纳入标准存在重大偏差而被排除。共有 400人接受了帕尼单抗，402人接受了贝伐单抗作为全分析；分别有 312和 292名患者患有左侧原发性肿瘤。在左侧患者发生 448次总生存事件后分析总生存，中位随访时间为 61个月。帕尼单抗显著改善了两个人群的总生存率相比于贝伐单抗：左侧（HR，0.82；95.798%CI，0.68-0.99，p = .031，跨越显著性边界 [0.042]）和全分析组（HR，0.84； 95%CI，0.72-0.98；p = .030，以 < 0.05为界）。尽管治疗组之间的无进展生相当，但与贝伐单抗相比，帕尼单抗 的响应率和治愈性切除率更高。右侧结直肠癌患者总生存率的 HR为 1.09。没有观察到新的安全信号。
结论： 在患有 RAS野生型转移性左侧结直肠癌患者中，与贝伐单抗相比，帕尼单抗加上mFOLFOX6显著改善了总生存率，从而为该人群建立了标准的一线联合治疗方案。
PARADIGM is an open-label, multicenter trial conducted in Japan (NCT02394795). Chemotherapy-naive patients with RAS wild-type, metastatic colorectal cancer received panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary endpoint was overall survival, which washierarchicallytested in patients with left-sided tumors, followed by those in the full analysis cohort. Key secondary endpoints included progression-free survival, response rate, and curative resection (R0) rate.
Results: From May 2015 to June 2017, 823 patients were randomized; 12 did not receive protocol treatment and 9 were excluded due to significant bias in inclusion criteria. A total of 400 patients received panitumumab and 402 received bevacizumab for the full analysis; 312 and 292 patients, respectively, had left-sided primary tumors. Overall survival was analyzed after 448 overall survival events in left-sided patients, with a median follow-up of 61 months. Panitumumab significantly improved overall survival compared to bevacizumab in both populations: left (HR, 0.82; 95.798% CI, 0.68-0.99, p = .031, crossing the boundary of significance [0.042]) and the full analysis group (HR, 0.84; 95% CI, 0.72-0.98; p = .030, with < 0.05 as the boundary). Although progression-free was comparable between treatment groups, panitumumab had higher response rate and curative resection rates than bevacizumab. The HR for overall survival in patients with right-sided colorectal cancer was 1.09. No new safety signals were observed.
Conclusions: In patients with RAS wild-type metastatic left-sided colorectal cancer, panitumumab plus mFOLFOX6 significantly improved overall survival compared with bevacizumab. Thus a standard first-line combination regime for this population was established.
参考文献 Reference Yoshino T et al. 2022 ASCO Ann Meeting abstr LBA1检查点抑制剂和靶向治疗作为晚期胃癌/胃食管交界处癌的一线治疗 (7/23/2022)
Checkpoint inhibitors and target therapy as first-line therapy for advanced stage Gastric/GEJ cancer
III期临床试验数据显示检查点抑制剂作为晚期胃癌/胃食管交界处癌(GEJ)的一线治疗提高了生存率，特别是对于肿瘤PD-L1高表达的患者。
CheckMate 649是一项III期、随机、开放标签试验,验证了在晚期胃癌,GEJ和食管腺癌中使用nivolumab加化疗与化疗相比达得到了总生存期和无进展生存期的益处。FDA批准 nivolumab联合化疗用于所有晚期食管癌,GEJ和胃腺癌患者，无论PD-L1表达如何。
ORIENT-16是另一项随机,双盲,III期试验,显示另一种PD-1抑制剂sintilimab与化疗联合有利于晚期胃癌或 GEJ腺癌，无论PD- L1表达如何。 但随访显示,PD-L1表达较高的人有更多的活性，而对于那些PD-L1表达较低的人来说，生存益处并不多。CheckMate 649中 60%的患者的PD-L1 CPS为 5或更高。对CheckMate649进行 24个月随访的扩展分析发现，CPS低于 10的患者没有受益;另一种可能为PD-L1并不是一个很好的生物标志物,受限于肿瘤异质性和测试方法灵敏度。
就靶向治疗而言.III期KEYNOTE-811试验的第一项中期分析显示，在既往未经治疗的不可切除或转移性HER2阳性胃癌/GEJ癌患者中，将派姆单抗加入曲妥珠单抗和化疗后，客观响应率显著提高。其他试验表明，靶向药物bemarituzumab（阻断FGFR2b）加改良FOLFOX6方案的一线治疗,改善晚期胃癌/GEJ癌无进展生存期和中位总生存期。II期试验（NCT01630083，FAST）显示zolbetuximab（一种嵌合单克隆抗体，可与CLDN18.2结合并介导癌细胞死亡），加EOX（表柔比星、奥沙利铂、卡培他滨），与EOX相比延长了晚期胃癌/GEJ癌的生存期。
Data from a number of phase III clinical trials show that checkpoint inhibitors improved survival as first-line treatment of advanced gastric/gastroesophageal junction (GEJ) cancer, especially in patients with tumors with high PD-L1 expression.
CheckMate 649 is a phase III, randomized, open-label trial that validated overall survival and progression-free survival benefit with nivolumab plus chemotherapy compared with chemotherapy in advanced gastric, GEJ, and esophageal adenocarcinoma. FDA has approved nivolumab in combination with chemotherapy for all patients with advanced esophageal cancer, GEJ and gastric adenocarcinoma, regardless of PD-L1 expression.
ORIENT-16 is another randomized, double-blind, phase III trial showing that another PD-1 inhibitor, sintilimab, in combination with chemotherapy benefited advanced gastric or GEJ adenocarcinoma, regardless of PD-L1 expression. However, follow-up showed that patients with higher PD-L1 expression demonstrated more benefit, while those with lower PD-L1 expression had less of a survival benefit. Sixty percent of patients in CheckMate 649 had a PD-L1 CPS of 5 or higher. Extended analysis of CheckMate 649 with 24-month follow-up found no benefit in patients with CPS less than 10; another possibility is that PD-L1 may not be a perfect biomarker, limited by tumor heterogeneity and testing sensitivity.
With regard to target therapy, the first interim analysis of phase III KEYNOTE-811 trial showed addition of pembrolizumab to trastuzumab plus chemotherapy in patients with previously untreated unresectable or metastatic HER2-positive gastric/GEJ cancer, objective response rate was significantly improved. Other trials have shown that first-line treatment with the target drug bemarituzumab (blocking FGFR2b) plus mFOLFOX6 regimen improved progression-free survival and median overall survival in advanced gastric/GEJ cancer. Phase II trial (NCT01630083, FAST) showed zolbetuximab (a chimeric monoclonal antibody that binds to CLDN18.2 and mediates cancer cell death), plus EOX (epirubicin, oxaliplatin, capecitabine), prolonged survival in advanced gastric/GEJ cancer compared with EOX.
参考文献 Reference Janjigian YY et al. Lancet 2021; 398: 27 Xu J et al. Ann Oncol 2021; 32 suppl 5 Janjigian YY et al. Nature 2021; 600:727 Smyth EC et al. J Clin Onc 2022; 40, (16_suppl June 01, 2022) Sahin U et al. J Clin Onc; 2021; 32:609新型术前治疗可提高可切除的非小细胞肺癌的响应 (7/10/2022)
Novel neoadjuvant therapy in resectable NSCLC
与PD-L1抑制剂durvalumab联合的新型药物包括抗CD73单克隆抗体oleclumab,抗NKG2A单克隆抗体monalizumab或抗STAT3反义寡核苷酸danvatirsen。
在 2019年 3月至 2020年 9月期间，全球 II期开放标签,多中心,多药物平台NeoCOAST试验将 84名可切除的I期至 IIIA期非小细胞肺癌患者随机分配到四个治疗组之一：1)每 4周一次的durvalumab单药治疗；2)Durvalumab每 4周一次加上 oleclumab每 2周一次；3) Durvalumab每 4周一次加上 Monalizumab每 2周一次；或4)durvalumab每 4周一次加上danvatirsen每周一次。治疗进行了一个 28天的周期。 患者按淋巴结受累进行分层。 患者可以在完成新辅助治疗后的第 29天至第 42天接受手术切除。研究中的随访一直持续到第 105天。 主要终点是主要病理反应率。次要终点包括病理完全缓解率、安全性/耐受性、计划手术的可行性、药代动力学和免疫原性。研究人员还对肿瘤、血液和粪便微生物组生物标志物进行了探索性分析，以及根据实体瘤 1.1版响应评估标准的最佳总体响应和客观响应率。
主要发现: 在意向治疗人群中，durvalumab单药治疗的主要病理缓解率和病理完全缓解率与之前发表的抗PD-1/PD-L1抗体研究结果相似。在治疗组之间未观察到病理完全缓解或客观缓解率存在重大差异。 四个治疗组的主要病理缓解率和病理完全缓解率如下：1) Durvalumab单药治疗：11.1%和 3.7%;2) Durvalumab加oleclumab：19%和 9.5%;3) Durvalumab加monalizumab：30%和 10%;4) Durvalumab加danvatirsen：31.3%和 12.5%。
安全概况 任何含有durvalumab的组合均未报告新的安全信号。在接受治疗的人群中，超过 90%的患者在没有明显延迟的情况下完成了手术。七名接受治疗的患者无法完成手术:五名是由于疾病进展，一名是由于严重的不良事件（非治疗-相关），1人失访。
对基于肿瘤和基于血液的生物标志物的探索性分析产生了一些初步观察结果，包括接受新辅助durvalumab加oleclumab或durvalumab加 monalizumab的具有主要病理反应的患者具有与免疫细胞功能相关的外周转录特征，这表明联合的多重免疫通路抑制可能优于免疫检查点抑制剂单一疗法。然而，这些患者数量很少，组织样本有限，并且正在进行进一步的转化分析。
Novel drugs used in combination with the PD-L1 inhibitor durvalumab include the anti-CD73 monoclonal antibody oleclumab, the anti-NKG2A monoclonal antibody monalizumab, or the anti-STAT3 antisense oligonucleotide danvatirsen.
Between March 2019 and September 2020, the global phase II open-label, multicenter, multidrug platform NeoCOAST trial randomized 84 patients with resectable stage I to IIIA NSCLC to one of four treatment arms. 1) durvalumab monotherapy every 4 weeks; 2) durvalumab every 4 weeks plus oleclumab every 2 weeks; 3) durvalumab every 4 weeks plus monalizumab every 2 weeks; or 4) durvalumab every 4 weeks plus danvatirsen once a week. Treatment was performed in a 28-day cycle. Patients were stratified by lymph node involvement. Patients could undergo surgical resection from days 29 to 42 after completion of neoadjuvant therapy. Follow-up in the study continued until day 105. The primary endpoint was the major pathological response rate. Secondary endpoints included pathological complete response rate, safety/tolerability, feasibility of planned surgery, pharmacokinetics, and immunogenicity. Also performed was exploratory analyses of tumor, blood, and fecal microbiome biomarkers, as well as best overall response and objective response rates according to the Version 1.1 Response Evaluation Criteria.
Main findings: In the intention-to-treat population, the rates of major pathologic response and pathologic complete response with durvalumab monotherapy were similar to those of previously published anti-PD-1/PD-L1 antibody studies. No major differences in pathological complete response or objective response rates were observed between treatment groups. The primary pathological response rates and pathological complete response rates for the four treatment groups were as follows: 1) Durvalumab monotherapy: 11.1% and 3.7%; 2) Durvalumab plus oleclumab: 19% and 9.5%; 3) Durvalumab plus monalizumab: 30% and 10%; 4) Durvalumab plus danvatirsen: 31.3% and 12.5%. Safety Profile:
No new safety signals have been reported for any durvalumab-containing combination. In the treated population, more than 90 percent of patients completed the procedure without significant delay. Seven treated patients were unable to complete surgery: five due to disease progression, one due to a serious adverse event (non-treatment-related), and one was lost to follow-up.
Exploratory analyses of tumor- and blood-based biomarkers yielded some preliminary observations. Patients with major pathological responses receiving neoadjuvant durvalumab plus oleclumab or durvalumab plus monalizumab had peripheral transcriptional signatures associated with immune cell function, This suggests that combined multiple immune pathway inhibition may be superior to immune checkpoint inhibitor monotherapy. However, the number of patients were small, and tissue samples wee limited. Further translational analysis were underway.
参考文献 Reference Cascone T et al. AACR Ann Meeting 2022; abstr CT011Herbst RS et al. J Clin Onc 2022; DOI: 10.1200/JCO.22.00227晚期上皮性卵巢癌的一线化学免疫疗法相比于化疗的III 期双盲研究(7/9/2022)
Front line phase III chemo-immunotherapy versus chemotherapy in advanced ovarian cancer
Oregovomab 是一种鼠单克隆抗体, 它结合肿瘤相关的 CA125，通过改变/增强抗原性, 向特定 T 细胞呈递，使靶抗原 CA125 更具免疫原性。在一项随机 II 期研究中, 先前未治疗的上皮性卵巢癌患者中，oregovomab与紫杉醇和卡铂联合使用显著改善中位无进展生存期（41.8个月相比于 12.3 个月，HR 0.44 p = 0.0027)，和中位总生存期 （尚未达到相比于43.2 个月, HR O.34, p = 0.0077)。
FLORA-5 是一项 3 期、多中心、双盲、安慰剂对照的全球性临床试验。接受辅助（队列 1）或新辅助（队列 2）化疗的III / IV 期上皮性卵巢癌和血清CA125 > 50 U / ml的患者, 接受最佳减瘤手术后随机分配至紫杉醇和卡铂联合或不联合oregovomab。具有种系 BRCA1/2 突变的患者将被排除在外。化疗将在两个队列中每 3 周进行一次。在队列 1 中，在第 1、3 和 5 周期同时给予 Oregovomab/安慰剂，在 12 周（第 5 周期后）再加一次。新辅助患者（队列 2）将在第 4 和 6周期进行减瘤手术后给予oregovomab/安慰剂, 在第 6 周期后的 6 周和 18 周再加二次。
主要目标是无进展生存期。队列 1 将招募 372 名患者，队列 2 将招募 232 名患者。次要目标包括总生存期率, 不良事件频率和严重程度以及生活质量。探索性目标包括 iRECIST、TFST、TSST、PFS2 和潜在生物标志物的评估。
该研究正在美国积极招收。临床试验资料: https://clinicaltrials.gov/ct2/show/NCT04498117。
Oregovomab is a murine monoclonal antibody that binds to tumor-associated CA125 and renders the target antigen CA125 more immunogenic by altering/enhancing antigenicity and presentating to specific T cells. In a randomized phase II study, oregovomab in combination with paclitaxel and carboplatin significantly improved median progression-free survival in patients with previously untreated epithelial ovarian cancer (41.8 months vs 12.3 months, HR 0.44 p = 0.0027), and median overall survival (not yet reached vs. 43.2 months, HR O.34, p = 0.0077).
FLORA-5 is a phase 3, multicenter, double-blind, placebo-controlled, global clinical trial. Patients with stage III/IV epithelial ovarian cancer and serum CA125 >50 U/ml receive adjuvant (cohort 1) or neoadjuvant (cohort 2) chemotherapy were randomized to paclitaxel and carboplatin in combination with oregovomab or placebo. Patients with germline BRCA1/2 mutations will be excluded. Chemotherapy will be given every 3 weeks in both cohorts. In cohort 1, oregovomab/placebo is co-administered at cycles 1, 3, and 5, andwith an additional dose at 12 weeks following cycle 5. Neoadjuvant patients (cohort 2) will be given oregovomab/placebo after debulking surgery at cycles 4 and 6, and two additional doses at 6 and 18 weeks following cycle 6.
The primary objective is progression-free survival. Cohort 1 will enroll 372 patients and cohort 2 will enroll 232 patients. Secondary objectives include overall survival rate, frequency and severity of adverse events, and quality of life. Exploratory goals include iRECIST, TFST, TSST, PFS2, and assessment of potential biomarkers.
The study is actively enrolling in the United States. Clinical trial data: https://clinicaltrials.gov/ct2/show/NCT04498117.
参考文献 Reference Secord AA et al. J Clin Onc 2022; 40 (16)_suppl (June 1)新发现的自我反应类先天性 T 细胞介导的癌症免疫 (7/3/2022)
A newly discovered self-reactive innate-like T cells in cancer immunity
Nature 上最近的一篇文章报导在一项对小鼠和人类恶性肿瘤的 T 细胞调查中，发现了一群表达 αβ T 细胞受体具有高细胞毒性的类先天性 T 细胞 (ILTCKs)。这些细胞来自不同的胸腺祖细胞,在早期遇到同源抗原后产生。这些细胞对未突变的自身抗原具有广泛的反应性，可以识别癌细胞的不同标记或抗原（传统杀伤性 T 细胞识别特定的突变抗原）。
ILTCK在肿瘤进展期间由胸腺祖细胞不断补充。ILTCK不依赖于抗原呈递细胞（antigen presenting cells, 如树突细胞）, 因此更像先天免疫细胞。ILTCK对一种叫做白细胞介素 15 (IL-15)的分子十分敏感，这种分子由许多癌细胞产生。肿瘤内 ILTCK 的扩增和效应分化依赖于癌细胞中IL-15的表达，研究者发现，如果从癌细胞中去除 IL-15，ILTCK提供的保护就会被消除，肿瘤生长会增加。
研究者在老鼠身上进行了大部分实验，但这些T 细胞也存在于人类肿瘤中，包括患者的结肠癌肿瘤。研究人员希望研究结果能尽快转化为临床应用。
A recent article in Nature reported the discovery of a population of highly cytotoxic innate-like T cells (ILTCKs) expressing the αβ T cell receptor in a study of mouse and human malignancies. These cells arise from different thymic progenitors and have encountered cognate antigens at an early stage. These cells are broadly reactive to unmutated self-antigens and can recognize different markers or antigens on cancer cells (traditional killer T cells recognize specific mutated antigens).
ILTCK is continually replenished by thymic progenitor cells during tumor progression. ILTCK is not dependent on antigen presenting cells (such as dendritic cells) and thus behaves more like innate immune cells. ILTCK is sensitive to interleukin 15 (IL-15), which is produced by many cancer cells. Intratumoral ILTCK amplification and effector differentiation depend on the expression of IL-15 in cancer cells. It was found that if IL-15 was removed from cancer cells, the protection afforded by ILTCK was abolished and tumor growth increased.
Nost of the experiments were performed in mice. However, these T cells were also present in human tumors, including colon cancer in patients. It was hoped that the findings will be translated into clinical applications in the future.
参考文献 Reference Chou C et al. Nature 2022; 605:139与双特异性抗体复合的自然杀伤细胞治疗难治性淋巴瘤 (7/2/2022)
Bridging bispecific antibody with NK cells in treating refractory lymphoma
一种双特异性抗体，AFM13,桥接淋巴瘤细胞上的 CD30和自然杀伤细胞上的CD16A ,帮助自然杀伤细胞更有效地对抗癌症。研究者发现将 AFM13与脐带血衍生的活化 NK细胞联系起来,比单独用AFM13或未连接的 NK细胞治疗小鼠更有效。从脐带血中分离出NK细胞，与外周血细胞相比，产生的免疫副作用更少。
这是一项I/II期临床试验,研究人员已经招募了 22名复发性 CD30+淋巴瘤患者，他们都曾接受过brentuximab vedotin的治疗，其中大多数人接受了干细胞移植。在免疫细胞耗竭后，患者接受AFM13-NK细胞复合物治疗。他们接受了100万细胞/公斤（3名患者）、1000万细胞/公斤（3名患者）或1亿细胞/公斤（13名患者）的两个周期，其中最高剂量被选为推荐的II期剂量。在用复合细胞治疗后 7, 14和 21天，患者被单独额外输注AFM13。 在所有剂量水平中，53%的患者完全缓解，37%的患者出现部分缓解，11%的患者出现疾病进展。值得注意的是，在推荐的II期剂量治疗的 13名患者中，总体反应率为 100%，包括 8名完全反应和 5名部分反应。 在所有剂量水平的中位随访 11个月时，无进展生存率为 53%，总生存率为 79%。
除了由免疫细胞耗竭导致的预期血液学毒性外，研究人员没有观察到自然杀伤细胞的不良事件，并且在随后的AFM13输注中仅观察到一个3级或更高级别的不良事件。
结论:初步结果表明该疗法具有良好的耐受性和高活性。局限性包括较短的随访时间和两个周期后反应持久性的信息。
A bispecific antibody, AFM13, bridges CD30 on lymphoma cells and CD16A on natural killer cells, helping natural killer cells fight cancer more effectively. The researchers found that linking AFM13 to cord blood-derived activated NK cells was more effective than treating mice with AFM13 alone or unlinked NK cells. NK cells isolated from umbilical cord blood produce fewer immune side effects than peripheral blood cells.
In this phase I/II clinical trial, researchers enrolled 22 patients with relapsed CD30+ lymphoma who had been previously treated with brentuximab vedotin, most of whom received stem cell transplants. After immune cell depletion, patients were treated with AFM13-NK cell complexes. They received two cycles of 1 million cells/kg (3 patients), 10 million cells/kg (3 patients), or 100 million cells/kg (13 patients), with the highest dose selected as the recommended phase II dose. Patients were additionally infused with AFM13 alone at 7, 14 and 21 days after treatment with composite cells. Across all dose levels, 53% of patients had a complete response, 37% had a partial response, and 11% had disease progression. Notably, among the 13 patients treated at the recommended phase II dose, the overall response rate was 100%, including 8 complete and 5 partial responses. At a median follow-up of 11 months across all dose levels, progression-free survival was 53% and overall survival was 79%.
Aside from the expected hematologic toxicity caused by immune cell depletion, no NK cell-related adverse events were observed, with only one grade 3 or higher adverse upon subsequent AFM13 infusions.
Conclusions: Preliminary results suggest that the therapy is well tolerated and highly active.Limitations include short follow-up time and limited information on the durability of response after two cycles.
参考文献 Reference Nieto Y et al. AACR 2022; abstr CT0003Sitravatinib 用于免疫治疗后疾病进展的非小细胞肺癌 (6/26/2022)
Sitravatinib in NSCLC patients who progressed after immunotherapy
Sitravatinib是一种选择性酪氨酸激酶抑制剂,包括TAM受体和 VEGFR2,它们参与肿瘤微环境的免疫抑制，并可能介导对检查点抑制剂治疗产生耐药性。使用sitravatinib的假设是，它将在免疫治疗难治性非小细胞肺癌患者中重建肿瘤微环境的免疫原性，从而增强对检查点抑制剂治疗的反应。
这是一项II期临床试验(MRTX-500 , NCT02954991),在 68名患者队列中的更新结果表明，使用Sitravatinib（120毫克每天一次）加 nivolumab（每 2或 4周一次）作为第二,或三线治疗与 15个月的中位总生存期和 56%的 1年总生存率相关。中位随访时间为 34个月。客观响应率为 18%,其中两名患者实现了完全缓解,中位响应持续时间为 13个月。治疗相关不良事件: 66%的患者发生 3-4级，最常见 (≥16%)是高血压和腹泻。 Sitravatinib和nivolumab的不良事件相关停药率分别为 21%和 9%。
一项Ib期试验研究了Sitravatinib（每天 120毫克）与Tislelizumab（一种抗PD-1抗体,每 3周 200毫克）联合使用,旨在最大限度地减少检查点抑制剂耐药性的发展（摘要 1P）。在 47名患者中，中位随访时间为 7.8个月，确认的客观响应率为 14%，中位响应持续时间为 7个月，中位无进展生存期为 5个月。 68%的患者出现≥3级不良事件；最常见的是高血压（19%）。
在这些早期试验中包括的经过多线治疗的免疫肿瘤学难治性患者，sitravatinib加检查点抑制剂治疗组合的疗效信号值得进一步调查。耐受性将成为临床使用Sitravatinib的一个因素， 3级高血压是一种与sitravatinib对 VEGFR2的作用一致的副作用，可能需要调整剂量。 III期SAPPHIRE试验（NCT03906071）在随机环境中比较sitravatinib加nivolumab与多西紫杉醇，将为了解这种新治疗方法的潜力提供进一步见解。
Sitravatinib is a spectrum-selective inhibitor of tyrosine kinases, including TAM receptors and VEGFR2, which are involved in immunosuppression of the tumor microenvironment and may mediate resistance to checkpoint inhibitor therapy. The hypothesis with sitravatinib is that it will re-establish the immunogenicity of the tumor microenvironment in NSCLC patients who were refractory to immunotherapy, thereby enhance the response to checkpoint inhibitor therapy.
This is a phase II clinical trial (MRTX-500, NCT02954991) with updated results in a cohort of 68 patients using sitravatinib (120 mg once daily) plus nivolumab (every 2 or 4 weeks) as a second, or third-line therapy. The combination demonstrated a median overall survival of 15 months and a 1-year overall survival rate of 56%. The median follow-up time was 34 months. The objective response rate was 18%, with two patients achieving complete responses and a median duration of response of 13 months. Treatment-related adverse events included grade 3-4 occurred in 66% of patients, the most common (≥16%) were hypertension and diarrhea. Adverse event-related discontinuation rates were 21% and 9% for sitravatinib and nivolumab, respectively.
Another phase Ib trial investigating sitravatinib (120 mg daily) in combination with Tislelizumab (an anti-PD-1 antibody, 200 mg every 3 weeks) designed to minimize the development of checkpoint inhibitor resistance (abstract 1P). Among 47 patients, with a median follow-up of 7.8 months, the confirmed objective response rate was 14%, the median duration of response was 7 months, and the median progression-free survival was 5 months. Grade adverse events（≥3）occurred in 68% of patients; the most common was hypertension (19%).
In this heavily-treated population including checkpoint inhibitors, the efficacy signal of sitravatinib plus checkpoint inhibitor therapy merits further investigation. Tolerability will be a factor in the clinical use of sitravatinib, and grade 3 hypertension is a side effect consistent with sitravatinib’s effect on VEGFR2 and may require dose adjustment. The Phase III SAPPHIRE trial (NCT03906071), comparing sitravatinib plus nivolumab with docetaxel in a randomized setting, will provide further insights into the potential of this new treatment.
参考文献 Reference Gao B et al. ESMO Targeted Anticancer Therapies Congress 2022, Abstr 1PLeal TA et al. ESMO Targeted Anticancer Therapies Congress 2022, Abstr 43pDatopotamab deruxtecan (Dato-DXd) 加上 durvalumab治疗晚期三阴性乳腺癌 (6/25/2022)
Datopotamab deruxtecan plus durvalumab in locally advanced triple negative breast cancer
Dato-DXd 是一种TROP2 抗体-药物偶联物(ADC)，在经过多线治疗的晚期三阴性乳腺癌中获得了 34% 的客观响应率。 在Ib/2期开放标签临床试验（BEGONIA, NCT03742102）中， durvalumab与其他疗法（包括 ADC）相结合，正在第一线晚期三阴性乳腺癌中进行评估。 以下是Dato-DXd 加上 durvalumab的初步结果。
方法: 无论 PD-L1/TROP2 状态如何，符合第一线治疗条件的不可切除/转移性晚期三阴性乳腺癌患者每 3 周接受一次 Dato-DXd 6 毫克/公斤 加上durvalumab 1120 毫克静脉注射，直至疾病进展或出现不可接受的毒性。主要终点是安全性和耐受性。次要终点包括研究者评估的客观响应率和反应持续时间。数据截止日期为 2021年11月。
结果: 29 名接受了 Dato-DXd加上durvalumab（24 名正在进行），27 名有机会进行 2 次基线后扫描。中位随访时间为 3.9（2-6）个月。确认的客观响应率为 20/27（74%；95% CI，54-89）； 2 (7%) 名患者有完全响应，18 名 (67%) 有部分响应，所有患者在数据截止时都有响应。
未观察到剂量限制性毒性。治疗相关不良事件 3/4 年级 8名 (28%), 5 级不良事件为0。 4 名患者（14%）因口腔炎接受了 1 次 Dato-DXd 剂量减少，4 名（14%）患者出现 1 次 Dato-DXd 剂量延迟，4 名（14%）患者出现 1 次剂量延迟。2名（7%）由于不良事件而停止治疗。
结论: 初步分析显示，在第一线晚期三阴性乳腺癌中, Datopotamab deruxtecan加上durvalumab的组合显示出良好的响应率和可控的安全性，值得进一步调查。
Dato-DXd is a TROP2 antibody-drug conjugate (ADC), which has been shown to achieve an objective response rate of 34% in advanced triple-negative breast cancer after multiple lines of therapy. In a Phase Ib/2 open-label clinical trial (BEGONIA, NCT03742102), durvalumab is being evaluated in first-line advanced triple-negative breast cancer in combination with other drugs, including ADC. There was a report that showed preliminary results for Dato-DXd plus durvalumab.
Methods: Patients with unresectable advanced/metastatic triple-negative breast cancer were eligible for first-line therapy, regardless of PD-L1/TROP2 status. They received Dato-DXd 6 mg/kg plus durvalumab 1120 mg IV every 3 weeks until disease progression or unacceptable toxicity. The primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed objective response rate and duration of response. Data cutoff date was November 2021.
Results: 29 received Dato-DXd plus durvalumab (24 patients ongoing) and 27 had access to 2 post-baseline scans. The median follow-up time was 3.9 (2-6) months. Confirmed objective response rate was 20/27 (74%; 95% CI, 54-89); 2 (7%) patients had a complete response and 18 (67%) had a partial response, all patients at data cutoff demonstrated a response.
No dose-limiting toxicity was observed. Treatment-related adverse events were grade 3/4 in 8 (28%), and grade 5 was 0. Four patients (14%) received a Dato-DXd dose reduction for stomatitis, four (14%) patients experienced a Dato-DXd dose delay, and four (14%) patients experienced a dose delay. Two (7%) discontinued treatment due to adverse events.
Conclusion: Preliminary analysis showed that the combination of datopotamab deruxtecan plus durvalumab in first-line unresectable advanced/metastatic triple-negative breast cancer showed favorable response rates and a manageable safety profile that warrants further investigation.
参考文献 Reference Schmid P et al. Ann Onc 2022; 33(supp 3): S194-223Sacituzumab govitecan 治疗激素受体阳性/HER2 阴性晚期乳腺癌的III 期研究 (6/19/2022)
A phase 3 study of sacituzumab govitecan in hormone receptor–positive/HER2-negative advanced breast cancer
Sacituzumab govitecan （SG） 是一种抗Trop-2 抗体-药物偶联物，已获FDA批准用于先前治疗过的转移性三阴性乳腺癌。TROPiCS-02 是一项 III 期随机研究 (NCT03901339)，用于确认SG在激素受体阳性/HER2 阴性 （HR+/HER2–） 晚期乳腺癌中的结果。
方法：参加者为不可切除的局部晚期或转移性HR+/HER2–乳腺癌, 以及 接受过2-4 次 既往化疗；如果在（新）辅助治疗后疾病进展≤12 个月，则允许对转移性乳腺癌 进行 1 次先前治疗。患者必须在任何环境中接受过≥1种紫杉烷、CDK4/6抑制剂和内分泌治疗。患者以 1:1 的比例随机接受 SG（第 1 天和第 8 天静脉注射 10 毫克/公斤，每 21 天一个周期）或化疗组（TPC, 卡培他滨、艾日布林、长春瑞滨或吉西他滨, capecitabine, eribulin, vinorelbine, or gemcitabine），直至疾病进展或不可接受的毒性。 主要终点是无进展生存期, 关键次要终点是总生存期（第一次计划的中期分析）。
结果： 在 2022 年 1 月 3 日数据截止时，272 对 271 名患者分别随机接受 SG 或化疗。 SG 组与化疗组相比改善了中位无进展生存期（5.5 与 4.0 个月；HR，0.66；95% CI，0.53-0.83；P = 0.0003）； 6 个月和 12 个月的无进展生存率分别为 46% 对 30% 和 21% 对 7%。 SG 与化疗组在总生存期上显示出差异但统计学上不显著（13.9 与 12.3 个月；HR，0.84；P = 0.143）； SG 相比于化疗组的总客观响应率（21% 对 14%）和临床受益率（34% 对 22%）更高，中位缓解持续时间分别为 7.4 对 5.6 个月。
不良事件: 74% 对 60% 的患者（SG 对化疗组）有≥3 级治疗出现的不良事件；中性粒细胞减少（51% 对 39%）和腹泻（10% 对 1%）最为常见。导致 SG 与化疗组终止治疗的不良事件较低（6% 与 4%）。 SG 组有 1 例与治疗相关的死亡； 化疗组中没有。
结论： 与单药化疗相比，SG 显示无进展生存期益处，并且在治疗选择有限的 HR+/HER2- 局部晚期或转移性乳腺癌患者中具有可控的安全性。
Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate that has been approved by FDA for previously treated metastatic triple-negative breast cancer. TROPiCS-02 is a randomized phase III study (NCT03901339) to confirm the results of SG in hormone receptor-positive/HER2-negative (HR+/HER2–) advanced breast cancer.
Methods: Eligible participants had unresectable locally advanced or metastatic HR+/HER2– breast cancer and 2-4 prior chemotherapy regimens; if disease progressed ≤12 months after (neo)adjuvant therapy, one prior therapy for metastatic disease was allowed. Patients must have received ≥1 taxane, CDK4/6 inhibitor, and endocrine therapy in any setting. Patients were randomized in a 1:1 ratio to receive SG (10 mg/kg IV on days 1 and 8, every 21-day cycle) or chemotherapy (TPC, capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the key secondary endpoint was overall survival (first planned interim analysis).
Results: At data cutoff on January 3, 2022, 272 vs 271 patients were randomized to receive SG vs chemotherapy, respectively. Median progression-free survival was improved with SG versus chemotherapy (5.5 vs. 4.0 months; HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003); progression-free survival at 6 and 12 months was 46% vs 30% and 21% vs 7%, respectively. There was a numerical but nonsignicant statistical difference in overall survival between the SG and chemotherapy groups (13.9 vs 12.3 months; HR, 0.84; P = 0.143). SG vs chemotherapy showed the overall objective response rates for SG vs chemotherapy (21% vs 14 %) and clinical benefit rates (34% vs 22%), with median duration of response of 7.4 vs 5.6 months, respectively.
Adverse Events: 74% vs 60% of patients (SG vs chemotherapy arm) had grade ≥3 treatment-emergent adverse events; neutropenia (51% vs 39%) and diarrhea (10% vs 1%) were the most common. Adverse events leading to treatment discontinuation in the SG versus chemotherapy arm were quite low (6% versus 4%). There was one treatment-related death in the SG group; none in the chemotherapy group.
Conclusions: SG showed a progression-free survival benefit compared to single-agent chemotherapy with a manageable safety profile in patients with HR+/HER2- locally advanced or metastatic breast cancer with limited treatment options.
参考文献 Reference Rugo HS et al. 2022 ASCO Ann Meeting abstr LBA1001曲妥珠单抗 deruxtecan用于HER2低表达的转移性乳腺癌(6/18/2022)
Trastuzumab deruxtecan in HER2-low metastatic breast cancer
目前的 HER2 导向疗法对HER2低表达的乳腺癌症患者无效（HER2低表达的定义为免疫组化分析为 1+，或2+，原位杂交结果为阴性）。一项 III 期试验招募之前接受过1-2线化疗的HER2低表达转移性乳腺癌患者。患者以 2:1 的比例随机分配接受 曲妥珠单抗 deruxtecan或医生选择的化疗。主要终点是激素受体阳性队列的无进展生存期。关键的次要终点是所有患者的无进展生存期和激素受体阳性队列和所有患者的总生存期。
结果: 在随机分组的 557 名患者中，494 名（88.7%）为激素受体阳性，63 名（11.3%）为激素受体阴性。在激素受体阳性队列中，曲妥珠单抗 deruxtecan 组的中位无进展生存期为 10.1 个月，医生选择组为 5.4 个月（疾病进展或死亡的风险比，0.51；P < 0.001），总生存期为分别为 23.9 个月和 17.5 个月（死亡风险比，0.64；P = 0.003）。在所有患者中，曲妥珠单抗 deruxtecan 组的中位无进展生存期为 9.9 个月，医师选择组为 5.1 个月（疾病进展或死亡的风险比，0.50；P < 0.001），总生存期为 23.4 个月和 16.8 个月个月（死亡风险比，0.64；P = 0.001）。
接受曲妥珠单抗 deruxtecan 治疗的患者中有 52.6% 发生 3 级或更高级别的不良事件，接受医生选择化疗的患者发生率为 67.4%。接受曲妥珠单抗德鲁替康治疗的患者中有 12.1% 发生了经裁定的与药物相关的间质性肺病或肺炎； 0.8% 有 5 级事件（死亡）。
结论: 在这项HER2低表达的转移性乳腺癌患者试验中，与医生选择的化疗相比，曲妥珠单抗 deruxtecan 显著延长了无进展生存期和总生存期。
Current HER2-directed therapies are ineffective in patients with breast cancer with HER2-low expression (defined as 1+, or 2+ by immunohistochemical analysis and negative by in-situ hybridization). A phase III trial enrolled patients with metastatic breast cancer with HER2-low expression who had previously received 1-2 lines of chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either trastuzumab deruxtecan or physician’s choice chemotherapy. The primary endpoint was progression-free survival in the hormone receptor-positive cohort. Key secondary endpoints were progression-free survival in all patients and overall survival in the hormone receptor-positive cohort and all patients.
Results: Of the 557 patients randomized, 494 (88.7%) were hormone receptor positive and 63 (11.3%) were hormone receptor negative. In the hormone receptor-positive cohort, median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice group (hazard ratio for disease progression or death, 0.51; P < 0.001), Overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P < 0.001), and overall survival were 23.4 months and 16.8 months (hazard ratio for death, 0.64; P = 0.001).
Adverse events of grade 3 or higher occurred in 52.6% of patients receiving trastuzumab deruxtecan and 67.4% of patients receiving physician’s choice chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients treated with trastuzumab deruxtecan; 0.8% had grade 5 events (death).
Conclusion: In this trial of patients with metastatic breast cancer with low HER2 expression, trastuzumab deruxtecan significantly prolonged progression-free survival and overall survival compared with physicians’ choice of chemotherapy.
参考文献 Reference
Modi S et al.Ne Engd J Med 2022; June 5. DOI: 10.1056/NEJMoa2203690
ZUMA-2 研究的三年随访: Brexucabtagene autoleucel (KTE-X19) 治疗复发/难治性套细胞淋巴瘤 (6/12/2022)
Three-year follow-up of ZUMA-2 study: KTE-X19in relapsed/recurrent mantle cell lymphoma
KTE-X19（自体性抗 CD19 嵌合抗原受体 [CAR] T 细胞疗法）被批准用于治疗复发/难治性套细胞淋巴瘤。该报告随访了先前接受过1 到 5 种治疗的患者（包括苯达莫司汀 [bendamustine]和BTK抑制剂亚组）或高-风险特征。他们接受单次输注 KTE-X19（2 × 106 CAR T 细胞/kg）。
中位随访 35.6 个月后，所有 68 名接受治疗的患者的客观响应率为 91%（95% CI，81.8 至 96.7），完全响应率为 68%（95% CI，55.2 至 78.5）；响应持续时间, 无进展生存期和总生存期的中位数分别为 28.2 个月（95% CI，13.5 至 47.1）、25.8 个月（95% CI，9.6 至 47.6）和 46.6 个月（95% CI，24.9 至无估计）。
事后分析表明，根据先前接受过BTK抑制剂或高风险特征，客观响应率和持续响应率在预先指定的亚组中是一致的。共有 37 名患者接受过苯达莫司汀治疗，31 名未接受过治疗。 在这两个子集中, 客观响应分别为84% 和 100% ，并且在数据截止时响应持续分别为 29% 和 48% 。在一项探索性分析中，先前使用苯达莫司汀的患者从 KTE-X19 中受益，但显示出 T 细胞功能减弱的趋势，在白细胞分离术的 6 个月内给予苯达莫司汀的影响比 12 个月更大。
迟发性毒性不常见。在这个随访期内，仅 3% 在 ZUMA-2 试验中因治疗引起值得关注的不良事件。评估显示与 KTE-X19长期益处相关的因数: 响应者中CAR T 细胞扩增的高峰值和最小残留疾病对复发的预测价值。
结论 这些数据代表了迄今为止对套细胞淋巴瘤患者进行 CAR T 细胞治疗的最长随访时间，表明 KTE-X19 在复发/难治性套细胞淋巴瘤患者中诱导了持久的长期响应，且安全性可控。
KTE-X19 (autologous anti-CD19 chimeric antigen receptor [CAR] T cell therapy) is approved for the treatment of relapsed/refractory mantle cell lymphoma. The report followed patients who received 1 to 5 prior treatments (including bendamustine and BTK inhibitor subsets) or high-risk characteristics. They received a single infusion of KTE-X19 (2 × 106 CAR T cells/kg).
After a median follow-up of 35.6 months, the 68 treated patients had an objective response rate of 91% (95% CI, 81.8 to 96.7) and a complete response rate of 68% (95% CI, 55.2 to 78.5); responses duration time, median progression-free survival and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 tonot estimable) respectively.
Post hoc analyses showed that objective and sustained response rates were consistent in prespecified subgroups based on prior BTK inhibitor exposure or high-risk characteristics. In these two subsets, objective response was 84% and 100%, respectively, and response persisted at data cutoff of 29% and 48%, respectively.In an exploratory analysis, patients who had previously used bendamustine benefited from KTE-X19 but showed a trend toward diminished T cell functionality, with more impact of bendamustine given within 6 months versus 12 months of leukapheresis.
Delayed toxicity is uncommon. During this follow-up period, only 3% of treatment-related adverse effects of interest in the ZUMA-2 trial occurred. Translational assessments showed factors associated with long-term benefit of KTE-X19: high peak CAR T-cell expansion in responders and predictive value of minimal residual disease for relapse.
Conclusions These data represent the longest follow-up of CAR T-cell therapy in patients with mantle cell lymphoma and demonstrate that KTE-X19 induces durable long-term responses with manageable safety in patients with relapsed/refractory mantle cell lymphoma and may benefit those with high-risk features.
参考文献 Reference Wang M et al. J Clin Onc 2022; June 4. DOI: 10.1200/JCO.21.02370Mirvetuximab Soravtansine 治疗耐铂类卵巢癌 (6/11/2022)
Mirvetuximab Soravtansine in platinum-resistant ovarian cancer
Mirvetuximab soravtansine是针对叶酸受体α阳性的抗体-药物偶联物。这是一项III期临床试验（SORAYA），招募了 106名FRα高表达的耐铂类的卵巢癌患者，这些患者之前曾接受过 1至 3次的全身治疗，其中至少有一种包括贝伐单抗。主要终点为研究者评估的客观响应率。次要终点包括研究者评估的响应持续时间,CA-125反应, 安全性和耐受性,无进展生存期,总生存期。
SORAYA的数据首次在妇科肿瘤学会2022年年会上公布。 研究者的客观响应率为 32.4%（95%置信区间 [CI]：23.6%、42.2%），包括 5个完全响应。中位响应时间为 1.5个月（范围 1.0至 5.6），71.4%的患者表现出肿瘤缩小。 疾病控制率（定义为完全响应,部分响应或疾病稳定持续≥12周），为51.4%。 研究者的中位响应持续时间为 6.9个月（95%CI：5.6, 9.7），截至 2022年 4月 29日，有 5名响应者继续使用mirvetuximab。 研究者评估的中位无进展生存期为 4.3个月 (95%CI: 3.7, 5.2)。 初步的中位生存期为 13.8个月，54%的可评估患者群体无事件发生。 在盲法独立中央审查的敏感性分析中，结果相似：客观响应率30.2%（95%CI：21.3%，40.4%），有 6个完全响应；未达到中位响应持续时间（95%CI：5.0，NR）； 中位无进展生存期5.5个月 (95%CI: 3.8, 6.9)。 在响应者中，响应的深度和持续时间似乎不受剂量减少的影响。
Mirvetuximab 耐受性良好，最常见的治疗相关不良事件包括视力模糊（所有级别 41%，3+级 6%）、角膜病变（所有级别 29%，3+级 9%）和恶心（所有级别 29%，0 % 3+级）。 不良事件通常通过支持治疗或必要时剂量调整来解决；因不良事件导致的停药率为 9%。
Mirvetuximab soravtansine is a folate receptor alpha antibody-drug conjugate.This is a phase III clinical trial (SORAYA) that enrolled 106 patients with FRα-expressing platinum-resistant ovarian cancer who had received 1 to 3 prior systemic therapies, at least one of which included bevacizumab. The primary endpoint was investigator-assessed objective response rate. Secondary endpoints included investigator-assessed duration of response, CA-125 response, safety and tolerability, progression-free survival, and overall survival.
Data from SORAYA were first presented at the Society of Gynecologic Oncology 2022 Annual Meeting. The investigators-assessed objective response rate was 32.4% (95% confidence interval [CI]: 23.6%, 42.2%), including 5 complete responses. The median time to response was 1.5 months (range 1.0 to 5.6), and 71.4% of patients showed tumor shrinkage. The disease control rate (defined as complete response, partial response, or stable disease for ≥12 weeks) was 51.4%. The investigators-assessed median duration of response was 6.9 months (95% CI: 5.6, 9.7), and as of April 29, 2022, five respondents remained on mirvetuximab. The investigator-assessed median progression-free survival was 4.3 months (95% CI: 3.7, 5.2). The preliminary median survival was 13.8 months, and 54% of the evaluable patient population was event-free. In a blinded independent centrally reviewed sensitivity analysis, the results were similar: objective response rate 30.2% (95% CI: 21.3%, 40.4%) with 6 complete responses; median duration of response was not reached (95% CI: 21.3%, 40.4%) 5.0, NR); median progression-free survival was 5.5 months (95% CI: 3.8, 6.9). In responders, the depth and duration of response did not appear to be affected by dose reduction.
Mirvetuximab was well tolerated, with the most common treatment-related adverse events including blurred vision (41% of all grades, 6% of grade 3+), keratopathy (29% of all grades, 9% of grade 3+), and nausea (29% of all grades) , 0 % Level 3+). Adverse events were usually resolved with supportive care or dose adjustment as necessary; discontinuation due to adverse events was 9%.
参考文献 Reference Matulonis UA et al. 2022 SGO Ann Meeting on Women’s Cancer. Abstr 242.[F-18]FES-PET 评估新诊断的转移性乳腺癌患者雌激素受体 (6/5/2022) [F-18]FES-PET evaluate estrogen receptor status in newly diagnosed metastatic breast cancer
一项期临床试验（IMPACT-MBC） 研究的亚分析中， [氟F-18]氟-17β-雌二醇PET-CT断层扫描（[F-18]FES-PET)在预测新诊断的转移性乳腺癌患者转移灶中的雌激素受体表达方面非常准确。
这项多中心研究的亚分析包括 2013年 8月至 2018年 5月期间入组的 200名患者。将活检转移灶中免疫组织化学测定的雌激素受体表达与[F-18]FES-PET全身定性评估,和局部[F-18]FES定量摄取进行比较。 在 200名患者中的 181名中，免疫组织化学活检转移的雌激素受体状态可以与全身 [F-18]FES-PET定性评估进行比较。在 200名患者中的 156名患者中，免疫组织化学测定的雌激素受体状态可以与相应转移灶中的定量[F-18]FES摄取进行比较。
全身定性[F-18]FES-PET评估预测活检转移灶中的雌激素受体表达，敏感性为 95%（95%置信区间 [CI] = 89%–97%），特异性为 80%（95%CI = 66%–89%)，阳性预测值为 93% (95%CI = 87%–96%)，阴性预测值为 85% (95% CI = 72%–92%)。 181例患者中，免疫组织化学测定的转移灶雌激素受体阳性132例，阴性49例。全身[F-18]FES-PET，雌激素受体阳性135例（其中免疫组织化学阴性10例），阴性46例（其中 7例免疫组织化学阳性）。
局部定量[F-18]FES摄取预测雌激素受体表达，敏感性为 91% (95%CI= 84%–95%)，特异性为 69% (95%CI = 54%–81%)，阳性预测值为 90 %（95%CI = 83%–94%），阴性预测值为 71%（95%CI= 55%–83%）。对于骨转移，阳性预测值和阴性预测值分别为92%和81%。在 156例定量预测患者中，117例转移灶经免疫组织化学测定为雌激素受体阳性，39例阴性。而定量[F-18]FES预测雌激素受体态阳性 118例（其中 12例免疫组织化学阴性），38例阴性（包括11例免疫组织化学阳性）。
当结果被纳入与其他 12项研究的荟萃分析时，总人群为 556名患者，[F-18]FES-PET的定性评估的汇总敏感性为 84%（95%CI = 75%–90% )和特异性 92% (95%CI= 64%–99%)。[F-18]FES-PET摄取的定量评估具有 89% (95%CI = 85%–92%)的汇总敏感性和 78% (95%CI = 69%–84%)的特异性。
总结:[F-18]FES-PET可用以确定转移性乳腺癌中的肿瘤雌激素受体状态,这种无创成像方式可以是活检的有效替代方法。
In a sub-analysis of a phase III clinical trial (IMPACT-MBC), [Fluoro-F-18]Fluoro-17 β-estradiol PET-CT tomography ([F-18]FES-PET) predicted accurately estrogen receptor status in newly diagnosed metastases from breast cancer.
A sub-analysis of this multicenter study included 200 patients enrolled between August 2013 and May 2018. Immunohistochemically determined estrogen receptor expression in biopsy metastases was compared with qualitative [F-18]FES-PET whole-body assessment, and local [F-18]FES quantitative uptake. In 181 of 200 patients, metastatic estrogen receptor status on immunohistochemical biopsy was comparable to qualitative assessment of whole body [F-18]FES-PET. In 156 of 200 patients, estrogen receptor status determined by immunohistochemistry could be compared with quantitative [F-18]FES uptake in corresponding metastases.
Whole-body qualitative [F-18]FES-PET assessment predicted estrogen receptor expression in biopsy metastases with 95% sensitivity (95% confidence interval [CI] = 89%–97%) and 80% specificity ( 95% CI = 66%–89%) with a positive predictive value of 93% (95% CI = 87%–96%) and a negative predictive value of 85% (95% CI = 72%–92%). In the analyses of 181 patients, 132 cases were positive for estrogen receptor in metastases determined by immunohistochemistry, and 49 cases were negative. Whole body [F-18]FES-PET showed estrogen receptor positive in 135 cases (10 cases were immunohistochemically negative), and 46 cases were negative (7 cases were immunohistochemically positive).
Quantitative local [F-18]FES uptake predicted estrogen receptor expression with 91% sensitivity (95% CI = 84%–95%) and 69% specificity (95% CI = 54%–81%), The positive predictive value was 90 % (95% CI = 83%–94%) and the negative predictive value was 71% (95% CI = 55%–83%). For bone metastases, the positive and negative predictive values were 92% and 81%, respectively. Of the 156 patients, 117 metastases were estrogen receptor positive by immunohistochemistry and 39 were negative. In comparison, quantitative [F-18]FES predicted estrogen receptor status positivity in 118 cases (12 of which were immunohistochemically negative) and 38 were negative (including 11 immunohistochemically positive).
When the results were included in a meta-analysis with 12 other studies, with a total population of 556 patients, the pooled sensitivity of qualitative assessment of [F-18]FES-PET was 84% (95% CI = 75%–90%) and specificity 92% (95% CI = 64%–99%). [F-18] Quantitative assessment of FES-PET uptake had a pooled sensitivity of 89% (95% CI = 85%–92%) and a specificity of 78% (95% CI = 69%–84%).
Summary: [F-18]FES-PET can be used to determine tumor estrogen receptor status in metastatic foci from breast cancer, and this noninvasive imaging modality can be an effective alternative to biopsy.
参考文献 Reference Van Geel JJL et al. J Clin Onc 2022 May 18. DOI: 10.1200/JCO.22.00400Nimotuzumab 治疗KRAS 野生型晚期胰腺癌 (6/4/2022)
Nimotuzumab and gemcitabine in KRAS-wild type pancreatic cancer
KRAS 基因突变占所有胰腺癌的 85% 至 90%； 10% 到 15% 的胰腺癌是 KRAS 野生型。 在前瞻性双盲 III 期临床试验中（NOTABLE），总共有 92 名中国患有局部晚期或转移性胰腺癌的患者接受每周 400 mg Nimotuzumab（针对表皮生长因子受体的人源化治疗性单克隆抗体）治疗，然后在每 28 天周期的第 1、8 和 15 天接受 1000 毫克/平方米 吉西他滨治疗，或者接受安慰剂加吉西他滨治疗，直至疾病进展或出现不可接受的毒性。主要终点是总生存期；次要终点包括无进展生存期、客观缓解率和安全性。
主要发现: Nimotuzumab/吉西他滨组患者的中位总生存期为10.9 个月相比于吉西他滨加安慰剂的患者的8.5 个月。Nimotuzumab组的 1 年总生存率为 43.6%，而安慰剂/吉西他滨组为 26.8%。Nimotuzumab组的中位无进展生存期为 4.2 个月，而安慰剂/吉西他滨组为 3.6 个月。 不需要手术切除胆道梗阻的患者的总生存期为 11.9 个月相比于8.5 个月。无胆道梗阻手术史的患者的无进展生存期分别为 5.5 个月和 3.4 个月。
Nimotuzumab组的不良事件发生率与安慰剂/吉西他滨组相似。接受Nimotuzumab/吉西他滨治疗的患者最常见的不良事件是中性粒细胞减少症（11.1%）和血小板减少症（6.7%）。
KRAS gene mutations account for 85% to 90% of all pancreatic cancers; 10% to 15% of pancreatic cancers are KRAS wild-type. In a prospective, double-blind, phase III clinical trial (NOTABLE), a total of 92 patients in China with locally advanced or metastatic pancreatic cancer received 400 mg of weekly nimotuzumab (a humanized therapeutic monoclonal antibody targeting the epidermal growth factor receptor), followed by gemcitabine 1000 mg/m² on days 1, 8, and 15 of every 28-day cycle, or placebo plus gemcitabine until disease progression or unacceptable toxicity. The primary endpoint was overall survival; secondary endpoints included progression-free survival, objective response rate, and safety.
Major findings: Median overall survival for patients in the nimotuzumab/gemcitabine arm was 10.9 months compared to 8.5 months in the gemcitabine plus placebo arm. The 1-year overall survival rate was 43.6% vs. 26.8% in the placebo/gemcitabine group. Median progression-free survival was 4.2 months in the nimotuzumab group vs. 3.6 months. Overall survival in patients who did not require surgical resection of biliary obstruction was 11.9 months compared to 8.5 months. Progression-free survival was 5.5 months and 3.4 months for patients without surgery for biliary obstruction.
The incidence of adverse events in the nimotuzumab group was similar to that in the placebo/gemcitabine group. The most common adverse events in patients receiving nimotuzumab/gemcitabine were neutropenia (11.1%) and thrombocytopenia (6.7%).
参考文献 Reference Qin S et al J Clin Oncol. 2022;40(suppl 17):LBA4011一种双特异性抗体Glofitamab用于侵袭性淋巴瘤 (5/29/2022)
A first-in-class bispecific antibody Glofitamab in aggressive lymphoma
Glofitamab 是一种双特异性抗体，旨在靶向 B 细胞表面的 CD20 和 T 细胞表面的 CD3。这种双重靶向激活并重定向患者现有的 T 细胞，通过将细胞毒性蛋白释放到 B 细胞中来接合和消除目标 B 细胞。
这是一项 I/II 期、多中心、开放标签、剂量递增和扩展研究（NP30179），评估 glofitamab 在复发或难治性弥漫性大 B 细胞淋巴瘤患者中的安全性、有效性和药代动力学。结果测量包括独立审查委员会的完全响应率（主要终点）、总体响应率、响应持续时间、无进展生存期、安全性和耐受性（次要终点）。患者接受过中位数为三种先前治疗, 均为高度难治性弥漫性大 B 细胞淋巴瘤的患者，其中 58.3% 的患者对初始治疗无效，约三分之一 (33.1%) 的患者之前接受过 CAR T 细胞治疗。
中位随访 12.6 个月，39.4% 的患者（n = 61/155）达到完全响应（主要疗效终点），其中一半（51.6%；n = 80/155）达到总体响应（部分或完全响应；次要疗效终点），由独立审查委员会评估。大多数 (77.6%) 完全响应在 12 个月时是持久且持续进行，尚未达到完全响应的中位持续时间（16.8 个月，无法评估） 。
细胞因子释放综合征是 63.0%的患者中最常见的不良事件,是可预测的，一般为低级别（主要是 1级 [47.4%]或 2级 [11.7%]），且发生在初始剂量，只有一名患者因细胞因子释放综合征停用glofitamab。 3级以上的发生率较低 (3.9%),没有 5级事件。
Glofitamab正在几项临床试验中进行研究，并在早期的淋巴瘤治疗中进行探索。
Glofitamab is a bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects the patient’s existing T cells to engage and eliminate targeted B cells by releasing cytotoxic proteins into the B cells.
This is a Phase I/II, multicenter, open-label, dose-escalation and expansion study (NP30179) evaluating the safety, efficacy and pharmacokinetics of glofitamab in patients with relapsed or refractory diffuse large B-cell lymphoma. Outcome measures included complete response rate by independent review committee (primary endpoint), overall response rate, duration of response, progression-free survival, safety and tolerability (secondary endpoints). Patients had received a median of three prior therapies, all with highly refractory diffuse large B-cell lymphoma. Among them, 58.3% were refractory to initial therapy and approximately one third (33.1%) of patients had previously received CAR T cell therapy. At a median follow-up of 12.6 months, 39.4% of patients (n = 61/155) achieved a complete response (primary efficacy endpoint), half of whom (51.6%; n = 80/155) achieved an overall response (partial or complete response; secondary efficacy endpoint), as assessed by an independent review committee. The majority (77.6%) of complete responses were durable and ongoing at 12 months, and the median duration of complete responses had not been reached (16.8 months, not evaluable).
Cytokine release syndrome was the most common adverse event in 63.0% of patients. It was predictable, and generally of low-grade (mostly grade 1 [47.4%] or grade 2 [11.7%]), and occurred at the initial dose. Only one patient discontinued glofitamab due to cytokine release syndrome. The incidence of grade 3 or higher was low (3.9%), and there were no grade 5 events.
Glofitamab is being studied in several clinical trials and is being explored in the treatment of early-stage lymphoma.
参考文献 Reference Dickinson M, et al. ASCO Annual Meeting; 2022 Jun 3-7; Abstr 7500腹腔内卡铂加静脉紫杉醇相比于静脉化疗治疗卵巢癌 (5/28/2022)
Intraperitoneal versus intravenous carboplatin plus intravenous taxane as first-line therapy for ovarian cancer
在II/III期iPocc试验中,对655名II至IV期卵巢癌,输卵管癌和原发性腹膜癌患者确定腹腔内卡铂与静脉卡铂联合静脉紫杉醇的疗效。 该研究包括初次手术后残留病灶最小和较大的患者。患者被随机分配在第 1, 8和 15天静脉注射80毫克/平方米的紫杉醇和为每 21天一次静脉注射卡铂,或每周静脉注射紫杉醇和21天一次腹腔内卡铂，卡铂剂量都为AUC = 6。治疗周期为6至 8次 。患者未接受贝伐单抗或维持治疗。主要终点是无进展生存期；次要终点包括总生存期,毒性和生活质量。
初次手术后残留病灶大于 2公分的占了入组患者的55%。腹腔内卡铂组中改良的意向治疗人群的无进展生存期明显更长（风险比 [HR] = 0.83；P =.041）。而在意向治疗人群中的无进展生存期的差异更加明显（HR = 0.78；P = .009）。腹腔内卡铂组的中位无进展生存期为 23.5个月,而静脉卡铂组为 20.7个月。在预先指定的亚组中（包括残留病灶大于 2公分）观察到腹腔内卡铂对无进展生存期的益处。 值得注意的是，即使在 10年后，Kaplan-Meier曲线也没有融合在一起，研究者认为,与静脉卡铂组相比，腹腔内卡铂组中存活且没有疾病进展的患者大约多 7%。
两个研究组之间的总体生存率和响应率没有显著差异。两组的不良事件也相似，但与导管相关的感染在 腹腔内卡铂组更常见（所有级别为0.7%相对于 10.1%；≥3级为0.3%相对于 8.4 %）。
关键点: 无论初始手术后残余肿瘤大小如何，腹腔内卡铂联合剂量密集型紫杉醇（不含贝伐单抗）与静脉内方案相比，均改善了卵巢癌、输卵管癌或原发性腹膜癌患者的无进展生存期。未来的试验对于阐明基于腹腔内卡铂的化疗在 PARP抑制剂时代的真正作用是必要的。还需要阐明基于腹腔内卡铂的化疗在 BRCA突变患者中的作用。
In the phase II/III iPocc trial, the efficacy of intraperitoneal carboplatin versus intravenous carboplatin combined with intravenous paclitaxel was determined in 655 patients with stage II to IV ovarian, fallopian tube, and primary peritoneal cancer. The study included patients with minimal and large residual disease after primary surgery. Patients were randomly assigned to receive intravenous paclitaxel at 80 mg/m2 and intravenous carboplatin every 21 days on days 1, 8, and 15, or weekly intravenous paclitaxel and intraperitoneal carboplatin once every 21 days, and carboplatin dose in both arms were AUC = 6. The treatment was 6 to 8 cycles. The patient did not receive bevacizumab or maintenance therapy. The primary endpoint was progression-free survival; secondary endpoints included overall survival, toxicity, and quality of life.
Residual disease greater than 2 cm after primary surgery accounted for 55% of enrolled patients. Progression-free survival was significantly longer in the modified intent-to-treat population in the intraperitoneal carboplatin group (hazard ratio [HR] = 0.83; P = .041). The difference in progression-free survival was more pronounced in the intent-to-treat population (HR = 0.78; P = .009). Median progression-free survival was 23.5 months in the intraperitoneal carboplatin group and 20.7 months in the intravenous carboplatin group. The benefit of intraperitoneal carboplatin on progression-free survival was observed in prespecified subgroups, including residual disease greater than 2 cm. Notably, the Kaplan-Meier curves did not converge even after 10 years, and the investigators concluded that approximately 7% more patients were alive without disease progression in the intraperitoneal carboplatin group compared with the intravenous carboplatin group.
There were no significant differences in overall survival and response rates between the two study groups. Adverse events were also similar in both groups, but catheter-related infections were more common in the intraperitoneal carboplatin group (0.7% vs 10.1% for all grades; 0.3% vs 8.4% for ≥ grade 3).
Key Points: Intraperitoneal carboplatin combined with dose-dense paclitaxel (without bevacizumab) improved progression-free survival in patients with ovarian, fallopian tube, or primary peritoneal cancer compared with intravenous regimens regardless of residual tumor size after initial surgery. Future trials are needed to elucidate the true role of intraperitoneal carboplatin-based chemotherapy in the era of PARP inhibitors. The role of intraperitoneal carboplatin-based chemotherapy in patients with BRCA mutations also needs to be elucidated.
参考文献 Reference Fujiwara K et al. 2022 SGO Ann Meeting on Women’s Cancer. Abstract 241FDA 批准 Opdualag 用于不可切除或转移性黑色素瘤 (5/22/2022)
FDA approves nivolumab/relatlimab-rmbw for unresectable or metastatic melanoma
Opdualag是LAG-3阻断抗体 relatlimab和程序性死亡受体 1阻断抗体nivolumab的固定剂量组合。 在RELATIVITY-047 (NCT03470922)中评估疗效，这是一项随机双盲试验，对 714名先前未治疗的转移性或不可切除的III或IV期黑色素瘤患者进行了评估。该试验排除了患有活动性自身免疫性疾病,需要使用皮质类固醇或免疫抑制药物进行全身治疗的疾病,葡萄膜黑色素瘤以及活动性或未经治疗的脑或软脑膜转移的患者。患者被随机分配接受Opdualag（nivolumab 480毫克 和relatlimab160）每 4周静脉输注或nivolumab 480毫克 每 4周静脉输注，直至疾病进展或出现不可接受的毒性。 主要疗效结果是无进展生存期。
该试验表明，与nivolumab相比，Opdualag对无进展生存期有统计学意义的改善（HR=0.75；95%置信区间 [CI]：0.62, 0.92；p值=0.0055）。Opdualag组和nivolumab组的中位无进展生存期为 10.1个月（95% CI：6.4, 15.7）相对于4.6个月（95% CI：3.4, 5.6）。另一个疗效结果指标是总生存期。总生存期在最终分析时没有统计学意义（HR=0.80；95%CI：0.64, 1.01），Opdualag臂中位生存期未达到（95%CI：34.2，NR）相对于34.1个月（95% CI: 25.2, NR)。
Opdualag最常见的不良反应 (≥ 20%)是肌肉骨骼疼痛,疲劳,皮疹,瘙痒和腹泻。最常见的实验室异常 (≥20%)是血红蛋白减少,淋巴细胞减少,AST增加,ALT增加和钠减少。 推荐的Opdualag剂量为每 4周静脉注射 480毫克nivolumab和 160毫克relatlimab。
*淋巴细胞激活基因 3 (LAG-3)属于免疫球蛋白超家族的跨膜蛋白。它在活化的T细胞上的表达是在抗原刺激后诱导的，它们具有多种功能包括在这些活化的 T细胞中抑制Th1细胞增殖和减少细胞因子产生。由于慢性感染或肿瘤相关抗原而导致的持续抗原暴露可导致 T细胞上LAG-3的持续高表达，最终通过功能“耗尽”而失去其效应功能。这种 T细胞功能的丧失导致免疫监视减弱并促进肿瘤逃逸。Relatlimab是一种人IgG4单克隆抗体，可结合LAG-3并抑制其信号通路，其拮抗作用可促进 T细胞增殖、细胞因子分泌，并随后恢复肿瘤免疫监视。
Opdualag is a fixed-dose combination of the LAG-3 blocking antibody relatlimab and the programmed death receptor-1 blocking antibody nivolumab. Efficacy was evaluated in RELATIVITY-047 (NCT03470922), a randomized, double-blind trial evaluating 714 patients with previously untreated metastatic or unresectable stage III or IV melanoma. The trial excluded patients with active autoimmune disease requiring systemic treatment with corticosteroids or immunosuppressive drugs, uveal melanoma, and active or untreated brain or leptomeningeal metastases. Patients were randomly assigned to receive either Opdualag (nivolumab 480 mg and relatlimab 160) intravenously every 4 weeks or nivolumab 480 mg intravenously every 4 weeks until disease progression or unacceptable toxicity. The primary efficacy outcome was progression-free survival.
The trial demonstrated a statistically significant improvement in progression-free survival with Opdualag compared with nivolumab (HR=0.75; 95% confidence interval [CI]: 0.62, 0.92; p-value=0.0055). Median progression-free survival was 10.1 months (95% CI: 6.4, 15.7) versus 4.6 months (95% CI: 3.4, 5.6) in the Opdualag vs. nivolumab groups. Another efficacy outcome measure was overall survival. Overall survival was not statistically significant at final analysis (HR=0.80; 95% CI: 0.64, 1.01), and median survival was not reached in the Opdualag arm (95% CI: 34.2, NR) versus 34.1 months (95% CI) CI: 25.2, NR).
The most common adverse reactions (≥ 20%) of Opdualag were musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. The most common laboratory abnormalities (≥ 20%) were decreased hemoglobin, decreased lymphocytes, increased AST, increased ALT, and decreased sodium. The recommended dose of Opdualag is 480 mg of nivolumab and 160 mg of relatlimab administered intravenously every 4 weeks.
*Lymphocyte activation gene 3 (LAG-3) belongs to the immunoglobulin superfamily of transmembrane proteins.Its expression on activated T cells is induced after antigenic stimulation, and they have multiple functions including inhibition of Th1 cell proliferation and reduction of cytokine production in these activated T cells.Persistent antigen exposure due to chronic infection or tumor-associated antigens can lead to persistently high expression of LAG-3 on T cells, ultimately losing its effector function through functional “exhaustion”.This loss of T cell function results in diminished immune surveillance and promotes tumor escape.Relatlimab, a human IgG4 monoclonal antibody, binds to LAG-3 and inhibits its signaling pathway, and its antagonism promotes T cell proliferation, cytokine secretion, and subsequent restoration of tumor immune surveillance.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-opdualag-unresectable-or-metastatic-melanomaTawbi HA et al. N Engl J Med 2022; 386:24 Yu X et al. MAbs. 2019; 11:1139 Sordo-Bahamonde C et al. Cancers (Basel) 2021; 13 Maruhashi T et al. J Immunother Cancer. 2020; 8Pemigatinib 治疗伴有 FGFR1 重排的髓样或淋巴样肿瘤 (5/21/20200)
Pemigatinib in patients with myeloid or lymphoid tumors with fibroblast growth factor receptor 1 (FGFR1) rearrangement
FIGHT-203 是一项 2 期多中心试验。在数据截止时（2020 年 12 月 31 日），有 34 名患者入组和治疗（安全人群）。平均年龄为 61.2（范围，36-78）岁，59% 为女性。先前治疗的平均次数为 1.6（范围，0-6）； 3名患者之前接受过造血干细胞移植； 5 人未接受过治疗。Pemigatinib暴露的最长持续时间为 192.4 周，中位给药持续时间为 29.3 周；患者完成了 10.0（范围，2-65）周期的中位数。在数据截止时，有 18 名患者（53%）正在接受治疗；停止治疗的原因包括过渡到造血干细胞移植 (n = 6, 18%)、疾病进展 (n =5, 15%)、不良事件 (n =3, 9%)、医生决定 (n =1, 3%) 和患者决定(n =1, 3%)。
名患者没有 FGFR1 重排，被排除在疗效分析之外。在可评估疗效的 33 例患者中，最常见的 FGFR1 融合伴侣基因是 13q12/ZMYM2（45.5%）和 22q11/BCR（24.2%）。骨髓和/或髓外疾病受累的 31 名患者中，研究者评估的完全缓解率和中央审查委员会评估的分别为 64.5% 和 77.4%。在 33 个可评估完全细胞遗传学反应的点中，完全细胞遗传学反应率分别为 72.7% 和 75.8%。尚未达到完全缓解率的中位持续时间。在 33 个可评估细胞遗传学反应的点中，完全细胞遗传学反应率分别为 72.7% 和 75.8%。尚未达到完全反应的中位持续时间。
最常见的治疗相关不良事件是高磷血症 (68%)、脱发 (59%)、腹泻 (50%)、口腔炎 (44%) 和贫血 (35%)。 ≥10% 患者的 ≥3 级不良事件为贫血（18%）、四肢疼痛和口腔炎（均为 12%）。
结论：Pemigatinib 是第一个在治疗伴有 FGFR1 重排的髓样或淋巴样肿瘤患者中证明持久和高完全缓解和完全细胞遗传学反应的疗法，其中大多数患者在先前的治疗（包括强化化疗或造血干细胞移植）后疾病进展。安全性与 FGFR 抑制剂一致，没有意外毒性。Pemigatinib 可能为治疗伴有 FGFR1 重排的髓样或淋巴样肿瘤患者中不适合造血干细胞移植 的患者提供长期治疗选择，或可能有助于在符合条件的患者中桥接至造血干细胞移植。
FIGHT-203 is a phase 2 multicenter trial. At data cutoff (December 31, 2020), 34 patients were enrolled and treated (safety population). The mean age was 61.2 (range, 36-78) years, and 59% were female. The mean number of previous treatments was 1.6 (range, 0-6); 3 patients had previously received hematopoietic stem cell transplantation; 5 were treatment naive. The longest duration of pemigatinib exposure was 192.4 weeks, and the median dosing duration was 29.3 weeks; patients completed a median of 10.0 (range, 2-65) cycles. At data cutoff, 18 patients (53%) were on treatment; reasons for discontinuation included transition to hematopoietic stem cell transplantation (n = 6, 18%), disease progression (n = 5, 15%), adverse events (n = 3, 9%), physician decision (n = 1, 3%), and patient decision (n = 1, 3%).
One patient had no FGFR1 rearrangement and was excluded from the efficacy analysis. Among the 33 patients evaluable for efficacy, the most common FGFR1 fusion partner genes were 13q12/ZMYM2 (45.5%) and 22q11/BCR (24.2%). Among 31 patients with bone marrow and/or extramedullary disease involvement, investigator-assessed complete response rate and central review board-assessed rate were 64.5% and 77.4%, respectively. Among the 33 points at which complete cytogenetic response could be assessed, complete cytogenetic response rate was 72.7% and 75.8%, respectively. The median duration of complete response rate has not been reached. At 33 points where cytogenetic response could be assessed, complete cytogenetic response rate was 72.7% and 75.8%, respectively. The median duration of complete response has not been reached.
The most common treatment-related adverse events were hyperphosphatemia (68%), alopecia (59%), diarrhea (50%), stomatitis (44%), and anemia (35%). Grade ≥3 adverse events in ≥10% of patients were anemia (18%), pain in extremities, and stomatitis (both 12%).
Conclusions: Pemigatinib is the first drug that demonstrated durable and high complete response and complete cytogenetic response in patients with myeloid or lymphoid tumors with FGFR1 rearrangement, while the majority of them had received prior therapy including intensive chemotherapy, and underwent disease progression after hematopoietic stem cell transplantation. The safety profile was consistent with that of FGFR inhibitors, with no unexpected toxicities. Pemigatinib may provide a long-term treatment option for patients who have myeloid or lymphoid tumors and FGFR1 rearrangements, and who are ineligible for hematopoietic stem cell transplantation. It may aid in bridging to hematopoietic stem cell transplantation in eligible patients.
参考文献 Reference Gotlib J, et al. 2021 ASH Ann Meeting & Exposition. Abstr 385Trastuzumab deruxtecan 治疗 HER2 阳性晚期胃或胃食管结合部腺癌患者 (5/15/2022)
Trastuzumab deruxtecan in HER-2-positive advanced gastric and GE junction adenocarcinoma
Trastuzumab deruxtecan (T-DXd) 是一种抗体-药物偶联物，包含抗 HER2 抗体, 和拓扑异构酶 I 抑制剂。 DESTINY-Gastric01（DS8201-A-J202；NCT03329690）是一项针对 HER2 阳性的晚期胃癌或胃食管结合部腺癌患者的开放标签、多中心, 随机2 期试验。研究者报告了最终的总生存期分析以及更新的疗效和安全性。
方法：患有局部晚期或转移性, HER2 阳性的胃癌或胃食管结合部腺癌患者在 ≥2 线治疗（包括曲妥珠单抗）后进展，被随机分配为 2:1（ 每3星期一次T-DXd 6.4 毫克/公斤或医师选择伊立替康 或紫杉醇 ）。主要终点是独立中央审查的总客观响应率。关键的次要终点是总生存期, 响应持续时间, 无进展生存期, 疾病控制率, 和安全性。在 133 个总生存期事件中进行最终总生存期分析。
结果：187 名患者接受了 T-DXd (n = 125) 或化疗 (n = 62 （伊立替康55 人; 紫杉醇7 人）；日本人占 79.7%，韩国人占 20.3%。患者之前接受过 2 线治疗的中位数，44.4% ≥ 3 线。在数据截止时（2020 年 6 月 3 日），8% 的 T-DXd 和 0% 的化疗患者仍在接受治疗（中位生存期随访时间为 18.5 个月）。与化疗相比，T-DXd 改善总生存期（中位总生存期，12.5 对 8.9 个月；风险比 [HR]，0.60 [95% CI，0.42-0.86]）。 T-DXd 的总客观响应率为 51.3%（61/119；11 人完全响应；50 人部分响应），而化疗的总客观响应率为 14.3%（8/56；所有都为部分响应）（P < 0.0001）；疾病控制率，86.6% 对 62.5% (P = 0.0003)；确认的中位响应持续时间，12.5 对 3.9 个月；中位无进展生存期，5.6 与 3.5 个月（HR，0.47 [95% CI，0.31-0.71]；P = 0.0003）。
副作用: 85.6% 的 T-DXd 患者发生≥3 级 副作用，而化疗患者为 56.5%；最常见的是中性粒细胞减少（49.6%相比对于22.6%）、贫血（38.4%相比对于22.6%）和白细胞减少（20.8%相比对于11.3%）。 16 名患者（12.8%）患有 T-DXd 相关的间质性肺病（13 名 1/2 级，2 名 3 级，1 名 4 级，无 5 级），而 化疗患者无。有 1 例 T-DXd 相关的肺炎死亡（非间质性肺病）。
结论：通过初步分析后的额外随访，在 HER2 阳性晚期 胃癌或胃食管结合部腺癌中，与标准化疗相比，T-DXd 继续显示总生存期益处和总客观响应率的临床相关改善，以及可控的安全性。
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate comprising an anti-HER2 antibody, and a topoisomerase I inhibitor. DESTINY-Gastric01 (DS8201-A-J202; NCT03329690) is an open-label, multicenter, randomized phase 2 trial in patients with HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma. The investigators reported the final analysis of overall survival and updated efficacy and safety.
METHODS: Patients with locally advanced or metastatic, HER2-positive gastric or gastroesophageal junction adenocarcinoma who progressed after ≥2 lines of therapy (including trastuzumab) were randomly assigned 2:1 (every 3 weeks) T-DXd 6.4 mg/kg or physician’s choice of irinotecan or paclitaxel. The primary endpoint was overall objective response rate from independent central review. Key secondary endpoints were overall survival, duration of response, progression-free survival, disease control rate, and safety. Final overall survival analysis was performed among 133 overall survival events.
RESULTS: 187 patients received T-DXd (n = 125) or chemotherapy (n = 62, 55 for irinotecan; 7 for paclitaxel). A total of 79.7% were Japanese and 20.3% were Korean. Patients had previously received median of 2 lines of therapy, and 44.4% had ≥ 3 lines. At data cutoff (June 3, 2020), 8% of T-DXd and 0% of chemotherapy patients were still on therapy (median survival follow-up 18.5 months). T-DXd improved overall survival compared with chemotherapy (median overall survival, 12.5 vs 8.9 months; hazard ratio [HR], 0.60 [95% CI, 0.42-0.86]). The overall objective response rate for DXd was 51.3% (61/119; 11 complete responses; 50 partial responses) compared to 14.3% for chemotherapy alone (8/56; all partial responses) (P < 0.0001 ); disease control rate was 86.6% vs 62.5% (P = 0.0003); confirmed median duration of response was 12.5 vs 3.9 months; median progression-free survival was 5.6 vs 3.5 months (HR, 0.47 [95%] CI, 0.31-0.71]; P = 0.0003).
SIDE-EFFECTS: Grade ≥ 3 side effects occurred in 85.6% of T-DXd patients versus 56.5% of chemotherapy patients; the most common was neutropenia (49.6% vs. 22.6%), anemia (38.4% vs. 22.6%) and leukopenia (20.8% vs. 11.3%). Sixteen patients (12.8%) had T-DXd-related interstitial lung disease (13 grade 1/2, 2 grade 3, 1 grade 4, none grade 5), but it did not occur in the chemotherapy patients. There was one death from T-DXd-related pneumonia (not interstitial lung disease).
CONCLUSIONS: With additional follow-up after the primary analysis, in HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma, T-DXd continued to show clinically relevant improvements in overall survival and overall objective response rate compared with standard chemotherapy, with manageable side-effects
参考文献 Reference Shitara K N Engl J Med. 2020;382:2419-2430); Yamaguchi K et al. J Clin Onc 2021;39: 15 (suppl 4048) Yamaguchi K et al. ASCO GI Cancer Symp 2022; abstr 242FDA 批准nivolumab（纳武单抗）和铂类化疗用于手术前早期非小细胞肺癌 (5/14/22)
FDA approved Nivolumab plus platinum-baed chemotherapy in neoadjuvant therapy for NSCLC
这是 FDA 首次批准用于早期 NSCLC 的新辅助治疗。CHECKMATE-816 (NCT02998528) 是一项随机, 开放标签试验，参加者患有可切除, 组织学证实的 IB 期（≥ 4 cm）、II 或 IIIA 期 NSCLC和可测量疾病。无论肿瘤 PD-L1 状态如何，患者都被纳入。共有 358 名患者被随机分配接受每 3 周一次的 nivolumab 加铂类双药化疗（最多 3 个周期），或以相同的时间表单独接受铂类化疗。 主要疗效指标是独立中央审查得出的无事件生存期和病理完全响应。
纳武单抗联合化疗组的中位无事件生存期为 31.6 个月（95% CI：30.2，未达到），单独接受化疗组的中位无事件生存期为 20.8 个月（95% CI：14.0, 26.7）。风险比为 0.63（97.38% CI：0.43, 0.91；p = 0.0052）。纳武单抗联合化疗组的病理完全响应率为 24% (95% CI: 18.0, 31.0)，而单独化疗组的病理完全响应率为 2.2% (95% CI: 0.6, 5.6)。
患者中最常见的不良反应（发生率≥ 20%）是恶心、便秘、疲劳、食欲下降和皮疹。在化疗中加入纳武单抗并没有导致更频繁的手术延迟或取消。两组患者在确定性手术后的中位住院时间和被确定为手术并发症的不良反应发生率相似。
推荐的纳武单抗剂量为 360 毫克，每 3 周在同一天进行铂类双药化疗，共 3 个周期。
This is the first FDA-approved neoadjuvant treatment for early-stage NSCLC. CHECKMATE-816 (NCT02998528) is a randomized, open-label trial. Participants with resectable, histologically confirmed stage IB (≥ 4 cm), II or IIIA NSCLC and measurable disease. Patients were included regardless of their tumor PD-L1 status. A total of 358 patients were randomly assigned to receive nivolumab plus platinum-based doublet chemotherapy every 3 weeks (up to 3 cycles) or platinum-based chemotherapy alone on the same schedule. The primary efficacy measures were event-free survival and pathological complete remission by independent central review.
The median event-free survival was 31.6 months (95% CI: 30.2, not reached) in the nivolumab plus chemotherapy group and 20.8 months (95% CI: 14.0) in the chemotherapy-alone group , 26.7). The hazard ratio was 0.63 (97.38% CI: 0.43, 0.91; p = 0.0052). The pathologic complete response rate was 24% (95% CI: 18.0, 31.0) in the nivolumab plus chemotherapy group, compared with 2.2% (95% CI: 0.6, 5.6) in the chemotherapy alone group. The most common adverse reactions (incidence ≥ 20%) in patients were nausea, constipation, fatigue, decreased appetite, and rash. Adding nivolumab to chemotherapy did not result in more frequent surgery delays or cancellations. The median length of hospital stay after definitive surgery and the incidence of adverse events identified as surgical complications were similar between the two groups.
The recommended dose of nivolumab is 360 mg with platinum doublet chemotherapy on the same day every 3 weeks for 3 cycles.
参考文献 Reference Forde PM et al. New Eng J Med 2022; Apr 11 https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neoadjuvant-nivolumab-and-platinum-doublet-chemotherapy-early-stage-non-small-cell-lung抗体-药物偶联物治疗患有脑转移的HER2 阳性乳腺癌 (5/8/2022)
Antibody-drug conjugate is promising in treating brain metastases in HER-2 positive breast cancer
TUXEDO-1 是一项单臂 II 期试验，15 名患有脑转移的HER2 阳性乳腺癌患者接受标准剂量的抗体-药物偶联物曲妥珠单抗-deruxtecan直至疾病进展或不可接受的毒性。截至数据截止，9 名患者已停止治疗（3 名因进展，6 名因其他原因）。患者中位年龄为 69 岁，除一名外，其余均为女性。九名 (60%) 患者的 ECOG 体能状态为 0，六名 (40%) 在基线时有神经系统症状。12 名患者（80%）出现内脏转移，40% 有新发脑转移，60% 在局部治疗后出现进行性脑转移。
在 15 名意向治疗人群中，妥珠单抗-deruxtecan的颅内客观响应率为 73.3%，在符合方案的 14 名患者人群中为 78.6%。 此外，在基线时有可测量颅外疾病的 8 名患者的颅外反应率为 62.5%。中位无进展生存期为 14 个月，中位总生存期未达到。
该疗法没有观察到新的安全信号，并且在治疗期间维持了生活质量。
TUXEDO-1 is a single-arm phase II trial in 15 patients with HER2-positive breast cancer and brain metastases. They received standard doses of the antibody-drug conjugate trastuzumab-deruxtecan until disease progression or unacceptable toxicity. As of data cutoff, 9 patients had discontinued treatment (3 due to progression and 6 for other reasons). The median age of the patients was 69 years, and all but one were female. Nine (60%) patients had an ECOG performance status of 0, and six (40%) had neurological symptoms at baseline. Twelve patients (80%) had visceral metastases, 40% had new brain metastases, and 60% had progressive brain metastases after local therapy.
The intracranial objective response rate for tocilizumab-deruxtecan was 73.3% in the intent-to-treat population of 15 patients and 78.6% in the per-protocol population of 14 patients. In addition, the 8 patients with measurable extracranial disease at baseline had an extracranial response rate of 62.5%. The median progression-free survival was 14 months, and the median overall survival was not reached.
No new safety signals were observed with this therapy and quality of life was maintained during treatment.
参考文献 Reference Bartsch R et al ESMO Breast Cancer Congress 2022; Abstr 165MO单独使用 Durvalumab 或联合 Oleclumab 或 Monalizumab 治疗不可切除的 III 期非小细胞肺癌 (5/7/2022)
Durvalumab alone or plus Oleclumab or Monalizumab in unresectable ST III NSCLC
Durvalumab 显著提高了不可切除的 III 期非小细胞肺癌并且在同步放化疗后无进展患者的总生存期。在该护理标准的基础上，一项II 期临床试验（COAST）研究了 durvalumab 单独或与抗 CD73 单克隆抗体 oleclumab 或抗 NKG2A 单克隆抗体 monalizumab 联合作为这种情况下的巩固治疗。
方法 患有不可切除的 III 期非小细胞肺癌. 在同步放化疗后无进展的患者被随机分配 1:1:1（按组织学分层），单独接受 durvalumab 或联合oleclumab 或 monalizumab 长达 12 个月。主要终点是研究者评估的确认客观响应率。
结果 2019 年 1 月至 2020 年 7 月期间，189 名患者被随机分配。在中期分析（数据截止日期，2021 年 5 月 17 日）中，中位随访时间为 11.5 个月（范围，0.4-23.4 个月）。 客观响应率为Durvalumab 加 oleclumab（30.0%；95% CI，18.8 至 43.2）, durvalumab 加 monalizumab（35.5%；95% CI，23.7 至 48.7）相比于 durvalumab（17.9%；95% CI，9.6 至 29.2）。而且与 durvalumab 相比，两种组合均延长了无进展生存期（durvalumab加 oleclumab：风险比，0.44；95% CI，0.26 至 0.75；durvalumab加monalizumab：风险比，0.42；95% CI，0.24 至 0.72），12 个月无进展生存率更高（durvalumab加 oleclumab：62.6% [95% CI，48.1 至 74.2], durvalumab 加monalizumab：72.7% [95% CI，58.8 至 82.6] 相对于单独使用 durvalumab：33.9% [95% CI，21.2 至 47.1 ]）。
不良事件 由于各种原因出现的 ≥ 3 级不良事件, durvalumab + oleclumab, durvalumab + monalizumab 和 durvalumab 分别发生 40.7%、27.9% 和 39.4%。
结论 与单独使用 durvalumab 相比，两种组合都增加了客观响应率并延长了无进展生存期。各组的安全性相似，两种组合均未发现新的或重要的安全信号。
Durvalumab significantly improved overall survival in patients with unresectable stage III non-small cell lung cancer patients who were progression-free after concurrent chemoradiation. Building on this standard of care, a phase II clinical trial (COAST) investigated durvalumab alone or in combination with the anti-CD73 monoclonal antibody oleclumab or the anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting.
Methods Patients with unresectable stage III non-small cell lung cancer, and remained progression-free after concurrent chemoradiotherapy were randomly assigned 1:1:1 (stratified by histology) to receive durvalumab alone or in combination with oleclumab or monalizumab for up to 12 months. The primary endpoint was investigator-assessed objective response rate.
RESULTS: Between January 2019 and July 2020, 189 patients were randomly assigned. At the interim analysis (data cutoff, May 17, 2021), the median follow-up was 11.5 months (range, 0.4-23.4 months). The objective response rate was durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2), durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2) ). Furthermore, both combinations improved progression-free survival compared with durvalumab alone (durvalumab plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; durvalumab plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72 ). Higher progression-free survival at 12 months was observed (durvalumab plus oleclumab: 62.6% [95% CI, 48.1 to 74.2], durvalumab plus monalizumab: 72.7% [95% CI, 58.8 to 82.6] vs. durvalumab alone: 33.9 % [95% CI, 21.2 to 47.1]).
Adverse all-cause grade ≥ 3 treatment-related adverse events occurred in 40.7%, 27.9% and 39.4% among durvalumab + oleclumab, durvalumab + monalizumab and durvalumab groups, respectively.
Conclusions Both combinations increased objective response rates and prolonged progression-free survival compared with durvalumab alone. Safety was similar across groups, with no new or important safety signals identified for either combination.
参考文献 Reference Herbst RS et al. J Clin Onc 2022; Published online April 22Atezolizumab 和 Bevacizumab 治疗神经内分泌肿瘤 (5/1/2022)
Treatment of neuroendocrine tumor with Atezolizumab and Bevacizumab
神经内分泌肿瘤（NET）是罕见癌症, 对该晚期肿瘤治疗仍然不足。
这是一项II期单臂、开放标签、非随机临床研究, 包括 40 名在三级医疗机构接受治疗的晚期进展性 1 至 2 级 NET 患者（20 名胰腺 NET和 20 名胰腺外 NET） 2017 年 3 月 31 日至 2019 年 2 月 19 日期间转诊癌症中心。数据分析时间为 2021 年 6 月至 2021 年 9 月。患者每 3 周接受标准剂量的静脉注射贝伐单抗和阿特珠单抗，直至疾病进展、死亡或退出。主要终点是实体瘤响应，无进展生存期作为关键的次要终点。
结果 在用贝伐单抗和阿特珠单抗治疗 40 名研究患者后，在 4 名胰腺 NET患者（20%；95% CI，5.7%-43.7%）和 3 名名胰腺外 NET患者（15%；95% CI，3.2%-37.9%）中观察到响应。 这些队列的无进展生存期分别为 14.9 (95% CI, 4.4-32.0) 个月和 14.2 (95% CI, 10.2-19.6) 个月。
结论 在这项非随机临床试验中， NET 患者的临床响应可能在贝伐单抗和阿特珠单抗联合治疗后出现，无进展生存期与有效治疗一致。
Neuroendocrine tumor (NETs) is a rare cancer that still lacks adequate treatment for advanced tumors. This is a phase II single-arm, open-label, non-randomized clinical study. That involved 40 patients (20 pancreatic NETs and 20 extrapancreatic NETs) with advanced progressive grade 1 to 2 NET and were treated at a tertiary care referral center between March 31 2017 and February 19, 2019. The data analysis period was from June 2021 to September 2021. Patients received standard doses of intravenous bevacizumab and atezolizumab every 3 weeks until disease progression, death, or withdrawal. The primary endpoint was solid tumor response, with progression-free survival as a key secondary endpoint.
Results Following treatment of 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pancreatic NETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with extrapancreatic NETs (15 %; 95% CI, 3.2%-37.9%). Progression-free survival in these cohorts was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months, respectively.
Conclusion In this nonrandomized clinical trial, patients with NET may have a clinical response following combination therapy with bevacizumab and atezolizumab, with progression-free survival consistent with effective therapy.
参考文献 Reference Halperin, DM et al. JAMA Onc 2022; April 7. doi:10.1001/jamaoncol.2022.0212Durvalumab 和 tremelimumab 与一线新辅助化疗在晚期卵巢癌患者中的 II 期研究 (4/30/2022)
Durvalumab and tremelimumab in combination with neoadjuvant chemotherapy in advanced ovarian cancer, a phase II study
KGOG 3046是一项单臂2期研究，评估双重免疫检查点抑制（durvalumab和tremelimumab）与新辅助化疗（手术前化疗NAC）联合治疗晚期上皮性卵巢癌。
该研究招募了FIGO IIIC-IV期晚期上皮性卵巢癌患者。患者被分配到以下新辅助化学免疫疗法之一：1) 原始队列（durvalumab 1,500 毫克, 每3星期一次, 加上 tremelimumab 75 毫克, 每3星期一次, 加上紫杉醇 175 毫克/平方米, 加上卡铂 AUC= 5, 每3 个周期）; 2) 扩展队列（durvalumab 1,500 毫克, 每3星期一次, 加上 tremelimumab 75 300 毫克 [1 次剂量] 加上相同原始化疗）。 扩展队列2 是在原始队列完成后启动的。 NAC后，所有患者均接受了减瘤手术。在减瘤手术后，给予三个周期的 durvalumab（1,120 毫克）和辅助化疗，然后是durvalumab维持（1,120 毫克, 共 12 个周期）。在治疗期间，进行了一系列活检以探索肿瘤微环境的免疫学变化。主要终点是 12 个月的无进展生存率。在所有患者接受减瘤手术后，进行中期分析以评估 NAC 后的结果 。
共有 45 名患者入组如下：原始队列1 (n =23) 和扩展队列2 (n =22)。大多数患者为高级别浆液性癌（91.1%）和 IV 期疾病（77.8%）。 NAC 后，总客观响应率为 86.7%（原始队列1为 95.7%，扩展队列2为 81.8%，P =0.17）。在减瘤手术中，30 名患者（66.7%）进行了 R0 切除（原始队列1为 73.9%，扩展队列2 为 59.1%，P=0.353）。 14 名患者（31.1%）的 CRS （化疗反应评分）为 3（原始队列1为 39.1%，扩展队列2为 22.7%，P =0.337），5 名患者（11.1%）有病理缓解。
不良事件 皮疹是最常见的不良事件（51.1%），3 名患者（15.6%）发生≥ 3 级事件，使用类固醇后完全解决。这些中期数据显示在化疗中加入免疫剂后的临床活性。
KGOG 3046 is a single-arm phase 2 study evaluating dual immune checkpoint inhibition (durvalumab and tremelimumab) in combination with neoadjuvant chemotherapy (preoperative chemotherapy NAC) in advanced epithelial ovarian cancer.
The study enrolled patients with FIGO stage IIIC-IV advanced epithelial ovarian cancer. Patients were assigned to one of the two neoadjuvant chemoimmunotherapy arms: 1) original cohort (durvalumab 1,500 mg every 3 weeks, plus tremelimumab 75 mg every 3 weeks, plus paclitaxel 175 mg/m2 and carboplatin AUC = 5, every 3 cycles); 2) expansion cohort (durvalumab 1,500 mg every 3 weeks, plus tremelimumab 75 300 mg [1 dose] plus the same original chemotherapy). Expansion cohort 2 was started after the completion of original cohort 1. After NAC, all patients underwent debulking surgery. After debulking surgery, three cycles of durvalumab (1,120 mg) and adjuvant chemotherapy were given, followed by maintenance durvalumab (1,120 mg for 12 cycles). During treatment, a series of biopsies were performed to explore immunological changes in the tumor microenvironment. The primary endpoint was progression-free survival at 12 months.
After all patients underwent cytoreductive surgery, an interim analysis was performed to assess outcomes after NAC. A total of 45 patients were enrolled as follows: original cohort 1 (n = 23) and expansion cohort 2 (n = 22). Most patients had high-grade serous carcinoma (91.1%) and stage IV disease (77.8%). After NAC, the overall objective response rate was 86.7% (95.7% in original cohort 1 and 81.8% in expansion cohort 2, P = 0.17). During debulking surgery, 30 patients (66.7%) underwent R0 resection (73.9% in original cohort 1 and 59.1% in expansion cohort 2, P=0.353). Fourteen patients (31.1%) had a CRS (chemotherapy response score) of 3 (39.1% in original cohort 1 and 22.7% in expansion cohort 2, P = 0.337), and 5 patients (11.1%) had a pathological response.
Adverse events Rash was the most common adverse event (51.1%), with grade ≥ 3 events occurring in 3 patients (15.6%), which resolved completely with steroids. These interim data showed clinical activity following the addition of dual immune checkpoint inhibitors to chemotherapy.
参考文献 Reference Park J et al. AACR Ann Meeting 2022; April 11.一项II期临床试验治疗对BCG无反应的非浸润性膀胱癌 (4/17/2022)
A phase II clinical trial in non-muscle-invasive bladder cancer unresponsive to BCG
BCG 是非肌肉浸润性膀胱癌患者的护理标准，但一小部分患者对 BCG 治疗没有反应。 II 期临床试验 （Core1, NCT04387461) 正在评估 CG0070 与pembrolizumab 联合使用的疗效。
患者必须患有复发性非肌肉浸润性膀胱癌, 并且至少一年前接受过 BCG 免疫治疗。截至中期分析（2022 年 4 月 7 日数据截止, 包括 18 名患者，目标入组人数为 37 名），18 名患者可评估疗效。 89% 可评估疗效的患者 (n = 18) 在最初的 3 个月时间点已达到完全响应 (CR)。85% (n = 13) 维持 CR 至 6 个月，78% (n = 9) 至 9 个月，75% (n = 8) 至 12 个月。
治疗相关不良事件通常仅限于短暂的 1-2 级局部泌尿生殖系统症状和免疫相关不良事件，包括尿频、膀胱痉挛、排尿困难、疲劳、夜尿、血尿、寒战、自身免疫性甲状腺炎和甲状腺功能减退。未观察到与治疗相关的 3 级或更高级别不良事件 或严重不良事件。
CG0070 是一种研究性溶瘤免疫疗法，其骨架基于改良的普通感冒腺病毒，包含癌症特异性启动子和 GM-CSF 转基因。CG0070 的 III 期 Bond-003 研究（NCT04452591）目前正在招募以实现 110 名参与者的目标。
BCG is the standard of care for patients with non-muscle-invasive bladder cancer. However, a small percentage of such patients do not respond to BCG therapy. A phase II clinical trial (Core1, NCT04387461) is evaluating CG0070 in combination with pembrolizumab in the refractory setting.
Patients must have recurrent non-muscle-invasive bladder cancer and have received BCG immunotherapy at least one year before. As of the interim analysis (data cutoff April 7, 2022, 18 patients included, target enrollment of 37), 18 patients were evaluable for efficacy. Eighty-nine percent of patients evaluable for efficacy (n=18) had achieved a complete response (CR) at the initial 3-month time point. 85% (n = 13) maintained CR to 6 months, 78% (n = 9) to 9 months, and 75% (n = 8) to 12 months.
Treatment-related adverse events were usually limited to transient grade 1-2 localized genitourinary symptoms and immune-related adverse events, including urinary frequency, bladder spasm, dysuria, fatigue, nocturia, hematuria, chills, autoimmune thyroiditis, and thyroid function decrease. No treatment-related adverse events of grade 3 or higher or serious adverse events were observed.
CG0070 is an investigational oncolytic immunotherapy with a backbone based on a modified common cold adenovirus containing a cancer-specific promoter and a GM-CSF transgene. The Phase III Bond-003 study of CG0070 (NCT04452591) is currently recruiting to achieve a goal of 110 participants.
参考文献 Reference Uchio E et al. Am Asso Can Res (AACR) Ann Meeting, 2022, April 13.溶瘤病毒加载 CAR-T 细胞用以治疗实体癌肿瘤 (4/16/2022)
Oncolytic virus-mediated CAR-T cells to treat solid tumors in mice
单独使用嵌合抗原受体 T 细胞（CAR-T）疗法难以治疗实体瘤。一种免疫治疗新技术将溶瘤病毒装载于CAR-T，以更有效地靶向和治疗实体癌肿瘤。溶瘤病毒是天然存在的病毒（如水泡性口炎病毒或呼肠孤病毒），可以感染和分解癌细胞, 经设计辑入多种转基因可以选择性地靶向癌细胞。 这项研究表明，CAR-T 细胞可以将溶瘤病毒传递给肿瘤。然后病毒可以渗入肿瘤细胞并复制, 在细胞破坏后，肿瘤变成一个非常炎症的环境, 刺激有效的免疫反应, 使肿瘤被病毒和 CAR-T 细胞杀死。
在小鼠模型中，这种双重疗法用于治疗人的神经胶质瘤和黑色素瘤。结果显示，联合疗法在多个部位的肿瘤中具有很高的治愈率，而不会引起明显的毒性。还可以保护治愈的小鼠免受肿瘤复发。这种治疗延长了患有皮下黑色素瘤和颅内神经胶质瘤的小鼠的生存期。
chimeric antigen receptor T-cell (CAR-T) therapy has limited activity for solid tumors. A new immunotherapy technique that loads oncolytic viruses to CAR-T to become more effectively targeting and treating solid tumors. Oncolytic viruses are naturally occurring viruses (such as vesicular stomatitis virus or reovirus) that can infect and break down cancer cells. They are engineered to selectively target cancer cells by incorporating multiple transgenes. This study shows that CAR-T cells can deliver oncolytic viruses to tumors. The virus can then infect tumor cells and replicate. Following cell destruction, the tumor becomes a very inflammatory environment, stimulating an effective immune response that allows the tumor to be killed by the virus and CAR-T cells.
In mouse models, this dual therapy was used to treat human-derived glioma and melanoma. The results showed that the combination therapy had a high cure rate in tumors of multiple sites without causing significant toxicity. Cured mice were also protected from tumor recurrence. This treatment prolonged the survival of mice with grafted melanoma and glioma.
参考文献 Reference Evgin L et al. Sci Translation Med 2022; 14: Issue 64070 岁以上乳腺癌患者的 Oncotype DX 复发评分和淋巴结状态 (4/10/2022)
Oncotype DX scores and lymph node status in beast cancer women over 70
目的：根据”明智选择指南”，>70 岁且临床淋巴结阴性、激素受体阳性 (HR+) AJCC 临床 I 期乳腺癌的女性不需要常规进行腋窝前哨淋巴结活检。然而，实际上淋巴结分期仍然在做。本研究的目的是检查 Oncotype Dx 乳腺癌复发评分在 > 70 岁的 HR + AJCC 临床 I 期乳腺癌女性中的分布，并确定与该患者群体中高复发评分相关的临床因素。
方法：使用国家癌症数据库，研究者检查了 2010-2018 年接受过 HR+、HER2- 乳腺癌治疗的年龄 > 70 岁的患者。根据前瞻性研究将 Oncotype Dx 评分分为 <26 和 ≥26，这些前瞻性研究表明该患者群体中评分≥26 的辅助化疗有益。研究者比较了病理淋巴结阳性和淋巴结阴性患者的 Oncotype 评分分布。对患者和肿瘤和因素进行调整的多变量逻辑回归用于确定与病理淋巴结阴性和淋巴结阳性患者的 Oncotype Dx 评分≥26 相关的因素。
结果：在 28,338 名患者中，5,640 名（19.9%）淋巴结阳性，22,698 名（80.1%）淋巴结阴性。总体而言，Oncotype Dx 评分≥ 26 的患者比例为：淋巴结阴性患者为 3,330（13.1%），淋巴结阳性患者为 740（14.7%）。 2010 年至 2018 年间，Oncotype Dx 评分≥26 的患者比例保持稳定在 13.1% （2010）和 13.5%（2018），但在淋巴结阳性患者中从 2010 年的 20.0% 下降到 2018 年的 15.2%。与 Oncotype Dx 评分≥26 相关的最强独立因素是肿瘤病理等级 3, 无论是淋巴结阳性（OR 12.71 [95% CI 9.27-17.44]，p < 0.0001）或淋巴结阴性（OR 18.00 [95% CI 15.57-20.81] , p < 0.0001) 患者。第二个最强因素是阴性孕酮受体状态, 无论是淋巴结阳性（OR 6.20 [95% CI 4.98-7.71, p<0.0001] 或 淋巴结阴性 （OR 7.19 [95% CI 6.51-7.93, p < 0.0001]）。
结论：无论其淋巴结状态如何，70 岁 AJCC I 期 HR+、HER2- 乳腺癌的Oncotype DX 评分≥26比例相似。研究者认为，前哨淋巴结活检可能无助于该患者群体的辅助化疗决策，但某些肿瘤因素可能更有帮助。
Objectives: Routine axillary sentinel lymph node biopsy is not needed for women >70 years of age with clinically node-negative, hormone receptor-positive (HR+) AJCC clinical stage I breast cancer, according to the “Choosing Wisely Guidelines.” However, in practice lymph node staging is still being done. The aim of this study was to examine the distribution of the Oncotype Dx breast cancer recurrence score among women >70 years of age with HR + AJCC clinical stage I breast cancer and to identify clinical factors associated with a high recurrence score in this patient population.
Methods Using the National Cancer Database, researchers examined patients aged >70 years who had been treated for HR+, HER2- breast cancer from 2010-2018. Oncotype Dx scores were divided into < 26 and ≥ 26 based on prospective studies that showed benefit of adjuvant chemotherapy with scores ≥ 26 in this patient population. Researchers compared the distribution of Oncotype scores between pathologically node-positive and node-negative patients. Multivariate logistic regression adjusting for patient and tumor and factors was used to identify factors associated with an Oncotype Dx score ≥ 26 in both pathologically node-negative and node-positive patients.
Results Of 28,338 patients, 5,640 (19.9%) were node-positive and 22,698 (80.1%) were node-negative. Overall, the proportion of patients with an Oncotype Dx score ≥ 26 was 3,330 (13.1%) among node-negative patients and 740 (14.7%) in node-positive patients. Between 2010 and 2018, the proportion of patients with an Oncotype Dx score ≥ 26 remained stable at 13.1% in 2010 and 13.5% in 2018, but decreased from 20.0% in 2010 to 15.2% in 2018 among node-positive patients. The strongest independent factor associated with Oncotype Dx score ≥26 was tumor pathological grade 3, in either node-positive (OR 12.71 [95% CI 9.27-17.44], p<0.0001) or node-negative (OR 18.00 [95% CI 15.57-] 20.81] , p<0.0001) patients. The second strongest factor was negative progesterone receptor status, either node-positive (OR 6.20 [95% CI 4.98-7.71, p<0.0001] or node-negative (OR 7.19 [95% CI 6.51-7.93, p<0.0001] ).
Conclusion A similar proportion of women greater than 70 with AJCC Stage I HR+, HER2- breast cancer have Oncotype DX scores ≥26 regardless of their nodal status.The investigators believed that sentinel lymph node biopsy may not be helpful in adjuvant chemotherapy decisions in this patient population, but certain tumor factors may be more helpful.
参考文献 Reference
Nicholson K et al. Am Soc Breast Surg Ann Meeting 2022; Abstr. April 6.Axicabtagene ciloleucel 作为高危的大 B 细胞淋巴瘤（LBCL）的一线治疗 (4/9/2022)
Axicabtagene ciloleucel as first-line therapy in high-risk large B cell lymphoma
这是第一个种嵌合抗原受体 (CAR) T 细胞疗法，作为高危 LBCL 的一线治疗。Axi-cel 是一种自体抗 CD19 CAR T 细胞疗法，由患者自身的 T 细胞被提取，然后用 CAR 分子重新编程，以帮助 T 细胞识别癌细胞。重新设计的 T 细胞被注入患者体内以攻击癌症。标准一线化学免疫疗法对高危LBCL结果不佳。
这是一项II期, 多中心, 单臂临床试验（ZUMA-12），入组 40 名高危 LBCL 患者, 95% 患者患有 III/IV 期疾病，25% 患者具有双重（double-hit）或三重打击状态，78% 的 IPI 评分≥3。试验主要结果是完全响应率。次要结果是客观响应率, 响应持续时间 , 无事件生存期, 无进展生存期 , 总生存期, 安全性评估, 中枢神经系统复发, CAR T 细胞和细胞因子的血液水平。
结果 疗效可评估患者（n = 37）的主要终点得到满足，完全响应率为 78%（95% 置信区间（CI），62-90）和 89% 客观响应率（95% CI，75-97）。截至 2021 年 5 月 17 日（中位随访时间，15.9 个月），73% 的患者保持客观响应, 未达到中位响应持续时间, 无事件生存期和无进展生存期。
安全性 ≥3 级细胞因子释放综合征和神经系统事件分别发生在 3 名患者 (8%) 和 9 名患者 (23%) 中。没有与治疗相关的 5级事件。所有患者均出现强劲的 CAR T 细胞扩增，达到峰值的中位时间为 8 天。
结论 Axi-cel 作为高危 LBCL 一线治疗十分有效，并且具有可控的安全性, 需要随机试验来确认这些结果。
This is the first clinical trial where chimeric antigen receptor (CAR) T-cell was used as first-line therapy for high-risk LBCL. Axi-cel is an autologous anti-CD19 CAR T cell therapy in which a patient’s own T cells are extracted and then reprogrammed with CAR molecules to help the T cells recognize cancer cells. The redesigned T cells are injected into the patient to attack the cancer. Standard first-line chemoimmunotherapy has poor outcomes for high-risk LBCL.
This is a phase II, multicenter, single-arm clinical trial (ZUMA-12). Among the 40 participants with high-risk LBCL, 95% had stage III/IV disease and 25% were double-hit or triple-hit lymphomas, 78% had an IPI score ≥3. The primary outcome of the trial was complete response rate. Secondary outcomes were objective response rate, duration of response, event-free survival, progression-free survival, overall survival, safety assessment, CNS relapse, and blood levels of CAR T cells and cytokines.
Results The primary endpoint of efficacy in evaluable patients (n = 37) was met with a complete response rate of 78% (95% confidence interval (CI), 62-90) and an objective response rate of 89% (95% CI, 75-97) . As of May 17, 2021 (median follow-up, 15.9 months), 73% of patients maintained an objective response, and the median duration of response, event-free survival, and progression-free survival were not reached.
Safety Grade ≥3 cytokine release syndrome and neurologic events occurred in 3 patients (8%) and 9 patients (23%), respectively. There were no treatment-related Grade 5 events. All patients experienced robust CAR T cell expansion with a median time to peak of 8 days.
Conclusions Axi-cel is effective as a first-line treatment for high-risk LBCL with a manageable safety profile. Randomized trials are needed to confirm these results.
参考文献 Reference Neelapu SS et al. Nature Med 2022; March 21.肿瘤萌芽显示 III 期结肠癌的预后价值 (4/3/2022)
Tumor budding demonstrates independent prognostic value in stage III colon cancer
TNM 分期系统仍然是恶性肿瘤分类的基本标准。 肿瘤萌芽是结肠癌中新兴的预后生物标志，目前影响 pT1 和 II 期结肠癌患者的护理。
肿瘤萌芽被定义为在肿瘤侵袭边缘最多有四个癌细胞的单个癌细胞。它可能反映了一种激进的增长模式, 作为代表癌症浸润动态过程的上皮-间质转化的形态表达的替代物。 2016 年，国际肿瘤萌芽共识会议 (ITBCC) 推荐了结直肠癌病理学家的标准化肿瘤萌芽评估及其报告。 在 pT1 结肠癌患者中，中间 (Bd2) 和高度 (Bd3) 肿瘤出芽类别与淋巴结受累有关，用于决定内镜切除后是否进行补充根治性手术。在 II 期结肠癌中，高肿瘤出芽类别 (Bd3) 代表不良预后因素，应考虑指导术后化疗。
IDEA-France III 期研究评估肿瘤出芽在 III 期结肠癌患者中的预后作用。这项事后研究是对来自 1,048 名 III 期结肠癌患者的组织切片进行的。根据 ITBCC 2016 标准通过中央审查对肿瘤出芽进行评分，分为 Bd1（0-4 个芽/0.785 mm2）、Bd2（5-9 个芽）和 Bd3（≥10 个芽）。临床病理学特征和 Immunoscore® 与肿瘤出芽相关。 总体而言，在 39%、28% 和 33% 的结肠癌患者中观察到 Bd1、Bd2 和 Bd3。 Bd2 和 Bd3 与血管 (p = 0.002) 和神经周围侵袭 (p = 0.0009) 相关。 肿瘤出芽的 3 年无进展生存率和 5 年总生存率（Bd1 对 Bd2-3）分别为 79.4% 对 67.2%（p = 0.001）和 89.2% 对 80.8%（p = 0.001）。在调整无进展生存率的相关临床病理学特征后证实了这一相关（风险比 [HR] 1.41，95% 置信区间 [CI] 1.12 至 1.77；p = 0.003）和总生存率（HR 1.65，95% CI 1.22 至 2.22；p = 0.001）的。 当与 pTN 分期和 Immunoscore® 亚组相结合时，肿瘤出芽显着改善了疾病预测。
在 IDEA-France 研究中, 接受奥沙利铂的标准辅助化疗的 III 期结肠癌患者中，中间 (Bd2) 和高度 (Bd3) 肿瘤出芽类别与较差的总生存率和无进展生存率密切相关。除了风险组和 Immunoscore® 之外，肿瘤出芽似乎提供了额外的和临床相关的预后信息。
作者认为，肿瘤出芽应根据 ITBCC 2016 标准, 作为切除的 III 期结肠癌患者的常规病理报告。
The TNM staging system remains the gold standard for the classification of cancers. Tumor budding is an emerging prognostic biomarker in colon cancer that affects the management of patients with pT1 and stage II colon cancer. Tumor budding is defined as the presence of a single tumor cell or small clusters of up to 4 cells at the invasive margin of the tumor. It may reflect an aggressive growth pattern. It may serve as a surrogate for the morphological expression of the epithelial-mesenchymal transition that represents the dynamic process of cancer invasion. In 2016, the International Tumor Budding Consensus Conference (ITBCC) recommended a standardized tumor budding assessment and reporting by colorectal cancer pathologists. In patients with pT1 colon cancer, intermediate (Bd2) and high-grade (Bd3) tumor budding categories were associated with lymph node involvement and were used to decide whether to perform complementary curative surgery after endoscopic resection. In stage II colon cancer, the high tumor budding category (Bd3) represents a poor prognostic factor and should be considered to guide adjuvant chemotherapy.
The IDEA-France phase III study evaluated the prognostic role of tumor budding in patients with stage III colon cancer. The post hoc study was conducted on tissue sections from 1,048 patients with stage III colon cancer. Tumor budding was scored by central review according to ITBCC 2016 criteria and classified as Bd1 (0-4 buds/0.785 mm2), Bd2 (5-9 buds), and Bd3 (≥10 buds). Clinicopathological features and Immunoscore® were associated with tumor budding.
Overall, Bd1, Bd2 and Bd3 were observed in 39%, 28% and 33% of colon cancer patients. Bd2 and Bd3 were associated with vascular (p = 0.002) and perineural invasion (p = 0.0009). The 3-year progression-free survival and 5-year overall survival for tumor budding (Bd1 vs Bd2-3) were 79.4% vs 67.2% (p = 0.001) and 89.2% vs 80.8% (p = 0.001), respectively. This was confirmed after adjustment for relevant clinicopathological features for DFS (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.12 to 1.77; p = 0.003) and overall survival (HR 1.65, 95 %CI 1.22 to 2.22; p = 0.001). When combined with pTN staging and Immunoscore® subgroups, tumor budding significantly improved disease prognostication.
In the IDEA-France study, intermediate (Bd2) and high-grade (Bd3) tumor budding categories were strongly associated with poorer overall and progression-free survival in patients with stage III colon cancer receiving standard oxaliplatin -based adjuvant chemotherapy. In addition to risk groups and Immunoscore®, tumor budding appears to provide additional and clinically relevant prognostic information.
The authors believe that tumor budding should be routinely reported as a microscopic biomarker in patients with resected stage III colon cancer according to ITBCC 2016 criteria.
参考文献 Reference Basile D et al. Ann Onc 2022; DOI:https://doi.org/10.1016/j.annonc.2022.03.002Efti 与 Pembrolizumab 联合用在难以治疗二线转移性肺癌 (4/2/2022)
Combination of Efti and pembrolizumab in second-line therapy for refractory nonsmall cell lung cancer
这是一项II期临床试验（TACTI-002）的B 部分，评估 eftigimod alpha（efti）与pembrolizumab用在先前PD-1 或 PD-L1 治疗后疾病进展的转移性非小细胞肺癌患者。Efti是一种可溶性 LAG-3 融合 蛋白 (LAG-3Ig)，一种抗原呈递细胞激活剂，正在癌症和传染病中试验。
共有 36 名患者入组并接受治疗。他们接受过抗 PD-(L)1 单一疗法 (28%) 或化疗和抗 PD-(L)1 联合治疗 (72%) 。大多数患者 (69%) 的 PD-L1 肿瘤比例评分 (TPS) 低于 50% 基线。数据反映了第 1 期（23 名患者）和 2 期（13 名患者）在 2 线非小细胞肺癌的第一个中期结果。
主要发现: 数据截止日期 2022 年 1 月 21 日 分析，疾病控制率为 36.1% (13/36)，其中 26% 在 6 个月无进展。73.7% 的可评估患者 (14/19) 出现肿瘤缩小或肿瘤生长减速; 6 个月的初步总生存率为 73%,。两名患者（5.6%）有持久的部分响应，参与 研究时间分别超过 9 个月和 23 个月, 6 名患者仍在试验中接受治疗。
安全性: Efti 加 pembrolizumab 的组合安全且耐受性良好。
This is the part B of a Phase II clinical trial (TACTI-002) evaluating eftigimod alpha (efti) plus pembrolizumab in patients with metastatic NSCLC whose disease has progressed after prior PD-1 or PD-L1 therapy. Efti is a soluble LAG-3 fusion protein (LAG-3Ig), an antigen-presenting cell activator that is being tested in cancer and infectious diseases.
A total of 36 patients were enrolled and treated. They had received anti-PD-(L)1 monotherapy (28%) or chemotherapy and anti-PD-(L)1 combination therapy (72%) and their disease progressed. Most patients (69%) had tumor proportion score (TPS) below 50% at baseline. The data reflect the first interim results for stage 1 (23 patients) and stage 2 (13 patients) in second-line NSCLC.
Findings: At data cutoff of 21 January 2022, disease control rate was 36.1% (13/36), of which 26% were progression-free at 6 months. Tumor shrinkage or deceleration in tumor growth occurred in 73.7% of evaluable patients (14/19); the 6-month preliminary overall survival rate was 73%. Two patients (5.6%) had durable partial responses over 9 and 23 months, respectively, and 6 patients remained on trial treatment.
Safety: The combination of Efti plus pembrolizumab was safe and well tolerated.
参考文献 Reference Krebs MG et al. ESMO’s European Lung Cancer Congress 2022, March 30FDA 批准Pluvicto用于治疗前列腺特异性膜抗原（PSMA）阳性转移性的去势抵抗性前列腺癌 (3/27/2022)
FDA approves Pluvicto for PSMA-positive metastatic castration-resistant prostate cancer
同一天，FDA 批准了 Locametz (gallium Ga 68 gozetotide)，一种用于 PSMA 阳性病变正电子发射断层扫描 (PET) 的放射性诊断剂。
这是一项随机 (2:1), 多中心, 开放标签试验（VISION, NCT03511664）,参加者为PSMA阳性的转移性去势抵抗性前列腺癌疾病进展的患者。该试验评估了 Pluvicto （lutetium Lu 177 vipivotide tetraxetan）加最佳护理 (n=551) 相比于单独使用最佳护理 (n=280) 。所有患者都接受了 GnRH 类似物或先前进行了双侧睾丸切除术。患者需要接受过至少一种雄激素受体抑制剂，以及 1 或 2 次基于紫杉烷的化疗方案。患者每 6 周接受一次 Pluvicto 7.4 GBq (200 mCi)，总共 6 剂加最佳护理或单独最佳护理。
该试验表明，总生存期和影像学无进展生存期的主要终点有统计学意义的改善。对于 Pluvicto组相比于对照组，总生存期的危险比 (HR) 为 0.62 (95% CI: 0.52, 0.74; p < 0.001)。中位总生存期分别为 15.3 个月（95% CI：14.2、16.9）和 11.3 个月（95% CI：9.8、13.5）。由于对照组早期退出的审查，对影像学无进展生存期的解释受到限制。
在接受 Pluvicto 的患者中发生率较高的最常见不良反应 (≥ 20%) 是疲劳、口干、恶心、贫血、食欲下降和便秘。在接受 Pluvicto 的患者中，≥ 30% 的患者从基线恶化的最常见实验室异常是淋巴细胞减少、血红蛋白减少、白细胞减少、血小板减少、钙减少和钠减少。使用 Pluvicto 治疗可能会导致辐射暴露、骨髓抑制和肾毒性的风险。 VISION 中的安全性随访时间比较短不能捕获晚期辐射相关毒性。
推荐的 Pluvicto 剂量为每 6 周静脉注射 7.4 GBq (200 mCi)，最多 6 剂，或直至疾病进展或出现不可接受的毒性。
FDA also approved Locametz (gallium Ga 68 gozetotide), a radioactive diagnostic agent for positron emission tomography (PET) of PSMA-positive lesions.
This is a randomized (2:1), multicenter, open-label trial (VISION, NCT03511664) in patients with PSMA-positive metastatic castration-resistant prostate cancer with disease progression. The trial evaluated Pluvicto (lutetium Lu 177 vipivotide tetraxetan) plus best supportive care (n=551) compared with best supportive care alone (n=280). All patients received GnRH analogs or had prior bilateral orchiectomy. Patients were required to have received at least one androgen receptor inhibitor and 1 or 2 taxane-based chemotherapy regimens. Patients received Pluvicto 7.4 GBq (200 mCi) every 6 weeks for a total of 6 doses plus best supportive care or best supportive care alone.
The trial demonstrated statistically significant improvements in the primary endpoints of overall survival and radiographic progression-free survival. The hazard ratio (HR) for overall survival was 0.62 (95% CI: 0.52, 0.74; p < 0.001) for the Pluvicto group compared to the control group. The median overall survival was 15.3 months (95% CI: 14.2, 16.9) and 11.3 months (95% CI: 9.8, 13.5), respectively. Interpretation of imaging progression-free survival was limited due to a high degree of censoring of early dropout in the control group.
The most common adverse reactions (≥ 20%) with a higher incidence in patients receiving Pluvicto were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that became worse from baseline in ≥ 30% of patients receiving Pluvicto were lymphopenia, hemoglobin reduction, leukopenia, thrombocytopenia, calcium reduction, and sodium reduction. Treatment with Pluvicto may lead to risks of radiation exposure, myelosuppression, and nephrotoxicity. The relatively short safety follow-up in VISION trial did not capture late radiation-related toxicity.
The recommended dose of Pluvicto is 7.4 GBq (200 mCi) intravenously every 6 weeks for a maximum of 6 doses, or until disease progression or unacceptable toxicity.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancerPD-1阻断剂单独用于错配修复缺陷 (dMMR) 局部晚期直肠癌 (3/26/2022)
PD-1 inhibitor alone used in mismatch repair deficient locally advanced rectal cancer
错配修复缺陷（dMMR）直肠肿瘤对新辅助（手术前）化疗反应不佳。 这项试验的目的是评估新辅助PD-1 阻断在 dMMR 局部晚期直肠癌中的临床益处。
方法：这是一项前瞻性、单臂、II 期研究，临床 II 期和 III 期 dMMR 直肠癌患者接受新辅助 dostarlimab（抗 PD-1）共 6 个月。共同主要目标是确定总响应率和病理完全响应或临床完全响应率，有或没有化放疗。在基线, 6 周, 3 个月和 6 个月时进行内窥镜肿瘤评估；在治疗前基线, 3 个月和 6 个月时进行成像。符合既定标准的临床完全响应患者有资格在没有化放疗的情况下进行非手术治疗。新辅助 dostarlimab 后有残留病灶的患者接受标准化放疗。化放疗后，任何未能达到临床完全响应的患者都将接受手术治疗。
结果：共纳入 13 名患者，中位年龄 52 岁（范围 26-78 岁），77% 为女性，92% 的患者经直肠 MRI 呈淋巴结阳性。在接受至少 3 个月评估的 12 名患者中，客观响应率为 100%。 7 名患者完成了诱导治疗，所有 7 名（100%）患者均达到了临床完全响应，并且正在接受未进行化放疗或手术的观察。迄今为止，疾病进展率为0%。没有患者需要化放疗或手术。没有发生严重的不良事件。
结论：在这项小型研究中, dostarlimab 单药新辅助治疗局部晚期 dMMR 直肠腺癌有效且耐受性良好，使患者避免放化疗和手术。进一步的患者招募正在进行中。
Mismatch repair deficient (dMMR) rectal tumors respond poorly to neoadjuvant (preoperative) chemotherapy. The purpose of this trial was to evaluate clinical benefit of neoadjuvant PD-1 blockade in dMMR locally advanced rectal cancer.
Methods: This is a prospective, single-arm, phase II study of patients with clinical stage II and III dMMR rectal cancer who received neoadjuvant dostarlimab (anti-PD-1) for 6 months. The co-primary objective was overall response rate and pathological complete response rate or clinical complete response rate, with or without chemoradiation. Endoscopic tumor assessments were performed at baseline, 6 weeks, 3 months, and 6 months; imaging was performed at baseline before treatment, 3 months, and 6 months. Patients who met the established criteria for a clinically complete response were eligible for nonoperative treatment in the absence of chemoradiation. Patients with residual disease after neoadjuvant dostarlimab received standardized radiotherapy. After chemoradiation, any patient who fails to achieve a complete clinical response will be treated with surgery.
Results: Thirteen patients were included, with a median age of 52 years (range, 26-78 years), 77% were female, and 92% were lymph node-positive by transrectal MRI. In 12 patients who were evaluated for at least 3 months, the objective response rate was 100%. Seven patients completed induction therapy, and all seven (100%) achieved a clinical complete response and were being observed without chemoradiation or surgery. To date, the disease progression rate was 0%. No patients required chemoradiation or surgery. No serious adverse events occurred.
Conclusions: In this small study, single-agent, Dostarlimab, neoadjuvant therapy was effective and well-tolerated in locally advanced dMMR rectal adenocarcinoma, allowing patients to avoid chemoradiotherapy and surgery. Additional patient recruitment is underway.
参考文献 Reference Lumish MA et al. J Clin Onc 2022; 40 (4)_suppl, 16循环肿瘤 DNA 分析用于中枢神经系统淋巴瘤的疾病检测 (3/20/2022)
Circulating tumor DNA for non-invasive disease detection of CNS lymphoma
目前对中枢神经系统淋巴瘤 (CNSL) 患者治疗失败的识别, 风险分层仍然具有挑战性。此外，CNSL 的诊断需要进行侵入性神经外科活检，这会带来手术风险。先前的研究显示 CNSL 患者血浆中的循环肿瘤 DNA (ctDNA) 检测率较低。在本项研究中，研究者利用超灵敏靶向高通量测序技术探索 ctDNA 在 CNSL 患者疾病分类, 微小残留病检测和临床结果早期预测中的作用。
方法：通过深度测序 (CAPP-Seq) 和分阶段变异富集和检测测序 (PhasED-Seq) 将癌症个性化分析应用于 85 个肿瘤活检样本, 131 个血浆样本和来自 62 个CNSL 患者的脑脊液和44 名患有其他脑癌或炎症性脑病的患者，研究针对 794 个不同的基因区域。
结果：在 100% 的 CNSL 肿瘤活检 (n=63) 中发现了遗传异常，每位患者的中位数为 262 个突变。在 78% 的血浆样本和 100% 的脑脊液样本中可检测到预处理血浆 ctDNA，血浆中 ctDNA 浓度范围为 0.0004 – 5.94% 等位基因频率（AF，中位数：0.01%）和 0.0049 – 50.47%脑脊液中的 AF（中位数：0.62%）。与全身性弥漫性大 B 细胞淋巴瘤患者的 ctDNA 浓度相比，CNSL 中的血浆 ctDNA 水平中位数低 200 倍以上 .在预处理时间点对 ctDNA 的评估预测了无进展生存和 总生存期，作为连续变量和二元变量。
通过将 ctDNA 和放射学肿瘤总体积结合作为预处理生物标志物，可以将患者分为预后特别好或预后差的风险组。此外，以治愈为目的的诱导治疗期间的 ctDNA 阳性与临床结果显著相关，包括无进展生存和 总生存期。CNSL 无创诊断的高特异性 (100%) 和阳性预测值 (100%)，对 CSF 和血浆的敏感性分别为 57% 和 21%，这表明很大一部分 CNSL 患者可能能够放弃侵入性诊断, 如手术活检。
结论 ctDNA 准确反映了肿瘤负荷，可作为 CNSL 风险分层, 结果预测和免手术淋巴瘤诊断的临床生物标志物。
The current evaluation of risk stratification and identification of treatment failure in patients with central nervous system lymphoma (CNSL) remains challenging. Furthermore, the diagnosis of CNSL requires an invasive biopsy, which carries surgical risks. Previous studies have shown lower detection rates of circulating tumor DNA (ctDNA) in the plasma of CNSL patients. In this study, researchers used ultrasensitive targeted high-throughput sequencing technology to explore the role of ctDNA in disease classification, minimal residual disease detection, and early prediction of clinical outcomes in CNSL patients.
Methods: Cancer personalized profiling was carried out by deep sequencing (CAPP-Seq) and Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) was applied to 85 tumor biopsy samples, 131 plasma samples, cerebrospinal samples from 62 CNSL patients and 44 patients with other brain cancers or inflammatory encephalopathy, targeting 794 different gene regions.
Results: Genetic abnormalities were found in 100% of CNSL tumor biopsies (n=63), with a median of 262 mutations per patient. Pretreated plasma ctDNA was detectable in 78% of plasma samples and 100% of cerebrospinal fluid samples, with plasma ctDNA concentrations ranging from 0.0004 – 5.94% allele frequencies (AF, median: 0.01%) and 0.0049 – 50.47% AF in CSF (median: 0.62%). Median plasma ctDNA levels in CNSL were more than 200-fold lower compared with ctDNA concentrations in patients with systemic diffuse large B-cell lymphoma. Assessment of ctDNA at pretreatment time points predicted progression-free survival and overall survival, as continuous and binary variables. By combining ctDNA and total radiographic tumor volume as pretreatment biomarkers, patients can be divided into risk groups with particularly favorable or poor prognosis. Furthermore, ctDNA positivity during induction therapy for cure was significantly associated with clinical outcomes, including progression-free survival and overall survival. The high specificity (100%) and positive predictive value (100%) for non-invasive diagnosis of CNSL, with sensitivities of 57% for CSF and 21% for plasma, respectively, suggest that a large proportion of CNSL patients may be able to forgo surgical biopsies.
Conclusions ctDNA accurately reflects tumor burden and can be used as a clinical biomarker for CNSL risk stratification, outcome prediction and surgery-free lymphoma diagnosis/classification.
参考文献 Reference Mutter JA et a. ASH Annual Meeting 2021; Dec. 12FDA批准奥拉帕尼用于高危早期乳腺癌的辅助治疗 (3/19/2022)
FDA approves Olaparib for adjuvant therapy of high-risk early breast cancer
FDA批准奥拉帕尼（Olaparib）用于辅助（术后）治疗（疑有）生殖系BRCA突变（gBRCAm）, HER2-阴性患者, 她们均已接受了新辅助或辅助化疗的高危早期乳腺癌。
这项批准基于 OlympiA (NCT02032823) 临床试验，一项随机, 双盲, 安慰剂对照的国际研究，共有1,836 名 gBRCAm HER2 阴性高危早期乳腺癌患者参加，她们完成了局部治疗和新辅助或辅助化疗。患者被随机分配接受为期 1 年的 olaparib 片剂 300 mg 每天两次口服或安慰剂。患者需要完成至少 6 个周期的新辅助或辅助化疗，包括蒽环类、紫杉类或两者兼有。根据当地指南，激素受体阳性乳腺癌患者继续内分泌同步治疗。 主要疗效终点是侵袭性无病生存期（IDFS），定义为从随机分组到首次复发日期的时间，包括侵袭性局部区域, 远处复发, 对侧侵袭性乳腺癌, 新发癌症或任何原因导致的死亡。
对于侵袭性无病生存期，奥拉帕尼组有 106 起事件（12%），安慰剂组有 178 起事件（20%）（HR 0.58；95% CI：0.46，0.74；p<0.0001）。接受奥拉帕尼的患者 3 年侵袭性无病生存期 为 86% (95% CI: 82.8, 88.4)，接受安慰剂的患者为 77% (95% CI: 73.7, 80.1)。另一个疗效终点是总生存期。奥拉帕尼组有 75 人死亡（8%），安慰剂组有 109 人死亡（12%）（HR 0.68；95% CI：0.50，0.91；p =0.0091）。与安慰剂组相比，奥拉帕尼组患者的侵袭性无病生存期和总生存期有统计学意义的改善。
OlympiA 研究中最常见的不良反应（≥10%）是恶心、疲劳（包括虚弱）、贫血、呕吐、头痛、腹泻、白细胞减少、中性粒细胞减少、食欲下降、味觉障碍、头晕和口腔炎。 推荐的奥拉帕尼剂量为每天两次口服 300 毫克，为期一年。
FDA has approved olaparib for the adjuvant (postoperative) treatment of (suspected) germline BRCA-mutated (gBRCAm), HER2-negative patients with high-risk early-stage breast cancer who have received neoadjuvant or adjuvant chemotherapy.
The approval was based on the OlympiA (NCT02032823) clinical trial, a randomized, double-blind, placebo-controlled, international study of 1,836 patients with gBRCAm HER2-negative high-risk early breast cancer who completed local therapy and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned to receive olaparib tablets 300 mg orally twice daily or placebo for 1 year. Patients were required to complete at least 6 cycles of neoadjuvant or adjuvant chemotherapy, including anthracyclines, taxanes, or both. Patients with hormone receptor-positive breast cancer could continue endocrine concurrent therapy according to local guidelines. The primary efficacy endpoint was invasive disease-free survival (IDFS), defined as the time from randomization to date of first recurrence, defined as invasive locoregional, distant recurrence, contralateral invasive breast cancer, new cancer or any cause of death.
For invasive disease-free survival, there were 106 events (12%) in the olaparib group and 178 events (20%) in the placebo group (HR 0.58; 95% CI: 0.46, 0.74; p<0.0001). The 3-year invasive disease-free survival was 86% (95% CI: 82.8, 88.4) for patients receiving olaparib and 77% (95% CI: 73.7, 80.1) for those receiving placebo. Another efficacy endpoint was overall survival. There were 75 deaths (8%) in the olaparib group and 109 deaths (12%) in the placebo group (HR 0.68; 95% CI: 0.50, 0.91; p = 0.0091). Patients in the olaparib group had statistically significant improvements in invasive disease-free survival and overall survival compared with the placebo group.
The most common adverse reactions (≥10%) in the OlympiA study were nausea, fatigue (including asthenia), anemia, vomiting, headache, diarrhea, leukopenia, neutropenia, decreased appetite, dysgeusia, dizziness, and stomatitis. The recommended dose of olaparib is 300 mg orally twice daily for one year.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-adjuvant-treatment-high-risk-early-breast-cancer术前免疫疗法和辅助纳武利尤单抗治疗局部微卫星不稳定性高/错配修复缺陷胃/胃食管腺癌 (3/13/2022)
Neoadjuvant nivolumab plus ipilimumab in localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) gastroesophageal adenocarcinoma
这是一项II期临床试验（GERCOR NEONIPIGA）, 目的是评估术前纳武利尤单抗（nivolumab）加上伊匹单抗（ipilimumab）和术后纳武利尤单抗, 对可切除的微卫星不稳定性高/错配修复缺陷（MSI/dMMR）, T2-T4 NxM0 肿瘤患者的疗效。治疗包括每 2 周 240 毫克 纳武单抗（共6 次）和每 6 周 1毫克/公斤伊匹单抗（共2 次），最后一次注射纳武单抗后 5 周（±1 周）内进行根治性手术。 Becker 肿瘤消退等级 (TRG) < 3 的患者, 术后每 4 周接受 480 毫克 纳武利尤单抗辅助治疗（共9 次）。主要目标是病理完全缓解率。
结果：从 2019 年 10 月至 2021 年 6 月，共纳入 32 例患者（均为 dMMR±MSI-H 状态；16例胃癌，16 例胃食管癌）。中位年龄为 65.5 岁（范围 40-80）。初始阶段是：超声内窥镜评估T3Nx = 22、超声内窥镜评估T2Nx = 4 和 超声内窥镜评估TxNx = 6（无法通过超声内窥镜评估）。在数据锁定时，32 名患者终止了术前治疗，27 名患者（84%）完成了所有 6 个术前治疗周期。 8 位患者 (32%) 在术前治疗期间经历了 3/4 级不良事件。 29 名患者接受了手术； 2 人拒绝手术，并且内镜检查活检无肿瘤, 完全缓解，1 人因转移进展未进行手术。最后一次注射和手术之间的中位延迟为 35 天（极端，25-170）。总体术后并发症（54%，n = 14）, 包括吻合口漏 = 4，胰腺炎 = 2，肺炎 = 2，其他 = 6。术后死亡率为 3.8%（n = 1），原因是术后第 3 天的心血管副作用。所有 29 名接受手术的患者均进行了 R0 切除：17 名 (59%) 达到病理完全缓解; 4 名 (14%) Beker分级为 TRG 1b（残留肿瘤 < 10%）; 1 例 TRG 2（残余肿瘤 10-50%）; 7 例 TRG 3（残余肿瘤 50%）。中位随访 10.9 个月，1 例转移复发，1 例无复发死亡，30 例无复发/无进展。
结论：纳武利尤单抗和易普利姆玛的术前治疗是可行的，并且与 MSI/dMMR 的胃食管癌患者的高完全缓解率相关。
This is a phase II clinical trial (GERCOR NEONIPIGA) to evaluate the effect of preoperative nivolumab plus ipilimumab and postoperative nivolumab on resectable microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) , T2-T4 NxM0 gastric/gastroesophageal cancer patients. Treatment consisted of nivolumab 240 mg every 2 weeks (total of 6 treatments) and ipilimumab 1 mg/kg every 6 weeks (total 2 treatments), followed by radical surgery 5 weeks (±1 week) after the last nivolumab injection. Patients with Becker tumor regression grade (TRG) < 3 received adjuvant nivolumab 480 mg every 4 weeks after surgery (nine doses). The primary objective was pathological complete response rate.
RESULTS: From October 2019 to June 2021, 32 patients (all with dMMR±MSI-H status; 16 gastric cancer, 16 gastroesophageal cancer) were included. The median age was 65.5 years (range 40-80). The initial stages were: usT3Nx = 22, usT2Nx = 4 and usTxNx = 6 (cannot be assessed by EUS). At the time of data lock, 32 patients terminated preoperative treatment and 27 patients (84%) completed all 6 preoperative treatment cycles. Eight patients (32%) experienced grade 3/4 adverse events during preoperative treatment. Twenty-nine patients underwent surgery; 2 refused surgery and had complete endoscopic response with tumor-free biopsies, and 1 did not undergo surgery due to metastatic progression. The median delay between the last injection and surgery was 35 days (extreme, 25-170). Overall surgical morbidity (54%, n = 14), including anastomotic leakage = 4, pancreatitis = 2, pneumonia = 2, and other = 6. Postoperative mortality was 3.8% (n = 1) due to cardiovascular side effects on postoperative day 3. All 29 patients who underwent surgery had R0 resection: 17 (59%) achieved pathological complete response; 4 (14%) Beker grade TRG 1b (residual tumor < 10%); 1 TRG 2 (residual tumor 10-50%); 7 TRG 3 (50% residual tumor). During a median follow-up of 10.9 months, 1 case had metastasis recurrence, 1 case died without relapse, and 30 cases were recurrence-free.
CONCLUSIONS: Preoperative treatment with nivolumab and ipilimumab is feasible and associated with high complete response rates in gastroesophageal cancer patients with MSI/dMMR.
参考文献 Reference Andre T. et al. J Clin Onc 2022; 40 suppl 244术前免疫疗法和辅助纳武利尤单抗治疗局部微卫星不稳定性高/错配修复缺陷胃/胃食管腺癌 (3/13/2022)
Neoadjuvant nivolumab plus ipilimumab in localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) gastroesophageal adenocarcinoma
这是一项II期临床试验（GERCOR NEONIPIGA）, 目的是评估术前纳武利尤单抗（nivolumab）加上伊匹单抗（ipilimumab）和术后纳武利尤单抗, 对可切除的微卫星不稳定性高/错配修复缺陷（MSI/dMMR）, T2-T4 NxM0 肿瘤患者的疗效。治疗包括每 2 周 240 毫克 纳武单抗（共6 次）和每 6 周 1毫克/公斤伊匹单抗（共2 次），最后一次注射纳武单抗后 5 周（±1 周）内进行根治性手术。 Becker 肿瘤消退等级 (TRG) < 3 的患者, 术后每 4 周接受 480 毫克 纳武利尤单抗辅助治疗（共9 次）。主要目标是病理完全缓解率。
结果：从 2019 年 10 月至 2021 年 6 月，共纳入 32 例患者（均为 dMMR±MSI-H 状态；16例胃癌，16 例胃食管癌）。中位年龄为 65.5 岁（范围 40-80）。初始阶段是：超声内窥镜评估T3Nx = 22、超声内窥镜评估T2Nx = 4 和 超声内窥镜评估TxNx = 6（无法通过超声内窥镜评估）。在数据锁定时，32 名患者终止了术前治疗，27 名患者（84%）完成了所有 6 个术前治疗周期。 8 位患者 (32%) 在术前治疗期间经历了 3/4 级不良事件。 29 名患者接受了手术； 2 人拒绝手术，并且内镜检查活检无肿瘤, 完全缓解，1 人因转移进展未进行手术。最后一次注射和手术之间的中位延迟为 35 天（极端，25-170）。总体术后并发症（54%，n = 14）, 包括吻合口漏 = 4，胰腺炎 = 2，肺炎 = 2，其他 = 6。术后死亡率为 3.8%（n = 1），原因是术后第 3 天的心血管副作用。所有 29 名接受手术的患者均进行了 R0 切除：17 名 (59%) 达到病理完全缓解; 4 名 (14%) Beker分级为 TRG 1b（残留肿瘤 < 10%）; 1 例 TRG 2（残余肿瘤 10-50%）; 7 例 TRG 3（残余肿瘤 50%）。中位随访 10.9 个月，1 例转移复发，1 例无复发死亡，30 例无复发/无进展。
结论：纳武利尤单抗和易普利姆玛的术前治疗是可行的，并且与 MSI/dMMR 的胃食管癌患者的高完全缓解率相关。
This is a phase II clinical trial (GERCOR NEONIPIGA) to evaluate the effect of preoperative nivolumab plus ipilimumab and postoperative nivolumab on resectable microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) , T2-T4 NxM0 gastric/gastroesophageal cancer patients. Treatment consisted of nivolumab 240 mg every 2 weeks (total of 6 treatments) and ipilimumab 1 mg/kg every 6 weeks (total 2 treatments), followed by radical surgery 5 weeks (±1 week) after the last nivolumab injection. Patients with Becker tumor regression grade (TRG) < 3 received adjuvant nivolumab 480 mg every 4 weeks after surgery (nine doses). The primary objective was pathological complete response rate.
RESULTS: From October 2019 to June 2021, 32 patients (all with dMMR±MSI-H status; 16 gastric cancer, 16 gastroesophageal cancer) were included. The median age was 65.5 years (range 40-80). The initial stages were: usT3Nx = 22, usT2Nx = 4 and usTxNx = 6 (cannot be assessed by EUS). At the time of data lock, 32 patients terminated preoperative treatment and 27 patients (84%) completed all 6 preoperative treatment cycles. Eight patients (32%) experienced grade 3/4 adverse events during preoperative treatment. Twenty-nine patients underwent surgery; 2 refused surgery and had complete endoscopic response with tumor-free biopsies, and 1 did not undergo surgery due to metastatic progression. The median delay between the last injection and surgery was 35 days (extreme, 25-170). Overall surgical morbidity (54%, n = 14), including anastomotic leakage = 4, pancreatitis = 2, pneumonia = 2, and other = 6. Postoperative mortality was 3.8% (n = 1) due to cardiovascular side effects on postoperative day 3. All 29 patients who underwent surgery had R0 resection: 17 (59%) achieved pathological complete response; 4 (14%) Beker grade TRG 1b (residual tumor < 10%); 1 TRG 2 (residual tumor 10-50%); 7 TRG 3 (50% residual tumor). During a median follow-up of 10.9 months, 1 case had metastasis recurrence, 1 case died without relapse, and 30 cases were recurrence-free.
CONCLUSIONS: Preoperative treatment with nivolumab and ipilimumab is feasible and associated with high complete response rates in gastroesophageal cancer patients with MSI/dMMR.
参考文献 Reference
Andre T. et al. J Clin Onc 2022; 40 suppl 244
高纤维饮食可能会改善黑色素瘤患者对免疫疗法的反应 (3/12/2022)
A high-fiber diet may improve response to immunotherapy among melanoma patients
一项新研究表明，富含纤维的饮食可能会通过影响肠道微生物组来帮助一些接受黑色素瘤治疗的人对免疫治疗产生响应。在接受免疫检查点阻滞剂治疗的晚期黑色素瘤患者中，每天摄入至少 20 克膳食纤维的患者存活时间最长，且疾病没有进展。相比之下，益生菌补充剂的使用似乎在一定程度上降低了免疫检查点阻滞剂方案的有效性。
纤维摄入与免疫治疗反应之间的联系并不清楚。在这项新研究中，在已知膳食纤维摄入量的 128 名患者中，那些自称每天摄入至少 20 克膳食纤维（研究人员将其定义为“足够”的量）的患者比那些报告摄入较少的膳食纤维的患者无进展生存期更长。每日纤维摄入量每增加 5 克，疾病进展的风险就会降低 30%。 在小鼠黑色素瘤模型中, 给小鼠喂食富含纤维或低纤维的饮食，并给小鼠注射黑色素瘤细胞，然后用抗 PD-1 疗法治疗小鼠。与给予低纤维饮食的小鼠相比，给予富含纤维饮食的小鼠在抗 PD-1 治疗后延缓了肿瘤的生长。
膳食纤维发挥其有益作用的一种可能机制是增加肠道中细菌的类型，例如瘤胃球菌科，与那些对免疫疗法无响应的患者相比，对免疫疗法有响应的患者肠道微生物群中的瘤胃球菌科细菌数量更多。这些细菌会产生高水平的具有抗肿瘤作用的短链脂肪酸。 喂食富含果胶（苹果中富含的一种纤维）饮食的小鼠能够通过激活免疫细胞和重编程肿瘤微环境。在喂食高纤维饮食的小鼠中发现了其中一种短链脂肪酸丙酸盐的增加，
研究人员还研究了益生菌对黑色素瘤小鼠模型中肠道细菌的影响。喂食益生菌的小鼠对抗 PD-L1 药物治疗的响应降低，并且比对照小鼠产生更大的肿瘤。喂食益生菌的小鼠具有较低水平的肿瘤杀伤免疫细胞，表明免疫反应减弱。
膳食纤维和益生菌对肠道微生物群的影响只是大局的一部分，许多因素会影响黑色素瘤患者对免疫疗法的反应能力。
A new study suggested a high-fiber diet may help some melanoma patients respond to immunotherapy by affecting the gut microbiome. Among patients with advanced melanoma treated with immune checkpoint inhibitors, those who consumed at least 20 grams of dietary fiber per day lived longer without disease progression. In contrast, the use of probiotics appeared to reduce the effectiveness of immune checkpoint inhibitors to some extent.
The link between dietary fiber intake and immunotherapy response is unclear. In this study, among 128 patients with known dietary fiber intake, those who reported taking at least 20 grams of dietary fiber per day (which the researchers defined as an “adequate” amount for the purpose of this study) lived longer without disease progression than those who reported taking less dietary fiber. For every 5-gram increase in daily fiber intake, the risk of disease progression was reduced by 30%.
In a mouse melanoma model, mice were fed a fiber-rich or low-fiber diet, injected with melanoma cells, and then given anti-PD-1 therapy. Mice given a fiber-rich diet had delayed tumor growth after anti-PD-1 treatment compared to mice given a low-fiber diet. One possible mechanism whereby dietary fiber exerts its beneficial effects was to increase the types of bacteria in the gut, such as Ruminococcaceae. In those melanoma patients who responded to immunotherapy, there were more numerous Ruminococcaceae in their gut compared to those who did not respond to immunotherapy. These bacteria produced high levels of short-chain fatty acids with antitumor effects. Mice fed a diet rich in pectin, a type of fiber found in apples, were able to reprogram the tumor microenvironment by activating immune cells. An increase in one of these short-chain fatty acids, propionate, was found in mice fed a high-fiber diet,
Researchers also studied the effect of probiotics on gut bacteria in a mouse model of melanoma. Mice fed probiotics had a reduced response to anti-PD-L1 drug treatment and developed larger tumors than control mice. Mice fed probiotics had lower levels of tumor-killing immune cells, suggesting a weakened immune response.
The impact of dietary fiber and probiotics on the gut microbiome is only part of the big picture, and many factors can affect the ability of melanoma patients to respond to immunotherapy.
参考文献 Reference https://www.nih.gov/news-events/news-releases/high-fiber-diet-may-improve-response-melanoma-patients-immunotherapy https://www.mdanderson.org/newsroom/high-fiber-diet-associated-with-improved-progression-free-survival-and-response-to-immunotherapy-in-melanoma-patients.h00-159466368.html肠道微生物组与晚期黑色素瘤免疫检查点抑制剂响应的关联 (3/6/2022)
Association of gut microbiome with response to immune checkpoint inhibitors in advanced melanoma
这是研究肠道微生物菌素与免疫检查点抑制剂响应的一项最大研究。研究者对晚期黑色素瘤患者（n = 165）的五个观察队列在免疫检查点抑制剂初治的开始前收集的粪便样本进行了鸟枪宏基因组测序（shotgun metagenomic sequencing）, 并且将这些数据与先前发表的 147 个宏基因（metagenomic）样本相结合，研究者发现肠道微生物组与对免疫检查点抑制剂的响应具有相关但依赖于队列的关联。机器学习分析证实了微生物组与总体缓解率和无进展生存期与免疫检查点抑制剂之间的联系，但也显示了微生物组的特征在队列中的重复性有限。
假链状双歧杆菌, Roseburia spp 和Akkermansia muciniphila与患者对免疫检查点抑制剂的响应相关，但没有一个菌种可以被确定为跨研究的共同一致的生物标志。总体而言，人类肠道微生物组在免疫检查点抑制剂响应中的作用似乎比以前认为的更复杂，超出了响应者和无响应者中存在或不存在的微生物种类。另一个发现是微生物组本身受到患者体质、质子泵抑制剂使用和饮食等因素的强烈影响，这些因素应在未来的纵向研究中予以考虑 。
未来的研究应该采用更大的样本量，并考虑到治疗过程中临床因素与肠道微生物组的复杂相互作用。
This is the largest study to investigate an association of gut microbiome with response to immune checkpoint inhibitors. Researchers performed shotgun metagenomic sequencing of stool samples collected before initiation of immune checkpoint inhibitor-naïve treatment in five observational cohorts of patients with advanced melanoma (n = 165) and compared these data with previous studies. Combining 147 published metagenomic samples, the researchers found a correlated but cohort-dependent association of the gut microbiome with response to immune checkpoint inhibitors. Machine learning analysis confirmed the association between the microbiome and overall response rate and progression-free survival with immune checkpoint inhibitors, with, however, limited reproducibility of microbiome signatures across cohorts.
Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, were all associated with patient response to immune checkpoint inhibitors, but no single species could be identified as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in the response to immune checkpoint inhibitors appears to be more complex than previously thought, extending beyond microbial species present or absent in responders and non-responders. Another finding is that the microbiome itself is strongly influenced by factors such as patient constitution, proton pump inhibitor use, and diet, which should be considered in future longitudinal studies.
Future studies should employ larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome during treatment.
参考文献 Reference Lee KA et al. Nature Med 2022; Feb 22FDA 批准 Ciltacabtagene Autoleucel 用于复发或难治性多发性骨髓瘤 (3/5/2022)
FDA has approved Ciltacabtagene Autoleucel for relapsed and refractory multiple myeloma
FDA 批准 ciltacabtagene autoleucel (Carvykti) 用于治疗成人复发或难治性多发性骨髓瘤，此前接受过四线或更多线治疗，包括蛋白酶体抑制剂、免疫调节剂和抗 CD38 单克隆抗体。Ciltacabtagene autoleucel 是一种 B 细胞成熟抗原 (BCMA) 导向的转基因自体嵌合抗原受体 (CAR) T 细胞疗法。每个剂量都是使用患者自己的 T 细胞定制的，这些 T 细胞被收集和基因改造，然后输回患者体内。
该批准基于关键的 CARTITUDE-1 研究的数据，其中包括接受过中位数 6 次先前治疗方案（范围 = 3-18）并且之前接受过蛋白酶体抑制剂、免疫调节剂和抗CD38 单克隆抗体。 在CARTITUDE-1 研究中，一次性使用 ciltacabtagene autoleucel 治疗产生了深度和持久的响应，98%（95% 置信区间 [CI] = 92.7%–99.7%）复发性或难治性多发性骨髓瘤患者对治疗有响应。值得注意的是，78% (95% CI = 68.8%–86.1%) 的患者达到这一水平的响应 (n = 76) 取得完全响应，即医生无法观察到或通过影像学或其他检查发现任何疾病迹。在中位 18 个月的随访中，中位缓解持续时间为 21.8 个月。 Ciltacabtagene autoleucel 只能通过称为 CARVYKTI REMS 计划的风险评估和缓解策略 (Risk Evaluation and Mitigation Strategy, REMS) 下的计划获得。
Ciltacabtagene autoleucel 的安全信息包括关于细胞因子释放综合征、免疫效应细胞相关神经毒性综合征、帕金森综合征和格林巴利综合征、噬血细胞性淋巴组织细胞增多症/巨噬细胞活化综合征以及长期和/或复发性血细胞减少症的黑框警告。警告和预防措施包括长期和复发性血细胞减少、感染、低丙种球蛋白血症、超敏反应、继发性恶性肿瘤以及对驾驶和使用机器能力的影响。最常见的不良反应 (≥ 20%) 是发热、细胞因子释放综合征、低丙种球蛋白血症、低血压、肌肉骨骼疼痛、疲劳、感染病原体不明、咳嗽、寒战、腹泻、恶心、脑病、食欲下降、上呼吸道感染、头痛、心动过速、头晕、呼吸困难、水肿、病毒感染、凝血障碍、便秘和呕吐。
FDA has approved ciltacabtagene autoleucel (Carvykti) for the treatment of adults with relapsed or refractory multiple myeloma who have received four or more lines of prior therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. Ciltacabtagene autoleucel is a B cell maturation antigen (BCMA)-directed transgenic autologous chimeric antigen receptor (CAR) T cell therapy. Each dose is customized using the patient’s own T cells, which are harvested and genetically modified, and then infused back into the patient.
The approval is based on data from the pivotal CARTITUDE-1 study, which enrolled patients who received a median of 6 prior regimens (range = 3-18) and prior proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies. In the CARTITUDE-1 study, single-use ciltacabtagene autoleucel produced deep and durable responses in 98% (95% confidence interval [CI] = 92.7%–99.7%) of patients with relapsed or refractory multiple myeloma. Notably, 78% (95% CI = 68.8%–86.1%) of patients achieved this level of response (n = 76) with a complete response, i.e. no disease was observed or detected by the physician or via imaging or other tests. At a median follow-up of 18 months, the median duration of response was 21.8 months. Ciltacabtagene autoleucel is only available through a program under the Risk Evaluation and Mitigation Strategy (REMS) known as the CARVYKTI REMS program.
Safety information for Ciltacabtagene autoleucel includes information on cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinson’s and Guillain-Barre syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and long-term and/or Boxed Warning for Recurrent Cytopenia. Warnings and precautions include prolonged and recurrent cytopenias, infections, hypogammaglobulinemia, hypersensitivity reactions, secondary malignancies, and effects on the ability to drive and use machinery. The most common adverse reactions (≥ 20%) were pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infection of unknown pathogen, cough, chills, diarrhea, nausea, encephalopathy, appetite Decline, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infection, coagulation disorder, constipation and vomiting.
参考文献 Reference https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma奥拉帕尼加阿比特龙一线治疗转移性去势抵抗性前列腺癌 (2/27/2022)
First line Olaparib plus Abiraterone in metastatic castration-resistant prostate cancer
这是一项III期临床试验（PROpel），旨在评估 PARP 抑制奥拉帕尼 （olaparib）和阿比特龙 (Abiraterone) 作为一线治疗转移性去势性前列腺癌的作用。来自美国、加拿大和澳大利亚等超过 15 个国家的研究人员随机分配 399 名患者接受奥拉帕尼和阿比特龙治疗，397 名患者接受安慰剂和阿比特龙治疗。
中期分析显示，无论同源重组修复 (HRR, homologous recombination repair status) 突变状态如何，联合治疗均可显著延长放射学无进展生存，奥拉帕尼/阿比特龙组的中位时间为 24.8 个月，而安慰剂/阿比特龙组为 16.6 个月。 每组报告的最常见的 3 级或更高级别的不良事件是贫血，分别为 15.1% 和 3.3%。
This is a Phase III clinical trial (PROpel) to evaluate PARP inhibitor (olaparib) and Abiraterone as first-line therapy in patients with metastatic castration-resistant prostate cancer. Researchers from more than 15 countries including the United States, Canada and Australia randomly assigned 399 patients to receive olaparib and abiraterone, and 397 patients to receive placebo and abiraterone.
Interim analysis showed the combination therapy significantly prolonged radiographic progression-free survival regardless of homologous recombination repair (HRR) mutation status, with a median duration of 24.8 months in the olaparib/abiraterone group , compared with 16.6 months in the placebo/abiraterone group. The most common adverse event of grade 3 or higher reported in each group was anemia, in 15.1% and 3.3%, respectively.
参考文献 Reference Saad F et al. J Clin Onc 2022;Pembrolizumab 加曲妥珠单抗和化疗治疗作为第一线治疗晚期 HER2 阳性胃癌 (2/26/2022)
Pembrolizumab plus Trastuzumab as first line therapy for advanced stage HER2-positive gastric cancer
KEYNOTE-811 试验的首次中期分析显示，在先前未治疗的晚期HER2 阳性胃癌或胃食管交界处腺癌患者中，在曲妥珠单抗和化疗的基础上添加派姆单抗可显著提高客观响应率。
方法 这是一项双盲III期临床试验，来自 20 个国家/地区的 434 名患者在 2018 年 10 月至 2020 年 6 月期间被随机分配每3 周接受 200 毫克 派姆单抗 (n = 217) 或安慰剂 (n = 217) 治疗, 加上曲妥珠单抗和研究者选择的5-氟尿嘧啶/顺铂（n = 189 对 187）或卡培他滨/奥沙利铂（n = 28 对 30）。在 8 毫克/公斤 曲妥珠单抗负荷剂量后，每 3 周给予一次 6 毫克/公斤。化疗包括：第 1 至 5 天5-氟尿嘧啶 800 毫克/平方米，顺铂 80 毫克/平方米，每 3 周一次；或卡培他滨 1,000 毫克/平方米，第 1 至 14 天每天两次，奥沙利铂 130 毫克/平方米每 3 周一次。治疗持续长达 35 个周期或直至疾病进展或出现不可接受的毒性。总体而言，81% 的患者的 PD-L1 综合阳性评分至少为 1。在最初的 264 名入组患者（疗效人群）中评估了盲法独立中央审查的客观响应率和接受至少一剂研究治疗的 433 名患者的安全性。疗效人群包括派姆单抗组的 133 名患者和对照组的 131 名患者。在疗效人群中，115 对 115 名患者选择的化疗方案是氟尿嘧啶/顺铂，18 对 16 名患者选择卡培他滨/奥沙利铂。 意向治疗人群的中位随访时间为 9.9 个月（范围 = 0.1-19.4 个月），疗效人群的中位随访时间为 12.0 个月（范围 = 8.5-19.4 个月）。
结果 帕博利珠单抗组 133 名患者中有 99 名（74.4%，95% 置信区间 [CI] = 66.2%–81.6%）观察到客观响应相对于 131 名对照组患者中有 68 名 （51.9%，95% CI = 43.0%–60.7%）。派姆单抗组改善了 22.7%（95% CI = 11.2%–33.7%，P = .00006）。完全响应为 15 名患者 (11.3%) 相对于 4 名患者 (3.1%) 。另外 29 名患者 (21.8%) 相对于 49 名患者 (37.4%) 中观察到疾病稳定。疾病控制率为 96.2% (95% CI = 91.4%–98.8%) 相对于 89.3% (95% CI = 82.7%–94.0%)。
帕博利珠单抗组的中位响应持续时间为 10.6 个月（范围 = > 1.1 至 > 16.5 个月），对照组为 9.5 个月（范围 = > 1.4 至 > 15.4 个月），截至数据显示，50.5% 相对于 44.1% 响应持续进行。估计有 70.3% 相对于 61.4% 的响应持续了至少 6 个月，58.4% 相对于 51.1% 的响应持续了至少 9 个月。
不良事件 在安全人群中的 217 名相对于 216 名患者中，派姆单抗组 57.1% 和对照组 57.4% 发生 3 级以上不良事件。两组中最常见的是贫血（8.5% 对 9.3%）、血小板减少（7.8% 对 6.9%）、腹泻（7.4% 对 8.3%）和中性粒细胞减少（7.4% 对 7.4%）。 31.3% 相对于38.4% 的患者发生严重不良事件。不良事件导致停止研究治疗的任何部分的比例分别为 24.4% 相对于 25.9%，包括停用派姆单抗和安慰剂的比例分别为 5.5% 和 6.9%。潜在的免疫相关不良事件或输液反应发生率为 33.6% 和 20.8%，其中输液反应分别为 18.0% 和 13.0%。派姆单抗组最常见的免疫相关事件是肺炎（5.1%）、结肠炎（4.6%）和甲状腺功能减退（4.6%）。不良事件导致 7 例 (3.2%) 和 10 例 (4.6%) 患者死亡，每组 2 例 (0.9%) 患者的死亡被认为与治疗有关。
结论：派姆单抗, 曲妥珠单抗和化疗的组合可能是 HER2 阳性胃癌或胃食管结合部腺癌的一种有希望的治疗选择。
The first interim analysis of KEYNOTE-811 trial showed that addition of pembrolizumab to trastuzumab/chemotherapy significantly increased objective response rate in previously untreated patients with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma.
Methods This was a double-blind phase III clinical trial in which 434 patients from 20 countries were randomly assigned to receive pembrolizumab (200 mg) (n=217) every 3 weeks or placebo (n = 217), plus trastuzumab and chemotherapy of investigator’s choice: 5-fluorouracil/cisplatin (n = 189 vs 187) or capecitabine/oxaliplatin (n = 28 to 30). Trastuzumab was given at 6 mg/kg every 3 weeks after a loading dose of 8 mg/kg. Chemotherapy included: 5-fluorouracil 800 mg/m2 on days 1 to 5, cisplatin 80 mg/m2 every 3 weeks; or capecitabine 1,000 mg/m2 twice daily on days 1 to 14, Oxaliplatin 130 mg/m2 every 3 weeks. Treatment continued for up to 35 cycles or until disease progression or unacceptable toxicity. Overall, 81% of patients had a PD-L1 composite positivity score of at least 1. Objective response rates were assessed in the initial 264 enrolled patients (the efficacy population) by blinded independent central review. Safety was evaluated in 433 patients who received at least one dose of study treatment. The efficacy population included 133 patients in the pembrolizumab group vs. 131 patients in the control group. In the efficacy population, the chemotherapy regimen of choice was fluorouracil/cisplatin for 115 vs. 115 patients, and capecitabine/oxaliplatin for 18 vs. 16 patients. Median follow-up was 9.9 months (range = 0.1-19.4 months) in the intent-to-treat population and 12.0 months (range = 8.5-19.4 months) in the efficacy population.
Results: Objective response was observed in 99 of 133 patients in the pembrolizumab group (74.4%, 95% confidence interval [CI] = 66.2%–81.6%) versus 68 of 131 patients in the control group (51.9%) , 95% CI = 43.0%–60.7%). The improvement in the pembrolizumab group was 22.7% (95% CI = 11.2%–33.7%, P = .00006). Complete response was 15 patients (11.3%) versus 4 patients (3.1%). Stable disease was observed in additional 29 patients (21.8%) versus 49 patients (37.4%). Disease control rate was 96.2% (95% CI = 91.4%–98.8%) versus 89.3% (95% CI = 82.7%–94.0%). Median duration of response was 10.6 months in the pembrolizumab group (range = > 1.1 to > 16.5 months) vs. 9.5 months in the control group (range = > 1.4 to > 15.4 months). As of data cut-off. 50.5% versus 44.1% responses persisted. Among 70.3% vs 61.4% of responses lasted at least 6 months, and 58.4% vs 51.1% of responses lasted at least 9 months.
Adverse Events Grade 3 or higher adverse events occurred in 57.1% of the pembrolizumab group and 57.4% of the control group of 217 versus 216 patients in the safety population. The most common adverse events in both groups were anemia (8.5% vs 9.3%), thrombocytopenia (7.8% vs 6.9%), diarrhea (7.4% vs 8.3%) and neutropenia (7.4% vs 7.4%). Serious adverse events occurred in 31.3% versus 38.4% of patients. Adverse events led to discontinuation of any part of study treatment were found in 24.4% versus 25.9%, respectively, including discontinuation of pembrolizumab vs. placebo in 5.5% vs. 6.9%, respectively. Potential immune-related adverse events or infusion reactions occurred in 33.6% and 20.8% of patients, with infusion reactions in 18.0% and 13.0%, respectively. The most common immune-related events in the pembrolizumab group were pneumonia (5.1%), colitis (4.6%), and hypothyroidism (4.6%). Adverse events resulted in death in 7 (3.2%) and 10 (4.6%) patients, with 2 (0.9%) deaths in each group considered treatment-related.
Conclusions: The combination of pembrolizumab, trastuzumab, and chemotherapy may be a promising treatment option for HER2-positive gastric or gastroesophageal junction adenocarcinoma.
参考文献 Reference Janjigian Y et al. Nature 2021; 600:727-30一些 雌激素受体和淋巴结阳性的绝经后乳腺癌患者可免于化疗：RxPONDER 试验的更新 (2/20/2022)
Some ER and lymph node-positive postmenopausal breast cancer patients can be spared with chemotherapy: update of RxPOINDER trial
SWOG S1007 RxPONDER试验在更新分析和更长的随访中证实了先前分析的关键要点：1) 对激素受体阳性,HER2阴性, 1-3个淋巴结阳性和 21基因Oncotype复发评分（RS）为 0-25的绝经后妇女,从内分泌治疗中添加化疗,没能受益。 2) 但RS为 0-25分的绝经前妇女受益于辅助化疗。
这是一项III期临床试验,参加者为激素受体阳性,HER2阴性, 1-3个淋巴结阳性,无远处转移，RS≤25。患者被随机分配接受化疗后内分泌治疗或单独内分泌治疗。在 4,984名符合条件的患者中，有 553例无侵袭性疾病生存期事件，中位随访时间为 6.1年。绝经后妇女 化疗对无侵袭性疾病生存期或无远处病生存期没有任何益处。然而，化疗对绝经前患者的无侵袭性疾病生存期或无远处病生存期的 5年绝对获益分别为 5.9%和 3.3%。
在绝经前患者中，对于所有RS值< 25，化疗与改善无远处复发间隔相关，RS为0-13和RS为 14-25的绝对改善分别为 2.3%和 2.8%。在绝经前患者中，12.4% (n= 206)患有微转移（0.2-2毫米, pNmi)疾病。在一项事后分析中，微转移患者有化疗获益的趋势 [风险比 (HR) = 0.44，置信区间 (CI) = 0.18-1.08]。相比之下，对于 1,403名pN1病（>2 mm）患者，绝对获益为 4.8%（HR = 0.64；95%CI = 0.46–0.90）。 两个治疗组的卵巢功能抑制率均较低，但单独内分泌治疗组的卵巢功能抑制率较高。简而言之，该研究无法确定化疗的益处与卵巢功能抑制有关。
The SWOG S1007 RxPONDER trial confirmed the key findings in an updated analysis and longer follow-up:1) Postmenopausal women with hormone receptor-positive, HER2-negative, 1-3 node-positive and 21-gene Oncotype recurrence score (RS) 0-25 did not benefit from adding chemotherapy to endocrine therapy.2) Premenopausal women with a RS of 0-25 benefited from adjuvant chemotherapy.
This is a phase III clinical trial, and the participants were hormone receptor positive, HER2 negative, 1-3 lymph node positive, without distant metastasis, and RS ≤ 25. Patients were randomly assigned to receive endocrine therapy followed by chemotherapy or endocrine therapy alone. Among 4,984 eligible patients, there were 553 invasive disease-free survival events with a median follow-up of 6.1 years. Chemotherapy in postmenopausal women did not show any benefit in invasive disease-free survival or distant disease-free survival. However, the 5-year absolute benefit of chemotherapy for invasive disease-free survival or distant disease-free survival in premenopausal patients was 5.9% and 3.3%, respectively.
In premenopausal patients, for all RS values < 25, chemotherapy was associated with improved distant recurrence-free interval, with absolute improvements of 2.3% and 2.8% for RS 0-13 and RS 14-25, respectively. Among premenopausal patients, 12.4% (n = 206) had micrometastatic (0.2-2 mm, pNmi) disease. In a post hoc analysis, patients with micrometastases there was a trend towards a benefit from chemotherapy [hazard ratio (HR) = 0.44, confidence interval (CI) = 0.18-1.08]. In comparison, for 1,403 patients with pN1 disease (> 2 mm), the absolute benefit was 4.8% (HR = 0.64; 95% CI = 0.46–0.90). The rate of ovarian function suppression was lower in both treatment groups, but higher in the endocrine therapy alone group. In short, the study was unable to establish that the benefit of chemotherapy was related to ovarian function suppression.
参考文献 Reference Kalinsky KM. San Antonio Breast Cancer Symposium, 2022, abstr GS2-07Ixabepilone加上贝伐单抗相比ixabepilone在铂类耐药/难治性卵巢癌中的活性 (2/19/2022)
Ixabepilone plus bevacizumab showed activity versus Ixabepilone in platinum-resistant or refractory ovarian cancer
这是一项多中心,随机II期临床试验,评估了ixabepilone加上贝伐单抗(bevacizumab)与ixabepilone相比在铂类耐药/难治性卵巢/输卵管/原发性腹膜癌中的活性/安全性。其他目标是检查先前贝伐单抗和紫杉烷的作用。
方法 参与者被随机分配接受ixabepilone(第 1、8、15天20毫克/平方米)，每 28天为一周期,加或不加贝伐单抗(第 1、15天 10毫克/公斤)。患者按先前的贝伐单抗分层。主要终点是无进展生存期;总生存期,安全性和客观响应率作为次要终点。
结果 联合组 (n = 39)与单药组 (n = 37)相比的 76名可评估患者中，客观响应率分别为 33% (n = 13)和 8% (n = 3)(P = 0.004)，6个月持续响应率分别为 37% (n = 14)和 3% (n = 1) (P < 0.001)。 贝伐单抗显著改善无进展生存期（中位数：5.5vs 2.2个月，HR= 0.33，95%CI 0.19–0.55，P < 0.001）和总生存期（中位数：10.0vs 6.0个月，HR = 0.52，95%CI 0.31–0.87，P = 0.006)。 两种方案均耐受良好。亚组分析显示，先前的贝伐单抗或紫杉烷耐药/难治状态对联合组反应的影响很小。
结论 Ixabepilone加上贝伐单抗是一种耐受性良好组合,对铂类/紫杉烷耐药或难治性卵巢癌有效，与Ixabepilone单药治疗相比，可延长无进展生存期和可能的总生存期。既往贝伐单抗治疗不应排除使用Ixabepilone加贝伐单抗联用。
This is a multicenter, randomized phase II clinical trial evaluating the activity and safety of ixabepilone plus bevacizumab versus ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional goals were to examine the role of previous exposure to bevacizumab and taxanes.
Methods Participants were randomly assigned to receive ixabepilone (20 mg/m2 on days 1, 8, and 15) with or without bevacizumab (10 mg/kg on days 1, 15) every 28 days. Patients were stratified by prior bevacizumab. The primary endpoint was progression-free survival; overall survival, safety and objective response rate were secondary endpoints.
Results Among 76 evaluable patients (n=39 in combination arm, n=37 in single drug arm), objective response rates were 33% (n = 13) combination arm vs. 8% (n = 3) in the single-agent arm (P = 0.004). Durable response rates at 6-month were 37% (n = 14) vs. 3% (n = 1), respectively (P < 0.001). Bevacizumab significantly improved progression-free survival (median: 5.5 vs 2.2 months, HR = 0.33, 95% CI 0.19–0.55, P < 0.001). Overall survival (median: 10.0 vs 6.0 months) , HR = 0.52, 95%CI 0.31–0.87, P = 0.006). Both regimens were well tolerated. Subgroup analyses showed that prior bevacizumab or taxane resistance/refractory status had minimal effect on response in the combination arm.
Conclusions Ixabepilone plus bevacizumab was a well-tolerated combination that was effective in platinum/taxane-resistant or refractory ovarian cancer. It prolonged progression-free survival and potentially overall survival. Prior bevacizumab therapy should not preclude the use of ixabepilone plus bevacizumab.
参考文献 Reference Roque DM et al. Br J cancer 2022, Feb 11.唾液微小 RNA作为肝细胞癌的生物标志物 (2/13/2022)
Salivary miRNAs as non-invasive biomarkers of hepatocellular carcinoma
微小 RNA(miRNA)是非编码RNA，可调节许多细胞功能并影响癌症的发展和进展。它可在唾液中检测到，并已显示出作为包括乳腺癌、口腔癌和肺癌在内的许多癌症的非侵入性生物标志物的潜力。研究者认为这是首次报告肝细胞癌中的唾液 miRNA，并将这些发现与肝硬化患者进行比较。
方法 20名肝细胞癌和 19名肝硬化患者进行了miRNA测序。 11名肝细胞癌患者患有慢性肝病，对这些样本进行分析，并根据慢性肝病的存在进行分层。使用错误发现率 (FDR)方法调整P值以进行多重比较，并且FDR P < 0.05的miRNA被认为具有统计学意义。将唾液miRNA的差异表达与先前发表的肝细胞癌与肝硬化患者肝组织中miRNA的报告进行了比较。进行支持向量机器和留一法交叉验证(Support vector machines and leave-one-out cross-validation)以确定唾液miRNA是否具有检测肝细胞癌的预测潜力。
结果 唾液中检测到 4,565个前体和成熟miRNA，其中 365个在肝细胞癌和肝硬化患者之间存在显著差异（FDR P < 0.05）。而且，其中 283个miRNA在肝细胞癌患者中显着下调。机器学习确定了 10种miRNA和变量的组合，可准确分类肝细胞癌患者（AUC = 0.87）。此外，还确定了三种在肝细胞癌患者唾液样本以及之前发表的肝硬化肝组织中差异表达的miRNA。
结论 唾液中可检测到与肝细胞癌相关的miRNA，它可能是肝细胞癌的高度敏感和特异性的非侵入性生物标志物，但需要利用更大的队列进行研究。
MicroRNAs (miRNAs) are noncoding RNAs that regulate many cellular functions and influence cancer development and progression. They are detectable in saliva and have shown potential as a non-invasive biomarker for many cancers including breast, oral and lung cancers. The researchers believed this is the first report of salivary miRNAs in hepatocellular carcinoma and compare these findings with patients with liver cirrhosis.
Methods Twenty hepatocellular carcinoma and 19 liver cirrhosis patients underwent miRNA sequencing. Samples from 11 patients with hepatocellular carcinoma and chronic liver disease were analyzed and stratified by the presence of chronic liver disease. P-values were adjusted for multiple comparisons using the false discovery rate (FDR) method, and miRNAs with FDR P < 0.05 were considered statistically significant. The differential expression of salivary miRNAs was compared with previously published reports of miRNAs in liver tissue from patients with hepatocellular carcinoma versus cirrhosis. Support vector machines and leave-one-out cross-validation were performed to determine whether salivary miRNAs had predictive potential for the detection of hepatocellular carcinoma.
Results 4,565 precursor and mature miRNAs were detected in saliva, of which 365 were significantly different between hepatocellular carcinoma and cirrhosis patients (FDR P < 0.05). Moreover, 283 of these miRNAs were significantly down-regulated in HCC patients. Machine learning identified 10 combinations of miRNAs and covariables that accurately classified patients with hepatocellular carcinoma (AUC = 0.87). In addition, three miRNAswere differentially expressed inhepatocellular carcinoma saliva samples and in a previously published study of miRNAs in HCC tissue compared to cirrhotic liver tissue.
Conclusions Hepatocellular carcinoma-related miRNAs can be detected in saliva, which may be a highly sensitive and specific non-invasive biomarker for hepatocellular carcinoma. Large cohorts are needed for further studies.
参考文献 Reference Mariam M et al. Biochem Biophy Mol Biol 2022: Jan 5, 2022.Eftilagimod Alpha 加紫杉醇治疗转移性乳腺癌 (2/11/20200)Eftilagimod Alpha treating metastatic breast cancer
Eftilagimod 是一种可溶性 LAG-3蛋白，它与主要组织相容性复合物II类分子的一个子集结合，并介导抗原呈递细胞的活化，然后是CD8阳性 T细胞的活化。
这是一项安慰剂对照、双盲、随机IIb期临床试验(AIPAC, NCT02614833），招募了既往接受过基于内分泌治疗的激素受体阳性, HER2阴性的转移性乳腺癌患者。共有 227名患者接受随机分配。 大多数患者对内分泌治疗耐药，大约一半患者接受过CDK4/6抑制剂的治疗。患者接受每周紫杉醇加Eftilagimod或安慰剂长达 24周，随后Eftilagimod或安慰剂长达 52周。 主要终点是独立中央审查的无进展生存期。次要终点包括最终总生存期数据, 在2021年的SITC上公布。
完整分析显示在紫杉醇中加入eftilagimod后，中位总生存期为 20.4个月，安慰剂组为 17.5个月（风险比 = 0.88，P = .197）, 统计学上并不显著。 在预先定义的单变量分析中，对照组 65岁以下(单核细胞数量少且疾病更具侵袭性)患者的总生存期为 14.8个月，而eftilagimod组为 22.3个月。差异具有统计学意义（P = .017）。Eftilagimod还显著增加了循环CD8阳性的T细胞，这与改善的总体存活率显着相关。
Eftilagimod的毒性很少见，主要是注射部位反应。联合组中导致停药的治疗相关不良事件低于安慰剂组。
Eftilagimod is a soluble LAG-3 protein that binds to a subset of major histocompatibility complex class II molecules and mediates the activation of antigen-presenting cells followed by CD8-positive T cells.
This is a placebo-controlled, double-blind, randomized phase IIb clinical trial (AIPAC, NCT02614833). It enrolled patients with hormone receptor-positive, HER2-negative metastatic breast cancer who had received prior endocrine-based therapy. A total of 227 patients were randomized. The majority of patients were resistant to endocrine therapy, and about half had been treated with CDK4/6 inhibitors. Patients received weekly paclitaxel plus eftilagimod or placebo for up to 24 weeks, followed by eftilagimod or placebo for up to 52 weeks. The primary endpoint was progression-free survival by independent central review. Secondary endpoints included final overall survival data, which was presented at SITC in 2021.
The full analysis showed that median overall survival was 20.4 months in the eftilagimod group compared with 17.5 months in the placebo group (hazard ratio = 0.88, P = .197), which was not statistically significant. In a pre-defined univariate analysis, overall survival was 14.8 months in the control group of patients younger than 65 years (those with a low number of monocytes and more aggressive disease) compared with 22.3 months in the eftilagimod group. The difference was statistically significant (P = .017). Eftilagimod also significantly increased circulating CD8-positive T cells, which was significantly associated with improved overall survival.
Toxicity of eftilagimod was rare, mainly reaction at injection site. Treatment-related adverse events leading to discontinuation were lower in the combination group than in the placebo group.
参考文献 Reference Wildiers, H et al. Society for Immunotherapy of Cancer (SITC) 2021 Annual Meeting 2021; abstr 948Brentuximab vedotin组合提高了新诊断的晚期霍奇金淋巴瘤患者的总体生存率 (2/6/2022)
Brentuximab vedotin combination improved overall survival in newly diagnosed advanced classic Hodgkin’s lymphoma
ECHELON-1是一项开放标签,国际性,随机3期临床试验，在 1,334名III或IV期经典霍奇金淋巴瘤患者中评估一线Brentuximab vedotin加多柔比星、长春碱和达卡巴嗪(A + AVD )与ABVD (AVD +博来霉素)的安全性和有效性。患者被随机分配在每个 28天周期的第 1天和第 15天静脉内接受A+AVD或ABVD，最多 6个周期。主要终点为改良的无进展生存期，作为全球监管批准的基础。 总生存期是试验的关键次要终点。中位随访时间约为 6年。
试验表明,brentuximab vedotin联合化疗一线治疗的晚期经典霍奇金淋巴瘤与接受ABVD的患者相比,死亡风险降低了 41%（HR 0.59；[95% CI：0.396至 0.879] )(p= 0.009)。 Brentuximab vedotin的安全性与之前的研究一致，没有观察到新的安全性信号。
完整数据将在即将举行的医学会议上报告。
ECHELON-1 is an open-label, international, randomized phase 3 clinical trial evaluating safety and efficacy of first-line brentuximab vedotin plus doxorubicin, vinblastine and dacarbazine (A + AVD) in 1,334 patients with stage III or IV classic Hodgkin lymphoma versus ABVD (AVD + bleomycin).Patients were randomly assigned to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for a maximum of 6 cycles.The primary endpoint was improved progression-free survival as the basis for global regulatory approval. Overall survival was a key secondary endpoint of the trial.Median follow-up was approximately 6 years.
The trial showed that brentuximab vedotin in combination with chemotherapy as first-line treatment of advanced classic Hodgkin lymphoma was associated with a 41% lower risk of death compared with patients receiving ABVD (HR 0.59; [95% CI: 0.396 to 0.879]) (p = 0.009).The safety profile of brentuximab vedotin was consistent with previous studies and no new safety signals were observed.
Complete data will be reported at an upcoming medical meeting.
参考文献 Reference https://investor.seagen.com/press-releases/news-details/2022/ADCETRIS-Combination-Significantly-Improves-Overall-Survival-in-Newly-Diagnosed-Patients-with-Advanced-Hodgkin-Lymphoma/default.aspx常见的化学物质会增加雌二醇和孕酮合成并是潜在乳腺癌风险 (2/5/2022)
Common chemicals that increase the synthesis of estradiol and progesterone are potential breast cancer risk factors
一项研究表明，数百种常见的化学物质，包括杀虫剂、消费品中的成分、食品添加剂和饮用水污染物，可能会通过导致乳房组织中的细胞产生更多的雌激素或黄体酮激素来增加患乳腺癌的风险。
研究者使用体外筛选数据来识别增加雌二醇或黄体酮合成的化学物质并评估潜在风险。结果发现 296 种化学物质增加了雌二醇(182)或黄体酮(185)，其中 71 种化学物质都增加了。体内数据通常显示出与这种机制一致的效果。在雌二醇和黄体酮化学品中，大约 30% 可能是生殖/发育的毒物或致癌物，而只有 5-13% 被归类为不太可能。
杀虫剂: 阿特拉津、特丁嗪、三嗪、氟氰菊酯、二氯苯酚、咪唑啉（柑橘和香蕉收获后使用的杀菌剂）。
消费品化学品：苯二胺（包括永久性和半永久性染发剂）硝基乙酸（洗涤剂中的螯合剂）。
燃烧产物（空气污染或烟草烟雾）: 对苯二酚（来自汽油）、苯并蒽（燃烧产物）。
预计在一般人群和饮用水中暴露的工业产品。 间二甲苯酚, 亚甲基二苯胺（聚乙烷的前体）,苯胺和联苯胺染料 （用于食品加工包装）。
Hundreds of common chemicals, including pesticides, ingredients in consumer products, food additives and drinking water contaminants, may cause cells in breast tissue to produce more estrogen or progesterone, and consequently increase the risk of breast cancer. The researchers used in vitro screening data to identify chemicals that increased estradiol or progesterone synthesis and assess potential risks. The study found that 296 chemicals increased either estradiol (182) or progesterone (185), and 71 of those increased both. In vivo data generally show effects consistent with this mechanism. Of the estradiol- and progesterone-up chemicals, approximately 30% were probable repro/dev toxicants or carcinogens, while only 5-13%weare classified as unlikely.
Pesticides: atrazine, terbutylazine, triazine, cyfluthrin, dichlorophenol, imazalil (post-harvest fungicides for citrus and bananas).
Consumer Products Chemicals: benzenediamine (including permanent and semi-permanent hair dyes). nitroacetic acid (chelating agent in detergents).
Combustion products (air pollution or tobacco smoke): hydroquinone (from gasoline), benzanthracene (combustion products).
Industrial chemicals expected to be exposed in the general population and drinking water. m-xylenol, methylenedianiline (polyurethane precursor), aniline and benzidine dyes (for food processing and packaging).
参考文献 Reference Cardona B and Rudel RA. Environ Health Perspectives 2021; CID: 077003https://doi.org/10.1289/EHP8608荟萃分析: 蒽环类加紫杉烷可降低 10 年乳腺癌复发风险 (1/30/2022)
Meta-analysis: anthracycline plus taxane reduces risk of breast cancer recurrence at 10 years
在 2021 年圣安东尼奥乳腺癌研讨会上发表的一项大型荟萃分析中, 对 16 个临床试验的研究发现，蒽环类（anthracycline）药物联合紫杉烷类（taxane）药物与紫杉烷类药物相比，10 年乳腺癌复发率显著降低了 15%，代表绝对减少 2.5% 的复发。
研究者对 2012 年之前开始的符合条件的随机试验进行了患者水平的荟萃分析。所有试验都包括每组至少六个周期的化疗。主要结果是通过标准早期乳腺癌试验者协作组方法分析的疾病复发和乳腺癌特异性死亡率，荟萃分析包括 18,000 多名患者的数据。分析了四种不同的比较：
A 组：6 个周期同时使用蒽环类药物 + 多西他赛 （docetaxel）+ 环磷酰胺 vs 6 个周期的相同剂量的多西他赛 + 环磷酰胺（三项试验，2,469 名受试者）;
B 组：顺序的蒽环类药物加多西他赛 vs 更高累积剂量的多西他赛加环磷酰胺（8 项试验，11,386 名受试者）;
C 组：蒽环类加紫杉烷药物vs更高累积剂量的紫杉烷药物加或不加卡培他滨（三项试验，1,552 名受试者）;
D 组：蒽环类加紫杉烷药物vs 更高累积剂量的紫杉烷加卡铂（两项试验，2,796 名参与者）。
综合所有四组中首次侵袭性复发的分析结果, 10 年时，蒽环类联合紫杉烷治疗组与紫杉烷单独治疗组相比，复发风险比例降低了 15%：蒽环类/紫杉烷联合治疗组降低了 16.4%，紫杉烷治疗组降低了 19%，绝对收益为 2.5% （P = .0003）。 从联合分析的乳腺癌特异性死亡率来看，蒽环类/紫杉烷组合为 10.4%相对于紫杉烷单药治疗为 12% (P = .02)，10 年绝对降低了 1.6%。
由于试验设计各不相同，四组之间存在异质性。在 A 组（同时使用蒽环类药物加紫杉烷）中观察到最大的复发比例减少。A 组的乳腺癌特异性死亡率在 10 年中绝对增加为 4.2% (P = .003) 相对于蒽环类加紫杉烷为 8.9% (P = .003)，而单独紫杉烷为 13.2%。比较A组和B 组, 这项分析包括 11 项符合条件的试验中的 13,855 人，中位随访时间为 5.3 年。 在这 11 项试验中，大多数患者激素受体阳性：A 组为 66%，B 组为 75%。淋巴结阳性疾病分别为 61% 和 46%。 HER2 阳性乳腺癌的发现率分别为 2% 和 3%。结果表明蒽环类药物加紫杉烷对雌激素受体阳性和阴性疾病以及淋巴结阳性和阴性疾病都有益 处。
在所有 16 项试验的毒性综合分析中，没有发现死亡与心血管原因或白血病之间有统计学上的显著差异。然而，这需要更长的随访时间。
In a large meta-analysis presented at the 2021 San Antonio Breast Cancer Symposium, a study of 16 clinical trials found that when anthracycline combined with taxane was compared with taxane, the 10-year breast cancer recurrence rate was significantly reduced by 15%, representing an absolute 2.5% reduction in recurrence
Researchers performed a patient-level meta-analysis of eligible randomized trials that began before 2012. All trials included at least six cycles of chemotherapy in each arm. The primary outcomes were disease recurrence and breast cancer-specific mortality, analyzed by standard Early Breast Cancer Trialists Collaboration methods, and the meta-analysis included data from more than 18,000 patients. Four different comparisons were analyzed:
Arm A: 6 cycles of concurrent anthracycline + docetaxel + cyclophosphamide vs 6 cycles of the same dose of docetaxel + cyclophosphamide (three trials, 2,469 participants);
Arm B: Sequential anthracycline plus docetaxel vs higher cumulative dose of docetaxel plus cyclophosphamide (8 trials, 11,386 participants);
Arm C: Taxane plus anthracycline vs higher cumulative dose of taxane with or without capecitabine (three trials, 1,552 participants);
Arm D: Taxane plus anthracycline vs higher cumulative dose of taxane plus carboplatin (two trials, 2,796 participants).
Combining the analysis of the first invasive recurrence in all four groups, at 10 years, the proportion of recurrence risk was reduced by 15% in the anthracycline plus taxane group compared with the taxane group: anthracycline/taxane group was 16.4% reduction and 19% reduction in the taxane group, for an absolute benefit of 2.5% (P = .0003). The combined analysis of breast cancer-specific mortality was 10.4% for the anthracycline/taxane combination versus 12% for taxane monotherapy (P = .02), an absolute reduction of 1.6% at 10 years.
There was heterogeneity among the four groups due to different trial designs. The largest reduction in the proportion of recurrences was observed in arm A (concurrent anthracycline plus taxane). The absolute increase in breast cancer-specific mortality at 10 years was 4.2% in arm A (P = .003) versus 8.9% with anthracycline plus taxane (P = .003) and 13.2% with taxane alone. Comparing arms A and B, this analysis included 13,855 people from 11 eligible trials with a median follow-up of 5.3 years. Across the 11 trials, the majority of patients were hormone receptor positive: 66% in arm A and 75% in arm B. Node-positive disease was 61% and 46%, respectively. The detection rate of HER2-positive breast cancer was 2% and 3%, respectively. The results suggest that anthracycline plus taxane are beneficial in both estrogen receptor-positive and negative disease, as well as in node-positive and negative disease.
In a pooled analysis of toxicity across all 16 trials, no statistically significant differences were found between death and cardiovascular causes or leukemia. However, this requires a longer follow-up.
参考文献 Reference Braybrooke J. et al. 2021 San Antonio Breast Cancer Symposium. Abstr GS2-06.Pepinemab 与 pembrolizumab联合用于复发性或转移性头颈癌患者 (1/29/2022)
Combination of pepinemab and pembrolizumab in relapsed and recurrent metastatic head-and-neck cancer
Pepinemab 是一种人源化 IgG4 单克隆抗体，旨在抑制 SEMA（Semaphorin）4D，后者可调节肿瘤微环境中的慢性炎症。先前的数据表明，该药物可促进树突状细胞/CD8 阳性 T 细胞的浸润和活化，并逆转肿瘤内的免疫抑制。
这是一项Ib期临床试验（KEYNOTE-B84, NCT04815720）, Pepinemab 与pembrolizumab（不包括化疗）用于复发性或转移性头颈部鳞状细胞癌患者的中期数据。 安全性观察部分评估 pepinemab 的潜在剂量限制毒性。两联合使用似乎具有良好的耐受性。在 28 天的安全观察期后继续治疗，并且根据方案，在第 5 周获得目标病变的活检，并在第 9 周和之后每 6 周进行一次肿瘤响应评估扫描。
根据 RECIST v.1.1，观察到安全性观察部分三名患者中的两名经历了完全响应。 案例#1, HPV阴性口咽癌, 完全响应（已确认）, 无明显严重不良事件。 靶病灶：转移性肺病灶（左11 mm，右15 mm） 第 5 周活检：左肺靶病灶, 无恶性肿瘤证据。 第 9 周扫描, 疾病稳定，目标病灶大小减少 19%; 第 15 周扫描：完全反应，目标病灶大小减少 100%; 第 21 周扫描, 确认完全响应。 生物标志：PD-L1综合阳性评分 (CPS) < 20。
案例#2。HPV阴性喉癌, 直接侵犯甲状腺和颈部, 完全响应（等待通过重复扫描确认）。 不良事件：1 级皮疹。 目标病变：颈部肿块（37mm） 第 5 周活检, 无恶性肿瘤证据; 第 9 周扫描：完全响应，病灶大小减少 100%; 第 15 周扫描：待确认。预计 2022 年 3 月上旬 生物标志物：PD-L1, CPS <1。
该组中第三位患有舌癌, 在第 6 周被研究者认为有临床进展并退出研究，这是在第 9 周第一次放射肿瘤响应评估之前，因此，无法评估肿瘤响应。患者还发生了严重的不良事件，包括脱水和高血糖，这些不良事件归因于与治疗无关的预先存在的合并症（糖尿病和其他并发症）。
KEYNOTE-B84 研究正在招募已开放的扩展阶段的患者，该阶段将在美国 18 个试验地点的 CPS <20 和 CPS ≥20 的大致相等的患者组中招募多达 62 名患者。
Pepinemab is a humanized IgG4 monoclonal antibody designed to inhibit SEMA (Semaphorin) 4D, which regulates chronic inflammation in the tumor microenvironment. Previous data suggest that the drug promotes infiltration and activation of dendritic cells/CD8-positive T cells and reverses immunosuppression within tumors.
This is a Phase Ib trial (KEYNOTE-B84, NCT04815720) using pepinemab and pembrolizumab (without chemotherapy) in patients with recurrent or metastatic head and neck squamous cell carcinoma. Safety Observations section assessed potential dose-limiting toxicity of pepinemab. The interim data suggested combination of the two drugs appeared to be well tolerated. Treatment continued after a 28-day safety observation period and, according to the protocol, biopsies of target lesions were obtained at week 5, and tumor response assessment scans were performed at week 9 and every 6 weeks thereafter.
According to RECIST v.1.1, two of the three patients in the safety observation portion experienced a complete response. Case #1, HPV-negative oropharyngeal carcinoma, complete response (confirmed), no apparent serious adverse events. Target lesion: metastatic lung lesion (left 11 mm, right 15 mm) 5th week biopsy: left lung target lesion, no evidence of malignancy. Scan at week 9, stable disease, 19% reduction in target lesion; scan at week 15: complete response, reduction in target lesion by 100%; scan at week 21, confirmed complete response. Biomarker: PD-L1 composite positive score (CPS) < 20.
Case #2. HPV-negative laryngeal carcinoma, directly invading thyroid and neck, complete response (pending confirmation by repeat scan). Adverse events: Grade 1 rash. Target lesion: neck mass (37mm) biopsy at week 5, no evidence of malignancy; scan at week 9: complete response, 100% reduction in size; scan at week 15: to be confirmed. Expected early March 2022 Biomarkers: PD-L1, CPS <1.
A third case in this group, tongue cancer, was considered clinical progression by the investigator at week 6 and dropped out of the study, which was before the first radiographic tumor response assessment at week 9, and therefore, tumor response could not be assessed. Patients also experienced serious adverse events, including dehydration and hyperglycemia, which were attributed to pre-existing comorbidities (diabetes and other complications) not related to treatment.
The KEYNOTE-B84 study is enrolling patients in an open-label expansion phase that will enroll up to 62 patients in approximately equal groups of patients with CPS <20 and CPS ≥20 at 18 trial sites in the United States.
参考文献 Reference https://ir.vaccinex.com/news-releases/news-release-details/vaccinex-reports-two-complete-responses-first-three-patients https://clinicaltrials.gov/ct2/show/NCT04815720Durvalumab 联合吉西他滨和顺铂治疗晚期胆道癌患者 (1/23/22)
Durvalumab in combination with gemcitabine and cisplatin in advanced stage biliary tract cancer
这是一项III期临床试验（TOPAZ-1, NCT03875235),是第一个在晚期胆道癌中评估一线免疫治疗联合吉西他滨加顺铂的全球研究。
方法： 在这项双盲研究中，未经治疗的不可切除的局部晚期、复发性或转移性胆道癌患者以 1:1的比例随机接受durvalumab（每 3周 1500mg或安慰剂）联合吉西他滨（1,000mg/m2和顺铂（第 1天和第 8天 25mg/m2，最多 8个周期），然后是durvalumab（1,500mg每4周）或安慰剂，直至疾病进展或出现不可接受的毒性。随机化按疾病状态（最初不可切除、复发）和原发肿瘤位置（肝内胆管癌、肝外胆管癌、胆囊癌）进行分层。主要目标是评估总生存期。次要终点包括无进展生存期,客观响应率和安全性。 在中期分析的数据截止时间（2021年 8月 11日），685名患者被随机分配至durvalumab +化疗（n= 341）或安慰剂 +化疗（n= 344）。该试验达得到主要目标：durvalumab +化疗与安慰剂 +化疗相比显著改善了总生存期（风险比 [HR]，0.80；95%置信区间 [CI]，0.66–0.97；p = 0.021）。与安慰剂相比，durvalumab也显著改善了无进展生存期（HR，0.75；95%CI，0.64-0.89；p= 0.001）。Durvalumab组的客观响应率为 26.7%，安慰剂组为 18.7%。
安全性: 接受durvalumab中62.7%的患者和接受安慰剂的64.9%患者发生 3/4级治疗相关不良事件,导致 8.9%的接受durvalumab的患者和 11.4%的接受安慰剂的患者停用任何研究药物。
结论： 在晚期胆道癌患者中，durvalumab联合吉西他滨加顺铂与安慰剂 +吉西他滨加顺铂相比显著改善了总生存期和无进展生存期，且安全性可以控制。
This is a Phase III clinical trial (TOPAZ-1, NCT03875235). It is the first global study evaluating first-line immunotherapy combined with gemcitabine plus cisplatin in advanced biliary tract cancer.
Methods: In this double-blind study, patients with untreated unresectable locally advanced, recurrent, or metastatic biliary tract cancer were randomized 1:1 to receive durvalumab (1500 mg every 3 weeks or placebo) plus gemcitabine (1,000 mg/m2 and cisplatin (25 mg/m2 on days 1 and 8 for a maximum of 8 cycles), followed by durvalumab (1,500 mg every 4 weeks) or placebo until disease progression or unacceptable toxicity. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder carcinoma). The primary endpoint was overall survival. Secondary endpoints included progression-free survival, objective response rate and safety.
At the data cutoff for the interim analysis (August 11, 2021), 685 patients were randomized to durvalumab + chemotherapy (n = 341) or placebo + chemotherapy (n = 344). The trial has met its primary objective: durvalumab + chemotherapy significantly improved overall survival compared with placebo + chemotherapy (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p = 0.021). Durvalumab also significantly improved progression-free survival compared with placebo (HR, 0.75; 95% CI, 0.64-0.89; p = 0.001). Objective response rate was 26.7% in the durvalumab group and 18.7% in the placebo group.
Safety: Grade 3/4 treatment-related adverse events occurred in 62.7% of patients receiving durvalumab and 64.9% receiving placebo, resulting in discontinuation of any study drug in 8.9% of patients receiving durvalumab and 11.4% of patients receiving placebo .
Conclusions: In patients with advanced biliary tract cancer, durvalumab in combination with gemcitabine plus cisplatin significantly improved overall survival and progression-free survival compared with placebo plus gemcitabine and cisplatin with manageable toxicity.
参考文献 Reference Oh D-Y et al. ASCO DOI 10.1200/JCO.2022.40.4_suppl.378新辅助化疗后的残余癌症负担和乳腺癌的长期生存结果 (1/22/2022)
Residual cancer burden after neoadjuvant therapy and long-term survival in breast cancer
这是一项多中心的汇总分析, 评估了欧洲和美国的 12 个机构和试验的5,161 名I-III 期乳腺癌患者。研究者获得了1994 年 9 月 12 日至 2019 年 11 月参与者的新辅助化疗后残留癌症负担 (RCB) 结果，以及临床和病理分期、肿瘤亚型和分级以及治疗和随访的数据。他们评估了连续 RCB 评分与主要研究结果、无事件生存率（event-free survival）之间的关联，使用混合效应 Cox 模型结合随机 RCB 和队列效应来解释研究间的异质性。
患者中位年龄为 49 岁（IQR 20-80）。随访期间发生了 1,164 例无事件生存事件（中位随访 56 个月 [IQR 0-186]）。RCB 评分在每种乳腺癌亚型中都具有预后意义，较高的 RCB 评分与较差的无事件生存率显着相关。单变量风险比 (HR) 与每一个RCB单位的增加相关: 从激素受体阳性、HER2 阴性患者的HR 1.55 (95% CI 1.41–1.71) , 到激素受体阴性、HER2 阳性组的HR 2.16 (1.79– 2.61) （有或没有 HER2 靶向治疗；所有亚型 p < 0.0001）。在根据年龄、等级、T 类别和基线淋巴结状态调整的多变量模型中，RCB 评分仍可预测无事件生存期：从激素受体阳性HER2 阴性组的调整后 HR 范围为 1·52 (1.36–1.69) , 到激素受体阴性, HER2 阳性组HR 范围为 2.09 (1.73–2.53) (所有亚型 p < 0.0001)。
研究者认为, RCB 与患者残余风险之间的关联表明，RCB 的前瞻性评估可被视为新辅助治疗后标准病理学报告的一部分。
This is a multicenter pooled analysis evaluating 5,161 patients with stage I-III breast cancer from 12 institutions and trials in Europe and the United States. Investigators obtained residual cancer burden (RCB) outcomes for participants after neoadjuvant chemotherapy between September 12, 1994, and November 2019, as well as data on clinical and pathological stage, tumor subtype and grade, and treatment and follow-up. They assessed the association between continuous RCB scores and the primary study outcome, event-free survival, using a mixed-effects Cox model combining random RCB and cohort effects to account for between-study heterogeneity.
Median age was 49 years (IQR 20-80). 1,164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB scores were prognostic within each breast cancer subtype, and higher RCB scores were significantly associated with worse event-free survival. The univariate hazard ratios (HR) was associated with one unit increase in RCB unit ranged from HR 1.55 (95% CI 1.41–1.71) for hormone receptor-positive, HER2-negative patients to 2.16 (95% CI 1.41–1.71)for the hormone receptor-negative, HER2-positive group ( 1.79–2.61) (with or without HER2-targeted therapy; p < 0.0001 for all subtypes). In multivariate models adjusted for age, grade, T class, and baseline nodal status, RCB score still predicted event-free survival. Adjusted HR ranged from 1·52 (1.36–1.69) for the hormone receptor-positive HER2-negative group, to 2.09 (1.73–2.53) (p < 0.0001 for all subtypes) for the hormone receptor negative, HER2 positive group.
According to the investigators, the association between RCB and a patient’s residual risk suggests that prospective assessment of RCB can be considered as part of standard pathology reporting after neoadjuvant therapy.
参考文献 Reference Yau C et al. Lancet Onc 2022; 23:149Durvalumab 加 Tremelimumab 单独或联合放射治疗对先前 PD(L)-1 治疗无效的转移性非小细胞肺癌 (1/16/2022)
Durvalumab plus Tremelimumab with or without radiation in NSCLC who progressed after prior anti-PD(L)-1 therapy
这是一项开放标签, 多中心, 随机, 2 期试验, 研究了 PD-L1 (durvalumab) 和 CTLA-4 抑制剂 (tremelimumab)单独或与放疗联合的潜在益处。
这项试验在美国 18 个地点完成。90 名患转移性非小细胞肺癌, 在先前 PD(L)-1 治疗期间出现进展的患者参加。患者入组并随机分配 (1:1:1)，其中 78 名（每组 26 名）接受了治疗。接受 durvalumab（每 4 周静脉注射 1500 mg，最多13 个周期）加tremelimumab（每 4 周静脉注射 75 mg，最多 4 个周期）。其中三分之二还接受了放射治疗。 主要终点是总体反应率，并与安全性一起在接受至少一剂研究治疗的患者中进行分析。
在两种药物方案中添加放射治疗并没有改善结果。大约 30% 的患者的疾病得到了控制，其中 10% 的患者对治疗有长期反应。研究人员发现那些肿瘤中富含免疫系统 T 细胞的人比那些肿瘤组织中 T 细胞较少的人更有可能对治疗产生反应。这项结果值得进一步研究。
This is an open-label, multicenter, randomized, phase 2 trial investigating the potential benefit of PD-L1 (durvalumab) and a CTLA-4 inhibitor (tremelimumab) alone or in combination with radiotherapy. The trial was conducted at 18 sites in the United States. Ninety patients with metastatic non-small cell lung cancer who had progressed after prior PD(L)-1 therapy participated. Seventy-eight patients were randomly assigned (1:1:1) (26 in each group) received treatment and received durvalumab (1500 mg IV every 4 weeks for up to 13 cycles) plus tremelimumab (75 mg IV every 4 weeks for up to 4 cycles). Two-thirds of them also received radiation therapy. The primary endpoint was overall response rate and was analyzed along with safety in patients who received at least one dose of study treatment.
Adding radiation therapy to the two-drug regimen did not improve outcomes. However, disease was controlled in about 30% of patients, and 10% of these patients had a long-term response to treatment. Considering that all participants had cancers that were resistant to PD(L)-1, this result warrants further study. As part of the study, the researchers found that those whose tumors were rich in T cells were more likely to respond to treatment than those whose tumor tissue had fewer T cells.
参考文献 Reference Schonfenld JD et al. Lancet Onc 2022; Jan 13. https://www.dana-farber.org/newsroom/news-releases/2022/immunotherapy-combination-shown-to-benefit-some-patients-with-non-small-cell-lung-cancer-resistant-to-single-immunotherapy术后 abemaciclib 联合内分泌治疗治疗高危早期乳腺癌：来自 monarchE 临床试验的最新疗效分析 (1/15/2022)
Adjuvant abemaciclib in combination with endocrine therapy in high-risk early breast cancer: update from monarchE study
报导展示了预先设定的主要结果分析和进一步后续分析的结果。 这项全球性 III 期开放标签试验随机 (1:1) 5,637 名患者（激素受体阳性, HER-2 阴性, 淋巴结阳性, 高危早期乳腺癌患者）接受 ≥ 5 年的辅助 分泌治疗治疗 ± abemaciclib 2 年。队列 1 入组的患者有 ≥ 4 个阳性腋窝淋巴结，或 1-3 个阳性腋窝淋巴结 和 3 级疾病或肿瘤 ≥ 5 cm。队列 2 招募了 1-3 个腋窝淋巴结阳性且中央确定的高 Ki-67 指数 (≥ 20%) 的患者。主要终点是意向治疗人群（队列 1 和 2）中的无侵袭性疾病生存。次要终点是高 Ki-67 患者的无侵袭性疾病生存, 远处无复发生存, 总生存期和安全性。
结果：在主要结果分析中，中位随访时间为 19 个月，abemaciclib 联合内分泌治疗 导致发生无侵袭性疾病生存事件的风险降低 29% [风险比 (HR) = 0.71, 95% 置信区间 (CI) 0.58-0.87；标称 P = 0.0009]。在进一步的随访分析中，中位随访时间为 27 个月，90% 的患者停止治疗, 无侵袭性疾病生存 (HR = 0.70, 95% CI 0.59-0.82; 标称 P < 0.0001) 和 远处无复发生存 (HR = 0.69, 95% CI 0.57-0.83；名义 P < 0.0001) 效益得以维持。 3 年无侵袭性疾病生存和远处无复发生存率的绝对改善分别为 5.4% 和 4.2%。尽管 Ki-67 指数具有预后意义，但无论 Ki-67 指数如何，abemaciclib 的益处都是一致的。安全性数据与已知的 abemaciclib 风险概况一致。
结论：Abemaciclib 联合内分泌治疗显著改善激素受体阳性, HER-2 阴性, 淋巴结阳性, 高危早期乳腺癌患者的无侵袭性疾病生存，安全性可接受。 Ki-67 指数具有预后意义，但无论 Ki-67 指数如何，都观察到 abemaciclib 的益处。总体而言，abemaciclib 的治疗益处超过了 2 年的治疗期。
The report presents the results of a prespecified primary outcome analysis and additional follow-up analyses. This global phase III open-label trial randomized (1:1) 5,637 patients (hormone receptor-positive, HER-2-negative, node-positive, high-risk early breast cancer) to receive adjuvant endocrine therapy for ≥ 5 years ± abemaciclib for 2 year. Patients enrolled in cohort 1 had ≥ 4 positive axillary lymph nodes, or 1-3 positive axillary lymph nodes and grade 3 disease or tumors ≥ 5 cm. Cohort 2 enrolled patients with 1-3 positive axillary lymph nodes and centrally determined high Ki-67 index (≥ 20%). The primary endpoint was invasive disease-free survival in the intention-to-treat population (Cohorts 1 and 2). Secondary endpoints were invasive disease-free survival, distant recurrence-free survival, overall survival and safety in patients with high Ki-67.
RESULTS: In the primary outcome analysis, with a median follow-up of 19 months, abemaciclib plus endocrine therapy resulted in a 29% reduction in the risk of invasive disease-free survival events [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. In additional follow-up analysis, with a median follow-up of 27 months, 90% of patients discontinued treatment, invasive disease-free survival (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and distant relapse-free survival (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year invasive disease-free survival and distant recurrence-free survival were 5.4% and 4.2%, respectively. Despite the prognostic significance of the Ki-67 index, the benefit of abemaciclib was consistent regardless of the Ki-67 index. Safety data were consistent with the known risk profile of abemaciclib.
Conclusions: Abemaciclib combined with endocrine therapy significantly improved invasive disease-free survival in patients with hormone receptor-positive, HER-2-negative, node-positive, high-risk early breast cancer with an acceptable safety profile. The Ki-67 index has prognostic significance, but the benefit of abemaciclib was observed regardless of the Ki-67 index. Overall, the therapeutic benefit of abemaciclib exceeded the 2-year treatment period.
参考文献 Reference Harbeck H. et al. Ann Onc 2021; 32:1571派姆单抗治疗微卫星不稳定性高度晚期子宫内膜癌 (1/9/2022)
Pembrolizumab in microsatellite instability–high advanced endometrial cancer
这是一项非随机、开放标签、多队列II期临床试验（KEYNOTE-158） ，报告了派姆单抗对微卫星不稳定/错配修复缺陷（MSI-H/dMMR） 的子宫内膜癌患者的疗效和安全性结果 。
方法: 该试验的队列包括来自队列 D（子宫内膜癌，无论 MSI-H/dMMR 状态如何）和 K（任何 MSI-H/dMMR 实体瘤，结直肠除外）中符合条件的先前接受过治疗的晚期 MSI-H/dMMR 子宫内膜癌患者, 她们接受派姆单抗 200 mg 每 3 周一次，共 35 个周期。主要终点是独立中央放射学审查的客观反应率。次要终点包括反应持续时间, 无进展生存期, 总生存期和安全性。
结果: 截至 2020 年 10 月 5 日，90 名接受治疗的患者中有 18 名 (20%) 完成了 35 个周期的派姆单抗治疗，52 名 (58%) 已停止治疗。在疗效人群（接受 ≥ 1 剂派姆单抗且随访 ≥ 26 周的患者；N = 79）中，从第一剂到数据截止的中位时间为 42.6个月（范围，6.4-56.1）。客观缓解率为 48%（95% CI，37 至 60），中位缓解持续时间未达到（2.9-49.7+ 个月）。中位无进展生存期为 13.1（95% CI，4.3 至 34.4）个月，中位总生存期尚未达到（95% CI，27.2 个月至未达到）。
在所有接受治疗的患者中，76% 有≥1 次治疗相关不良事件（3-4 级，12%）。没有致命的治疗相关事件。 28% 的患者发生了免疫介导的不良事件或输液反应（3-4 级，7%；无致命事件）。
结论 派姆单抗在既往接受过治疗的晚期 MSI-H/dMMR 子宫内膜癌患者中表现出有效持久的抗肿瘤活性，而且毒性可以控制。
This is a nonrandomized, open-label, multi-cohort phase II clinical trial (KEYNOTE-158). The study was aimed to evaluate efficacy and safely of pembrolizumab in endometrial cancer with microsatellite instability/mismatch repair defect (MSI-H/dMMR).
Methods: Eligible patients from cohorts D (endometrial cancer, regardless of MSI-H/dMMR status) and K (any MSI-H/dMMR solid tumor, except colorectal) with previously-treated advanced MSI-H/dMMR endometrial cancer received pembrolizumab 200 mg once every 3 weeks for 35 cycles. The primary endpoint was objective response rate as evaluated by an independent central radiologic review. Secondary endpoints included response duration, progression-free survival, overall survival, and safety.
Results: As of October 5, 2020, 18 (20%) of the 90 treated patients had completed 35 cycles of pembrolizumab, and 52 (58%) had stopped treatment. In the efficacy population (patients who received ≥ 1 dose of pembrolizumab and followed up for ≥ 26 weeks; N = 79), the median time from the first dose to the data cutoff was 42.6 months (range, 6.4-56.1). The objective response rate was 48% (95% CI, 37 to 60), and median duration of response was not reached (2.9-49.7+ months). Median progression-free survival was 13.1 (95% CI, 4.3 to 34.4) months, and median overall survival was not reached (95% CI, 27.2 months to not reached).
Of all patients receiving treatment, 76% had ≥1 treatment-related adverse events (Grade 3-4, 12%). There were no fatal treatment-related incidents. Immune-mediated adverse events or infusion reactions occurred in 28% of patients (Grade 3-4, 7%; no fatal events).
Researches believed pembrolizumab exhibited robust and durable anti-tumor activity in patients with advanced MSI-H/dMMR endometrial cancer who had previously received treatment with manageable toxicity.
参考文献 Reference O’Malley DM et al. J Clin Onc published 2022, Jan 6. DOI: 10.1200/JCO.21.01874HLA-A*03 与免疫检查点抑制剂治疗晚期癌症结果的关联 (1/8/2022)
Association of HLA-A*03 and response to immune checkpoint inhibitor in cancer
一项流行病研究发现 HLA-A*03 的存在与接受免疫检查点抑制剂治疗晚期癌症的患者的较差结果相关。
鉴于 HLA 分子在免疫中的核心作用，HLA 基因座的变异可能会不同地影响对免疫检查点抑制剂的反应。这项流行病学研究的目的是确定 HLA-A*03 作为预测免疫治疗反应的生物标志物的作用。
该研究评估了以下队列: 三个不同晚期肿瘤患者的观察性队列，包括：1) 斯隆凯特琳癌症中心 (MSK-IMPACT) 队列（n = 1,166 人接受免疫检查点抑制剂治疗，21.8% HLA-A*03 携带者，进行了总生存期分析）。 2) Dana-Farber Cancer Institute (DFCI) 队列（n = 1,326 接受免疫检查点抑制剂治疗，21.8% HLA-A*03携带者，进行了总生存期分析） 3) 癌症基因组图谱 (TCGA)（n = 10,328 名接受非免疫检查点抑制剂治疗的患者，进行了总生存期分析）。
临床试验队列来自： 1)AVELIN 实体瘤晚期膀胱癌试验（n = 168 接受免疫检查点抑制剂治疗，21.3% 携带者，进行了总生存期分析）。 2) 晚期肾细胞癌 CheckMate-009、CheckMate-010、CheckMate-025 的汇总人群（n = 324 接受免疫检查点抑制剂治疗，28.1% 携带者，进行了客观反应和无进展生存期分析）。3) JAVELIN Renal 101 晚期肾细胞癌试验（n = 350 接受免疫检查点抑制剂治疗，23.4% 携带者，进行了客观反应和无进展生存期分析）。
总共有 3,335 名接受免疫检查点抑制剂（PD-1,PD-L1 或 CTLA-4 抑制剂）治疗的患者和 10,917 名接受非免疫检查点抑制剂治疗的患者 。
主要发现: HLA-A*03 以加性方式（additive manner）与免疫检查点抑制剂治疗后较差的总生存期相关，每个 HLA-A*03 等位基因的风险比 (HR) 在 MSK-IMPACT 队列中为 1.48（95% 置信区间 [CI] = 1.20–1.82，P = .00022); 在 DFCI Profile 队列中为1.22 (95% CI = 1.05–1.42, P = .0097); 在JAVELIN 实体瘤试验中为1.36 (95% CI = 1.01–1.85, P = .047)。 在 TCGA 队列中，HLA-A*03 与接受非免疫检查点抑制剂治疗的患者的总生存期无关。
在三项 CheckMate 试验中，HLA-A*03 等位基因的存在与接受纳武单抗的患者较差的无进展生存期相关（HR = 1.31，95% CI = 1.01–1.71，P = .044），但与接受对照治疗（依维莫司 everolimus）的患者无关。在接受纳武单抗治疗的患者中客观反应为，8 个 HLA-A*03 纯合子中有 0 个（0%）, 222 个 HLA-A*03 非携带者中有 59 个（26.6%）和 76 个 HLA-A*03 杂合子中有 13 个（17.1%）。
同样，在 JAVELIN Renal 101 试验中，HLA-A*03 与接受免疫检查点抑制剂（avelumab 加 axitinib）的患者的无进展生存期较差相关（每个等位基因 HR = 1.59，95% CI = 1.16–2.16，P = . 0036）, 但在接受对照（舒尼替尼）治疗的患者中则无关。在接受 avelumab 加 axitinib 的患者中，客观反应为: 在 8 个 HLA-A*03 纯合子中有 1 个（12.5%）, 254 个 HLA-A*03 非携带者中有 162 个（63.8%）和72 个HLA-A*03 杂合子中有 40 个（55.6%）。 在一项荟萃分析中，HLA-A*03 与较差的总生存期或无进展生存期相关。
结论：HLA-A*03 是预测对免疫检查点抑制剂反应不佳的生物标志物。需要在随机试验中进一步评估 HLA-A*03。在决定开始使用癌症患者免疫检查点抑制剂时，可以考虑HLA-A*03携带状态。
A study found that the presence of HLA-A*03 was associated with poorer outcomes in patients receiving immune checkpoint inhibitors (ICI) for advanced cancer.
In view of the central role of HLA molecules in immunity, variations in HLA loci may differentially affect the response to immune checkpoint inhibitors. The purpose of this epidemiological study was to determine the role of HLA-A*03 as a biomarker for predicting response to immunotherapy.
The study evaluated the following cohorts: Three observational cohorts of patients with different advanced cancers, including: 1) Sloan Kettering Cancer Center (MSK-IMPACT) cohort (n = 1,166 people receiving ICI therapy, 21.8% HLA-A*03 carriers, overall survival [OS] analyzed). 2) Dana-Farber Cancer Institute (DFCI) cohort (n = 1,326 received ICI therapy, 21.8% of HLA-A*03 carriers, OS analyzed). 3) Cancer Genome Atlas (TCGA) (n = 10,328 patients treated with non-immune checkpoint inhibitors, OS analyzed).
The clinical trial cohort comes from: 1) JAVELIN solid tumor advanced bladder cancer trial (n = 168 received ICI therapy, 21.3% carriers, OS analyzed). 2) The pooled population of CheckMate-009, CheckMate-010, CheckMate-025 for advanced renal cell carcinoma (n = 324 received ICI therapy, 28.1% carriers, objective response and progression-free survival analysis were analyzed) 3) JAVELIN Renal 101 Advanced Renal Cell Carcinoma Test (n = 350 received ICI treatment, 23.4% carriers, objective response and progression-free survival were analyzed). A total of 3,335 patients were treated with ICIs (PD-1, PD-L1 or CTLA-4 inhibitors) and 10,917 patients were treated with non-immune checkpoint inhibitors.
Main findings: HLA-A*03 was associated with poorer overall survival after ICI treatment in an additive manner. The hazard ratio (HR) in the MSK -IMPACT cohort was 1.48 per HLA-A*03 allele (95% confidence interval [CI] = 1.20–1.82, P = .00022); in the DFCI Profile cohort, it was 1.22 per HLA-A*03 allele (95% CI = 1.05–1.42, P = .0097); in the JAVELIN entity In the tumor test, it was 1.36 per HLA-A*03 allele (95% CI = 1.01–1.85, P = .047). In the TCGA cohort, HLA-A*03 was not associated with the overall survival of patients treated with non-immune checkpoint inhibitors.
In the three CheckMate trials, the presence of the HLA-A*03 allele was associated with poor progression-free survival in patients receiving nivolumab (HR = 1.31, 95% CI = 1.01–1.71, P = .044 ), but not related to patients receiving control therapy (everolimus). Objective response in patients treated with nivolumab was seen in none out of 8 HLA-A*03 homozygotes (0%), 59 out of 222 HLA-A*03 non-carriers (26.6%) and 13 out of 76 HLA-A*03 heterozygotes (17.1%). Similarly, in the JAVELIN Renal 101 trial, HLA-A*03 was associated with poor progression-free survival in patients receiving ICI (avelumab plus axitinib) (HR = 1.59 per HLA-A*03 allele, 95% CI = 1.16–2.16, P =. 0036), but not in patients receiving control (sunitinib) treatment. In patients receiving avelumab plus axitinib, objective response was 1 out of 8 HLA-A*03 homozygotes (12.5%), 162 out of 254 HLA-A*03 non-carriers (63.8%) and 40 out of 72 HLA-A*03 heterozygotes (55.6%). In a meta-analysis, HLA-A*03 was associated with poor overall survival or progression-free survival.
Conclusion: HLA-A*03 is a biomarker that predicts poor response to ICIs. It is warranted to conduct randomized trials to further evaluate the role of HLA-A*03. HLA-A*03 carrying status could be considered when deciding to initiate ICIs for cancer treatment.
参考文献 Reference Naranbhai V et al. Lancet Onc 2021;DOI: https://doi.org/10.1016/S1470-2045(21)00582-9TEAD 抑制剂控制癌症生长和凋亡的功能 (1/2/2022)
TEAD inhibitor controls cancer growth and apoptosis
Hippo 信号在控制细胞增殖和限制细胞凋亡方面发挥作用，但当失调时会导致癌症的发生, 进展和治疗抵抗。TEAD 转录因子家族，受 Hippo 通路信号传导并调节细胞生长和增殖。IK-930（一种新型 TEAD 抑制剂）提供了抑制 TEAD-依赖性人类癌症异种移植物的生长。通过利用合成致死率，IK-930 单药在 TEAD-依赖性癌症中的活性可以在抑制某些致癌途径后扩展到其他适应症。先前的研究表明其他癌基因如EGFR 突变或 KRAS 激活 TEAD-依赖性转录介导对多种靶向治疗的耐药性。
临床前数据支持使用 IK-930 联合疗法来增强 EGFR 和 MEK 阻断在EGFR 突变型非小细胞肺癌中的抗肿瘤影响，或在几种 BRAF 和 KRAS 突变型癌症中使用 MEK 抑制。在这些研究中，EGFR 和 MEK1/2 被抑制，IK-930 用于增强 EGFR 突变非小细胞肺癌细胞的抗肿瘤活性。当用奥希替尼（osimertinib）,曲美替尼（trametinib）和 IK-930 的组合治疗时，这些对奥希替尼和/或曲美替尼基本上不敏感的非小细胞肺癌细胞在体外凋亡显著增加。在非小细胞肺癌 异种移植物中，奥希替尼和 IK-930 的组合阻止了肿瘤生长，而奥希替尼、IK-930 和曲美替尼的三联组合推动了肿瘤的完全消退，并显示出比任何单一药物或双联药物更高的疗效。另一组研究测试了 IK-930 和 MEK 抑制在 RAF 和 RAS 突变肿瘤中的合成致死效应。 TEAD 抑制与 MEK 抑制的组合增强了几种 KRAS 突变非小细胞肺癌, PDAC, CRC, KRAS- 突变细胞系和 BRAF-突变黑色素瘤的细胞凋亡。曲美替尼和 IK-930 的组合阻止了这些异种移植物中的肿瘤生长，其中任何一种药物只具有中等或很小的活性。
这些数据表明，通过将 IK-930 与 MEK 和/或 EGFR 抑制联合可用于多种癌症适应症，包括突变型 EGFR 驱动的非小细胞肺癌和突变型 KRAS 结肠癌、肺癌和胰腺癌。FDA已接受IK-930的I期临床试验申请。
Hippo signaling plays a role in controlling cell proliferation and apoptosis. When it is dysregulated, it can lead to the development of cancer, progression, and treatment resistance. The TEAD transcription factor family binds to YAP1 or WWTR1/TAZ, is signaled by the Hippo pathway and regulates cell growth and proliferation. IK-930 (a new type of TEAD inhibitor) inhibits the growth of TEAD-dependent human cancer xenografts. By using synthetic lethality, the activity of single agent IK-930 in TEAD-dependent cancers can be extended to other indications after inhibiting certain carcinogenic pathways. Previous studies have shown that other oncogenes such as EGFR mutations or KRAS activate TEAD-dependent transcription to mediate resistance to multiple targeted therapies.
Preclinical data supports the use of IK-930 combination therapy to enhance the anti-tumor effects of EGFR and MEK blockade in EGFR mutant non-small cell lung cancer, or use MEK inhibition in several BRAF and KRAS mutant cancers. In these studies, EGFR and MEK1/2 were inhibited, and IK-930 was used to enhance the anti-tumor activity of EGFR mutant non-small cell lung cancer cells. When treated with a combination of osimertinib, trametinib and IK-930, these non-small cell lung cancer cells that were essentially insensitive to osimertinib and/or trametinib demonstrated significant increase in apoptosis in vitro. In non-small cell lung cancer xenografts, the combination of osimertinib and IK-930 prevented tumor growth, while the triple combination of osimertinib, IK-930 and trametinib promoted the complete regression of the tumor. The combination showed higher efficacy than any single drug or two-drug combination. Another study tested the synthetic lethal effects of IK-930 and MEK inhibition in RAF and RAS mutant tumors. The combination of TEAD inhibition and MEK inhibition enhanced apoptosis in several KRAS mutant non-small cell lung cancers, PDAC, CRC, KRAS-mutant cell lines, and BRAF-mutant melanoma. The combination of trametinib and IK-930 prevented tumor growth in these xenografts, and any one of these drugs had only modest or low activity.
These data indicated that a combination of IK-930 with MEK and/or EGFR inhibition can be used in a variety of cancers, including mutant EGFR-driven non-small cell lung cancer and mutant KRAS-associated colon, lung, and pancreatic cancers. FDA has approved the application of IK-930 in a phase I clinical trial.
参考文献 Reference
Amidon B. et al. Mol Cancer Therapeutics 2021; 20; 12(suppl) https://www.biospace.com/article/fda-green-lights-multiple-investigational-new-drug-applications/淋巴结阳性乳腺癌患者接受新辅助化疗和前哨淋巴结活检后的淋巴结复发率 (1/1/2022)
Lymph node recurrence rate after neoadjuvant chemotherapy and sentinel lymph node biopsy alone in lymph node-positive breast cancer patients
在临床淋巴结阳性的乳腺癌患者中, 接受了新辅助（术前）化疗导致临床淋巴结阴性的，当活检了 3 个或更多前哨淋巴结 后，假阴性率低于 10%。然而，这些仅接受前哨淋巴结活检治疗患者的淋巴结复发率尚不清楚。
该研究是在一个三级癌症中心进行的。从 2013 年 11 月到 2019 年 2 月，一组连续诊断的 cT1 至 cT3, 活检证实淋巴结阳性 (cN1) 的乳腺癌患者接受新辅助化疗而导致临床淋巴结阴性 （cN0），如果有 3 个或更多前哨淋巴结经鉴定均为病理学阴性，则省略腋窝手术清扫。主要测量结果是新辅助化疗后仅接受前哨淋巴结活检治疗的 cN1 乳腺癌患者的淋巴结复发率。
结果：在 610 名接受新辅助化疗治疗的 cN1 乳腺癌患者中，555 名 (91%) 转为 cN0 并接受了前哨淋巴结活检； 234 人 (42%) 有 3 个或更多阴性前哨淋巴结，并且只有前哨淋巴结活检。这 234 名患者的中位年龄为 49 (40-58) 岁；中位肿瘤大小为 3 厘米； 144 人（62%）为HER2阳性，43 人（18%）为三阴性。大多数（212 [91%]）接受了基于阿霉素的新辅助化疗； 205 人 (88%) 接受了辅助放疗，164 人 (70%) 也接受了淋巴结放疗。在中位随访 40 个月时，一名拒绝放疗的患者有 1 例腋窝淋巴结复发与同步局部复发。在接受放疗的患者中（n = 205），没有淋巴结复发。
研究者认为，在cN1乳腺癌患者中, 接受了新辅助化疗导致临床淋巴结阴性，而且3 个或更多前哨淋巴结为阴性，她们淋巴结复发率低，无需常规淋巴结切除。这些发现可能支持在此类患者中省略腋窝淋巴结清扫。
Prospective clinical trials have shown that a false-negative rate of less than 10% when 3 or more sentinel lymph nodes were retrieved among breast cancer patients with clinically positive lymph nodes, which were rendered clinically negative with neoadjuvant chemotherapy. However, the rate of lymph node recurrence in these patients who only received sentinel lymph node biopsy is unclear.
The research was conducted in a single tertiary cancer center. From November 2013 to February 2019, a cohort of consecutively identified breast cancer patients with cT1 to cT3, and biopsy-proven lymph node positive (cN1) breast cancer patients received neoadjuvant chemotherapy which resulted in clinical lymph node negative (cN0). They underwent sentinel lymph node biopsy with dual tracer mapping and omission of axillary lymph dissection If 3 or more sentinel lymph nodes were identified and were all pathologically negative. The main measurement was the rate of lymph node recurrence in cN1 breast cancer patients who received only sentinel lymph node biopsy after neoadjuvant chemotherapy.
Results: Of the 610 cN1 breast cancer patients treated with neoadjuvant chemotherapy, 555 (91%) converted to cN0 and underwent sentinel lymph node biopsy; 234 (42%) had 3 or more negative sentinel lymph nodes, and had only sentinel lymph node biopsy. The median age of these 234 patients was 49 (40-58) years; the median tumor size was 3 cm; 144 (62%) were HER2 positive, and 43 (18%) were triple negative. Most (212 [91%]) patients received doxorubicin-based neoadjuvant chemotherapy; 205 (88%) received adjuvant radiotherapy, and 164 (70%) also received lymph node radiotherapy. At a median follow-up of 40 months, one patient who refused radiotherapy had 1 axillary lymph node recurrence synchronous with local recurrence. Among the patients who received radiotherapy (n = 205), there were no lymph node recurrences.
Researchers believed that in patients with cN1 breast cancer who received neoadjuvant chemotherapy which rendered cN0 with 3 or more negative sentinel lymph nodes, lymph node recurrence rate was low, and routine lymph node resection was not required. These findings may support the omission of axillary lymph node dissection in such patients.
参考文献 Reference BarrinoAV et al. JAMA ONc 2021; 7: 1851.