Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Lancet Oncol. 2022 Jul;23(7):876-887. doi: 10.1016/S1470-2045(22)00274-1. Epub 2022 May 27.
Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer.
AtezoTRIBE was a multicentre, open-label, randomised, controlled, phase 2 study of patients (aged 18-70 years with an Eastern Cooperative Oncology Group [ECOG] performance status of 0-2 and aged 71-75 years with an ECOG performance status of 0) with histologically confirmed, unresectable, previously untreated metastatic colorectal cancer and adequate organ function, who were recruited from 22 oncology centres in Italy. Patients were stratified according to centre, ECOG performance status, primary tumour site, and previous adjuvant therapy. A randomisation system incorporating a minimisation algorithm randomly assigned (1:2) patients via a masked web-based allocation procedure to two groups: the control group received first-line FOLFOXIRI (intravenous 165 mg/m irinotecan, 85 mg/m oxaliplatin, 200 mg/m leucovorin, and 3200 mg/m fluorouracil as a 48 h infusion) plus bevacizumab (5 mg/kg intravenously), and the atezolizumab group received the same regimen plus atezolizumab (840 mg intravenously). Combination treatments were administered up to eight 14-day cycles followed by maintenance with fluorouracil and leucovorin plus bevacizumab with or without atezolizumab, according to randomisation group, until disease progression, unacceptable adverse events, or consent withdrawal. The primary endpoint was progression-free survival, analysed by the intention-to-treat principle. Safety was assessed in patients who received at least one dose of the study treatment. The study recruitment is completed. The trial is registered with Clinicaltrials.gov, NCT03721653.
Between Nov 30, 2018, and Feb 26, 2020, 218 patients were randomly assigned and received treatment (73 in the control group and 145 in the atezolizumab group). At the data cutoff (Aug 1, 2021), median follow-up was 19·9 months (IQR 17·3-23·9). Median progression-free survival was 13·1 months (80% CI 12·5-13·8) in the atezolizumab group and 11·5 months (10·0-12·6) in the control group (hazard ratio [HR] 0·69 [80% CI 0·56-0·85]; p=0·012; adjusted HR 0·70 [80% CI 0·57-0·87]; log-rank test p=0·018). The most frequent all-cause grade 3-4 adverse events were neutropenia (59 [42%] of 142 patients in the atezolizumab group vs 26 [36%] of 72 patients in the control group), diarrhoea (21 [15%] vs nine [13%]), and febrile neutropenia (14 [10%] vs seven [10%]). Serious adverse events were reported in 39 (27%) patients in the atezolizumab group and in 19 (26%) patients in the control group. Two (1%) treatment-related deaths (due to acute myocardial infarction and bronchopulmonary haemorrhage) were reported in the atezolizumab group; none were reported in the control group.
The addition of atezolizumab to first-line FOLFOXIRI plus bevacizumab is safe and improved progression-free survival in patients with previously untreated metastatic colorectal cancer.
GONO Foundation, ARCO Foundation, F Hoffmann-La Roche, and Roche.
在先前的研究中，对于存在错配修复 proficient（pMMR）或微卫星稳定（MSS）肿瘤的转移性结直肠癌患者，免疫检查点抑制剂并未显示出临床获益。氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康的联合化疗（FOLFOXIRI）和贝伐珠单抗似乎都能增加 pMMR 或 MSS 肿瘤的免疫原性。我们旨在为抗 PD-L1 药物阿替利珠单抗联合一线 FOLFOXIRI 加贝伐珠单抗在转移性结直肠癌患者中的应用提供初步的获益证据。
AtezoTRIBE 是一项多中心、开放性标签、随机对照、Ⅱ期研究，纳入了来自意大利 22 个肿瘤中心的组织学证实、不可切除、未经治疗的转移性结直肠癌患者，这些患者年龄在 18-70 岁（ECOG 体能状态为 0-2）和 71-75 岁（ECOG 体能状态为 0），且器官功能良好。患者根据中心、ECOG 体能状态、原发肿瘤部位和辅助治疗进行分层。采用包含最小化算法的随机分配系统，通过一个屏蔽的基于网络的分配程序，将患者（1:2）随机分为两组：对照组接受一线 FOLFOXIRI（静脉注射 165 mg/m 伊立替康、85 mg/m 奥沙利铂、200 mg/m 亚叶酸和 3200 mg/m 氟尿嘧啶持续 48 小时输注）加贝伐珠单抗（5 mg/kg 静脉注射），阿替利珠单抗组接受相同的方案加阿替利珠单抗（840 mg 静脉注射）。联合治疗最多进行 8 个 14 天周期，随后根据随机分组，用氟尿嘧啶和亚叶酸加贝伐珠单抗联合或不联合阿替利珠单抗进行维持治疗，直至疾病进展、不可接受的不良事件或同意退出。主要终点是无进展生存期，通过意向治疗原则进行分析。在至少接受一剂研究治疗的患者中评估安全性。研究招募已完成。该试验在 ClinicalTrials.gov 上注册，NCT03721653。
在 2018 年 11 月 30 日至 2020 年 2 月 26 日期间，共有 218 名患者被随机分配并接受治疗（对照组 73 名，阿替利珠单抗组 145 名）。在数据截止日期（2021 年 8 月 1 日），中位随访时间为 19.9 个月（IQR 17.3-23.9）。阿替利珠单抗组的中位无进展生存期为 13.1 个月（80%CI 12.5-13.8），对照组为 11.5 个月（10.0-12.6）（风险比[HR]0.69 [80%CI 0.56-0.85]；p=0.012；调整 HR 0.70 [80%CI 0.57-0.87]；对数秩检验 p=0.018）。最常见的所有原因的 3-4 级不良事件为中性粒细胞减少症（阿替利珠单抗组 142 名患者中有 59 名[42%]，对照组 72 名患者中有 26 名[36%]）、腹泻（21 名[15%] vs 9 名[13%]）和发热性中性粒细胞减少症（14 名[10%] vs 7 名[10%]）。阿替利珠单抗组有 39 名（27%）患者发生严重不良事件，对照组有 19 名（26%）患者发生严重不良事件。阿替利珠单抗组有 2 例（1%）与治疗相关的死亡（因急性心肌梗死和支气管肺出血），对照组无死亡报告。
阿替利珠单抗联合一线 FOLFOXIRI 加贝伐珠单抗治疗未经治疗的转移性结直肠癌患者安全，并改善了无进展生存期。
GONO 基金会、ARCO 基金会、罗氏制药和罗氏。
