Department of Oncology, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
Medical Oncology Unit 1, Department of Clinical and Experimental Oncology, IRCCS, Padua, Italy.
Lancet Oncol. 2020 Apr;21(4):497-507. doi: 10.1016/S1470-2045(19)30862-9. Epub 2020 Mar 9.
BACKGROUND: The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. METHODS: TRIBE2 was an open-label, phase 3, randomised study of patients aged 18-75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m of intravenous oxaliplatin concurrently with 200 mg/m of leucovorin over 120 min; 400 mg/m intravenous bolus of fluorouracil; 2400 mg/m continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m of intravenous irinotecan over 120 min concurrently with 200 mg/m of leucovorin; 400 mg/m intravenous bolus of fluorouracil; 2400 mg/m continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m of intravenous irinotecan over 60 min; 85 mg/m intravenous oxaliplatin concurrently with 200 mg/m of leucovorin over 120 min; 3200 mg/m continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov, NCT02339116. FINDINGS: Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1-41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3-21·4) in the experimental group and 16·4 months (15·1-17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63-0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3-4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). INTERPRETATION: Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. FUNDING: The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann-La Roche.
背景：与 FOLFIRI（氟尿嘧啶、亚叶酸、伊立替康）联合贝伐珠单抗相比，三联 FOLFOXIRI（氟尿嘧啶、亚叶酸、奥沙利铂和伊立替康）联合贝伐珠单抗可改善转移性结直肠癌患者的预后。然而，与预先计划的双药序贯策略相比， upfront 暴露于三种细胞毒性药物的实际获益尚不清楚，疾病进展后的治疗可行性和疗效也不清楚。我们旨在比较预先计划的 upfront FOLFOXIRI 方案，随后在疾病进展后重新引入相同方案，与 mFOLFOX6（氟尿嘧啶、亚叶酸、奥沙利铂）和 FOLFIRI 联合贝伐珠单抗的序贯方案进行比较。
方法：TRIBE2 是一项开放标签、III 期、随机研究，纳入了 58 家意大利肿瘤中心的 18-75 岁、东部肿瘤协作组（ECOG）体能状态为 2 分、不可切除、未经治疗的转移性结直肠癌患者。患者按中心、ECOG 体能状态、原发肿瘤部位和辅助化疗情况分层。使用包含最小化算法的随机系统通过基于网络的随机分配程序将患者（1:1）随机分配至两组不同的治疗策略。在对照组中，患者接受一线 mFOLFOX6（85 mg/m2 静脉奥沙利铂与 120 min 时 200 mg/m2 亚叶酸；400 mg/m2 静脉氟尿嘧啶推注；48 h 持续输注氟尿嘧啶 2400 mg/m2）联合贝伐珠单抗（5 mg/kg 静脉输注 30 min），随后疾病进展时使用 FOLFIRI（120 min 时 180 mg/m2 静脉伊立替康与 200 mg/m2 亚叶酸；400 mg/m2 静脉氟尿嘧啶推注；48 h 持续输注氟尿嘧啶 2400 mg/m2）联合贝伐珠单抗。在实验组中，患者接受 FOLFOXIRI（60 min 时 165 mg/m2 静脉伊立替康；120 min 时 85 mg/m2 静脉奥沙利铂与 200 mg/m2 亚叶酸；48 h 持续输注氟尿嘧啶 3200 mg/m2）联合贝伐珠单抗，疾病进展后重新引入相同方案。在疾病进展之前，每 14 天重复联合治疗，最多 8 个周期，然后给予氟尿嘧啶和亚叶酸（与最后诱导周期相同的剂量）联合贝伐珠单抗维持治疗，直至疾病进展、无法耐受的不良事件或同意退出。患者和研究者均未设盲。主要终点为无进展生存期 2，定义为首次疾病进展后任何治疗后疾病进展或死亡的时间，按意向治疗进行分析。至少接受一次治疗的患者进行安全性评估。研究招募已经完成，随访正在进行中。本试验在 Clinicaltrials.gov 注册，NCT02339116。
结果：2015 年 2 月 26 日至 2017 年 5 月 15 日，679 名患者被随机分配并接受治疗（对照组 340 名，实验组 339 名）。截至 2019 年 7 月 30 日，中位随访时间为 35.9 个月（IQR 30.1-41.4）。实验组无进展生存期 2 为 19.2 个月（95%CI 17.3-21.4），对照组为 16.4 个月（15.1-17.5）（风险比[HR]0.74，95%CI 0.63-0.88；p=0.0005）。在一线治疗期间，实验组最常见的所有原因 3-4 级事件为腹泻（57 [17%] vs 18 [5%]）、中性粒细胞减少（168 [50%] vs 71 [21%]）和高血压（25 [7%] vs 35 [10%]），而对照组分别为 168 [50%] vs 71 [21%]和 25 [7%] vs 35 [10%]）。实验组有 84 名（25%）患者发生严重不良事件，对照组有 56 名（17%）患者发生严重不良事件。实验组报告了 8 例与治疗相关的死亡（2 例肠阻塞、2 例肠穿孔、2 例脓毒症、1 例心肌梗死和 1 例出血），对照组报告了 4 例（2 例肠阻塞、1 例穿孔和 1 例肺栓塞）。在首次疾病进展后，对照组和实验组之间报告的 3-4 级不良事件的发生率除神经毒性外，无显著差异，而实验组仅报告了神经毒性（132 例患者中有 6 例[5%]）。实验组首次疾病进展后有 20 名（15%）患者发生严重不良事件，对照组有 25 名（12%）患者发生严重不良事件。实验组首次疾病进展后报告了 3 例与治疗相关的死亡（2 例肠阻塞和 1 例脓毒症），对照组报告了 4 例（1 例肠阻塞、1 例肠穿孔、1 例脑血管事件和 1 例脓毒症）。
解释：与根据研究标准选择的转移性结直肠癌患者的贝伐珠单抗联合化疗双药序贯治疗相比， upfront FOLFOXIRI 联合贝伐珠单抗，随后在疾病进展后重新引入相同方案似乎是一种更可取的治疗策略。
资金来源：GONO 合作组、ARCO 基金会和罗氏公司。
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