A randomised study of encorafenib, cetuximab, and FOLFIRI versus FOLFIRI with or without bevacizumab in BRAF V600E-mutant colorectal cancer: BREAKWATER Cohort 3

IF 80.4 1区医学 Q1 ONCOLOGY

Annals of Oncology Pub Date : 2026-08-01 Epub Date: 2026-05-31 DOI:10.1016/j.annonc.2026.04.017

S. Kopetz, J. Tabernero, S. Lonardi, L. Shen, H.S. Wasan, T. Yoshino, E. Van Cutsem, T.W. Kim, C. Eng, F. Ciardiello, J. Desai, T.S. Maughan, R. Yaeger, T. Usari, Xiaoxi Zhang, E. Beyzarov, A. Mori, E. Whalley, Xiaosong Zhang, E. Elez

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引用次数: 0

Abstract

Background

Encorafenib + cetuximab (EC) and mFOLFOX6 or irinotecan, leucovorin, and fluorouracil (FOLFIRI) is approved in several countries for BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on results from the BREAKWATER trial.

Patients and methods

In BREAKWATER Cohort 3, eligible patients with previously untreated BRAF V600E-mutant mCRC were randomly assigned 1:1 to receive EC+FOLFIRI or FOLFIRI with or without bevacizumab (control). The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR), and the key secondary endpoint was progression-free survival (PFS) by BICR. Other secondary endpoints included overall survival (OS) and safety.

Results

A total of 147 patients were randomly allocated in Cohort 3 (EC+FOLFIRI, n = 73; control, n = 74) with similar baseline demographics and disease characteristics across arms. EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvement in ORR by BICR {64.4% versus 39.2%, odds ratio = 2.756 [95% confidence interval (CI) 1.420-5.348], one-sided P-value = 0.0011}, meeting the primary endpoint (1 March 2025, data cutoff). At the 6 January 2026 data cutoff, the key secondary endpoint was met, with EC+FOLFIRI demonstrating a clinically meaningful and statistically significant PFS [hazard ratio = 0.44 (95% CI 0.27-0.70), one-sided P-value = 0.0002, 15.2 versus 8.3 months]. Prolonged OS was also observed with EC+FOLFIRI (hazard ratio = 0.56 [95% CI 0.34-0.94], not estimable versus 20.3 months). Serious adverse event rates were 49.3% versus 44.1% for the EC+FOLFIRI versus control arms, respectively. The safety profile was consistent with that known for each agent.

Conclusions

EC+FOLFIRI demonstrated clinically meaningful and statistically significant improvements in ORR and PFS, with prolonged OS versus control in BRAF V600E-mutant mCRC. The safety profile was generally manageable, with no new safety signals. These data support EC+FOLFIRI as an additional new standard of care for patients with BRAF V600E-mutant mCRC, enabling treatment personalisation.

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在BRAF v600e突变型结直肠癌中，恩科非尼、西妥昔单抗和FOLFIRI与有或没有贝伐单抗的FOLFIRI的随机研究：BREAKWATER队列3。

背景：根据BREAKWATER试验的结果，恩科非尼+西妥昔单抗（EC）和mFOLFOX6或伊立替康、亚叶酸钙素和氟尿嘧啶（FOLFIRI）已在多个国家被批准用于治疗BRAF v600e突变性转移性结直肠癌（mCRC）。患者和方法：在BREAKWATER队列3中，先前未接受治疗的BRAF v600e突变mCRC的符合条件的患者被随机分配为1:1，接受EC+FOLFIRI或FOLFIRI联合或不联合贝伐单抗（对照）。主要终点是盲法独立中心评价（BICR）的客观缓解率（ORR），关键次要终点是BICR的无进展生存期（PFS）。其他次要终点包括总生存期（OS）和安全性。结果：共有147名患者被随机分配到队列3 (EC+FOLFIRI, n = 73；对照组，n = 74)，各组基线人口统计学和疾病特征相似。EC+FOLFIRI显示BICR对ORR有临床意义和统计学意义的改善[64.4%对39.2%，优势比= 2.756[95%可信区间（CI） 1.420-5.348]，单侧p值= 0.0011]，达到主要终点（2025年3月1日，数据截止）。在2026年1月6日的数据截止点，达到了关键的次要终点，EC+FOLFIRI显示出具有临床意义和统计学意义的PFS[风险比= 0.44 (95% CI 0.27-0.70)，单侧p值= 0.0002,15.2对8.3个月]。EC+FOLFIRI组也观察到延长的OS（风险比= 0.56 [95% CI 0.34-0.94]，无法估计，vs . 20.3个月）。EC+FOLFIRI组与对照组的严重不良事件发生率分别为49.3%和44.1%。其安全性与已知的每种药物一致。结论：EC+FOLFIRI在BRAF v600e突变的mCRC中显示出具有临床意义和统计学意义的ORR和PFS改善，与对照组相比，OS延长。安全概况总体上是可控的，没有新的安全信号。这些数据支持EC+FOLFIRI作为BRAF v600e突变mCRC患者的额外新护理标准，实现治疗个性化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Oncology 医学-肿瘤学

CiteScore

63.90

自引率

1.00%

发文量

3712

审稿时长

2-3 weeks

期刊介绍： Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.