编者按：2025年1月25日，美国临床肿瘤学会胃肠道肿瘤研讨会（ASCO GI 2025）已于当地时间圆满落幕，展示了该领域国内外学者的最新研究进展与诊疗策略。其中，一项关于BRAF V600E突变型转移性结直肠癌（mCRC）治疗的BREAKWATER研究（摘要号：16）引起了广泛关注，该研究不仅显著提高缓解率，还显示出良好且持久的疗效，为BRAF V600E突变型mCRC患者提供了更优的一线治疗选择。同时，该研究也为精准医学在mCRC领域的应用提供了新的证据，推动靶向治疗在更早期治疗阶段的实践。《肿瘤瞭望》特邀德克萨斯大学MD安德森癌症中心Scott Kopetz教授，深入解读BREAKWATER研究的最新结果和临床意义。

 

Scott Kopetz教授：基于BEACON III期研究（NCT02928224），康奈非尼（Encorafenib，又称恩考芬尼、恩可非尼）+西妥昔单抗（EC）已被批准用于既往接受过治疗的BRAF V600E突变型转移性结直肠癌（mCRC）患者。既往回顾性研究数据显示，采用化疗方案一线治疗BRAF V600E突变型mCRC的疗效有限，无进展生存期（PFS）中位数约为6个月，总生存期（OS）通常也仅略超过一年。因此，本研究的核心目的是探索更有效的治疗策略，以改善这一患者人群的临床结局。BREAKWATER（NCT04607421）是一项开放标签、全球性、随机、III期研究，旨在评估EC±化疗vs标准治疗（SOC；化疗±贝伐珠单抗）一线靶向治疗BRAF V600E突变型mCRC患者的疗效和安全性。本研究报道了EC+FOLFOX（奥沙利铂+亚叶酸钙+氟尿嘧啶）vs标准治疗（SOC）的疗效和安全性，具体包括：由盲态独立中心审查评估（BICR）的客观缓解率（ORR）的主要分析结果（亦是双重主要终点之一），总生存期（OS）的首次中期分析结果（关键次要终点），以及其他次要终点的数据。

 

本研究纳入了未经治疗的BRAF V600E突变型mCRC、具有可测量病灶（依据RECIST 1.1标准）和美国东部肿瘤协作组体力状态评分（ECOG PS）为0-1的患者，按1:1:1的比例随机接受EC、EC+FOLFOX或SOC治疗。双主要终点分别为ORR（评估前110例随机分配至EC+FOLFOX vs SOC亚组的患者）和BICR评估的PFS（EC+FOLFOX vs SOC）；OS为关键次要终点（EC+FOLFOX vs SOC），其他次要终点包括缓解持续时间（DOR）和至缓解时间（TTR）。

 

共有479例患者被随机分配到EC+FOLFOX和SOC两组（EC+FOLFOX组：236例；SOC组：243例）。各组的人口统计学和疾病基线特征相似，中位年龄为61岁，男性占比50.5%，ECOG PS评分为0的患者占比54.3%。在数据截止时（2023年12月22日），EC+FOLFOX组与SOC组相比，经确认的ORR具有临床和统计学意义上的显著改善。两组的ORR分别为60.9%vs 40.0%，优势比（OR）=2.443，单侧P值=0.0008，达到双主要终点。观察到EC+FOLFOX组疗效迅速且持久。

 

 

OS数据尚不成熟，但研究表明，EC+FOLFOX治疗组与SOC治疗组相比，具有持续的生存获益。治疗期间出现的严重不良事件（EC+FOLFOX：231例；SOC：228例）发生率分别为37.7%vs 34.6%。安全性与每种药物的已知安全性一致。

 

BREAKWATER研究表明，EC+FOLFOX联合疗法可显著提高BRAF V600E突变型mCRC患者的缓解率，且疗效迅速、持久，安全可控，未出现新的安全性信号。

 

Dr.Scott Kopetz:The BREAKWATER study is an international，randomized phase 3 trial designed to evaluate novel targeted therapy for BRAF V600E-mutated metastatic colorectal cancer(mCRC)in the first-line setting.This study acknowledges that current standard-of-care treatment—cytotoxic chemotherapy with or without Bevacizumab—has demonstrated limited efficacy in this patient population.Historically，the median progression-free survival(PFS)has been around six months，and overall survival(OS)has been only slightly over a year in many retrospective analyses.Given the poor prognosis associated with this mutation，the study aimed to improve treatment outcomes by introducing a targeted regimen.

 

The study was structured as a three-arm randomized trial.The control arm consisted of standard chemotherapy regimens，which could include FOLFOX，FOLFIRI，or FOLFOXIRI，with Bevacizumab allowed at the investigator’s discretion.This was compared against an experimental arm of encorafenib plus cetuximab(EC)and another experimental arm of encorafenib，cetuximab，and FOLFOX(EC+FOLFOX).The decision to include FOLFOX was based on safety and feasibility data from an initial lead-in phase.A FOLFIRI-based regimen was also included in the study but will be reported separately at a later time.

 

The co-primary endpoints were objective response rate(ORR)and PFS.The trial followed the FDA’s Project FrontRunner framework，which supports accelerated approval for novel therapies in earlier treatment lines.Under this approach，if a study demonstrates a clinically meaningful improvement in response rate and durability，it can lead to accelerated approval，with full approval contingent on the PFS data.

 

At GI ASCO 2025，we reported the ORR results and an early interim analysis of OS.The ORR was significantly improved in the EC+FOLFOX arm，increasing from 40%in the control arm to 60.5%，which was both statistically and clinically meaningful.Importantly，the durability of responses at six and twelve months was approximately twice as high in the EC+FOLFOX arm compared to standard chemotherapy.

 

It’s important to note that the EC arm was discontinued following a protocol amendment and did not complete full enrollment.However，this decision was strategic and not based on an interim analysis related to efficacy or safety.The remaining two arms completed enrollment as planned.

 

Regarding overall survival(OS)，an early interim analysis showed promising trends favoring EC+FOLFOX.The hazard ratio for OS was 0.47，with a p-value of 4.5×10??，meeting the pre-specified statistical threshold for significance.However，since this was an early interim analysis，OS results remain inconclusive per protocol guidelines.

 

In terms of safety，the combination of encorafenib，cetuximab，and chemotherapy was well tolerated，with a manageable safety profile.The observed adverse events were consistent with expectations，including slightly higher rates of anemia，skin rash，and arthralgia，which align with the known toxicities of the individual agents.

 

Scott Kopetz教授：BREAKWATER研究结果表明，EC+FOLFOX方案在BRAF V600E突变型mCRC的一线治疗中具有临床意义上的显著获益，改善了既往标准化疗方案的疗效。EC+FOLFOX方案将ORR从40%提高至60%，且缓解时间显著延长，表明靶向治疗与化疗联合应用能有效提升疾病控制率。此外，OS的早期数据也呈现出良好趋势，提示该方案可能带来更长的生存期。

 

从临床角度看，该研究结果支持将EC+FOLFOX方案作为BRAF V600E突变型mCRC患者的一线治疗选择。目前，BRAF靶向治疗主要用于后线治疗，但随着更多数据的积累，该方案有望成为新的治疗标准。

 

BREAKWATER研究进一步强调了精准医学在肿瘤治疗中的作用，表明针对特定基因突变的靶向治疗策略不仅可以提高缓解率，还可能改善患者的长期生存结局。

 

Dr.Scott Kopetz:The BREAKWATER study results demonstrate that encorafenib+cetuximab+chemotherapy provides a clinically meaningful benefit in BRAF V600E-mutant metastatic colorectal cancer when used as first-line therapy.This is particularly important given that this patient population historically experiences poor outcomes with standard chemotherapy alone.

 

The higher response rate(60.5%vs.40%)and the increased durability of responses in the EC+FOLFOX arm strongly suggest that integrating targeted therapy with chemotherapy significantly enhances disease control.Additionally，the early OS data is very encouraging，showing a favorable trend toward improved survival.

 

From a clinical perspective，these findings suggest that encorafenib-based regimens should be considered as first-line therapy for patients with BRAF V600E-mutant mCRC.At present，BRAF-targeted therapies are only approved in later treatment lines.If these findings are confirmed with further data，they could reshape the treatment landscape，establishing encorafenib+cetuximab+chemotherapy as the new standard of care in the first-line setting.

 

More broadly，the BREAKWATER study supports the growing role of precision medicine in early-line oncology treatment，reinforcing the importance of targeted approaches in improving both response rates and survival outcomes for patients with aggressive tumor mutations.

 

Scott Kopetz教授：BREAKWATER研究的设计包括多个研究队列，目前已公布的是EC+FOLFOX的研究数据，而FOLFIRI方案（伊立替康+亚叶酸钙+氟尿嘧啶）的研究数据尚未发布。未来，我们需要评估伊立替康为基础的化疗方案是否具有与FOLFOX方案相当或更优的临床获益。

 

此外，该研究与FDA鼓励肿瘤早期治疗药物加速审批的“Project FrontRunner”计划高度契合，推动创新疗法进入前线治疗。EC+化疗联合方案已在ORR和DOR方面显示出显著优势，后续的研究重点将是长期生存获益和OS的后续随访数据。

 

未来，我们还将继续探索该方案在不同患者亚组中的疗效，并评估其与其他新兴疗法的联合应用，例如免疫治疗联合BRAF靶向治疗的可能性。这些研究将进一步推动精准医学的发展，为BRAF V600E突变型mCRC患者提供更优的治疗选择。

 

Dr.Scott Kopetz:Certainly.The BREAKWATER study was designed with multiple treatment arms，and while we have presented data on encorafenib+cetuximab+FOLFOX，a FOLFIRI-based regimen was also included in the study design.Data from this cohort will be reported separately，and it will be valuable to evaluate whether an irinotecan-based chemotherapy backbone provides comparable or additional benefits to FOLFOX.

 

Additionally，this study aligns with the FDA’s Project FrontRunner initiative，which seeks to introduce novel therapeutics in earlier treatment settings.With the encorafenib-based regimen already showing a significant improvement in response rates and durability，the next focus will be on long-term survival outcomes，with further follow-up on OS data expected.

 

▌参考文献：

 

Scott Kopetz，et al.2025 ASCO GI，BREAKWATER:Analysis of first-line encorafenib+cetuximab+chemotherapy in BRAF V600E-mutant metastatic colorectal cancer.Abstract 16.

 

Scott Kopetz教授

肿瘤内科医生兼转化研究副主任

精通胃肠道癌患者的多学科诊疗以及转化研究

MD安德森癌症中心-癌症中心支持基金（CCSG）胃肠道项目负责人

美国国家癌症研究所（NCI）结肠癌特别工作组主席，美国国家外科辅助乳腺和肠道项目/放射治疗肿瘤学组/妇科肿瘤学组（NSABP/RTG/GOG，现合并为NRG）合作组中结肠癌领域副主席