BRAF突变肠癌是结直肠癌（CRC）中的一类特殊分型，这类患者对标准治疗效果欠佳，预后较差，多年来都是临床医生和学者们关注的热点和难点。目前随着精准医疗水平的进步，以及诸多研究的开展，BRAF突变转移性结直肠癌（mCRC）的预后得到一定改善，总生存期（OS）得以延长。在第21届日本肿瘤内科学会年会（JSMO 2024）-Mini Oral Session 40专场中，研究者汇报了两项关于BRAF V600E突变转移性结直肠癌的研究进展，本文对其进行了整理，以飨读者。

【摘要号：MO40-5】早期肿瘤缩小和缓解深度对BRAF V600E突变转移性结直肠癌患者的影响 

背景:早期肿瘤缩小（ETS）和缓解深度（DpR）是转移性结直肠癌（mCRC）患者早期治疗疗效的替代标志物。然而，ETS和DpR对预后不良的BRAF V600E突变型mCRC的效用仍不清楚。本研究的目的是评估BRAF V600E突变mCRC中ETS和DpR与临床预后的关系。

结果:总共有54例BRAF V600E突变mCRC患者至少有一处靶病变。ETS≥20%和DpR≥25%的患者分别为24例（44.4%）和27例（50%）。PFS为7.5个月（95%CI：5.0~9.9），OS为17.1个月（95%CI：11.7~20.2）。

与非ETS患者相比，ETS≥20%的患者的PFS更长，OS也更长：中位PFS为9.8 vs. 4.8个月（P=0.048，HR 0.55，95%CI：0.30~1.00）；中位OS为22.6 vs. 11.6个月（P=0.18，HR 0.67，95%CI：0.37~1.21）。

DpR≥25%的患者也比非DpR患者的PFS和OS更长：中位PFS为11.0 vs. 4.3个月（P＜0.01，HR 0.36，95%CI：0.20~0.66），中位OS为22.6 vs. 10.1个月（P=0.047，HR 0.55，95%CI：0.31~1.00）。

在多变量分析中，DpR与较长的PFS（HR 0.27，95%CI：0.14~0.55，P＜0.01）和OS（HR 0.52，95%CI：0.29~0.96，P=0.04）显著相关。

结论:ETS和DpR可能是接受一线化疗的BRAF V600E突变mCRC患者临床预后的早期替代标志物。

【摘要号：MO40-6】encorafenib联合西妥昔单抗和binimetinib治疗BRAF V600E突变转移性结直肠癌的临床预后

结果：本研究纳入58例患者，其中45例患者接受三联方案治疗，13例患者接受双联方案治疗。41例患者既往接受过一线治疗，17例患者既往接受过二线或更多线治疗。5例患者表现出MSI-H/dMMR状态。

总体患者客观缓解率为37.9%（三联方案为42.2%，二联方案为23.1%），疾病控制率为81.0%（三联方案为84.4%，二联方案为69.2%）。中位无进展生存期和总生存期分别为5.3个月（三联方案为5.4个月，双联方案为4.9个月）和10.8个月（三联方案10.5个月，双联方案为20.5个月）。

5例MSI-H/dMMR患者均接受了抗PD-1治疗，其中3例患者的无进展生存期比encorafenib联合西妥昔单抗联合或不联合binimetinib的患者更长。 

结论：在BRAF V600E突变的mCRC中，encorafenib联合西妥昔单抗加或不加binimetinib的临床预后与关键试验中的结果一致。

MO40-5

Impact of early tumor shrinkage and depth of response in patients with BRAF V600E-mutant metastatic colorectal cancer

Background

Early tumor shrinkage (ETS) and the depth of response (DpR) are early on-treatment surrogate markers for survival in patients with metastatic colorectal cancer (mCRC). However, the utility of ETS and DpR for BRAF V600E mutant (MT) mCRC which has a poor prognosis remains unclear. The aim of this study is to evaluate the association between ETS and DpR and clinical outcomes in BRAF V600E MT mCRC.

Methods

mCRC patients who were diagnosed BRAF V600E MT and treated with 1st line chemotherapy from June 2011 to March 2023 at single cancer institute were enrolled. We analyzed the association between ETS and DpR and clinical outcome. Subgroup analysis of clinical factors related to progression free survival (PFS) and overall survival (OS) was performed using multivariate analysis.

Results

In total, 54 patients of BRAF V600E MT mCRC had at least one target lesion. Patients with ETS ≥ 20% and DpR ≥ 25% (median value) were 24 (44.4%) and 27 (50%) respectively. PFS was 7.5 months (95% confidence interval (CI), 5.0-9.9) and OS was 17.1 months (95% CI, 11.7-20.2). Patients with ETS ≥ 20% had longer PFS and tended to have longer OS than those with non-ETS, with a median PFS of 9.8 months vs. 4.8 months (P = 0.048, hazard ratio (HR), 0.55; 95% CI, 0.30-1.00), and a median OS of 22.6 months vs. 11.6 months (P = 0.18, HR, 0.67; 95% CI, 0.37-1.21). Patients with DpR ≥ 25% had also longer PFS and OS than those with non-DpR, with a median PFS of 11.0 vs. 4.3 months (P < 0.01, HR, 0.36; 95% CI, 0.20-0.66) and a median OS of 22.6 vs. 10.1 months (P = 0.047, HR, 0.55; 95% CI, 0.31-1.00). In multivariate analysis, DpR was significantly associated with both longer PFS (HR: 0.27, 95% CI: 0.14–0.55, P < 0.01) and OS (HR: 0.52, 95% CI: 0.29–0.96, P = 0.04).

Conclusions

ETS and DpR may be early surrogate markers for clinical outcome in BRAF V600E MT mCRC who were treated with 1st line chemotherapy.

MO40-6

Clinical outcome of encorafenib, cetuximab and binimetinib in BRAF V600E-mutated metastatic colorectal cancer

Background

BEACON CRC trial demonstrated the clinical efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC). This study aimed to perform a comprehensive molecular analysis to identify determinants of responsiveness to the combination therapy in BRAF V600E-mutated mCRC.

Methods

We investigated clinical outcome in patients with BRAF V600E-mutated mCRC who received encorafenib, binimetinib and cetuximab (triplet) or encorafenib and binimetinib (doublet) at National Cancer Center Hospital East from April 2018 to May 2023.

Results

Fifty-eight patients (45 with triplet and 13 doublet) were included in this study. Forty-one patients had received one prior line of therapy, while 17 patients had received two or more prior lines of therapy. Five patients exhibited MSI-high or dMMR status. The objective response rate was 37.9% (42.2% with triplet and 23.1% with doublet) and the disease control rate was 81.0% (84.4% with triplet and 69.2% with doublet). The median progression-free survival and overall survival were 5.3 months (5.4 months with triplet and 4.9 months with double) and 10.8 months (10.5 months with triplet and 20.5 months with doublet), respectively. All five patients with MSI-high or dMMR received anti-PD-1 therapy, with three of them showed longer progression-free survival compared with that of encorafenib plus cetuximab with or without binimetinib.

Conclusion

Clinical outcomes of encorafenib plus cetuximab with or without binimetinib in BRAF V600E-mutated mCRC were comparable to those in the pivotal trial. Biomarker analysis including whole-exome sequencing, RNA sequencing consensus, molecular subtypes and multiplex fluorescence immunohistochemistry will be presented at the meeting.