Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, AP-HP, Paris, France; Department of Medical Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
Department of Hepatology and Gastroenterology, Poitiers University Hospital, Poitiers, France.
Eur J Cancer. 2024 Oct;210:114290. doi: 10.1016/j.ejca.2024.114290. Epub 2024 Aug 22.
Immune checkpoint inhibitors (ICIs) are the guideline endorsed first choice for patients with deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) mCRC, however a significant proportion experience primary or secondary resistance. BRAF V600E mutated (BRAFm) and dMMR/MSI-H mCRC can be treated with BRAF + EGFR inhibitors but specific data on the efficacy after progression to ICIs are missing.
We collected consecutive patients with BRAFm dMMR/MSI-H mCRC treated from 2017 to 2024 with a combination of BRAFi+EGFRi+/-MEKi, after disease progression on ICIs. A control cohort of BRAFm pMMR/MSS mCRC patients treated with encorafenib+cetuximab+/-binimetinib from 2nd line was used.
dMMR/MSI-H (n = 50) BRAFm mCRC patients were more often > 70-year-old, with right-sided primary tumors, without liver but more lymphnode metastases than pMMR/MSS (n = 170). They were treated more frequently beyond 2nd line and 45 % were primary progressors to ICIs. Lower ORR (18 % versus 32 %, p = 0.09) and DCR (60 % versus 73 %, p = 0.11) was seen without reaching significance in dMMR/MSI-H as compared to pMMR/MSS patients. After a median follow-up of 14.04 months, no differences in PFS (median 5.13 versus 4.50 months, HR 0.83, 95 %CI: 0.57-1.20, p = 0.31) and OS (median 10.75 versus 9.11 months, HR 0.89, 95 %CI: 0.59-1.32, p = 0.55) were observed.
Our results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.
免疫检查点抑制剂（ICI）是指南推荐的首选治疗方案，适用于错配修复缺陷或微卫星不稳定高（dMMR/MSI-H）结直肠癌患者，但相当一部分患者会出现原发性或继发性耐药。BRAF V600E 突变（BRAFm）和 dMMR/MSI-H 结直肠癌可以用 BRAF+EGFR 抑制剂治疗，但缺乏关于 ICI 进展后疗效的具体数据。
我们收集了 2017 年至 2024 年期间连续接受 BRAFi+EGFRi+/-MEKi 联合治疗的 BRAFm dMMR/MSI-H 结直肠癌患者的资料，这些患者在 ICI 进展后出现疾病进展。我们还使用了第二个队列的 BRAFm pMMR/MSS 结直肠癌患者的数据，这些患者接受了 encorafenib+cetuximab+/-binimetinib 二线治疗。
dMMR/MSI-H（n=50）BRAFm 结直肠癌患者的年龄大于 70 岁、右侧原发肿瘤、无肝转移但更多淋巴结转移的比例高于 pMMR/MSS（n=170）。他们更频繁地接受二线以上治疗，45%的患者为 ICI 的原发性进展者。dMMR/MSI-H 组的客观缓解率（18%与 32%，p=0.09）和疾病控制率（60%与 73%，p=0.11）较低，但未达到显著差异。中位随访 14.04 个月后，dMMR/MSI-H 组的无进展生存期（中位 5.13 个月与 4.50 个月，HR 0.83，95%CI：0.57-1.20，p=0.31）和总生存期（中位 10.75 个月与 9.11 个月，HR 0.89，95%CI：0.59-1.32，p=0.55）无差异。
我们的结果表明，BRAFm dMMR/MSI-H 结直肠癌患者在 ICI 进展后接受 BRAFi+EGFRi+/-MEKi 治疗获益。尽管客观缓解率和疾病控制率较低，但结果与 pMMR/MSS BRAFm CRC 观察到的结果无差异，与 BEACON 注册试验的结果一致。
