基于真实世界的微卫星稳定型晚期结直肠癌免疫联合策略优化研究

Optimization of immunotherapy combination strategies for microsatellite-stable advanced colorectal cancer: a real-world study

摘要:

背景与目的 微卫星稳定型（MSS）结直肠癌（CRC）对免疫检查点抑制剂（ICI）反应不佳，缺乏有效的免疫治疗策略。抗血管生成药物如贝伐珠单抗（BEV）可改善肿瘤免疫微环境并与ICI协同。本研究基于多中心真实世界数据，比较MSS/MSI-L/pMMR型晚期CRC患者不同免疫联合方案的疗效，探索最优治疗模式。方法 回顾性纳入2019年11月—2025年2月在湖南四家三甲医院接受系统治疗的100例MSS/MSI-L/pMMR型晚期CRC患者，患者的治疗方案分为单纯化疗、化疗+靶向、单纯免疫、免疫+化疗、免疫+靶向及免疫+化疗+靶向。主要终点为总生存期（OS）和无进展生存期（PFS），次要终点为客观缓解率（ORR）和疾病控制率（DCR）。此外，在接受免疫治疗的患者中，根据是否联合BEV进一步进行亚组分析。结果 在全部100例患者中，免疫+化疗+靶向组的ORR与DCR最高（分别为32.0%和76.0%），且该组为唯一出现完全缓解（CR）病例的治疗方式。与化疗或免疫单药相比，免疫+化疗+靶向组OS明显延长（P<0.05），虽PFS改善未达统计学意义，但生存曲线在治疗后期出现明显分离趋势。在免疫治疗亚组分析中，含BEV方案的疗效显著优于无BEV方案：DCR分别为75.0%和48.8%，中位OS为18.9个月和11.5个月，中位PFS为13.8个月和7.2个月，差异均具有统计学意义（均P<0.001）。Cox回归分析显示，与单纯化疗相比，免疫+化疗+靶向组的死亡风险（HR=0.11）及疾病进展风险（HR=0.25）明显降低（均P=0.002）。脉管侵犯是PFS的不良影响因素（HR=3.0，P=0.007）。结论 多中心真实世界研究结果显示，免疫联合化疗及靶向治疗可显著改善MSS/MSI-L/pMMR型晚期CRC患者的DCR和生存结局，其中含BEV的三联方案表现最优。BEV可能通过改善免疫微环境、促进效应T细胞浸润实现免疫增敏效应，为免疫“冷”型CRC提供新的治疗方向。未来需开展前瞻性随机研究，以进一步验证其临床价值并明确适用人群。

Abstract:

Background and Aims Microsatellite-stable (MSS) colorectal cancer (CRC) generally exhibits poor responsiveness to immune checkpoint inhibitors (ICIs), and effective immunotherapy strategies remain lacking. Anti-angiogenic agents such as bevacizumab (BEV) can improve the tumor immune microenvironment and act synergistically with ICIs. This multicenter real-world study compared the efficacy of different immunotherapy-based combination regimens in patients with MSS/MSI-L/pMMR advanced CRC, aiming to identify the optimal treatment strategy.Methods A total of 100 patients with MSS/MSI-L/pMMR advanced CRC who received systemic treatment between November 2019 and February 2025 at four tertiary hospitals in Hunan, China, were retrospectively enrolled. Patients were classified into six treatment groups: chemotherapy alone, chemotherapy + targeted therapy, immunotherapy alone, immunotherapy + chemotherapy, immunotherapy + targeted therapy, and immunotherapy + chemotherapy + targeted therapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS), while secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Additionally, among patients receiving immunotherapy, subgroup analysis was performed according to BEV administration.Results Among all 100 patients, the immunotherapy + chemotherapy + targeted therapy group achieved the highest ORR (32.0%) and DCR (76.0%) and was the only regimen yielding a complete response (CR). Compared with chemotherapy or immunotherapy alone, the triplet regimen significantly improved OS (P<0.05); although PFS improvement did not reach statistical significance, a clear late-stage separation of survival curves was observed. In the immunotherapy subgroup, BEV-containing regimens achieved markedly better outcomes than non-BEV regimens, with DCR of 75.0% vs. 48.8%, median OS of 18.9 vs. 11.5 months, and median PFS of 13.8 vs. 7.2 months (all P<0.001). Cox regression analysis showed that compared with chemotherapy alone, the triplet regimen significantly reduced the risk of death (HR=0.11) and disease progression (HR=0.25) (both P=0.002). Vascular invasion was identified as an adverse prognostic factor for PFS (HR=3.0, P=0.007).Conclusion This multicenter real-world study demonstrated that combining immunotherapy with chemotherapy and targeted therapy significantly improves DCR and survival outcomes in patients with MSS/MSI-L/pMMR advanced CRC, with BEV-containing triplet regimens providing the most pronounced benefit. BEV may enhance immune responsiveness by modulating the tumor microenvironment and promoting effector T-cell infiltration, offering a promising therapeutic direction for "immune-cold" CRC. Prospective randomized studies are warranted to further validate its clinical value and define appropriate patient populations.