尽管具有微卫星不稳定性的转移性结直肠癌（CRC）患者可从免疫检查点抑制剂中受益，但化疗联合靶向疗法仍是微卫星稳定性（MSS）肿瘤的唯一治疗选择。单臂1b/2期MEDITREME试验评估了durvalumab与tremelimumab联合mFOLFOX6化疗在57例RAS突变不可切除的转移性CRC患者中的安全性和疗效。安全性是1b期的主要目标；未观察到安全问题。在MSS肿瘤患者中，2期的主要目标3个月无进展生存（PFS）方面的疗效达到了，3个月的PFS为90.7%（95%置信区间（CI）：79.2-96%）。对于次要目标，反应率为64.5%；中位PFS为8.2个月（95% CI：5.9-8.6）；MSS肿瘤患者的总生存期尚未观测到。我们观察到在响应者中，肿瘤突变负荷更高、基因组不稳定性更低。整合转录组分析强调高免疫特征和低上皮-间质转变与较好的结果相关。免疫监测显示诱导新抗原和NY-ESO1以及TERT血液肿瘤特异性T细胞应答与较好的PFS相关。durvalumab-tremelimumab与mFOLFOX6的联合疗法在MSS mCRC中耐受良好且具有良好的临床活性。Clinicaltrials.gov识别码：NCT03202758.© 2023. 作者。

Although patients with microsatellite instable metastatic colorectal cancer (CRC) benefit from immune checkpoint blockade, chemotherapy with targeted therapies remains the only therapeutic option for microsatellite stable (MSS) tumors. The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line, in 57 patients with RAS-mutant unresectable metastatic CRC. Safety was the primary objective of phase Ib; no safety issue was observed. The phase 2 primary objective of efficacy in terms of 3-month progression-free survival (PFS) in patients with MSS tumors was met, with 3-month PFS of 90.7% (95% confidence interval (CI): 79.2-96%). For secondary objectives, response rate was 64.5%; median PFS was 8.2 months (95% CI: 5.9-8.6); and overall survival was not reached in patients with MSS tumors. We observed higher tumor mutational burden and lower genomic instability in responders. Integrated transcriptomic analysis underlined that high immune signature and low epithelial-mesenchymal transition were associated with better outcome. Immunomonitoring showed induction of neoantigen and NY-ESO1 and TERT blood tumor-specific T cell response associated with better PFS. The combination of durvalumab-tremelimumab with mFOLFOX6 was tolerable with promising clinical activity in MSS mCRC. Clinicaltrials.gov identifier: NCT03202758 .© 2023. The Author(s).