Prognostic impact of metastatic distribution in microsatellite-stable metastatic colorectal cancer.

55 Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) due to immune-resistant tumor microenvironment. As MSS accounts for ~95% of mCRC, identifying responsive subgroups remains an unmet need. Although liver metastasis is a known adverse prognostic factor, the impact of other sites remains less defined. This study evaluated the prognostic impact of metastatic site distribution in MSS mCRC. Methods: This retrospective, single-center study included MSS mCRC patients treated with anti-PD-1/PD-L1 ICIs in clinical trials as second- or third-line therapy between November 2014 and September 2024. MSS status was assessed by PCR, immunohistochemistry, or next-generation sequencing. Results: A total of 84 patients were included (median age, 52 years; 45% male), with a median follow-up of 9.1 months. Patients were stratified by metastatic distribution: liver or peritoneal metastasis (n=54), any metastasis without liver or peritoneal involvement (n=17), and lung-only metastasis (n=13). Overall response rates (ORR) were 3.7%, 11.8%, and 15.4%, and disease control rates (DCR) were 35.2%, 64.7%, and 76.9% in the liver/peritoneal, non-liver/peritoneal, and lung-only groups, respectively. Compared with the liver or peritoneal group, the lung-only group showed significantly prolonged median overall survival (OS, 26.6 vs. 7.6 months; HR 0.24; P =0.003) and progression-free survival (PFS, 10.7 vs. 1.9 months; HR 0.35; P =0.005). The non-liver/peritoneal group also had longer OS (13.4 months; HR 0.52; P =0.047) and PFS (5.8 months; HR 0.56; P =0.048) relative to those with liver or peritoneal involvement. In a time-dependent Cox model applied due to non-proportional hazards, lung-only metastasis remained associated with a significantly reduced risk of death compared to liver or peritoneal metastasis (time effect HR, 0.11; P =0.015). Conclusions: MSS mCRC patients with lung-only metastasis showed favorable survival outcomes with ICI therapy and may represent a clinically meaningful subgroup. Further studies on the tumor microenvironment and predictive biomarkers are warranted to optimize ICI efficacy in this population.