202 Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC), though selected patients may derive durable benefit. We evaluated survival outcomes of MSS mCRC patients treated with ICI-based regimens versus standard of care (SOC), with a focus on the impact of the presence or absence of liver metastases and the type of ICI-based regimen. Methods: We retrospectively identified chemo-refractory MSS (non- POLE ) mCRC patients treated with ICIs between 2014 and 2025. ICI-based regimens were classified as single-ICI ± other (vaccines, targeted therapies, immunomodulatory agents), double-ICI ± other, and multi-tyrosine kinase inhibitor (mTKI) + ICI (single or double). A comparison cohort of chemo-refractory mCRC patients treated with trifluridine/tipiracil ± bevacizumab, regorafenib, or fruquintinib as SOC from 2012 to 2025 was generated through 1:1 propensity score matching by age, sex, ECOG PS, liver metastases (present vs absent), and RAS / BRAF status. Kaplan-Meier and Cox regression were used for comparing overall survival (OS). Results: A total of 354 patients treated with ICIs and 354 patients treated with SOC were matched. Median age was 55 years, 52% were male, 32% were ECOG PS 0, 30% had right-sided primaries, and 68% were RAS mutated in both groups, while 61% and 60% had liver metastases, respectively. In the overall population, median OS (mOS) was 10.8 months in the ICI group and 9.0 months in the SOC group (HR 0.76, 95% CI 0.64-0.92, p = 0.004). In patients without liver metastases, mOS was significantly longer with ICI compared with SOC (19.1 vs 13.2 months, HR 0.59, 95% CI 0.43-0.80, p < 0.001), whereas outcomes were similar in patients with liver metastases (6.4 vs 6.5 months, p = 0.303). Among patients without liver metastases, mOS was 18.4 months with single-ICI ± other, 20.5 with double-ICI ± other, and 20.4 with mTKI + ICI. In the univariable analysis, age, sex, primary tumor site, and RAS / BRAF status did not significantly affect OS. mTKI + ICI, absence of liver metastases, and ECOG PS 0 were associated with the most favorable outcomes in both univariable and multivariable models (Table). Conclusions: In chemo-refractory MSS mCRC without liver metastases, ICI-based regimens yielded longer overall survival than SOC. Further investigation of ICI therapy in this patient population is warranted. n univariable 95% CI p multivariable 95% CI p SOC 354 ref ref single-ICI ± other 255 0.80 0.65-0.97 0.023 0.82 0.67-0.99 0.043 double-ICI ± other 51 0.78 0.54-1.12 0.182 0.80 0.56-1.16 0.245 mTKI + ICI 48 0.58 0.40-0.86 0.006 0.54 0.36-0.80 0.003 Liver metastases 429 ref ref No liver metastases 279 0.47 0.39-0.57 <0.001 0.52 0.43-0.63 <0.001 ECOG PS 0 228 ref ref ECOG PS 1 464 1.80
Vetere et al. (Sat,) studied this question.