Durable Responses to Immunotherapy in dMMR/MSI-H Metastatic Colorectal Cancer Patients With Poor Performance Status.

BACKGROUND: Immune checkpoint blockers (ICBs) are front-line therapy for mismatch repairdeficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Poor ECOG performance status (PS) is widely recognized as a negative prognostic factor, often leading physicians to avoid treatment. We aimed to assess the effect of ECOG PS on patient outcomes in dMMR/MSI-H mCRC receiving ICBs. METHODS: This is an international multicenter retrospective cohort study of ICBs-naïve dMMR/MSI-H mCRC patients who received ICBs between 2014-2024. Exposure variables included best treatment response and patient characteristics including line of treatment, RAS/BRAF status, single-agent versus doublet ICBs, and metastatic sites. The main outcome was overall survival. Kaplan-Meier analysis was used to analyze the association of best treatment response with overall survival according to ECOG PS of 2-3 and 0-1. RESULTS: The study cohort included 51 dMMR/MSI-H mCRC patients with ECOG PS of 2-3 and 633 patients with ECOC PS of 0-1 that were treated with ICBs. Median follow-up time was 35.3 months (IQR 23.9-54.9) and 49.9 months (IQR 46.7-53.8), respectively. For patients with ECOG PS of 2-3 ORR and DCR rates were 37.3% and 60.8%. Median overall survival (mOS) was 14.4 months - not reached for those who achieved CR/PR and 1.7 months for those whose best response was PD. For patients with ECOG PS of 0-1, mOS was not reached, and ORR was 60.0%. CONCLUSIONS: Patients with dMMR/MSI-H mCRC and ECOG PS 2-3 derive durable benefit from ICBs, mainly among those who achieved CR/PR, and should therfore be considered candidates for ICBs.