Dual CTLA-4/PD-1 Blockade Versus Anti–PD-1 in MSI-H Metastatic Colorectal Cancer: Early Survival Benefit and Exploratory Clinical Predictors

Abstract

Introduction

Immune checkpoint inhibitors (ICI) are standard for MSI-H/dMMR metastatic colorectal cancer (mCRC). We compared their efficacy and sought subgroups deriving greater benefit from ICI combination.

Patients and Methods

All patients with MSI/dMMR mCRC treated by anti-PD-1 ± anti-CTLA-4 in the prospective monocenter immunoMSI cohort were analyzed. Treatment choice followed trials availability and regulatory approvals. Main endpoints were progression-free survival (PFS, iRECIST) and overall survival (OS). Landmark analysis at 6 months, restricted mean survival time (τ = 7 years) and piecewise Cox models were used. Interactions were tested in a single Cox model including subgroup terms, treatment, and interaction terms.

Results

Among 210 patients, 97 received ICI combination and 113 monotherapy with anti–PD-1. Median follow-up was 4.4 years (4.1 combo; 5.4 mono). About 165 patients (78.5%) received ICI in second line or latter. Combination improved PFS (hazard ratios [HR] 0.48, 95% CI 0.31-0.76) and OS (HR 0.49, 0.29-0.84). RMST was 5.27 versus 3.91 years (+1.36 years, 0.55-2.17). Piecewise HRs showed an early benefit (0-6 months HR 0.32, 0.16-0.66) that attenuated thereafter. Objective responses were 78% versus 60%; progressive disease 5% versus 15%. Interactions were observed for sex (PFS HR 0.21 vs. 0.87 for females vs. males; P-interaction = .0067), liver metastases (0.30 vs. 0.79; 0.0479) and sidedness (0.27 vs. 0.64; 0.0922).

Conclusion

Dual CTLA-4/PD-1 blockade improved PFS and OS versus anti–PD-1 alone, driven by higher early response rates. Female sex, absence of liver metastases, and left-sided tumor location may predict greater benefit from combination.