AbstractIntroduction 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 the 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 (data lock: April 23, 2024). 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). 165 patients (78.5%) received ICI in second line or latter. Combination improved PFS (HR 0.48, 95% CI 0.31–0.76) and OS (HR 0.49, 0.29–0.84). RMST was 5.27 vs 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% vs 60%; progressive disease 5% vs 15%. Interactions were observed for sex (PFS HR 0.21 vs 0.87 for females vs males; P-interaction = 0.0067), 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 therapy. Micro abstract: In MSI-H/dMMR metastatic colorectal cancer, the optimal intensity of immune checkpoint blockade remains debated. In a prospective cohort of 210 patients treated with anti–PD-1 alone or combined with anti–CTLA-4, dual blockade improved early response rates and survival. This benefit was mainly driven by early tumor control and was more pronounced in women, patients without liver metastases, and those with left-sided tumors.
Jehanno et al. (Fri,) studied this question.