Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): first results of the CheckMate 8HW study

Introduction: Patients (pts) with MSI-H/dMMR mCRC have poor outcomes with standard chemo±targeted therapies. NIVO±IPI are approved in previously treated pts with MSI-H/dMMR mCRC in many countries, based on the phase 2 CheckMate 142 study Objective: CheckMate 8HW (NCT04008030) is a randomized phase 3 study comparing NIVO+IPI with NIVO or chemo in pts with MSI-H/dMMR mCRC. We report progression-free survival (PFS) by blinded independent central review (BICR) at a prespecified interim analysis for NIVO+IPI vs chemo in the 1L setting. Methods: Pts ≥18 years with recurrent or mCRC not amenable to surgery and MSI-H/dMMR status per local testing were enrolled across different lines of therapy. Previously untreated pts were randomized 2:2:1 to NIVO (240 mg)+IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), or chemo±targeted therapies; treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO±IPI arms). For pts with BICR-documented progression with chemo, optional crossover to NIVO+IPI was permitted. Dual primary endpoints were PFS by BICR per RECIST v1.1 for NIVO+IPI vs chemo (1L) and NIVO+IPI vs NIVO (all lines) in pts with centrally confirmed MSI-H/dMMR mCRC. Abb. 1 Results: In the 1L setting, 303 pts were randomized to NIVO+IPI (n=202) or chemo (n=101); of these pts, 171 pts in the NIVO+IPI arm and 84 pts in the chemo arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests. With 24.3 months of median follow-up, NIVO+IPI demonstrated clinically meaningful and statistically significant improvement in PFS vs chemo, with a 79% reduction in the risk of disease progression or death (HR 0.21 [95% CI 0.14–0.32]; P < 0.0001) ( Table ). No new safety signals were identified ( Table ). Conclusions: NIVO+IPI demonstrated superior PFS vs chemo in previously untreated pts with MSI-H/dMMR mCRC. NIVO+IPI had a different safety profile compared to chemo, with fewer grade 3–4 treatment-related adverse events (TRAEs). These results support 1L NIVO+IPI as a SOC option for pts with MSI-H/dMMR mC präsentiert in der Sitzung: Individualisierte Präzisionsmedizin Freitag, 04. Oktober 2024, 10:30 – 12:00, Saal 3 Publication History Article published online: 26 September 2024 © 2024. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany