Background: 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. 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. 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 standard-of-care option for pts with MSI-H/dMMR mCRC. Clinical trial information: NCT04008030.

^aOne death was reported during crossover treatment and deemed not related to chemo. NE, not evaluable; NR, not reached.