Final results of nivolumab plus ipilimumab versus nivolumab or chemotherapy in microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer from CheckMate 8HW

BACKGROUND: The phase III CheckMate 8HW trial met its dual primary endpoints of superior progression-free survival (PFS) with nivolumab plus ipilimumab (NIVO+IPI) versus chemotherapy (first-line [1L]) and versus NIVO (all lines) in patients with centrally confirmed microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). We report prespecified final overall survival (OS) analyses and updated efficacy outcomes. METHODS: Immunotherapy-naïve adults with mCRC across different lines and MSI-H/dMMR by local testing were randomized 2:2:1 to NIVO (240 mg) plus IPI (1 mg/kg) Q3W for four doses, then NIVO 480 mg Q4W; NIVO (240 mg) Q2W (six doses), then 480 mg Q4W; or chemotherapy ± targeted therapies. Secondary endpoints include PFS in NIVO+IPI versus NIVO (1L), and OS and objective response rate (ORR) in the centrally confirmed MSI-H/dMMR population. RESULTS: 839 patients across all lines were randomized; efficacy analyses were conducted in those with centrally confirmed MSI-H/dMMR. Median follow-up across all lines and treatment groups was 68.0 months (range 37.6-81.4). NIVO+IPI demonstrated significant OS benefit versus NIVO across all lines (HR 0.61; 95% CI 0.46-0.82; P=0.0009) and versus chemotherapy in 1L (HR 0.37; 95% CI 0.24-0.57; P<0.0001]). Clinically meaningful OS benefit was noted with 1L NIVO+IPI versus NIVO (HR 0.66; 95% CI 0.44-0.99; P=0.0432), not meeting the prespecified threshold for significance (P<0.006). PFS continued to favor NIVO+IPI across all three comparisons: NIVO (all lines; HR 0.60), chemotherapy (1L; HR 0.21), and NIVO (1L: HR: 0.68). Grade 3/4 treatment-related adverse events occurred in 78 (22%) versus 50 (14%) patients treated with NIVO+IPI versus NIVO across all lines, with no new safety concerns or additional treatment-related deaths from the previous follow-up. CONCLUSIONS: NIVO+IPI showed significant OS benefit versus NIVO across all lines and versus chemotherapy in 1L, while providing a clinical OS benefit versus NIVO in 1L, reinforcing its standard-of-care status in MSI-H/dMMR mCRC.