First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW.

LBA143 Background: The CheckMate 8HW study met its dual primary endpoint with NIVO + IPI demonstrating superior progression-free survival (PFS) by blinded independent central review (BICR) vs chemotherapy (chemo) in patients (pts) with centrally confirmed MSI-H/dMMR mCRC in the first-line (1L) setting (HR 0.21; 95% CI 0.14–0.32; P < 0.0001). We report first results from the other dual primary endpoint of PFS for NIVO + IPI vs NIVO across all lines of therapy in pts with centrally confirmed MSI-H/dMMR mCRC. Methods: Immunotherapy-naive pts with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0 or 1 prior line of therapy were randomized 2:2:1 to (i) NIVO (240 mg) Q2W (6 doses, then NIVO 480 mg Q4W), (ii) NIVO (240 mg) + IPI (1 mg/kg) Q3W (4 doses, then NIVO 480 mg Q4W), or (iii) chemo ± targeted therapies. Pts who had received ≥ 2 prior lines of therapy were randomized 1:1 to the NIVO + IPI or NIVO arms. Treatments continued until disease progression or unacceptable toxicity (all arms), or a maximum of 2 years (NIVO ± IPI arms). Results: Across all lines of therapy,707 pts were randomized to NIVO + IPI (n = 354) or NIVO (n = 353); 55% and 52% received study treatment in the 1L setting, respectively. Of all randomized pts, 296 in the NIVO + IPI arm and 286 in the NIVO arm had centrally confirmed MSI-H/dMMR status. With 47.0 months (mo) of median follow-up (range, 16.7–60.5), NIVO + IPI demonstrated clinically meaningful and statistically significant improvement in PFS by BICR vs NIVO (HR 0.62; 95% CI 0.48–0.81; P = 0.0003) and higher 12-, 24-, and 36-mo PFS rates vs NIVO (Table). Objective response rate (ORR) by BICR was significantly higher with NIVO + IPI vs NIVO (71% vs 58%; P = 0.0011; Table); best overall response of progressive disease was reported in 10% and 19% of pts, respectively. No new safety concerns were identified (Table). Conclusions: In the first randomized study to compare dual- vs single-agent immunotherapy in MSI-H/dMMR mCRC, NIVO + IPI demonstrated superior PFS vs NIVO across all lines of therapy, with a manageable safety profile. These results establish NIVO + IPI as the potential new standard-of-care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . Efficacy by BICR (all lines; centrally confirmed MSI-H/dMMR by IHC and/or PCR test) NIVO + IPI(n = 296) NIVO(n = 286) Median PFS (95% CI), mo NR (53.8–NE) 39.3 (22.1–NE) HR (95% CI); P value 0.62 (0.48–0.81); 0.0003 PFS rate (12/24/36-mo), % 76/71/68 63/56/51 ORR, n (%); 95% CI, % 209 (71); 65–76 165 (58); 52–64 P value 0.0011 Safety (all lines; all treated), n (%) NIVO + IPI (n = 352) NIVO (n = 351) Any-grade/grade 3–4 TRAEs 285 (81)/78 (22) 249 (71)/50 (14) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (14)/33 (9) 21 (6)/14 (4) Treatment-related deaths 2 (< 1) 1 (< 1) IHC, immunohistochemistry; NE, not estimable; NR, not reached; PCR, polymerase chain reaction; TRAE, treatment-related adverse event.