Background: Standard 1L therapies for mCRC include a fluoropyrimidine with oxaliplatin and/or irinotecan, and a biologic agent. NIVO may enhance antitumor activity in combination with 1L standard therapies within a subset of patients (pts) with mCRC. CheckMate 9X8 evaluated NIVO + mFOLFOX6/BEV vs mFOLFOX6/BEV in 1L mCRC (NCT03414983). Methods: Adults with previously untreated, unresectable, mCRC were randomized 2:1 to NIVO 240 mg + mFOLFOX6/BEV Q2W (NIVO + standard-of-care [SOC]) or mFOLFOX6/BEV Q2W (SOC). Primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1. Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), overall survival (OS), and safety. Results: 195 pts were randomized to NIVO + SOC (n = 127) or SOC (n = 68). Median (range) follow-up was 23.7 (0–33.2) months (mo; NIVO + SOC) vs 23.2 (0–32.3) mo (SOC). Median (range) duration of therapy was 9.9 (0.1–31.8+) mo (NIVO + SOC) and 7.7 (0.1–26.7+) mo (SOC). The HR (95% CI) for PFS was 0.81 (0.53–1.23; P = 0.30), which did not meet the prespecified threshold for statistical significance (median PFS, 11.9 mo in both arms; Table). PFS rates after 12 mo were higher with NIVO + SOC vs SOC (Table). ORR was 60% (NIVO + SOC) and 46% (SOC; odds ratio 1.72 [95% CI 0.96–3.10]) and median (95% CI) DOR was 12.9 (9.0–13.1) mo (NIVO + SOC) and 9.3 (7.5–11.3) mo (SOC; Table). Rates of grade 3−4 treatment-related adverse events (TRAEs) were higher with NIVO + SOC; however, no new safety signals were identified (Table). Biomarker analyses, including tumor mutational burden and baseline CD8 levels, will be presented. Conclusions: The primary endpoint of PFS was not met; however, NIVO + SOC showed higher PFS rates after 12 mo, a higher response rate, and more durable responses compared with SOC, along with acceptable safety, in 1L mCRC. Clinical trial information: NCT03414983.

^aBICR; ^bResponders only (NIVO + SOC, n = 76; SOC, n = 31); ^cMinimum follow-up for OS, 21.5 mo; ^dOne grade 5 event. NE, not estimable.