Background: Approximately 4% of metastatic colorectal cancers (mCRCs) are associated with high microsatellite instability (MSI-H), indicating a deficient DNA mismatch repair (dMMR) system. dMMR/MSI-H CRC exhibits an increased tumor neoantigen load and immune cell infiltration and is hypothesized to be targetable by immune checkpoint inhibitors. CheckMate 142 (NCT02060188) evaluates the efficacy and safety of nivolumab (nivo) in patients (pts) with dMMR/MSI-H mCRC. Methods: Pts with dMMR/MSI-H mCRC who progressed on/were intolerant to ≥1 prior line of therapy received nivo 3 mg/kg (nivo 3) every 2 weeks (Q2W). The primary endpoint was objective response rate (ORR) per investigator (INV). The secondary endpoint was ORR per independent radiology review committee (IRRC); exploratory endpoints included safety, PFS, OS, and efficacy in biomarker-defined populations. Results: Among pts treated with nivo 3 Q2W (N = 74), 84% had received ≥2 prior lines of therapy. ORRs were 31% (INV) and 27% (IRRC); disease control rates were 69% (INV) and 62% (IRRC). The median time to response was ≈2.7 mo (INV/IRRC). PFS rates at 12 mo were 48.4% (INV) and 45.6% (IRRC). The duration of response and OS medians were not yet reached; OS rates were 83.4% (6 mo) and 73.8% (12 mo). Responses were observed in pts regardless of tumor programmed death-1 ligand 1 (PD-L1) expression level or BRAF or KRAS mutation status and were observed in pts with or without a history of Lynch syndrome (Table). Grade 3–4 treatment-related adverse events (TRAEs) occurred in 20% of pts. TRAEs leading to discontinuation included acute kidney injury, increased ALT, colitis, and stomatitis (1 each). No treatment-related deaths occurred in this arm. Conclusions: Nivo showed durable responses and disease control in heavily pretreated pts with dMMR/MSI-H mCRC. Treatment was well tolerated, with no new safety signals. Clinical trial information: NCT02060188.ORR, n/N; %Nivo 3 Q2WTumor PD-L1 expression    <1%11/45; 24%    ≥1%7/21; 33%Mutation status    BRAF mutant2/12; 17%    KRAS mutant6/26; 23%    BRAF/KRAS wild type9/28; 32%Lynch syndrome (clinical history)    Yes8/23; 35%    No6/26; 23%