A phase 2 trial (CheckMate 9X8) evaluated the addition of nivolumab to standard-of-care (SOC) therapy (FOLFOX6 plus bevacizumab) in first-line treatment of metastatic colorectal cancer (mCRC). Patients were randomized 2:1 to receive nivolumab plus SOC or SOC alone. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR), which did not meet the prespecified threshold for statistical significance. Median PFS was 11.9 months in both arms, with no significant difference. However, nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher objective response rate (ORR), and more durable responses compared to SOC. Grade 3–4 treatment-related adverse events were more common in the nivolumab plus SOC group (75% vs 48%). Subgroup analyses showed numerically higher PFS in patients with certain biomarkers, such as those with KRAS G12D/V/C mutations. However, the study did not meet its primary endpoint, and further investigation is needed to identify subgroups that may benefit from nivolumab plus SOC. The trial also found that the addition of nivolumab to SOC did not improve overall survival (OS) compared to SOC alone. The median OS was 29.2 months in the nivolumab plus SOC group and not reached in the SOC group. The safety profile of nivolumab plus SOC was consistent with known safety profiles of the chemotherapy and immunotherapy components, with no new safety signals identified. The trial explored biomarkers that may segment mCRC by expected response to therapy, but the results were limited by the small number of patients and the potential confounding effect of KRAS mutations. The study highlights the need for further research to identify subgroups that may benefit from nivolumab plus SOC in the first-line setting.A phase 2 trial (CheckMate 9X8) evaluated the addition of nivolumab to standard-of-care (SOC) therapy (FOLFOX6 plus bevacizumab) in first-line treatment of metastatic colorectal cancer (mCRC). Patients were randomized 2:1 to receive nivolumab plus SOC or SOC alone. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR), which did not meet the prespecified threshold for statistical significance. Median PFS was 11.9 months in both arms, with no significant difference. However, nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher objective response rate (ORR), and more durable responses compared to SOC. Grade 3–4 treatment-related adverse events were more common in the nivolumab plus SOC group (75% vs 48%). Subgroup analyses showed numerically higher PFS in patients with certain biomarkers, such as those with KRAS G12D/V/C mutations. However, the study did not meet its primary endpoint, and further investigation is needed to identify subgroups that may benefit from nivolumab plus SOC. The trial also found that the addition of nivolumab to SOC did not improve overall survival (OS) compared to SOC alone. The median OS was 29.2 months in the nivolumab plus SOC group and not reached in the SOC group. The safety profile of nivolumab plus SOC was consistent with known safety profiles of the chemotherapy and immunotherapy components, with no new safety signals identified. The trial explored biomarkers that may segment mCRC by expected response to therapy, but the results were limited by the small number of patients and the potential confounding effect of KRAS mutations. The study highlights the need for further research to identify subgroups that may benefit from nivolumab plus SOC in the first-line setting.