Background: Targeting multiple immune checkpoint pathways and combining checkpoint inhibition with chemotherapy may enhance response in MSS-CRC. In a Phase 1/2, multicenter, open-label study, the anti-PD-L1 antibody durvalumab (D) was added to monalizumab (M; an anti-NKG2A antibody). In dose-exploration cohorts, D+M was added to chemotherapy and a biologic agent (bevacizumab [DMCB] or cetuximab [DMCC]) for first-line treatment of advanced/metastatic MSS-CRC. Initial data showed DMCB was well tolerated and clinically active. Here we report updated efficacy and safety of DMCB and initial safety of DMCC. Methods: Eligible patients (pts) had MSS-CRC (RAS/BRAF wt with a left-sided colon primary tumor in the DMCC cohort) and ECOG PS 0–1. They received D 1500 mg Q4W, M 750 mg Q2W, mFOLFOX6 Q2W and bevacizumab 5 mg/kg Q2W or cetuximab 250/400 mg/m² QW (up to 500 mg/m² Q2W) for up to 3 yr. The primary endpoint was safety and tolerability; secondary endpoints included antitumor activity. Results: As of Aug 26, 2019, 18 pts received DMCB and 17 pts received DMCC. Treatment-emergent adverse events (AEs) occurred in 100.0% of the DMCB cohort (most commonly fatigue, nausea and peripheral neuropathy) and 94.1% of the DMCC cohort (most commonly peripheral neuropathy, rash and dermatitis acneiform). The AEs were grade 3/4 in 77.8% of pts receiving DMCB and 70.6% of pts receiving DMCC, and were serious in 38.9% and 47.1%, respectively. Response was evaluable in 17 pts receiving DMCB; objective response rate was 41.2% (all PRs; Table). Responses occurred early and the median duration of response has not yet been reached. Conclusions: In advanced/metastatic MSS-CRC, first-line DMCB and DMCC had a manageable safety profile and DMCB showed promising preliminary activity. Clinical trial information: NCT02671435