TPS278 Background: The standard of care (SoC) for first-line management of non-microsatellite instability-high/deficient mismatch repair (non-MSI-H/dMMR; also referred to as microsatellite-stable/proficient MMR) mCRC includes systemic chemotherapy and targeted agents that improve overall survival (OS). However, in patients (pts) with later-line disease, current SoC treatments (including regorafenib and TAS-102) are associated with poor responses (objective response rates ORR < 2%) that are not durable, limited OS (6.4-7.1 months) and substantial toxicity. Immunotherapies targeting programmed death (PD)-1 show promising efficacy in pts with MSI-H mCRC; however, single-agent immunotherapy does not provide benefit for pts with non-MSI-H/dMMR mCRC. Therefore, additional treatment options with an improved benefit-risk profile in pts with later-line non-MSI-H/dMMR mCRC are needed. Emerging data suggest that dual inhibition of LAG-3 and PD-1 has the potential to boost immune surveillance and elicit durable responses in non-MSI-H/dMMR mCRC. RELA is a human immunoglobulin G4 lymphocyte-activation gene 3 (LAG-3)-blocking antibody that enhances the antitumor immune response. Here we describe the RELATIVITY-123 study investigating NIVO + RELA FDC in later-line mCRC. Methods: RELATIVITY-123 (NCT05328908) is a phase 3, randomized (1:1), open-label study to assess NIVO + RELA FDC versus regorafenib or TAS-102 in adult pts with later lines of non-MSI-H/dMMR mCRC. Inclusion criteria include metastatic or recurrent unresectable CRC, recent progression following 1–4 prior lines of treatment (or documented intolerance of prior systemic chemotherapy regimens), ECOG performance status ≤ 1, and measurable disease per RECIST version (v) 1.1. Exclusion criteria include confirmed MSI-H/deficient mismatch repair, prior treatment with an immunotherapy, regorafenib, or TAS-102 and history of significant cardiovascular disease, interstitial lung disease/pneumonitis, or autoimmune disease. Dual primary endpoints are OS in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. Secondary endpoints include ORR, progression-free survival, and duration of response by blinded independent central review and investigator per RECIST v1.1, safety, and time until definitive deterioration-physical function and -quality of life in all randomized pts and in randomized pts with PD-L1 CPS ≥ 1. The study initiated in April 2022 and is enrolling globally. Clinical trial information: NCT05328908 .