3554 Background: Lymphocyte-activation gene 3 (LAG-3) is an immunosuppressive signal, impairing T effector (Teff) activation. Pre-clinical studies suggest LAG-3 inhibition promotes anti-tumor immunity by enhancing Teff function. Correlative studies linked increased LAG-3 levels with reduced overall survival (OS) in CRC. These data prompted optimism that combined LAG-3/PD-1 inhibition might promote anti-tumor responses in MSS CRC. Methods: We conducted a phase 2 study of nivolumab (Nivo) (aPD1)/relatlimab (Rela) (aLAG3) in patients with previously treated advanced MSS CRC. This study enrolled patients onto 1 of 3 arms. Arms A and B used a Composite PD-L1 and acellular Mucin (CPM) score to define patients as CPM(+) in Arm A (CPM≥ 15%) and CPM(-) in Arm B (CPM< 15%). Patients in Arm A and B received Nivo 480mg/Rela 160mg IV q4 weeks. Arm C enrolled patients without biomarker selection who received Nivo 480mg/Rela 960mg or Rela 480mg/Nivo 480mg. The primary endpoint was objective response, and each arm was powered to detect an objective response rate (ORR) of ≥20%. Results: Fifty nine evaluable patients were enrolled (Arm A: 12, Arm B: 15, Arm C: 32). Patient characteristics and responses are outlined. Treatment was well tolerated with no new safety signals over aPD1 alone. Three (5%) patients achieved a partial response (PR), 6 (10%) stable disease (SD), and 50 with progression of disease (PD) as best response. The median progression-free survival was (Arm A: 2.2 mo., Arm B: 2.8 mo., Arm C: 2.6 mo.) while median OS was (Arm A: 4.3 mo., Arm B: 14.2 mo., Arm C: 12.4 mo.). In N=6 patients with lung-only metastases, 2 (33%) experienced a PR, and 1 (17%) a SD, for a clinical benefit rate of 50%. The trial incorporated translational correlates. We will report mass cytometry on PBMCs, RNAseq on baseline biopsies, and imaging mass cytometry on pre- and on-treatment biopsies. Conclusions: This combination did not meet the primary endpoint of 20% ORR for any of the 3 cohorts, but there was intriguing possible activity in patients with lung only metastases, consistent with emerging data. Clinical trial information: NCT03642067 .