Background: Trifluridine/tipiracil (FTD/TPI) is approved for use in patients (pts) with pretreated mCRC. In vivo studies have shown an increase in anti-tumor activity when combining FTD/TPI, oxaliplatin or bevacizumab, and an increase in tumor immunogenicity after treatment with FTD/TPI and oxaliplatin (Ghiringhelli, 2018). The recommended dose for expansion had been defined as FTD/TPI 35 mg/m² bid, days 1–5 q14, together with oxaliplatin 85 mg/m² (day 1). Methods: In addition to FTD/TPI and oxaliplatin, eligible pts received bevacizumab 5 mg/kg (Cohort A) or nivolumab 3 mg/kg (Cohort B) on day 1. Eligibility criteria included measurable disease, performance status (PS) 0-1, normal organ function, progression after > 1 prior anti-tumor therapy (excluding oxaliplatin), and confirmed MSS status (Cohort B). A Bayesian design was used for futility and efficacy assessments. Efficacy endpoints of objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and adverse events (AEs) were assessed for each cohort; biomarkers of immune function including PD-L1 expression for Cohort B. Results: A total of 37 and 17 pts were enrolled in Cohorts A and B respectively; with a median age of 64 years (range 33 to 83 years), 61% and 39% had an PS of 0 and 1. At baseline, no pt showed PD-L1 expression on tumor cells, and only 1 pt on immune cells (5% threshold). At data cutoff, 32 and 12 pts were evaluable for response in Cohorts A and B. In Cohort A, ORR was 13% (1 CR; 3 PR), and DCR was 91%. The mPFS was 6.9 months (95% IC, 4.3-9.3). In Cohort B, ORR was 8% (1 PR), DCR was 67%. The mPFS was 6.5 months (95% IC, 1.8-8.6). Overall, the most common treatment-related AEs (≥20% of pts) included neutropenia, nausea, diarrhoea, and fatigue; only 1 pt reported grade 3 febrile neutropenia; 5 pts discontinued due to AEs and no treatment-related death were reported. Conclusions: In this study, bevacizumab in addition to FTD/TPI and oxaliplatin showed antitumor activity. The cohort of nivolumab was prematurely discontinued due to lack of efficacy. Both cohorts showed an acceptable safety profile in pretreated mCRC pts. Clinical trial information: NCT02848443