Approved treatments for 3rd-line mCRC are limited and outcomes remain poor. Trifluridine/tipiracil (TT) is a standard of care option for patients previously treated/not considered candidates for available therapies. Futuximab/modotuximab (FuMo) is a biological composed of a 1:1 mixture of two monoclonal antibodies, futuximab and modotuximab, that bind to non-overlapping epitopes on the extracellular domain (ECD) of EGFR. FuMo has demonstrated activity in RAS/BRAF wt mCRC EGFR-pretreated patients in the Sym004-05 phase II study. Anti-EGFR Mabs have been safely combined with TT. COLSTAR (NCT05223673) is a randomized, open-label, phase III study comparing FuMo + TT with TT alone with a safety lead-in (SLI) part. Main eligibility criteria include KRAS/NRAS (exons 2, 3 and 4) and BRAF wt (V600E mutation) (double negative; DN) assessed by centralized analysis of ctDNA at screening, and previous treatment with at least 2 regimens including fluoropyrimidine, irinotecan, oxaliplatin, at least one anti-VEGF (bevacizumab, aflibercept, ramucirumab, regorafenib) and at least one anti-EGFR mAb (cetuximab or panitumumab) for ≥4 months. Randomization will be done in a 1:1 ratio to TT (35 mg/m2 BID on days 1-5 and days 8-12 of a 28-day cycle) or to the same dose of TT + FuMo (9 mg/kg loading dose on day 1 of cycle 1 followed by 6 mg/kg weekly). Stratification will be done according to performance status (ECOG 0 vs 1), previous regimens of treatment (2 vs ≥3), and EGFR ECD mutations (presence vs absence). Approximately 25 patients will be enrolled in the SLI part and 500 in the randomized part of the study. Primary objectives are: safety and tolerability of FuMo + TT according to CTCAE v5.0 (part 1) and superiority of the combination in terms of OS in the DN population (part 2). The key secondary endpoint is OS in the triple-negative (KRAS/NRAS, BRAF, and EGFR-ECD wt) population (part 2). A group sequential design with 3 interim analyses (IA) will allow to stop the trial prematurely for futility at each IA as well as for efficacy at last IA. NCT05223673. Institut de Recherches Internationales Servier.