Ozekibart (INBRX-109) DR5 agonist + FOLFIRI delivers 23% ORR in 4L+ metastatic CRC

Ozekibart (INBRX-109) is a next-generation tetravalent death receptor 5 (DR5) agonist designed to induce tumor cell apoptosis; here it was combined with FOLFIRI in an open-label Phase 1 expansion cohort (C4d; NCT03715933) for locally advanced/metastatic, unresectable colorectal adenocarcinoma after 2–3 prior systemic lines (44 treated; 26 response-evaluable; >70% treated in 4th line; 81.8% prior irinotecan). At the October 15, 2025 cutoff, ORR was 23% (all PRs) with 92% disease control; 63.6% remained on treatment, with 1 AE-related discontinuation and 11 progressions. Safety looked broadly “FOLFIRI-like” (anemia 36.4% any-grade/9.1% G3+, diarrhea 34.1%/9.1%, nausea 31.8%/0%, fatigue 27.3%/2.3%), with grade ≥3 hepatotoxicity limited to 1 case of ALT increase—worth noting given the DR5 class history; efficacy appears well above typical late-line SOC ORRs of ~1% with regorafenib and ~1.6% with trifluridine/tipiracil (TAS-102) in refractory mCRC.