BT5528 (EphA2-targeted Bicycle Drug Conjugate delivering MMAE) + nivolumab shows 30% ORR in EphA2+ post–checkpoint mUC

BT5528 is a low–molecular weight EphA2-targeting Bicycle Drug Conjugate (BDC) linked to the microtubule toxin MMAE via a cleavable linker; here it was combined with nivolumab (anti–PD-1) in a Phase 1/2 dose-escalation study (NCT04180371) in heavily pretreated metastatic solid tumors (n=21; median 2 prior lines). As of Nov 10, 2025, the key signal was in metastatic urothelial carcinoma at BT5528 6.5mg/m² q2w + nivolumab 480mg q4w (all 14 pts): ORR was 3/10 (30%) among EphA2+ mUC with confirmed PRs, including 2/3 (67%) responses in the small EphA2+ MMAE-naïve subset; overall ORR across all tumor types/doses was 14% and clinical benefit rate was 24%. Safety looked ADC-like but relatively clean for an EphA2 program: most common TRAEs were fatigue (29%), nausea (24%), diarrhea (19%), vomiting (14%); grade ≥3 TRAEs were fatigue (10%) and ALT/AST elevation (5% each), with only grade 1/2 skin reactions (24%) and peripheral neuropathy (10%) and no hemorrhage signal—benchmarked against post–platinum/post–IO mUC where single-agent chemo or PD-1 re-challenge typically yields ~10% ORR and sacituzumab govitecan historically reported ~27% ORR in that later-line setting (not specifically post-EV).