Phase 1/2 ivonescimab PD-1×VEGF-A bispecific with Dato-DXd TROP2 ADC or osimertinib EGFR TKI

MSK is running a non-randomized, open-label Phase 1/2 trial in metastatic EGFR-activating–mutant NSCLC after prior EGFR TKI therapy, testing a fixed dose of ivonescimab (a PD-1 and VEGF-A–targeted bispecific antibody; originally developed by Akeso and partnered by Summit Therapeutics) combined with either datopotamab deruxtecan (Dato-DXd; a TROP2-directed antibody-drug conjugate delivering a topoisomerase I inhibitor payload, from AstraZeneca and Daiichi Sankyo) or osimertinib (a third-generation EGFR inhibitor from AstraZeneca). Phase 1 uses 3+3 dose escalation (two dose levels) in each cohort to identify tolerable combination dosing, then Phase 2 expands to look for anti-tumor activity. The key angle is “vertical stacking” of immune + anti-angiogenic blockade (PD-1×VEGF) on top of either an ADC with broad epithelial target expression (TROP2 is common across NSCLC) or continued EGFR suppression, aiming to improve outcomes in a setting where options after EGFR TKI progression are limited. Today’s care after progression on osimertinib commonly becomes platinum-based chemotherapy (often pemetrexed-based) ± amivantamab-based strategies when eligible, plus local therapy for oligoprogression; this explores whether adding ivonescimab can deepen or extend responses beyond those approaches.