Zanidatamab + Evorpacept Delivers 56% ORR in Centrally-Confirmed HER2-Positive mBC After T-DXd

Zanidatamab is a bispecific antibody that dimerizes HER2 receptors and triggers ADCC/ADCP, while evorpacept is a “silent-Fc” CD47 blocker that augments macrophage phagocytosis. In the open-label phase 1b/2 trial NCT05027139, 21 heavily pre-treated HER2-positive and 15 HER2-low metastatic breast-cancer patients received zanidatamab 1.2–1.6 g plus evorpacept 30 mg kg every 2 weeks (median six prior regimens; all HER2-positive patients and one-third of HER2-low patients had failed trastuzumab deruxtecan). In the HER2-positive cohort treated at the recommended dose (n = 19), confirmed ORR reached 37% overall and 56% (5/9) when central HER2 testing verified IHC 3+ or ISH-positive disease; disease-control was 74%. Median response duration has not yet been reached (range 2–22 mo). HER2-low tumors showed a 20% ORR and 40% disease control. Grade 3 treatment-related events were limited to diarrhea (6%) and infusion reactions (4%); no grade 4–5 toxicities or drug-related pneumonitis were reported. By comparison, tucatinib-trastuzumab-capecitabine produces a 40% ORR with median PFS ~7.6 mo in a similar post-T-DM1 setting.

https://aacrjournals.org/clincancerres/article/31/12_Supplement/PS8-09/753445/Abstract-PS8-09-Zanidatamab-in-combination-with