72P Exploratory biomarker analysis from a phase Ib/II trial of zanidatamab (zani) + evorpacept (evo) in patients (pts) with HER2+ metastatic breast cancer (mBC)

Background: Zani (dual HER2-targeted bispecific antibody) + evo (CD47 inhibitor) showed promising antitumor activity and manageable safety in pts with heavily pretreated HER2+ mBC post-T-DXd.We sought to identify biomarkers of response to zani + evo.Methods: Pts with HER2+ mBC, locally assessed with retrospective central confirmation (ccHER2+), received zani (1200 mg [<70 kg]/1600 mg [70 kg]) + evo (20 mg/kg or 30 mg/kg) every 2 wks in 28-day cycles.Analyses included CD47 expression by IHC at baseline and change in total ctDNA, ERBB2 copy number (CN), and tumor alterations by ctDNA NGS from cycle (C) 1 day (D) 1 to C2D15.Results: 24 HER2+ pts were included, and 10 were ccHER2+.Greater antitumor activity was observed in pts with ccHER2+ mBC (cORR: 6/10; 60%) than overall (cORR: 8/24; 33%) with zani + evo.CD47 expression was evaluable in 17 pts, and moderatehigh expression was observed in 5/7 responders (CR/PR) vs 1/10 pts with SD/PD.Of the 17 pts, 9 were ccHER2+, and moderate-high CD47 expression was seen in 5/6 responders vs 0/3 with SD/PD.ctDNA was analyzed in 17 pts; 10 were ERBB2amplified at C1D1 by ctDNA despite prior T-DXd.ERBB2 amplification by ccFISH showed 86% (6/7) concordance with ctDNA.In responders, ERBB2 CN and total ctDNA were undetectable at C2D15.Pts with SD/PD had variable CN reductions and changes in ctDNA levels (20%-175%).At C1D1, 4/5 responders had fewer than 3 alterations in the RTK, RAS/MAPK, and PI3K/AKT pathways, and 10/12 pts with SD/ PD had >3 alterations.Most alterations were undetectable at C2D15 in responders but persisted in pts with SD/PD.Additional analysis to be reported. Conclusions:Responses to zani + evo with ccHER2+ mBC were largely restricted to pts with higher CD47 expression, supporting a CD47-dependent, HER2-driven biology.Most ccHER2+ pts remained ERBB2-amplified post-T-DXd, supporting use of HER2-targeted therapy, including zani, after progression.Also, on-treatment ERBB2 CN and ctDNA reductions and fewer alterations in RTK signaling pathways support HER2-driven signaling with minimal compensatory pathway activation.A biomarkerdriven approach incorporating CD47 may optimize pt selection for this combination regimen and warrants further study.