Jaclyn Frances Hechtman

Early change in tumor-matched maxVAF in patients who received induction trastuzumab and pembrolizumab stratified by 6 month PFS (n=16 evaluable).

Plasma ctDNA Alterations by Source.

Univariable Cox Proportional Hazard for PFS in HER2-targeted retrospective cohort.

Baseline biopsies from a patient demonstrating significant intra-patient heterogeneity with diffusely HER2+ and PD-L1– primary tumor and HER2– but PD-L1 CPS 100 retroperitoneal lymph node with neuroendocrine differentiation.

Survival and response in patients receiving trastuzumab/chemotherapy + PD-1 inhibition on- or off-protocol (n=66). a, Progression-free survival and objective response rate by cohort. b, Overall survival by cohort.

Pembrolizumab/Trastuzumab/Chemotherapy Protocol Patient Demographics

Consort diagram of HER2-directed therapy patient cohorts.

Lesions without pre-treatment ERBB2 amplification appear less likely to respond to pembrolizumab and trastuzumab induction. Lesion-level CT response after 1 dose of pembrolizumab and trastuzumab among patients with baseline tumor-matched ctDNA color-coded according to pre-treatment a, ctDNA ERBB2 amplification status and b, tissue WES ERBB2 amplification status.

HER2 heterogeneity and RTK alterations are more frequent among patients with shorter PFS. HER2 testing and tissue/plasma ctDNA NGS upon progression demonstrate that 8 of 16 (50%) of patients had HER2 negative tumors post-treatment, and 2 ERBB2 amplified tumors pre-treatment were non-amplified post-treatment. Additionally, frequent alterations in PI3K, cell cycle proteins, Ras-Raf, EGFR, FGFR1/2, and MET were found upon progression, and potentially associated with treatment resistance.

Genes with Oncogenic Alterations Identified by MSK-IMPACT with Frequency > 5%.