Determinants of sensitivity to HER2-targeted antibody drug conjugates in urothelial cancer

Abstract

Abstract HER2, encoded by the ERBB2 gene, is a receptor tyrosine kinase frequently activated in human cancers via gene amplification, mutation, and/or protein overexpression. In an analysis of 42,415 prospectively analyzed solid tumors, we show that 14.5% of urothelial cancers (n = 295/2,035) have oncogenic or likely oncogenic ERBB2 alterations (6.7% ERBB2 mutation, 6.3% amplification of wildtype ERBB2 , and 1.5% concurrent mutation and amplification). Discordance of ERBB2 mutational status between primary and metastatic disease sites is common in patients with urothelial cancer as is discordance of ERBB2 mutational status between patient-derived organoid/xenograft models and the tumors from which they were derived. In patient-derived urothelial cancer models, the HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan is significantly more effective than the HER kinase inhibitor neratinib. In a real-world cohort of patients with urothelial cancer treated with trastuzumab deruxtecan, co-mutation and amplification of ERBB2 is associated with exceptional clinical response. Our data support expanded clinical trials of HER2-targeted ADCs for urothelial cancers with low HER2 expression, the clinical testing of HER2 ADCs with alternative cytotoxic payloads, and the development of functional precision oncology platforms capable of assessing payload sensitivity pre-treatment as a guide to individualized therapy selection.