HER2 PET imaging to assess HER2 heterogeneity and predict response to HER2-targeted ADC therapy in urothelial carcinoma - PROJECT ABSTRACT The management of metastatic bladder/upper tract (urothelial) cancer has been transformed over the past five years, with FDA approval of anti-PD-1/PD-L1 antibodies, an FGFR-selective kinase inhibitor, and most recently two antibody-drug conjugates (ADCs). Despite these advances, most patients with metastatic urothelial cancer still die from their disease. The HER2 receptor tyrosine kinase (encoded by the ERBB2 gene) is implicated in the pathogenesis of several cancer types, and drugs that target HER2 have an established role in the management of breast, lung, and esophagogastric cancers. While HER2 mutations and/or amplification are present in approximately 20% of metastatic urothelial cancers, older HER2-targeted antibodies and kinase inhibitors had only modest clinical activity in urothelial cancer. Unprecedented clinical activity was recently demonstrated with a new generation of HER2-directed ADCs in breast and lung cancers resistant to older HER2- targeted therapies, including HER2-low breast cancer and ERBB2-mutated lung cancer. The current proposal is based on 1) preliminary data indicating frequent mutational discordance of ERBB2 in paired primary and metastatic tumors collected from individual patients with urothelial cancer; and 2) durable responses to second- generation HER2-directed ADCs in a subset of patients with HER2-expressingurothelial cancer. We hypothesize that pre-existing HER2 expression heterogeneity will be a common mechanism of resistance to HER2-targeted ADCs in urothelial cancer and that molecular imaging can identify those patients most likely to achieve durable responses. To test this hypothesis, we will leverage a largest-of-its-kind prospective molecular characterization effort and a novel molecular imaging platform (89Zr-ss-pertuzumab PET) to define the prevalence of HER2 expression heterogeneity in urothelial cancer, its association with ERBB2 mutational status, and its impact on HER2-targeted ADC response. We will accomplish these translational objectives through three broad approaches: 1) We will perform molecular analyses of paired primary and metastatic tumors collected from patients with urothelial cancer; 2) We will explore the extent of lesion-to-lesion HER2 heterogeneity in metastatic urothelial cancer using a bespoke HER2 PET imaging platform (89Zr-ss-pertuzumab PET); and 3) We will use 89Zr-ss-pertuzumab PET and tumors collected before treatment and at the time of disease progression on HER2- targeted ADCs to study the impact of HER2 heterogeneity on the durability of response to this novel drug class. Mechanisms of HER2 ADC resistance will be functionally explored using patient-derived urothelial cancer organoid and xenograft models. Given the promising clinical activity of HER2-directed ADCs in patients with urothelial cancer, we predict that the studies proposed will directly influence the design of future clinical trials of HER2-targeted therapies for patients and establish the clinical utility of HER2 PET as a predictive biomarker of response in patients with urothelial cancer being considered for HER2-targeted therapy.
