HER2 PET imaging to assess HER2 heterogeneity and predict response to HER2-targeted therapy in biliary tract cancer

The management of metastatic biliary tract cancer (BTC) has been transformed over the past 5 years, with FDA approval of anti-PD-1/PD-L1 antibodies and several molecularly targeted therapies. Despite these advances, most patients with metastatic BTC 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, colorectal, and esophagogastric cancers. While ERBB2 amplification and/or mutations are present in up to 30% of metastatic BTCs, older HER2-targeted antibodies and kinase inhibitors had only modest clinical activity in patients with BTCs. Unprecedented clinical activity was recently demonstrated with a new generation of HER2-targeted therapies 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) durable responses to next-generation HER2-directed therapies in a subset of patients with HER2-expressing BTC; 2) preliminary data indicating frequent mutational discordance of ERBB2 and heterogeneity of HER2 expression in paired primary and metastatic tumors collected from individual patients with BTCs; and 3) loss of ERBB2 expression at progression on HER2 targeted therapies in paired samples from patients with BTCs. Based on these preliminary data, we hypothesize that pre-existing HER2 expression heterogeneity will be a common mechanism of resistance to a novel HER2-targeted bispecific antibody in BTC and that molecular imaging can identify patients with biliary tract tumors 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 BTC, its association with ERBB2 mutational status, and its impact on HER2-targeted bispecific antibody therapy 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 BTC; 2) We will explore the extent of lesion-to-lesion HER2 heterogeneity in metastatic BTC 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 bispecific antibody therapy to study the impact of HER2 genomic and expression heterogeneity on depth of response to this novel drug class. Mechanisms of HER2-targeted therapy resistance will be functionally explored using patient-derived BTC organoid and xenograft models. Given the promising clinical activity of novel HER2-directed therapies in patients with BTC, we predict that the studies proposed will directly influence the design of future clinical trials of HER2- targeted therapies and establish the clinical utility of HER2 PET as a predictive biomarker of response in patients. Project Number: 1R01CA309345-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: James Harding (+2 co-PIs) | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $715,002 | Activity Code: R01 | Study Section: Clinical Translational Imaging Science Study Section[CTIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11275885