Project Summary Resistance to the standard of care treatments contributes to mortality in patients with metastatic triple negative breast cancer (TNBC) or non-small cell lung cancer (NSCLC). In metastatic TNBC, the epidermal growth factor receptor (EGFR) and cytoplasmic mesenchymal-epithelial transition (cMET) receptor are both overexpressed in the basal-like subtype of TNBC. Metastatic NSCLC often harbors mutations in the epidermal growth factor receptor (EGFR), in which patients can develop resistance to EGFR tyrosine kinase inhibitors (TKI). MET gene amplification is also a resistance mechanism for EGFR TKIs. To overcome resistance to EGFR TKI, a bispecific antibody called JNJ-61186372 (BsAb) was developed that targets both EGFR and cMET receptors simultaneously, inhibiting receptor-ligand activation and degrading these receptors upon internalization of the bsAb. Currently, there are no effective methods to predict and monitor response to bsAb, making it difficult to select patients most likely to respond to this new therapy in a clinical trial setting and save those unlikely to respond from undue drug exposure. We aim to develop PET imaging biomarkers to look at the multifaceted response to bsAb therapy: bsAb delivery to the tumor (Aim 1) and changes in individual receptor status in vivo (Aim 2). Through correlative studies among PET imaging, response to bsAb therapy, and known genetic mutation status in EGFR, we will produce the right PET imaging toolkit to understand the mechanisms of action of bsAb in vivo. Our techniques can complement standard of care analysis of EGFR mutation status to select patients most likely to respond to bsAb therapy and monitor response to treatment. This future goal will require an IND, for which our studies will provide proof-of-feasibility in preclinical models. Ultimately, establishing our imaging techniques as companion diagnostic agents could have high impact in accelerating FDA-approval of bsAb for the treatment of patients with NSCLC or TNBC who have developed resistance to standard of care of treatments.