Diverse ERBB2/ERBB3 Activating Alterations and Coalterations Have Implications for HER2/3-Targeted Therapies across Solid Tumors.

abstractAlthough ERBB2 (HER2) is an established oncogenic driver and therapeutic biomarker in several cancers, current drug approvals do not reflect the diverse spectrum of activating alterations across indications in which HER2-targeted therapies may yield clinical benefit. In most cancer types, HER2 status is defined by HER2 overexpression/amplification assessed by IHC and FISH, which do not provide genomic context. We sought to define the pan-tumor landscape of activating ERBB2 and ERBB3 genomic alterations detected by comprehensive genomic profiling (CGP). We queried institutional databases of solid tumor CGP, including 429,666 patients who underwent Foundation Medicine testing and 83,332 patients whose tumors were profiled using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). We identified activating ERBB2 and ERBB3 alterations across solid tumor types, including many off-label for current HER2 drug approvals. Whereas non–small cell lung cancer represented the highest proportion of ERBB2-mutated (i.e., single-nucleotide variants and short insertions/deletions) cancers (19.0%), breast, colorectal, bladder, and gastroesophageal cancers combined accounted for 50.4% of ERBB2-mutated tumors. Within non–small cell lung cancer, 26% of activating mutations were not included in clinical trials that led to approval of the antibody–drug conjugate trastuzumab deruxtecan. We also present three clinical cases demonstrating clinical benefit from off-label use of HER2-targeted therapies. We identified substantial populations of patients with diverse ERBB2/ERBB3 activating alterations, which represent unmet therapeutic needs. We demonstrate that CGP provides additional genomic information, inclusive of ERBB2 amplification and mutation status together with potential resistance/response-modifying co-alterations, allowing for more nuanced HER2 status interpretation than is possible with IHC/FISH alone. SIGNIFICANCE: CGP provides genomic context for HER2 status beyond the information provided by IHC and FISH, including detection of ERBB2 mutations and co-alterations that may suggest sensitivity/resistance to HER2-directed therapies, and is therefore crucial for guiding treatment choice and understanding individual patient response.