Abstract
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380 .