Tucatinib and trastuzumab in HER2-mutated metastatic breast cancer: a phase 2 basket trial
Alicia F C Okines1, Giuseppe Curigliano2,3, Nobumasa Mizuno4
1The Royal Marsden NHS Foundation Trust, London, UK.
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 .
Insights
Tucatinib and trastuzumab demonstrated significant antitumor activity in heavily pretreated patients with HER2-mutated breast cancer. This chemotherapy-free regimen showed durable responses and good tolerability, supporting further HER2-targeted therapy research.
Area of Science:
- Oncology
- Medical Genetics
- Pharmacology
Background:
- Human epidermal growth factor receptor 2 (HER2) signaling is crucial for cell growth and is implicated in various cancers.
- HER2-targeted therapies are approved for HER2-overexpressing tumors, but their efficacy in HER2-mutated cancers remains under-investigated.
- HER2 mutations represent a distinct molecular subset with potential therapeutic vulnerabilities.
Purpose of the Study:
- To evaluate the efficacy and safety of tucatinib plus trastuzumab in patients with HER2-mutated solid tumors.
- To assess the overall response rate (ORR) as the primary endpoint in a cohort of heavily pretreated HER2-mutated metastatic breast cancer patients.
- To explore secondary endpoints including duration of response (DoR) and progression-free survival (PFS).
Main Methods:
- An open-label, phase 2 basket study (SGNTUC-019) was conducted.
- 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer received tucatinib and trastuzumab.
- Hormone receptor-positive patients also received fulvestrant.
Main Results:
- The ORR was 41.9% (90% CI: 26.9-58.2), indicating significant clinical activity.
- Median DoR was 12.6 months (90% CI: 4.7 to NE) and median PFS was 9.5 months (90% CI: 5.4-13.8).
- Responses were observed across diverse HER2 mutations, and no new safety signals were identified.
Conclusions:
- The combination of tucatinib and trastuzumab demonstrated clinically meaningful antitumor activity and durable responses in heavily pretreated patients with HER2 mutations.
- This chemotherapy-free regimen exhibited favorable tolerability, supporting its potential in this patient population.
- Further investigation of HER2-targeted therapies in HER2-mutated solid tumors is warranted based on these findings.
