Abstract OT1-15-01: SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: HER2-mutated breast cancer cohort (ongoing clinical trial)

Abstract Background: Tucatinib (TUC), approved in multiple regions for HER2+ metastatic breast cancer, is a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition. TUC is being developed as a novel therapy for patients with HER2+ metastatic breast cancer, colorectal cancer, and gastric cancer. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with TUC and trastuzumab showed superior activity to either agent alone. Somatic HER2 mutations occur in approximately 3% of breast cancers, mostly in patients with hormone receptor-positive disease and the lobular sub-type. HER2 mutations lead to enhanced tyrosine kinase activity and tumorigenesis in preclinical models and have been postulated as a mechanism of endocrine therapy resistance. The SGNTUC-019 basket study (NCT04579380) is evaluating TUC in combination with trastuzumab in patients with HER2+ or HER2-mutated solid tumors, including a cohort of patients with locally advanced unresectable or metastatic breast cancer that is HER2-mutated and not overexpressed/amplified. Trial Design: SGNTUC-019 is a multi-cohort, open-label, international Phase 2 study evaluating patients with previously treated solid tumors displaying HER2 overexpression/amplification or activating mutations. Eligible breast cancer patients must have HER2-mutated, locally advanced unresectable or metastatic disease with progression on or after ≥1 prior line of therapy (chemotherapy, endocrine or targeted therapy) in the locally advanced or metastatic disease setting. Additionally, an ECOG Performance Status of ≤1; adequate hepatic, hematological, renal, and cardiac functions; and no previous HER2-directed therapy are required for enrollment. For eligibility, HER2 mutations can be demonstrated in a previous or on-study next-generation sequencing (NGS) assay of circulating tumor DNA or a previous tissue NGS assay. The breast cancer cohort will enroll 30 response-evaluable patients with HER2-mutated disease. Patients with HER2+ (overexpression/amplification) breast cancer will not be enrolled. The primary objective in each cohort is antitumor activity. The primary endpoint is a confirmed objective response rate, and secondary endpoints are the disease control rate, duration of response, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized descriptively. For response rates, the 2-sided exact interval using the Clopper-Pearson method will be calculated. Patients will receive TUC 300 mg orally twice a day and trastuzumab 8 mg/kg intravenously on Cycle 1 Day 1 and 6 mg/kg every 21 days from Cycle 2 Day 1. Hormone receptor-positive HER2-mutated breast cancer patients will also receive fulvestrant 500 mg intramuscularly every 4 weeks and on Cycle 1 Day 15. Disease assessments per RECIST v1.1 are every 6 weeks for 24 weeks, then every 12 weeks. Patients in the breast cancer cohort will undergo baseline brain magnetic resonance imaging, and those patients with brain metastases may be eligible for the study. Quality of life will be evaluated using EQ-5D-5L every 2 cycles. Enrollment began in December 2020 and is ongoing globally. Citation Format: Alicia Okines, Paula R. Pohlmann, Jorge Ramos, Luke Walker, Erika Hamilton. SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations: HER2-mutated breast cancer cohort (ongoing clinical trial) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-15-01.