SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations—Biliary tract cancer cohort.

TPS489 Background: Tucatinib (TUC), a highly selective HER2-directed TKI approved in multiple regions for HER2+ metastatic breast cancer, is being investigated as a novel therapy for patients (pts) with metastatic colorectal cancer, gastric cancer, and other GI tumors. Preclinical and clinical data have shown HER2-targeted agents may improve clinical outcomes. In xenograft models of HER2+ and HER2-mutated tumors, dual targeting of HER2 with TUC + trastuzumab (Tras) showed superior activity to either agent alone (Kulukian 2020). Interim results from the MOUNTAINEER study have shown promising activity for TUC + Tras in HER2+ colorectal cancer. In 23 response-evaluable pts, an objective response rate (ORR) of 52% was observed with a median progression-free survival (PFS) of 8.1 months (mo) (Strickler 2019). The prognosis for pts with biliary tract cancers (BTCs) remain poor, and treatment options are limited. Given that approximately 12%-15% of BTC pts are HER2+, and 1%-8% have HER2 mutations, TUC + Tras warrants further evaluation in this patient population. The SGNTUC-019 basket study (NCT04579380) is evaluating TUC + Tras in pts with previously treated, locally advanced, unresectable or metastatic solid tumors including BTC that display HER2 overexpression/amplification or activating mutations. We describe the design of the BTC cohort. Methods: SGNTUC-019 is a multi-cohort, open-label, international Phase 2 study. Pts must be ≥18 years old; have an ECOG PS of ≤1; have adequate hepatic, hematological, renal, and cardiac functions; and have no previous exposure to HER2-directed therapy. BTC pts must have progressed on or after ≥1 previous line of treatment. The HER2+ BTC cohort will enroll 12 response-evaluable pts. If >2 responses are observed, the cohort will be expanded to 30 pts. HER2-mutated BTC patients may also be enrolled in a 30 pts cohort for other HER2-mutated solid tumors. The primary objective is antitumor activity with confirmed ORR as the primary endpoint. Secondary efficacy endpoints include disease control rate, duration of response, PFS, and OS. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH, or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts will receive TUC 300 mg orally twice a day and Tras 8 mg/kg intravenously on Cycle 1 Day 1 then 6 mg/kg every 21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 are every 6 weeks for the first 24 weeks, then every 12 weeks. Quality of life will be evaluated every 2 cycles using EQ-5D-5L. Sites are currently enrolling within the US, EU and Asia-Pacific. Clinical trial information: NCT04579380.