Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved in combination with trastuzumab (Tras) and capecitabine (Cape) for HER2 overexpressed/amplified (HER2+) metastatic breast cancer (BC), based on a statistically significant and clinically meaningful PFS, OS, and ORR benefit over Tras and Cape. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. While various HER2-directed agents have been evaluated in HER2+ and HER2-mut tumors, there are no approved HER2 therapies outside of breast and gastric cancers. The SGNTUC-019 basket study is evaluating TUC combined with Tras in patients (pts) with HER2+ or HER2-mut locally-advanced unresectable or metastatic solid tumors. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase 2 study. Eligible pts must have progressed on or after the last systemic therapy for advanced disease. Metastatic cervical cancer: must have received platinum-based chemotherapy ± bevacizumab; hormone receptor positive (HR+) HER2-mut BC: must have received a prior CDK4/6 inhibitor. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulation, and cardiac function, and no prior HER2-directed therapy (except Tras for uterine serous carcinoma). For eligibility, HER2 alterations can be demonstrated by HER2+ in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts with HER2+ disease will be enrolled in cohorts for cervical, uterine, biliary tract, and urothelial cancers, non-squamous NSCLC, and other solid tumors (except GEC, BC, and CRC). Pts with HER2-mut disease will be enrolled in cohorts for non-squamous NSCLC, BC, and other solid tumors. Except for solid tumor and BC cohorts, 12 RECIST 1.1 evaluable pts will be enrolled in each cohort. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Other solid tumor and BC cohorts will enroll 30 pts in a single stage. If justified, additional HER2+ or HER2-mut disease-specific cohorts may be opened. Approximately 162-270 pts are planned. The primary objective is antitumor activity in each cohort, with confirmed ORR per investigator as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. HR+ BC pts will also receive fulvestrant 500 mg IM every 4 weeks and C1 D15. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. TUC PK will be evaluated in all pts in Cycles 2-6. QoL is evaluated q2 cycle using EQ-5D-5L. Sites are open in the US; EU and Asia will be opened. Enrollment began in Dec 2020. Clinical trial information: NCT04579380