Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer

Inclusion Criteria: * Histologically or cytologically confirmed diagnosis of locally-advanced unresectable or metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC) * HER2+ disease documented since progression of the most recent line of systemic therapy, as follows: * Phase 2 paclitaxel dose optimization stage: * HER2 amplification in a blood-based NGS assay performed at a central laboratory, or * HER2 overexpression/amplification immunohistochemistry (IHC) and in situ hybridization (ISH) (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample * Phase 2 dose expansion stage: * Cohort 2A: HER2 amplification in a blood-based NGS assay performed at a central laboratory * Cohort 2B: No HER2 amplification by blood-based NGS assay, but HER2 overexpression/amplification by IHC and ISH (IHC3+ or IHC2+/ISH+) assay of a tumor tissue sample * Phase 3: HER2 amplification in a blood-based NGS assay performed at a central laboratory * History of prior treatment with a HER2-directed antibody * Progressive disease during or after first-line therapy for locally-advanced unresectable or metastatic GEC * Phase 2: Measurable disease according to RECIST version 1.1 * Phase 3: Measurable or non-measurable disease according to RECIST version 1.1 * Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 * Life expectancy of at least 3 months, in the opinion of the investigator Exclusion Criteria: * Subjects with squamous cell or undif…