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 undifferentiated GEC
Having received more than 1 line of prior systemic therapy for locally-advanced unresectable or metastatic disease
Having received taxanes ≤12 months prior to enrollment, prior treatment with ramucirumab, or prior treatment with tucatinib, lapatinib, neratinib, afatinib, or any other investigational anti-HER2 and/or anti-EGFR tyrosine kinase inhibitor, or with T-DM1, T-Dxd, or any other HER2-directed antibody-drug conjugate
Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy
Unable to swallow pills