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

Prior treatment

• Having received more than 1 line of prior systemic therapy for locally-advanced unresectable or metastatic disease
• Phase 2 paclitaxel dose optimization stage only: history of prior partial or total gastrectomy

Lab values

• 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

Other

• Subjects with squamous cell or undifferentiated GEC
• Unable to swallow pills

• 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