P-156 MOUNTAINEER-02: Phase 2/3 study of tucatinib, trastuzumab, ramucirumab, and paclitaxel in previously treated HER2+ gastric or gastroesophageal junction adenocarcinoma: Trial in progress

Abstract

Tucatinib (TUC), a highly selective HER2-directed tyrosine kinase inhibitor (TKI) approved in multiple regions for HER2+ metastatic breast cancer, is being developed as a novel therapy for patients with GI tumors including gastric or gastroesophageal junction adenocarcinoma (GEC). While trastuzumab (Tras) with chemotherapy is standard in the first-line setting for metastatic HER2+ GEC, no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy as second-line therapy, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. (Kulukian 2020) Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras for HER2+ mCRC.(Strickler 2019) The MOUNTAINEER-02 study (NCT04499924) is evaluating the efficacy and safety of TUC with Tras, ramucirumab (Ram), and paclitaxel (Pac) in patients with HER2+ GEC in the second-line setting. MOUNTAINEER-02 is a phase 2/3 study evaluating TUC + Tras with Ram and Pac. Eligible patients have locally-advanced unresectable or metastatic HER2+ GEC and have received a HER2-directed antibody and 1 prior line of therapy for advanced disease. Patients are ≥18 years of age; have an ECOG ≤1; and have had no prior exposure to Ram, an anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Patients receive TUC 300 mg or placebo PO BID and Tras or placebo (IV on Days 1 and 15 of each 28-day cycle) in combination with Pac (IV on Days 1, 8, and 15) and Ram (IV on Days 1 and 15). The study includes an initial Pac-dose optimization stage because of the potential impact of TUC on Pac metabolism. The open-label phase 2 part determines the recommended dose of Pac (60 or 80 mg/m2) combined with TUC, Tras, and Ram in 6–18 patients and evaluates safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part compares the efficacy and safety of TUC and Tras (Arm 3A, ∼235 patients) vs placebo (Arm 3B, ∼235 patients), both in combination with Ram and Pac, and evaluates activity of TUC with Ram and Pac (Arm 3C, ∼30 patients). The coprimary phase 3 endpoints are OS and PFS per investigator, and secondary endpoints include DOR, confirmed ORR, and DCR. Secondary objectives include patient-reported outcomes. HER2 status is determined by blood-based NGS assay or IHC/ISH assay of a tumor tissue sample (IHC3+ or IHC2+/ISH+) at screening. In Cohort 2A and phase 3, patients must be HER2+ by blood-based NGS. In Cohort 2B, patients must be HER2+ by biopsy but HER2 negative by blood-based NGS after progression in first-line or subsequent therapy. Disease assessments per RECIST v1.1 occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites are evaluated in a subset of patients, including a cohort with gastrectomies. Enrollment in phase 2 is ongoing. NCT04499924. The authors thank Joseph Giaconia of MMS Holdings, Michigan, USA for providing medical writing support/editorial support, which was funded by Seagen Inc., Bothell, WA, USA in accordance with Good Publication Practice (GPP3) guidelines. Seagen Inc.