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Poster

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

Background 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 (pts) with metastatic colorectal cancer (mCRC) and other GI tumors. While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC), no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy in second-line, 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. Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras for HER2+ mCRC. The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC in combination with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC in the second-line setting. Trial design MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC and Tras with Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally advanced, unresectable or metastatic HER2+ GEC and have received a HER2-directed antibody and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose-finding stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m2) combined with TUC, Tras, and Ram in 6–18 pts, and evaluate the safety and activity of the regimen in Cohorts 2A and 2B (30 pts each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ∼235 pts) vs. placebo (Arm 3B; ∼235 pts), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ∼30 pts). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment in phase 2 is ongoing in the US with sites planned in Canada and South Korea. Clinical trial identification NCT04499924. Legal entity responsible for the study The authors. Funding Sponsored by Seagen Inc. Disclosure J. Strickler: Advisory / Consultancy: AbbVie, Bayer, Pfizer; Research grant / Funding (institution): Amgen, Roche/Genentech, Seagen. Y. Nakamura: Research grant / Funding (institution): Taiho Pharmaceutical, Guardant Health, Chugai Pharmaceutical. K. Shitara: Honoraria (self): Novartis, AbbVie Inc, Yakult; Advisory / Consultancy: Astellas Pharma; Bristol-Myers Squibb; Novartis; Taiho Pharmaceutical; Merck Pharmaceutical, Eli Lilly and Company; Pfizer Inc; AbbVie Inc; GlaxoSmithKline; Amgen, Takeda Pharmaceuticals; Ono Pharmaceutical; Daiichi Sankyo; Boehringer Ingelheim; Research grant / Funding (institution): Astellas Pharma; Daiichi Sankyo; Merck Pharmaceutical; Medi Science, Ono Pharmaceutical; Taiho Pharmaceutical, Dainippon Sumitomo Pharma; Chugai Pharma; Eisai. Y. Janjigian: Advisory / Consultancy: Bristol-Myers Squibb, Merck Serono, RGENIX, Eli Lilly, Daiichi-Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks, Seattle Genetics, Basilea Pharmaceutica, AstraZeneca; Research grant / Funding (institution): NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genetech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck. H. Lenz: Honoraria (self): Bayer, Merck KG, Roche; Advisory / Consultancy: Bayer, Merck KG, Roche. E. Van Cutsem: Advisory / Consultancy: Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER); Advisory / Consultancy: Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. T. Yoshino: Honoraria (self): Bayer, Chugai, Taiho, Eli Lilly, Merck Biopharma; Research grant / Funding (institution): Daiichi Sankyo, MSD, Ono, Parexel International, Taiho, Amgen. J. Garrido-Mayor: Full / Part-time employment: Seagen Inc. M. Palanca-Wessels: Shareholder / Stockholder / Stock options: Seagen; Full / Part-time employment: Seagen. J. Marshall: Honoraria (self): Bayer, Taiho, Daiichi, Pfizer, Caris, Indivumed, Merck; Advisory / Consultancy: Caris, Indiviumed, Bayer; Speaker Bureau / Expert testimony: Merck, Bayer, Taiho, Daiichi; Leadership role: Caris, Indivumed. All other authors have declared no conflicts of interest.

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