ADVERTISEMENT
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 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.
Trial design
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.
Clinical trial identification
NCT04499924.
Editorial acknowledgement
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.
Legal entity responsible for the study
Seagen Inc.
Funding
Seagen Inc.
Disclosures
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: scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc. J. Strickler: Advisory / Consultancy: Seagen, 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): Takeda, Bristol-Myers Squibb; Advisory / Consultancy: Eli Lilly and Company; Bristol Myers Squibb; Takeda; Pfizer, Ono Pharmaceutical; Merck Pharmaceutical; Taiho Pharmaceutical; Novartis, AbbVie; GlaxoSmithKline; Daiichi Sankyo; Amgen; Boehringer Ingelheim; Janssen; Research grant / Funding (institution): Astellas; Ono Pharmaceutical; Daiichi Sankyo; Taiho Pharmaceutical; Chugai; Merck Pharmaceutical, Medi Science; Eisai; Amgen. Y. Janjigian: Advisory / Consultancy: Bristol-Myers Squibb, Merck Serono, RGENIX, Eli Lilly, Daiichi-Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks, Seagen, Basilea Pharmaceutica, AstraZeneca, Michael J. Hennessy Associates, Paradigm Medical Communications; Research grant / Funding (institution): NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genetech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck; Shareholder / Stockholder / Stock options: RGENIX. T. Bekaii-Saab: Honoraria (self): Royalties: Uptodate; Advisory / Consultancy: Consulting (to institution): Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai and Merck. , Consulting (to self): Stemline, AbbVie, Boehringer Ingelheim, Janssen, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, MJH Life Sciences, Aptitude Health, Illumina and Foundation Medicine, IDMC/DSMB: Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan and 1Globe. ; Research grant / Funding (institution): Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS.; Licensing / Royalties: WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF – Licensed to Imugene, WO/2019/055687: METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA – Licensed to Recursion. H. Lenz: Honoraria (self): BMS, Bayer, Roche ; Advisory / Consultancy: Bayer, Merck, Roche; Travel / Accommodation / Expenses: BMS, Bayer, Merck KG; Shareholder / Stockholder / Stock options: Fulgent . T. Yoshino: Honoraria (self): Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical and MSD; Research grant / Funding (institution): Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex, Chugai Pharmaceutical and Nippon Boehringer Ingelheim. J. Garrido-Mayor: Shareholder / Stockholder / Stock options: Seagen Inc.; Full / Part-time employment: Seagen Inc. M. Ubowski: Shareholder / Stockholder / Stock options: Seagen Inc.; Full / Part-time employment: Seagen Inc. J. Marshall: Honoraria (self): Bayer, Taiho, Daiichi, Pfizer, Caris, Indivumed, Merck, AZ; Advisory / Consultancy: Caris, Indiviumed, Bayer; Speaker Bureau / Expert testimony: Merck, Bayer, Taiho, Daiichi, Pfizer; Leadership role: Caris, Indivumed. All other authors have declared no conflicts of interest.
