Abstract 523TiP
Background
HER2 is a validated target in breast and gastric cancers, with monoclonal antibodies (mAB) and small-molecule tyrosine kinase inhibitors (TKI) approved for breast cancer and mAB for gastric cancer. There is interest in exploring HER2-targeting strategies for patients (pts) with metastatic colorectal cancer (mCRC), where amplification occurs in ∼3-5% of pts. Tucatinib (TUC), recently approved in the US for HER2+ metastatic breast cancer, is an oral, small-molecule TKI highly selective for HER2 with minimal inhibition of EGFR. In pt-derived xenograft models of HER2+ mCRC, the combination of TUC + trastuzumab (TRAS) showed significantly greater antitumor activity compared with either agent alone. The MOUNTAINEER study was initiated to evaluate the efficacy and safety of TUC + TRAS in pts with HER2+ RAS wild-type mCRC.
Trial design
MOUNTAINEER is an open-label, pivotal phase II study that initially consisted of a single cohort of up to 45 pts (Cohort A) treated with TUC (300 mg BID) and TRAS (8 mg/kg IV followed by 6 mg/kg IV every 3 weeks). To enable better estimation of ORR and safety, the study was expanded to include 70 additional pts randomized 4:3 into 2 cohorts: Cohort B (N=40) will receive TUC + TRAS and Cohort C (N=30) will receive TUC monotherapy. Pts in Cohort C will be initially treated with TUC (300 mg orally twice daily) and will have the option to crossover to TUC + TRAS if an objective response is not achieved by 12 weeks, or if progressive disease develops at any time. Eligible pts are RAS wild-type with HER2+ mCRC and must have previously received regimens that include fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and an anti-PD-1 if the tumor has dMMR proteins or is MSI-H. Pts who have received prior HER2-directed therapies are not eligible. Additionally, pts must have measurable disease and ECOG PS of 0 to 2. The primary endpoint of this study is confirmed ORR (per RECIST v1.1) in Cohorts A + B as assessed by blinded independent central review. Secondary endpoints include duration of response, progression-free and overall survival, and safety and tolerability. Enrollment is ongoing in the US and is planned for the EU.
Clinical trial identification
NCT03043313.
Editorial acknowledgement
Medical writing assistance was funded by Seattle Genetics, Inc., and provided by Gyen Musgrave of MMS Holdings, Inc.
Legal entity responsible for the study
Seattle Genetics.
Funding
Seattle Genetics.
Disclosure
J. Strickler: Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy: Bayer; Advisory/Consultancy: Chengdu Kanghong Biotech; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): OncoMed; Advisory/Consultancy: Proteus Digital Health; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Seattle Genetics; Advisory/Consultancy: Natera; Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): Curegenix; Research grant/Funding (institution): Exelixis; Research grant/Funding (institution): Gilead; Research grant/Funding (institution): Leap Therapeutics; Research grant/Funding (institution): Macrogenics; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Nektar; Research grant/Funding (institution): Sanofi. K. Ng: Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Tarrex Biopharma; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Gilead; Research grant/Funding (institution): Pharmavite; Research grant/Funding (institution): Revolution Medicines; Research grant/Funding (institution): Trovagene. A. Cercek: Advisory/Consultancy: Array Pharma; Advisory/Consultancy: Bayer; Advisory/Consultancy: Proteus Digital Health; Research grant/Funding (institution): Abbvie; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Tesaro. C. Fountzilas: Honoraria (institution): Society for Immunotherapy of Cancer (SITC); Research grant/Funding (institution): Astellas Pharma; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): Kinex; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Puma Biotech; Research grant/Funding (institution): Rafael Pharma; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Erytech Pharma; Research grant/Funding (institution): Merrimack; Research grant/Funding (institution): National Comprehensive Cancer Network; Research grant/Funding (institution): Hoosier Oncology Group. F. Sanchez: Advisory/Consultancy: Via Oncology. J. Hubbard: Advisory/Consultancy, Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Boston Biomedical; Research grant/Funding (institution): eFFECTOR Therapeutics; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Senhwa Biosciences; Research grant/Funding (institution): Taiho Pharma; Research grant/Funding (institution): Treos Bio. C. Wu: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Array Biopharma; Honoraria (self), Advisory/Consultancy: Signatera; Research grant/Funding (institution): Boston Biomedical; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Lycera; Research grant/Funding (institution): RAPT Therapeutics; Research grant/Funding (institution): Seattle Genetics; Research grant/Funding (institution): Symphogan; Research grant/Funding (institution): Vaccinex. M. Stecher: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Seattle Genetics. L.N. Walker: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment, Patents as inventor via status as employee of Seattle Genetics: Seattle Genetics. T. Bekaii-Saab: Advisory/Consultancy: Abbvie; Advisory/Consultancy, Research grant/Funding (institution): Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Advisory/Consultancy: Genentech/Roche; Advisory/Consultancy: Imugene; Advisory/Consultancy, Research grant/Funding (institution): Incyte; Advisory/Consultancy, Research grant/Funding (institution): Ipsen; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): NCCN; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Regeneron; Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Advisory/Consultancy: Sirtex Medical; Advisory/Consultancy: Taiho Pharma; Research grant/Funding (institution): NCI; Research grant/Funding (institution): Oncolytics; Research grant/Funding (institution): Boston Biomedical; Advisory/Consultancy, Research grant/Funding (institution): Merck; Research grant/Funding (institution): Clovis; Advisory/Consultancy, Research grant/Funding (institution): Array Biopharma; Advisory/Consultancy, Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Abgenomics; Research grant/Funding (institution): BMS; Advisory/Consultancy: TreosBio; Advisory/Consultancy: Sobi; Advisory/Consultancy: Immuneering.