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

Authors

Daniel Catenacci

Daniel V.T. Catenacci

Gastrointestinal Oncology Program, University of Chicago, Chicago, IL

Daniel V.T. Catenacci , John H. Strickler , Yoshiaki Nakamura , Kohei Shitara , Yelena Y. Janjigian , Afsaneh Barzi , Tanios S. Bekaii-Saab , Heinz-Josef Lenz , Hyun Cheol Cheol Chung , Josep Tabernero , Takayuki Yoshino , Salvatore Siena , Joal Garrido Mayor , Maria Corinna Palanca-Wessels , Diqiong Xie , John Marshall

Organizations

Gastrointestinal Oncology Program, University of Chicago, Chicago, IL, Duke University School of Medicine, Durham, NC, National Cancer Center Hospital East, Kashiwa, Japan, Memorial Sloan Kettering Cancer Center, New York, NY, City of Hope Comprehensive Cancer Center/AccessHope, Duarte, CA, Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA, Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, Vall d'Hebron University Hospital and Vall d'Hebron Institute, Barcelona, Spain, Ospedale Niguarda Ca' Granda, Milan, Italy, Seagen Inc., Bothell, WA, Fred Hutchinson Cancer Rsrch Ctr, Seattle, WA, Georgetown University, Washington, DC

Research Funding

Other

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 GI tumors including gastric or gastroesophageal junction adenocarcinoma (GEC). While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ GEC, no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy as 2nd-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 is evaluating the efficacy and safety of TUC with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC in the 2nd-line setting. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC + 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 optimization 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 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. Clinical trial information: NCT04499924.

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Abstract Details

Meeting

2022 ASCO Gastrointestinal Cancers Symposium

Session Type

Trials in Progress Poster Session

Session Title

Trials in Progress Poster Session A: Cancers of the Esophagus and Stomach and Other GI Cancers

Track

Esophageal and Gastric Cancer,Other GI Cancer

Sub Track

Therapeutics

Clinical Trial Registration Number

NCT04499924

DOI

10.1200/JCO.2022.40.4_suppl.TPS371

Abstract #

TPS371

Poster Bd #

M5

Abstract Disclosures