MOUNTAINEER:open-label, phase II study of tucatinib combined with trastuzumab for HER2-positive metastatic colorectal cancer (SGNTUC-017, trial in progress).
Authors: Strickler John H. , Ng Kimmie , Cercek Andrea , Fountzilas Christos , Sanchez Federico Augusto , Hubbard Joleen M. , Wu Christina , Siena Salvatore , Tabernero Josep , Van Cutsem Eric , Kardosh Adel , Saeed Anwaar , Andre Thierry , Stecher Michael , Palanca-Wessels Maria Corinna , Bekaii-Saab Tanios S. 
Published: January 2021

TPS153 Background: The clinical benefit of approved therapies in patients (pts) with metastatic colorectal cancer (mCRC) who progress on first- and second-line chemotherapy (FOLFOX and FOLFIRI) is limited. In pts with chemotherapy-refractory RAS wild type mCRC, antibodies targeting EGFR offer a monotherapy response rate of approximately 20% and a progression-free survival (PFS) of 4 months (Price 2014). HER2 is a validated target in gastric and breast cancers, with HER2 amplification occurring in ~3–5% of pts with mCRC. Tucatinib (TUC), recently approved for HER2+ metastatic breast cancer, is a tyrosine kinase inhibitor (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 (Kulukian 2020). The MOUNTAINEER trial was initiated to evaluate the efficacy and safety of TUC in combination with TRAS in pts with HER2+ RAS wild-type mCRC. Interim analysis of the initial 26 pts enrolled in MOUNTAINEER demonstrated an objective response rate (ORR) of 52.2% (12 partial responses [PRs] in 23 evaluable pts), median duration of response of 10.4 months, with a median PFS of 8.1 months and a median overall survival (OS) of 18.7 months (Strickler 2019). Based on these results, the trial was expanded to enable better estimation of ORR and safety. Methods: MOUNTAINEER (NCT03043313) is an open-label, pivotal phase 2 trial 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). The trial was expanded to include an additional 70 pts randomized 4:3 into 2 cohorts: Cohort B (N = 40) who will receive TUC + TRAS, and Cohort C (N = 30) who will receive TUC monotherapy. Pts in Cohort C will be treated with TUC (300 mg orally twice daily) with 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 have RAS wild-type and 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 trial is confirmed ORR (per RECIST v1.1) in Cohorts A + B as assessed by blinded independent central review. Secondary endpoints include duration of response, PFS, OS, and safety and tolerability. Enrollment is ongoing in the US and planned for the EU. Clinical trial information: NCT03043313.