Tucatinib in combination with trastuzumab has shown promising results in treating patients with chemotherapy-refractory, HER2-positive metastatic colorectal cancer. The findings from the MOUNTAINEER trial indicate clinically meaningful anti-tumor activity and manageable tolerability, marking a significant advancement in the treatment landscape for this patient population.
The global, open-label, phase 2 MOUNTAINEER study enrolled patients with unresectable or metastatic colorectal cancer across 34 sites in five countries. Patients had HER2-positive, RAS wild-type tumors that were refractory to chemotherapy. The study initially involved a single cohort (Cohort A) receiving tucatinib (300 mg orally twice daily) plus intravenous trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 21 days). Following an interim analysis, the study expanded to include a randomized component (Cohort B: tucatinib plus trastuzumab; Cohort C: tucatinib monotherapy).
The primary endpoint was the confirmed objective response rate per blinded independent central review (BICR) for cohorts A and B combined. As of the data cutoff on March 28, 2022, the confirmed objective response rate was 38.1% (95% CI: 27.7-49.3) among 84 patients in cohorts A and B. Three patients achieved a complete response, and 29 had a partial response.
Safety and Tolerability
The most common adverse event in cohorts A and B was diarrhea, affecting 64% of patients. The most common grade 3 or worse adverse event was hypertension, observed in 7% of patients. Three percent of patients experienced tucatinib-related serious adverse events, including acute kidney injury, colitis, and fatigue. No deaths were attributed to adverse events; all deaths were due to disease progression.
Clinical Significance
Colorectal cancer is a significant global health burden, and HER2-positive status is an actionable target in metastatic disease. This treatment is the first FDA-approved anti-HER2 regimen for metastatic colorectal cancer and is an important new treatment option for chemotherapy-refractory HER2-positive metastatic colorectal cancer.
John Strickler, MD, of the Duke Cancer Institute, a lead investigator in the trial, noted that the combination provides a much-needed option for patients who have progressed on standard therapies. “The results of the MOUNTAINEER trial are encouraging, and this combination represents a significant step forward in treating this challenging cancer,” he said.
The study was funded by Seagen and Merck & Co.
