On January 19, the U.S. Food and Drug Administration (FDA) granted accelerated approval to the kinase inhibitor tucatinib (Tukysa) in combination with the monoclonal antibody trastuzumab for RAS wild-type, HER2-positive, unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
MOUNTAINEER Trial
Efficacy was evaluated in 84 patients in MOUNTAINEER (ClinicalTrials.gov identifier: NCT03043313), an open-label, multicenter trial. Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and to have received prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti–vascular endothelial growth factor monoclonal antibody. Patients whose tumors were deficient in mismatch repair proteins or were microsatellite instability–high must also have received an anti–PD-1 monoclonal antibody. Patients who received prior anti-HER2 targeting therapy were excluded.
Patients received tucatinib at 300 mg orally twice daily with trastuzumab (or a non–U.S. approved trastuzumab product) administered at a loading dose of 8 mg/kg intravenously on day 1 of cycle 1, followed by a maintenance dose of trastuzumab at 6 mg/kg on day 1 of each subsequent 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The major efficacy measures were overall response rate and duration of response as assessed by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. The overall response rate was 38% (95% confidence interval [CI] = 28%–49%) and the median duration of response was 12.4 months (95% CI = 8.5–20.5).
The most common adverse events (occurring in ≥ 20% of patients) were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities (occurring in ≥ 20% of patients) were increased creatinine, increased glucose, increased alanine transaminase, decreased hemoglobin, increased aspartate transferase, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.
The recommended tucatinib dose is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration; the application review is ongoing at the other regulatory agency.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Priority Review and Breakthrough Therapy designation. Tucatinib was also granted Orphan Drug designation for the treatment of HER2-positive colorectal cancer.
