On January 19, 2023, the FDA accelerated the approval of tucatinib (Tukysa; Seagen), a BTK inhibitor, in combination with trastuzumab, a HER2/neu receptor agonist, for the treatment of RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer (CRC) that progressed after fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies. This combination was granted a breakthrough therapy designation for this indication.
The combination of tucatinib plus trastuzumab was previously approved for patients with unresectable advanced or metastatic HER2-positive breast cancer.
This new approval was based on results of an open-label, multicenter MOUNTAINEER clinical trial of 84 patients with HER2-positive, RAS wild-type, unresectable or metastatic CRC who received previous treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti-VEGF monoclonal antibody. Patients with mismatch repair-deficient tumor or with microsatellite instability-high tumor also received a PD-L1 inhibitor. Patients who previously received an anti–HER2-targeting therapy were excluded from the study.
Patients received tucatinib 300 mg orally twice daily, plus a trastuzumab loading dose of 8 mg/kg intravenously on day 1 of cycle 1, followed by trastuzumab 6 mg/kg on day 1 of each subsequent 21-day cycle, until disease progression or unacceptable adverse events.
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 (≥20%) adverse events were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. The most common (≥20%) laboratory abnormalities were increased creatinine, increased glucose, increased alanine aminotransferase, decreased hemoglobin, increased aspartate aminotransferase, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.