Tukysa, in Combination with Trastuzumab, Now FDA Approved for HER2-Positive, Unresectable or Metastatic Colorectal Cancer

February 2023, Vol 14, No 1

On January 19, 2023, the FDA accelerated the approval of tucatinib (Tukysa; Seagen), a Bruton tyrosine kinase inhibitor, in combination with trastuzumab (Herceptin), 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 the 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.

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