On January 19, 2023, the Food and Drug Administration (FDA) granted accelerated approval to tucatinib in combination with trastuzumab for RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.

Efficacy was evaluated in 84 patients in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). Patients whose tumours were deficient in mismatch repair (dMMR) proteins or were microsatellite instability-high (MSI-H) must also have received an anti-programmed cell death protein-1 mAb. Patients who received prior anti-HER2 targeting therapy were excluded.

Patients received tucatinib 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 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 (ORR) and duration of response (DOR) as assessed by blinded independent central review (RECIST version 1.1.). ORR was 38% (95% CI: 28, 49) and median DOR was 12.4 months (95% CI: 8.5, 20.5).

The most common adverse events (≥20%) were diarrhoea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia. The most common laboratory abnormalities (≥20%) were increased creatinine, increased glucose, increased ALT, decreased haemoglobin, increased AST, 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 concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA). 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. FDA expedited programmes are described in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. Tucatinib was granted orphan drug designation for the treatment of HER2+ colorectal cancer.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

View full prescribing information for tucatinib 

Source: FDA