On January 19, 2023, tucatinib was grated accelerated approval for use in combination with trastuzumab for RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.¹

Supporting Efficacy Data

Approval was based on findings in 84 patients in the multicenter MOUNTAINEER trial (ClinicalTrials.gov identifier NCT03043313). In addition to chemotherapy, patients had to have received an anti-VEGF monoclonal antibody. Prior anti-HER2 therapy was not permitted. Patients with tumors that were deficient in mismatch-repair proteins or were microsatellite instability–high must also have received an anti–PD-1 antibody. Patients received oral tucatinib at 300 mg twice daily with trastuzumab (or a non–U.S.-approved trastuzumab product) at a loading dose of 8 mg/kg on day 1 of cycle 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle; treatment continued until disease progression or unacceptable toxicity.

An objective response on blinded independent central review was observed in 32 patients (38%, 95% confidence interval [CI] = 28%–49%), with a complete response in 3 (4%). The median duration of response was 12.4 months (95% CI = 8.5–20.5 months); response persisted for at least 6 and at least 12 months in 81% and 34% of responders, respectively.

How It Is Used

The recommended dose of tucatinib is 300 mg twice daily in combination with trastuzumab until disease progression or unacceptable toxicity. Product labeling provides instructions on dosage modification, including dose reduction, for adverse reactions including diarrhea, hepatotoxicity, and other grade 3 or 4 reactions; severe hepatic impairment; and concomitant use of strong CYP2C8 inhibitors (gemfibrozil, sorafenib, erlotinib) if concomitant use cannot be avoided. Concomitant use with strong CYP3A inducers (carbamazepine, enzalutamide, phenobarbital) or moderate CYP2C8 inducers (bosentan, efavirenz, etravirine) and CYP3A substrates (acetaminophen, diazepam, erythromycin) should be avoided.

Safety Profile

In the MOUNTAINEER trial, the median duration of exposure to tucatinib was 6.9 months (range = 0.7–49.3 months). The most common adverse events of any grade (≥ 20%) were diarrhea (64%), fatigue (44%), rash (37%), nausea (35%), abdominal pain (21%), infusion-related reactions (21%), and pyrexia (20%). The most common grade 3 or 4 adverse events included diarrhea (3.5%) and abdominal pain, fatigue, and back pain (2.3% each). The most common grade 3 or 4 laboratory abnormalities were decreased lymphocytes (12%) and increased aspartate aminotransferase, increased bilirubin, and decreased sodium (6% each).

Serious adverse events occurred in 22% of patients, most commonly intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%), and rectal perforation (2.3%). Adverse events led to discontinuation of tucatinib in 6%, most commonly increased alanine aminotransferase (2.3%).

Tucatinib has warnings/precautions for diarrhea, hepatotoxicity, and embryofetal toxicity. Patients should be advised not to breastfeed while receiving tucatinib. 

REFERENCE

1. Tukysa  (tucatinib) tablets, for oral use, prescribing information, Seagen Inc, January 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213411s004lbl.pdf. Accessed January 30, 2023.