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Jump to Key Points The FDA has approved tucatinib (Tukysa, Pfizer) in combination with trastuzumab and pertuzumab for the maintenance treatment of adults with unresectable locally advanced or metastatic HER2-positive breast cancer following induction treatment.
The standard approach for advanced/metastatic HER2-positive disease has been upfront chemotherapy along with trastuzumab and pertuzumab, both HER2-targeted monoclonal antibodies, followed by maintenance with both antibodies until progression. Tucatinib, an anti-HER2 tyrosine kinase inhibitor, works intracellularly while trastuzumab and pertuzumab work extracellularly, so adding it to maintenance creates a double check on HER2 signaling.
Tucatinib is already approved in combination with trastuzumab and capecitabine for HER2-positive advanced unresectable/metastatic breast cancer, including patients with brain metastases, after one or more prior anti-HER2 breast cancer treatments in the metastatic setting.
The new approval was based on the HER2CLIMB-05 trial with 654 patients with HER2-positive metastatic breast cancer with or without brain metastases. Eligibility criteria included having no evidence of progression after induction treatment with four to eight cycles of trastuzumab, pertuzumab, and a taxane.
- Tucatinib + trastuzumab/pertuzumab approved for maintenance HER2+ unresectable locally advanced/metastatic breast cancer.
- Use after 4–8 cycles induction trastuzumab/pertuzumab + taxane, if no progression.
- HER2CLIMB-05: median PFS 24.9 vs 16.3 months with tucatinib add-on.
- Grade ≥3 AEs: 42% vs 24%; 13% discontinued, mainly hepatic toxicity.
- Common AEs: diarrhea 72.7%, ALT ↑ 28.2%, AST ↑ 25.8%; boxed hepatotoxicity warning.
Patients were randomly assigned evenly to tucatinib 300 mg or placebo orally twice daily on a background of trastuzumab and pertuzumab. Hormone receptor-positive patients were allowed to continue endocrine therapy.
Median progression-free survival was 24.9 months with tucatinib add-on compared with 16.3 months in the placebo arm. Overall survival data were immature at the time of the analysis.
Overall, 42% of tucatinib patients had grade ≥ 3 adverse events compared with 24% of patients in the placebo arm; 13% of tucatinib subjects stopped treatment due to adverse events, most commonly hepatic side effects.
The most common adverse events with tucatinib were diarrhea (72.7%; grade ≥ 3, 6.1%), nausea (33.1%; grade ≥ 3, 0.9%), elevated alanine aminotransferase (28.2%; grade ≥ 3, 13.5%), and elevated aspartate aminotransferase (25.8%; grade ≥ 3, 7.1%). Serious adverse reactions included hepatotoxicity (3.9%), which was fatal in one patient.
Tucatinib labeling includes a boxed warning for severe hepatotoxicity plus warnings and precautions for diarrhea, embryo-fetal toxicity, and increased serum creatinine.
The recommended dosage is the same as in HER2CLIMB: 300 mg orally twice daily in combination with trastuzumab and pertuzumab until disease progression or unacceptable toxicity.
M. Alexander Otto is a physician assistant and award-winning journalist. He is also an MIT science journalism fellow. Email: aotto@medscape.net.
