On April 17, 2020, the FDA approved tucatinib (Tukysa; Seattle Genetics), an oral kinase inhibitor, in combination with trastuzumab (Herceptin; Genentech) and capecitabine (Xeloda; Genentech) for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more previous anti-HER2–based regimens in the metastatic setting.
The FDA’s approval of tucatinib was based on results of the HER2CLIMB clinical trial, a global, double-blind, randomized phase 3 study that enrolled 612 patients with HER2-positive advanced unresectable or metastatic breast cancer who had received previous treatment. Nearly half (48%) of patients had brain metastases at the start of the trial.
Patients were randomized in a 2:1 ratio to the 3-drug regimen of tucatinib 300 mg twice daily plus trastuzumab and capecitabine or to the 2-drug regimen of trastuzumab plus capecitabine. The primary end point was progression-free survival (PFS); secondary end points included overall survival and PFS among patients with brain metastases.
The median PFS with the 3-drug regimen with tucatinib was 7.8 months versus 5.6 months for the 2-drug regimen, respectively. The median OS rates were 21.9 months and 17.4 months, respectively. The median PFS in patients with brain metastases at baseline who received the 3-drug regimen was 7.6 months compared with 5.4 months in patients who received the 2-drug regimen.
The most common (≥20%) adverse reactions were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
The FDA collaborated on this review with the Australian Therapeutic Goods Administration, Health Canada, Health Sciences Authority in Singapore, and Swissmedic in Switzerland as part of an international collaboration known as Project Orbis. The application remains under review by the other agencies.