FDA Approves First New Breast Cancer Drug With International Group

Nick Mulcahy

April 17, 2020

The US Food and Drug Administration today approved the oral therapy tucatinib (Tukysa, Seattle Genetics) for the treatment of advanced HER2-positive breast cancer. This is the first new drug approved under Project Orbis, an international collaboration.

Tucatinib, which is a small-molecule tyrosine kinase inhibitor, is used in combination with trastuzumab and capecitabine and is indicated for patients who have received one or more prior treatments for advanced disease.

The FDA collaborated with the regulatory authorities of Australia, Canada, Singapore, and Switzerland on this review. However, only the FDA approved tucatinib today; the application is still under review at the other agencies.

While working with Project Orbis in 2019, the FDA granted an accelerated, conditional approval to a drug combination that included previously approved agents.

"The FDA's Project Orbis provides a framework for concurrent submission and review of oncology drug applications among the FDA's international collaborators," said Richard Pazdur, MD, acting director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research, in a statement.

Collaboration among regulators may allow patients with cancer to receive earlier access to products in other countries where there may be significant delays in regulatory submissions, according to the FDA.

The new drug is a "valuable addition" to the roster of treatments for advanced HER2-positive breast cancer, said study investigator Eric Winer, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, in a company press statement.

"With highly significant and clinically important results for overall and progression-free survival, the addition of [tucatinib] to trastuzumab and capecitabine has the potential to become a standard of care for people with HER2-positive metastatic breast cancer after having received one or more previous anti-HER2 therapies in the metastatic setting," he said.

The new approval is based on safety and efficacy results from the phase 3 HER2CLIMB trial that enrolled 612 patients with HER2-positive unresectable locally advanced or metastatic breast cancer who had previously received, either separately or in combination, trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1).

Nearly half (48%) of patients in the study had brain metastases at the start of the trial. The primary outcome measure was progression-free survival (PFS). All patients received trastuzumab and capecitabine and were randomly assigned to either tucatinib or placebo.

Median PFS in the tucatinib patient group was 7.8 months compared with 5.6 months in the placebo group. The PFS results in the subgroup of patients with brain metastases were nearly the same.

Median overall survival in the tucatinib patient group was 21.9 months vs 17.4 months in the placebo group.

The new drug is a rare success in the treatment of breast cancer brain metastases, said Jawad Fares, MD, Northwestern University, Chicago, Illinois, who spoke to Medscape Medical News when the phase 3 trial data were first presented at the 2019 San Antonio Breast Cancer Symposium.

"Outcomes in the field have been pretty dismal," summarized Fares, who was lead author of a 2018 review of systemic drug treatments for breast cancer brain metastases (Neurooncol Pract. 2019;5:392-401) and was not involved in the tucatinib study.

The results of the study, which was funded by Seattle Genetics, were published in the New England Journal of Medicine last year.

According to the FDA, common side effects with tucatinib were diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Tucatinib can cause serious side effects, including diarrhea associated with dehydration, acute kidney injury, and death. Healthcare professionals should start antidiarrheals as clinically indicated if diarrhea occurs and should interrupt treatment or reduce the dosage. Tucatinib can also cause severe hepatotoxicity; patients should be monitored with liver tests.

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