On April 17, the U.S. Food and Drug Administration (FDA) granted approval to tucatinib (Tukysa) in combination with trastuzumab/capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti–HER2-based regimens in the metastatic setting.
Tucatinib is an oral small-molecule tyrosine kinase inhibitor of HER2.
The FDA previously granted Breakthrough Therapy designation and Priority Review to tucatinib and reviewed this application for approval under the Real-Time Oncology Review pilot program. The tucatinib new drug application is also part of Project Orbis, an initiative of the FDA Oncology Center of Excellence that provides a framework for concurrent submission and review of oncology drugs among participating international health authorities.
Eric P. Winer, MD
“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,” said Eric P. Winer, MD, Chief of the Division of Breast Oncology, Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute.
“Cancer spreads to the brain in up to half of patients with HER2-positive metastatic breast cancer, and this approval is based on a unique clinical trial that included patients with active brain metastases, either untreated or progressing. Tucatinib is well tolerated by patients and is a valuable addition to the agents we have for HER2-positive metastatic breast cancer,” he added.
The triplet therapy was evaluated in the HER2CLIMB trial, a randomized, double-blind, placebo-controlled 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). Forty-eight percent of patients in the study had a presence or history of brain metastases.
The primary efficacy outcome measure was progression-free survival as assessed by blinded independent central review in the first 480 randomly assigned patients. Additional efficacy outcome measures were evaluated in all randomly assigned patients and included overall survival, progression-free survival in patients with a history or presence of brain metastases, and confirmed objective response rate.
Patients who received tucatinib in combination with trastuzumab/capecitabine had a 46% reduction in the risk of cancer progression or death compared to patients who received trastuzumab and capecitabine alone (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.42–0.71, P < .00001). The addition of tucatinib reduced the risk of death by 34% compared to trastuzumab and capecitabine alone (HR = 0.66, 95% C = 0.50–0.87, P = .0048).
Nearly twice the number of patients who received tucatinib in combination with trastuzumab and capecitabine had a confirmed objective response compared to those who received trastuzumab and capecitabine alone (40.6% vs 22.8%). For patients with brain metastases, the addition of tucatinib reduced the risk of cancer progression or death by 52% compared to trastuzumab and capecitabine alone (HR = 0.48, 95% CI = 0.34–0.69, P < .00001).
Serious adverse reactions occurred in 26% of patients who received tucatinib. Serious adverse reactions occurring in 2% or more of patients who received tucatinib include diarrhea (4%), vomiting (2.5%), nausea, abdominal pain, and seizure (2% each). The most common adverse reactions occurring in 20% or more of patients who received tucatinib were diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.
Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received tucatinib. Adverse reactions leading to treatment discontinuation of tucatinib (in 1% or more of patients) were hepatotoxicity (1.5%) and diarrhea (1%).
The recommended dosage for tucatinib is 300 mg taken orally twice daily with or without food.