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The FDA has now approved tucatinib (TukysaTM, Seattle Genetics) in combination with trastuzumab and capecitabine for adults with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer, previously treated with at least one anti-HER2-based regimen in the metastatic setting. The tucatinib indication includes patients with brain metastases.
The approval for tucatinib, a highly selective inhibitor of the HER2 tyrosine kinase, is based on data from HER2CLIMB (NCT02614794), a phase 3 trial in which 612 patients with HER2-positive metastatic breast cancer with or without brain metastases who had received prior treatment with trastuzumab, pertuzumab, and trastuzumab emtansine were randomized to receive either tucatinib or placebo in combination with trastuzumab and capecitabine. The trial's primary end point was progression-free survival among the first 480 patients to undergo randomization, with secondary end points, assessed in all 612 patients, of overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.
The one-year progression-free survival rate was higher for patients receiving tucatinib compared with those receiving placebo (33.1% vs 12.3%), with median progression-free survival durations of 7.8 versus 5.6 months. The two-year overall survival rate was also higher for patients receiving tucatinib (44.9% vs 26.6%), with longer median overall survival (21.9 vs 17.4 months). Among patients with brain metastases, the one-year progression-free survival rate was 24.9% for those receiving tucatinib compared with 0% for those receiving the placebo-containing regimen, with median progression-free survival durations of 7.6 months versus 5.4 months.
"Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options," write the investigators in their February publication in The New England Journal of Medicine, led by first author Rashmi K. Murthy, MD, Assistant Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, Texas.
"Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, the addition of tucatinib to trastuzumab and capecitabine resulted in a clinically meaningful lower risk of disease progression or death than the addition of placebo. Most importantly, overall survival was longer by 4.5 months with tucatinib," state Dr. Murthy and colleagues. "In conclusion, tucatinib plus trastuzumab and capecitabine is an active combination in heavily pretreated patients with HER2-positive metastatic breast cancer, including those with previously untreated, treated and stable, or treated and progressing brain metastases."
Adverse events affecting at least 20% of patients taking tucatinib included diarrhea, palmar-plantar erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash. Grade 3 or higher diarrhea and elevated aminotransferase levels were more frequent among patients taking the tucatinib-containing regimen than among those assigned to the placebo-containing regimen. Liver tests should be monitored every three weeks while the patient is taking tucatinib, or as clinically indicated. Tucatinib is contraindicated in women who are pregnant or breastfeeding. Women of reproductive potential and men with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least one week following the last dose.
The recommended dose of tucatinib is 300 mg taken orally twice a day in combination with a standard dosage of trastuzumab and capecitabine at a dosage of 1,000 mg/m2, taken orally twice a day on days 1-14 of a 21-day cycle, until disease progression or unacceptable toxicity.
For More Information
US Food and Drug Administration (2020). FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer
Image credit: Ewa Krawczyk. Courtesy of the National Cancer Institute / Georgetown Lombardi Comprehensive Cancer Center