December 18, 2019
2 min read

FDA grants breakthrough therapy designation to tucatinib for advanced breast cancer

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The FDA granted breakthrough therapy designation to tucatinib, in combination with trastuzumab and capecitabine, for the treatment of locally advanced unresectable or metastatic HER2-positive breast cancer, according to a press release from the agent's manufacturer.

The designation applies to use of tucatinib (Seattle Genetics) for patients — including those with brain metastases — who received prior treatment with trastuzumab (Herceptin, Genentech), pertuzumab (Perjeta, Genentech) and ado-trastuzumab emtansine (Kadcyla, Genentech).

Tucatinib is an investigational tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR.

The FDA based the breakthrough therapy designation on results of the randomized phase 3 HER2CLIMB trial, presented earlier this month at San Antonio Breast Cancer Symposium.

The trial included 612 patients with locally advanced or metastatic HER2-positive breast cancer who received prior treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine.

Eligibility criteria allowed patients with untreated, treated stable or treated progressive brain metastases to enroll.

Researchers randomly assigned patients 2:1 to tucatinib 300 mg or placebo twice daily in combination with trastuzumab — dosed at 6 mg/kg once every 21 days, with a loading dose of 8 mg/kg on day 1 of the first cycle — and capecitabine, dosed at 1,000 mg/m² twice daily on days 1 to 14 of each 21-day cycle.

PFS among the first 480 patients as assessed by blinded independent central review served as the primary endpoint. Multiplicity-adjusted secondary endpoints in the entire cohort included OS, PFS among those with brain metastases, and confirmed overall response rate among patients with measurable disease.

Median follow-up for the entire cohort was 14 months.

As Healio previously reported, results showed the addition of tucatinib to trastuzumab and capecitabine conferred a statistically significant improvement in PFS (median, 7.8 months vs. 5.6 months; HR = 0.54; 95% CI, 0.42-0.71). A higher percentage of patients in the tucatinib group remained progression free at 1 year (33% vs. 12%).

The PFS benefit extended to patients with brain metastases (median, 7.6 months vs. 5.4 months; HR = 0.48; 95% CI, 0.34-0.69). In this subgroup, 25% of those assigned tucatinib remained progression free at 1 year, compared with 0% in the control group.

Researchers reported a 34% reduction in risk for death among tucatinib-treated patients (median OS, 21.9 months vs. 17.4 months; HR = 0.66; 95% CI, 0.5-0.88). A higher percentage of those assigned tucatinib remained alive at 2 years (45% vs. 27%).

“I hope it’s going to be the next standard of care,” Rashmi K. Murthy, MD, assistant professor of breast medical oncology at The University of Texas MD Anderson Cancer Center and a researcher involved with HER2CLIMB, told Healio. “No clinical trial has shown an OS benefit for patients who are this heavily pretreated, and also for a patient population that included those with untreated and progressing brain metastases, so I would say these are unprecedented results.”


The most common adverse events observed among tucatinib-treated patients included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue and vomiting.

Grade 3 or higher adverse events that occurred at higher frequency in the tucatinib group included diarrhea (12.9% vs. 8.6%), increased aspartate transaminase level (4.5% vs. 0.5%) and increased alanine transaminase level (5.4% vs. 0.5%). A higher percentage of patients in the placebo group experienced increased bilirubin (2.5% vs. 0.7%).

Adverse events led to treatment discontinuation by 5.7% of patients assigned tucatinib and 3% of those assigned placebo.

These results prompted investigators to unblind the study to allow patients assigned placebo to cross over to tucatinib treatment.

Seattle Genetics expects to submit a new drug application for tucatinib to the FDA in the first quarter of 2020.