The Food and Drug Administration (FDA) has accepted for Priority Review the New Drug Application (NDA) for tucatinib (Seattle Genetics), in combination with trastuzumab and capecitabine, for the treatment of patients with locally advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least 3 prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant or metastatic setting.

Tucatinib is an oral, small molecule, highly selective inhibitor of the HER2 tyrosine kinase. The investigational drug is able to target HER2 with minimal inhibition of EGFR that allows for reduced toxicities, including skin rash and diarrhea. 

The application is based on data from a multicenter, randomized, phase 2 study (HER2CLIMB) that compared tucatinib with placebo, as an add-on to trastuzumab and capecitabine, in patients with locally advanced unresectable or metastatic HER2-positive breast cancer. The primary end point was progression-free survival (PFS) for the first 480 patients who underwent randomization. Secondary end points, assessed in all 612 patients, included overall survival (OS), PFS among patients with brain metastases, confirmed objective response rate, and safety.

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Results showed that tucatinib improved the median duration of PFS at 1 year vs placebo (7.8 months vs 5.6 months) with 33.1% of patients in the tucatinib treatment arm achieving PFS vs 12.3% in the placebo arm (HR for disease progression or death, 0.54; 95% CI, 0.42-0.71; P <.001). Additionally, tucatinib improved the median OS at 2 years vs placebo (21.9 months vs 17.4 months); OS was 44.9% in the tucatinib arm vs 26.6% in the placebo arm (HR for death, 0.66; 95% CI, 0.50-0.88; P=.005). 

Among patients with brain metastases, the PFS at 1 year was 24.9% in the tucatinib arm vs 0% in the placebo arm (HR 0.48; 95% CI, 0.34-0.69; P <.001), and the median PFS was 7.6 months vs 5.4 months, respectively.

Regarding safety, the most common adverse events in the tucatinib arm included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Patients treated with tucatinib also experienced a higher frequency of diarrhea and elevated aminotransferase levels of grade 3 or higher compared with placebo.

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“The FDA’s filing of the tucatinib NDA marks an important step forward for patients with locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases,” said Clay Siegall, PhD, President and CEO of Seattle Genetics. “We are working collaboratively with the FDA throughout the review process to bring this important medicine to patients as quickly as possible.”

A Prescription Drug User Fee Act (PDUFA) target date of August 20, 2020 has been set for this application.

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This article originally appeared on MPR