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FDA Grants Priority Review to Tucatinib Plus Trastuzumab/Capecitabine for Treatment of HER2+ Breast Cancer

Nichole Tucker
Published Online:6:00 PM, Thu February 13, 2020
The FDA has granted Priority Review to the New Drug Application for the combination of tucatinib, trastuzumab (Herceptin), and capecitabine for 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. The FDA has set a prescription Drug User Fee Act (PDUFA) target action date of August 20, 2020. 

The NDA was filed based on results from the HER2CLIMB trial (NCT02614794), which after being presented at the 2010 San Antonio Breast Cancer Symposium, were published in the New England Journal of Medicine.

The addition of tucatinib to trastuzumab and capecitabine achieved a 34% reduction in the risk of death in patients with heavily pretreated unresectable locally advanced or metastatic HER2-positive breast cancer. At 1 year, the progression-free survival (PFS) was 33.1% with the tucatinib combination compared with 12.3% in the control arm receiving placebo/trastuzumab/capecitabine (HR, 0.54; 95% CI, 0.42-0.71; P <0.001).2 The median duration of progression-free survival was 7.8 months in the tucatinib group versus 5.6 months in the placebo group.

At 2 years, the tucatinib combination led to a 44.9% overall survival rate compared with 26.6% for the placebo combination (HR, 0.66; 95% CI, 0.50-0.88; P = 0.005), and the median OS was 21.9 months and 17.4 months, respectively. Results were different among patients with brain metastases. The PFS at 1 year was 24.9% in the tucatinib group and 0% in the control group (HR, 0.48; 95% CI, 0.34-0.69; P < 0.001) with a median PFS of 7.6 months and 5.4 months, respectively.

The most common adverse events (AEs) observed in patients who were treated with tucatinib plus trastuzumab and capecitabine versus the control group were diarrhea (80.9% vs. 53.3%), palmar-plantar erythrodysesthesia syndrome (63.4% vs. 52.8%), nausea (58.4% vs. 43.7%), fatigue (45.0% vs. 43.1%), and vomiting (35.9% vs. 25.4%).

HER2CLIMB is an international, randomized, double-blind trial randomizing patients 2:1 to tucatinib 300 mg orally twice daily plus capecitabine 100 mg/m2 orally twice daily and trastuzumab 8 mg/kg intravenously on day 1 of cycle 1 followed by 6 mg/kg on day 1 of each 21-day cycle or equivalent dosages of placebo in combination with capecitabine and trastuzumab.

The primary end point of the study is PFS, and the secondary end points are PFS in patients with brain metastases, OS, ORR, DOR, clinical benefit rate, and the incidence of AEs.

Patients with histologically confirmed HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab (Perjeta), and T-DM1 (Kadcyla), progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy, an ECOG performance status of 0 or 1, and adequate hepatic and renal function were included in the study. For reasons related to prior treatments, previous and existing conditions, some individuals with HER2-positive breast cancer were excluded from the study.

Tucatinib is an investigational orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2. The drug was previously granted Breakthrough Therapy designation by the FDA 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 been treated with trastuzumab, pertuzumab, and T-DM1, which was also based on the HER2CLIM trial.

“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 chief executive officer 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.”
  1. Seattle Genetics announces FDA filing acceptance for priority review of tucatinib new drug application (NDA) for patients with locally advanced or metastatic her2-positive breast cancer [news release]. Bothell, Washington: Seattle Genetics; February 13, 2020. https://bit.ly/2uKKDVv. Accessed February 13, 2020.
  2. Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020; 382:597-609 DOI: 10.1056/NEJMoa1914609.

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