Seattle Genetics has submitted an application requesting U.S. Food and Drug Administration (FDA) approval for its investigational therapy tucatinib, in combination with trastuzumab and Xeloda (capecitabine), for treating people with locally advanced inoperable or metastatic HER2-positive breast cancer.
The new drug application, which also includes patients with brain metastases, is specific for those who have received at least three prior HER2-targeted therapies, like trastuzumab (sold under the brand name Herceptin, among others), Perjeta (pertuzumab), and Kadcycla (ado-trastuzumab emtansine).
“Today’s submission marks another important milestone for Seattle Genetics and tucatinib, and a potential advance for patients with either locally advanced or metastatic HER2-positive breast cancer, including those with and without brain metastases,” Roger Dansey, MD, Seattle Genetics’ chief medical officer, said in a press release. “We look forward to working with the FDA on the review of this application.”
Tucatinib is an oral investigational small molecule that potently blocks the HER2 receptor. Since it is able to cross the blood-brain barrier — a highly selective, protective membrane that prevents large molecules in the blood from reaching the brain — tucatinib has the potential to fight brain metastases in people with HER2-positive cancers.
The therapy has received the FDA’s orphan drug designation for the treatment of breast cancer patients with brain metastases. It also earned the FDA’s breakthrough therapy designation, in combination with trastuzumab and Xeloda, for locally advanced inoperable or metastatic HER2-positive breast cancer patients who had received prior treatment with trastuzumab, Perjeta, and Kadcyla.
These designations are meant to provide regulatory support and financial benefits, accelerate the therapy’s development and review, and ensure seven years of marketing exclusivity in the U.S. upon regulatory approval.
Both the breakthrough designation and Seattle Genetics’ NDA application for tucatinib were based on positive data from the Phase 2 HER2CLIMB trial (NCT02614794). Its results showed that adding tucatinib to the commonly used combination of trastuzumab and Xeloda was superior to the combination alone in people with pre-treated, advanced HER2-positive breast cancer, with or without brain metastases.
HER2CLIMB’s top-line data were announced in October 2019, while additional findings were recently presented at the 2019 San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine.
The study enrolled a total of 612 patients who had received prior treatment with trastuzumab, Perjeta, and Kadcyla. Nearly half had brain metastasis at the beginning of the study.
Participants were randomly assigned to receive either tucatinib or a placebo, in combination with Xeloda and trastuzumab. The study’s main goal was to determine if tucatinib was better than a placebo at prolonging the time patients lived without disease progression or death (progression-free survival; PFS) among the first 480 dosed participants.
Secondary goals, assessed in the total population, included overall survival, PFS among patients with brain metastases, treatment response rates, duration of response, and safety.
The results showed that individuals receiving the tucatinib combination had a 46% lower risk of disease progression or death, compared with those on placebo — meaning the trial met its primary goal.
Two secondary goals also were achieved, as the tucatinib combo significantly reduced the risk of death by 34% in the overall population and the risk of disease progression or death by 52% among those who had brain metastases at enrollment.
The tucatinib triple combo was generally safe and well-tolerated, with the most commonly reported adverse events including diarrhea, pain on the palms of the hands or the soles of the feet, nausea, fatigue, and vomiting.
Among the serious-to-life-threatening adverse events reported during the trial, diarrhea and elevated levels of aminotransferase (a marker of liver damage) were more common in the tucatinib-combo group than in the placebo-combo group.
Treatment discontinuations due to adverse events were rare among both groups (5.7% on tucatinib and 3% on placebo). Six patients (1.5%) treated with tucatinib and five (2.5%) on placebo died during the study due to treatment-related adverse events.
Seattle Genetics also plans to submit a marketing authorization application to the European Medicines Agency requesting the approval of this tucatinib triple combo for the same indication.
A Phase 3 clinical trial — called HER2CLIMB-02 (NCT03975647) — also is evaluating the combination of tucatinib with Kadcyla in people with the same condition but who did not respond to prior taxane chemotherapy and trastuzumab. The trial, which is being conducted in the U.S. only, is still recruiting patients; more information on recruitment locations can be found here.