The U.S. Food and Drug Administration (FDA) has granted priority review to Seattle Genetics’ application seeking approval of its investigational therapy tucatinib, in combination with trastuzumab and Xeloda (capecitabine), for treating people with locally advanced inoperable or metastatic HER2-positive breast cancer.
This indication applies to patients with or without brain metastases who have received at least three prior HER2-targeted therapies, such as Perjeta (pertuzumab), Kadcycla (ado-trastuzumab emtansine), and trastuzumab (sold under the brand name Herceptin, among others).
The priority review status will shorten tucatinib’s regulatory review for this indication to six months from the standard 10 months. Seattle Genetics submitted the new drug application (NDA) to the FDA in December 2019, and the agency has set a Prescription Drug User Fee Act action date for Aug. 20 this year, meaning that a decision is due by then.
“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,” Clay Siegall, PhD, Seattle Genetics’ president and CEO, said in a press release.
“We are working collaboratively with the FDA throughout the review process to bring this important medicine to patients as quickly as possible,” he added.
The NDA is being reviewed under the Real-Time Oncology Review (RTOR) Pilot Program and Project Orbis of the FDA Oncology Center of Excellence.
RTOR is exploring a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible. Project Orbis provides a framework for simultaneous submission and review of cancer treatments between international partners, which may allow patients to receive earlier access to treatments in countries with delays in regulatory submissions.
The FDA previously granted tucatinib breakthrough therapy designation — in combination with trastuzumab and Xeloda — for the same indication and orphan drug designation for the treatment of breast cancer patients with brain metastases.
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.
Seattle Genetics also filed a similar marketing authorization application to the European Medicines Agency, which has already validated it for review.
Tucatinib is an oral small molecule that 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.
Seattle Genetics’ applications for tucatinib were based on positive data from the Phase 2 HER2CLIMB trial (NCT02614794). Its 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.
HER2CLIMB evaluated whether adding tucatinib to the commonly used combination of trastuzumab and Xeloda resulted in greater survival benefits than the standard combination alone in 612 people with pre-treated, advanced HER2-positive breast cancer, with or without brain metastases.
Participants had received prior treatment with trastuzumab, Perjeta, and Kadcyla, and nearly half had brain metastasis at the beginning of the study. They were randomly assigned to receive either tucatinib or a placebo, in combination with trastuzumab and Xeloda.
The trial’s main goal was to determine if tucatinib was superior to 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 patient population, included PFS among patients with brain metastases, overall survival, treatment response rates, duration of response, and safety.
Results showed that, compared to placebo, the tucatinib combination significantly reduced the risk of disease progression and death by 46% among the first dosed patients and by 52% among those who had brain metastases at enrollment.
Patients treated with the tucatinib triple combo also had a 34% lower risk of death and a significantly higher overall response rate (41% vs. 23% on placebo).
Tucatinib combination was generally safe and well-tolerated.
Among the serious-to-life-threatening adverse events reported, diarrhea and high levels of aminotransferase (a marker of liver damage) were more common in the tucatinib group than in the placebo group. Treatment discontinuations and deaths due to adverse events were rare among both groups.
A combination of tucatinib with Kadcyla is also being investigated in people with the same condition but who did not respond to previous taxane chemotherapy and trastuzumab in the HER2CLIMB-02 Phase 3 clinical trial (NCT03975647). The trial, which is being conducted in the U.S. only, is still recruiting patients; more information on recruitment locations can be found here.