On February 13, 2020 Seattle Genetics, Inc. (Nasdaq:SGEN) reported that the U.S. Food and Drug Administration (FDA) has accepted for priority review the Company’s New Drug Application (NDA) for the investigational medicine tucatinib (Press release, Seattle Genetics, FEB 13, 2020, View Source [SID1234554301]). This NDA requests FDA approval of tucatinib in combination with trastuzumab 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 three prior HER2-directed agents separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. The filing is based on the results of HER2CLIMB, a randomized pivotal trial comparing tucatinib added to trastuzumab and capecitabine versus trastuzumab and capecitabine alone. HER2CLIMB trial results were recently presented at the 2019 San Antonio Breast Cancer Symposium and published in the New England Journal of Medicine(NEJM). Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target action date of August 20, 2020. Tucatinib is an oral, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2.

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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, Ph.D., 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."

The NDA for tucatinib was submitted in December 2019 and is being reviewed under the Real-Time Oncology Review (RTOR) Pilot Program. The review of the tucatinib NDA is also being conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among participating international partners. Tucatinib was recently 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. This designation was based on data from the pivotal HER2CLIMB trial.

About HER2-Positive Breast Cancer

Patients with HER2-positive breast cancer have tumors with high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. An estimated 271,270 new cases of invasive breast cancer will be diagnosed in the U.S. in 2019.1 Between 15 and 20 percent of breast cancer cases worldwide are HER2-positive.2 Historically, HER2-positive breast cancer tends to be more aggressive and more likely to recur than HER2-negative breast cancer.2, 3, 4 In patients with metastatic breast cancer, the most common site of first metastasis is in bone, followed by lung, brain, and liver.5, 6 Up to 50 percent of metastatic HER2-positive breast cancer patients develop brain metastases over time.2, 7 Despite recent treatment advances, there is still a significant need for new therapies that can impact metastatic disease, especially brain metastases. There are currently no approved therapies demonstrating progression-free survival or overall survival benefit for the treatment of patients with HER2-positive metastatic breast cancer after progression on T-DM1.8, 9, 10

About Tucatinib

Tucatinib is an investigational, orally bioavailable, potent tyrosine kinase inhibitor that is highly selective for HER2 without significant inhibition of EGFR. Inhibition of EGFR has been associated with significant toxicities, including skin rash and diarrhea. Tucatinib has shown activity as a single agent and in combination with both chemotherapy and other HER2 targeted agents such as trastuzumab.1,2 Studies of tucatinib in these combinations have shown activity both systemically and in brain metastases. HER2 is a growth factor receptor that is overexpressed in multiple cancers, including breast, colorectal and gastric cancers. HER2 mediates cell growth, differentiation and survival. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.

In addition to HER2CLIMB, tucatinib is being evaluated in a randomized, double-blind, placebo-controlled, multi-center phase 3 trial of tucatinib called HER2CLIMB-02. This trial is evaluating tucatinib in combination with T-DM1 compared to T-DM1 alone, in patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have had prior treatment with a taxane and trastuzumab. The primary endpoint is progression-free survival (PFS) per RECIST criteria. Secondary endpoints include overall survival, objective response rate and duration of response. This global trial is expected to enroll approximately 460 patients. More information about the phase 3 trial, including enrolling centers, is available at www.clinicaltrials.gov.

Tucatinib is also being evaluated in a multi-center, open-label, single-arm phase 2 clinical trial known as MOUNTAINEER, with tucatinib in combination with trastuzumab in patients with HER2-positive, RAS wildtype metastatic or unresectable colorectal cancer. The primary endpoint of the trial is overall response rate by RECIST criteria. Duration of response, PFS, overall survival and safety and tolerability of the combination regimen are secondary objectives. Results for the first 26 patients were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress. Enrollment of up to 110 patients is ongoing. More information about the MOUNTAINEER trial, including enrolling centers