On November 9, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported clinical data on its investigational anaplastic lymphoma kinase (ALK) inhibitor, brigatinib, were published in The Lancet Oncology (Gettinger, S.; ed al. The Lancet Onc. 2016, DOI: 10.1016/S1470-2045(16)30392-8 Published 8 November 2016) (Press release, Ariad, NOV 9, 2016, View Source [SID1234516436]). ARIAD has submitted a New Drug Application (NDA) for brigatinib to the U.S. Food and Drug Administration (FDA), seeking U.S. marketing approval for patients with metastatic ALK-positive (ALK+) non-small cell lung cancer (NSCLC) who are resistant or intolerant to crizotinib.

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"The publication reports the results of the first clinical evaluation of brigatinib in patients with advanced malignancies, including ALK+ NSCLC," stated Scott N. Gettinger, M.D., associate professor of medicine at Yale Cancer Center and lead author. "Brigatinib yielded responses in the majority of patients with crizotinib-treated ALK+ NSCLC, with median progression free survival of over one year. Additionally, responses in the brain were achieved in this crizotinib refractory population. Early onset pulmonary adverse events, which occurred in eight percent of patients, generally within 48 hours of first dose, appeared to be related to starting dose."

The data published this week include safety analyses on all patients in the trial (N=137) and efficacy analyses on all patients with ALK+ NSCLC (n=79). Of the 79 ALK+ NSCLC patients, all but eight had previously been treated with crizotinib. With patient data as of June 2015, the median time on treatment for ALK+ NSCLC patients was 15.4 months (range, 0.03 – 39.4 months, ongoing).

The confirmed objective response rate (ORR) was 62% (44/71) in ALK+ NSCLC patients with prior crizotinib treatment. The median progression free survival (PFS) of ALK+ NSCLC patients previously treated with crizotinib was 13.2 months. Eight ALK+ NSCLC patients in the trial were crizotinib-naive. Of these, all eight achieved a confirmed objective response, including three complete responses. At the time of analysis, median PFS was not reached in these patients. Brain metastases were identified in 63% of ALK+ NSCLC patients (50/79) at baseline. The intracranial ORR was 53% (8/15) among evaluable patients with measurable brain metastases.

The most common grade 3–4 treatment-emergent adverse events across all doses were increased lipase (9%; 12/137), dyspnea (6%; 8/137), and hypertension (5%; 7/137). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in ≥5% of all patients were dyspnea (7%; 10/137), pneumonia (7%; 9/137), and hypoxia (5%; 7/137). Eight percent of patients (11/137) experienced a subset of pulmonary adverse events with early onset, most occurring within 48 hours of dosing. The frequency of these events appeared dose-related. Among patients who started at 90 mg once daily and continued at this dose or escalated to 180 mg once daily after seven days, 2% (1/50) had such events.

Data from the Phase 1/2 trial and pivotal ALTA trial of brigatinib have been included in the NDA submitted to the FDA. The FDA has granted ARIAD’s request for Priority Review and has set an action date of April 29, 2017 under the Prescription Drug User Fee Act (PDUFA). ARIAD is seeking accelerated U.S. marketing approval for brigatinib in patients with metastatic ALK+ NSCLC who are resistant or intolerant to crizotinib and plans to submit a Marketing Authorization Application (MAA) for brigatinib to the European Medicines Agency (EMA) in early 2017.

"This in-depth publication provides a thorough review of the Phase 1/2 trial of brigatinib, ARIAD’s internally developed targeted cancer candidate under regulatory review," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "We are excited to continue to work with academic collaborators to provide additional clinical detail on the brigatinib trials, including upcoming presentations at the World Conference on Lung Cancer in December."

About Brigatinib

Brigatinib is an investigational, targeted cancer medicine discovered internally at ARIAD. It is in development for the treatment of patients with anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC). The global Phase 2 ALTA trial, in patients with locally advanced or metastatic ALK+ NSCLC who were previously treated with crizotinib, is the primary basis for brigatinib’s initial regulatory review. ARIAD has also initiated the Phase 3 ALTA 1L trial to assess the efficacy and safety of brigatinib in comparison to crizotinib in patients with locally advanced or metastatic ALK+ NSCLC who have not received prior treatment with an ALK inhibitor. More information on brigatinib clinical trials, including the expanded access program (EAP) for ALK+ NSCLC can be found here.

Brigatinib received Breakthrough Therapy designation from the FDA for the treatment of patients with ALK+ NSCLC whose tumors are resistant to crizotinib, and was granted orphan drug designation by the FDA for the treatment of ALK+ NSCLC.

About ALK+ NSCLC

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for approximately 85 percent of the estimated 228,190 new cases of lung cancer diagnosed each year in the United States, according to the American Cancer Society. Anaplastic lymphoma kinase (ALK) was first identified as a chromosomal rearrangement in anaplastic large-cell lymphoma (ALCL). Genetic studies indicate that chromosomal rearrangements in ALK are key drivers in a subset of NSCLC patients as well. Approximately three to eight percent of patients with NSCLC have a rearrangement in the ALK gene.