FDA Submission Completed for Brigatinib in ALK-Positive NSCLC

Corey Langer, MD

A new drug application (NDA) has been submitted for brigatinib (AP26113) as a potential treatment for patients with advanced ALK-positive non—small cell lung cancer (NSCLC) following resistance or intolerance to crizotinib (Xalkori), according the developer of the ALK inhibitor, Ariad Pharmaceuticals.

The application was based on findings from the phase II ALTA study, which was presented at the 2016 ASCO Annual Meeting, along with results from an earlier phase I/II trial. In ALTA, the confirmed objective response rate (ORR) for brigatinib at 180 mg daily was 54%, which included a complete response rate of 4%. In those with measurable, active brain metastases treated with the 180 mg dose (n = 18), the intracranial ORR was 67%. Median progression-free survival (PFS) was 12.9 months.

“Many patients with ALK-positive non—small cell lung cancer eventually develop disease progression,” Corey Langer, MD, director of thoracic oncology in the Abramson Cancer Center of the University of Pennsylvania and a professor of Hematology-Oncology in Penn’s Perelman School of Medicine, said in a statement. “We are excited that the brigatinib NDA submission is now complete and are hopeful that brigatinib’s data, including the observation of complete responses and activity in the central nervous system, will provide patients and their oncologists with a new treatment option.”

The ALTA trial enrolled 222 patients with ALK-positive NSCLC following progression on crizotinib. Patients were randomized to receive brigatinib at either 90 mg daily (n = 112) or 180 mg daily with a 7 day lead in period at 90 mg per day (n = 110). Sixty-nine percent of patients had brain metastases at the time of enrollment.

The median age of patients across the study was 54 years, and ECOG performance status (PS) was primarily 0 and 1 (93%), with 7% having an ECOG PS of 2. Sixty percent of patients did not have a smoking history prior to entering the trial and 74% had received prior chemotherapy. Sixty-five percent of patients had experienced a complete or partial response to crizotinib.

The confirmed ORR was 45% in the 90 mg arm. In those who had not received prior chemotherapy, the ORR was 52% with the lower dose. In the 180 mg dose group, those who had not received chemotherapy had an ORR of 52%. There were 4 confirmed (4%) complete responses in the 180 mg arm and 1 in the 90 mg group. When considering stable disease rates, the disease control rate (DCR) was 86% with the 180 mg arm and 82% in the 90 mg arm. The confirmed ORR for the 90 mg dose was 42%.

Median PFS in the 90 mg arm was 9.2 months. There was a 45% reduction in the risk of progression or death with the 180 mg dose of brigatinib versus the 90 mg dose (HR, 0.55; 95% CI, 0.35-0.86). The 1-year PFS rate was 39% with the 90 mg dose and 54% in the 180 mg arm.

The 1-year overall survival (OS) rate was 71% with the 90 mg dose versus 80% with the larger 180 mg dose, representing a non-statistically significant 43% reduction in the risk of death with the larger dose (HR, 0.57; 95% CI, 0.31-1.05). The median OS had not yet been reached in both arms.

The intracranial DCR was 83% with the 180 mg dose of brigatinib. In those with brain metastases treated with the 90 mg dose, the intracranial ORR was 36%. The intracranial DCR was 88%. The median PFS in this group was 15.6 months with the 90 mg dose versus not reached in the 180 mg arm (HR, 0.66; 95% CI, 0.32-1.35).

The most common all-grade treatment-emergent adverse events (AEs) in the 90 mg and 180 mg arms, respectively, were nausea (40% and 33%), diarrhea (38% and 19%), cough (34% and 18%), and headache (27% and 28%). The most common grade ≥3 treatment emergent AEs in the 90 mg and 180 mg arms, respectively, were increased blood creatinine phosphokinase (9% and 3%) and hypertension (6% each).

There was a subset of patients (6%) who experienced early onset pulmonary AEs, which occurred within a median of 2 days (range, 1-9). These events occurred prior to dose escalation in the 180 mg arm. Overall, 8% and 3% of patients discontinued treatment due to AEs in the 90 mg and 180 mg arms, respectively.

“With the completion of the brigatinib submission this week, we are excited by its potential, if approved, to offer additional hope to patients and their families,” Paris Panayiotopoulos, president and chief executive officer of Ariad, said in a statement. “We are thankful to the patients and physicians who participated in the clinical trials of brigatinib. We remain grateful to the FDA for granting brigatinib a breakthrough designation and the benefit of a rolling submission process, unique to the US regulatory system.”

The phase III ALTA-1L study has been initiated to compare brigatinib with crizotinib as a frontline therapy for patients with ALK-positive NSCLC. This study is assessing the 180 mg regimen of brigatinib (NCT02737501).

Kim D-W, Tiseo M, Ahn M-J, et al. Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): First report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA). J Clin Oncol. 2016;34 (suppl; abstr 9007).

The application was completed following a rolling submission of data, which was permitted as part of a breakthrough therapy designation that was received in October 2014. Ariad has requested a priority review for the ALK inhibitor, under which the FDA would make a decision 4 months earlier than a standard review. The FDA will assign a regulatory timeline within 60 days.