FDA Approval Sought for Brigatinib in ALK-Positive NSCLC

Paris Panayiotopoulos

Rolling submission of a new drug application (NDA) for brigatinib (AP26113) has been initiated for patients with advanced ALK-positive non—small cell lung cancer (NSCLC) who are resistant to prior crizotinib (Xalkori), according to a statement from the drug's developer, Ariad Pharmaceuticals.

The rolling submission of the NDA, which was allowed as part of a breakthrough therapy designation that was received in October 2014, is based on findings from the ongoing phase II ALTA trial. In findings presented at the 2016 ASCO Annual Meeting from the ALTA trial, the confirmed objective response rate (ORR) for brigatinib at 180 mg daily was 54% and the median progression-free survival (PFS) was 12.9 months.

The company plans to complete the rolling submission within the third quarter of 2016, according to a statement. The FDA will assign a review timeline within 60 days, once the submission is complete. Ariad is requesting a priority review from the FDA, under which the FDA would render a decision within 6 months rather than 10 months for a standard review.

“We are ahead of our previously announced schedule for initiating the submission of our brigatinib NDA to the FDA and we are grateful to have breakthrough status from the FDA, which provides the opportunity to utilize the rolling submission process,” stated Paris Panayiotopoulos, president and chief executive officer of Ariad. “If approved, we believe that brigatinib will become an important new medicine for ALK+ NSCLC patients who have become resistant or intolerant to prior crizotinib therapy and will offer additional hope to these patients and their families.”

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%. In the 180 mg dose group, those who had not received chemotherapy had an ORR of 52%. There were 4 confirmed 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 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.

In those with measurable, active brain metastases treated with the 180 mg dose (n = 18), the intracranial ORR was 67%. The intracranial DCR was 83%. 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).

"Brigatinib has the potential to be a promising new treatment option for patients with crizotinib-resistant ALK-positive NSCLC," lead investigator Dong-Wan Kim MD, PhD, Seoul National University Hospital, said when he presented the data at ASCO. "Brigatinib demonstrated substantial efficacy and an acceptable safety profile in both arms."

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.

"There was a subset of pulmonary AEs with early onset, including dyspnea, hypoxia, cough, or pneumonia that occurred in 6% of patients," said Kim. "Although pathophysiology is unclear, there is a trend toward lower frequency of AEs with the greater than or equal two 7 day crizotinib washout compared with less than 7 day washout."

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 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.