FDA Approves Brigatinib for ALK-Positive NSCLC

The FDA has granted brigatinib (Alunbrig) an accelerated approval as a treatment for patients with metastatic ALK-positive non—small cell lung cancer (NSCLC) who are resistant to prior crizotinib (Xalkori).

The approval is based on findings from the phase II ALTA trial, in which the confirmed objective response rate for brigatinib at 180 mg daily was 53% (95% CI, 43-62) and the median progression-free survival (PFS) was 13.8 months.

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 48% (95% CI, 39-58) 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. The median duration of response was 13.8 months in both arms.

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 nonstatistically 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%. In those with brain metastases treated with the 90-mg dose (n = 26), the intracranial ORR was 42% (95% CI, 23-63).

The median intracranial duration of response was not estimable in the 90-mg arm and was 5.6 months among patients receiving 180 mg. In the group achieving an intracranial response, the response lasted for at least 4 months in 78% and 68% of patients in the 90- and 180-mg arms, respectively.

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 (3% and 9%) 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 180 mg and 90 mg arms, respectively.

The accelerated approval of brigatinib is contingent upon results from a confirmatory trial. 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).