Early-Onset Pulmonary Events Associated With Brigatinib Use in Advanced NSCLC.

Introduction: We evaluated pulmonary adverse events observed within 7 days after drug initiation in phase 1 to phase 3 studies of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib.

Methods: The phase 1/2 study enrolled patients with advanced malignancies (dosage range, 30 mg-300 mg once a day); the phase 2 ALK in Lung Cancer Trial of AP26113 study treated patients with advanced ALK+ NSCLC postcrizotinib at either 90 mg once a day or 90 mg once a day for 7 days followed by 180 mg once a day; and the phase 3 ALK in Lung Cancer Trial of Brigatinib in first Line study treated inhibitor-naive patients with ALK+ NSCLC with brigatinib (180 mg once a day [with 7-day lead-in at 90 mg once a day]) or crizotinib (250 mg twice a day). Early-onset pulmonary events (EOPEs) at least possibly associated with brigatinib were captured.

Results: In the phase 1/2, ALK in Lung Cancer Trial of AP26113, and ALK in Lung Cancer Trial of Brigatinib in first Line studies, 8% (11/137), 6% (14/219), and 3% (4/136) of patients, respectively, had at least possible EOPEs on brigatinib, with frequency appearing to increase with the starting dosage. Across trials, at the 90-mg once-a-day starting dosage (alone or step-up dosing), 4.5% of patients (20/440) had at least possible events (median time to onset, 2 days). A total of 12 patients (3%) had grade 3 or higher events leading to brigatinib discontinuation. Seven patients (1.5%) had grade 1 to grade 2 events and successfully continued brigatinib with or without brigatinib interruption, steroids, or supplemental oxygen. In pooled analysis of these trials, occurrence of EOPEs was significantly associated with continuous 10-year increases in patient age in unadjusted logistic regression analysis, and with Eastern Cooperative Oncology Group performance status and number of previous regimens in multivariate regression.

Conclusions: Clinically apparent EOPEs can occur within days of commencing brigatinib in a subset of patients with NSCLC. Identifying clinical parameters associated with a higher risk of developing such events may help mitigate these events.