Approximately 3–5% of patients with non-small cell lung cancer (NSCLC) have oncogenic anaplastic lymphoma kinase (
ALK) rearrangements [
1‐
3], which leads to dysregulation and incorrect signaling through the ALK kinase domain [
4,
5].
ALK-rearrangement targeted therapies, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib, have improved outcomes for patients with
ALK-positive NSCLC [
6‐
14]. Although first- (crizotinib) and next-generation (alectinib, ceritinib, brigatinib, and lorlatinib) ALK inhibitors show high initial activity, resistance eventually develops. The central nervous system has been identified as the primary site of failure in most patients with crizotinib resistance, likely owing to its limited blood–brain barrier penetration [
14]. These findings highlight the need for highly potent ALK inhibitors with enhanced blood–brain barrier penetration, acceptable tolerability, and the potential to overcome resistance in order to provide further clinical benefit for patients with
ALK-activating mutations and rearrangements [
15].
Owing to the resistance associated with the first-generation (crizotinib) and second-generation (alectinib and ceritinib) ALK inhibitors, brigatinib was developed to achieve potent activity against a broad range of
ALK resistance mutations [
16]. In preclinical studies, brigatinib showed higher potency and the capability to overcome mechanisms of resistance associated with crizotinib [
16]. In a single-arm, open-label, phase I/II study (NCT01449461) in patients with advanced malignancies, which included a high proportion (58%) of patients with
ALK-positive NSCLC, brigatinib demonstrated promising clinical activity and an acceptable safety profile in both crizotinib-treated and ALK inhibitor-naive patients with
ALK-positive NSCLC [
17]. Among those patients with
ALK+ NSCLC, brigatinib daily doses ranged from 60 to 180 mg. The confirmed objective response rate (ORR) was 62 and 100% in crizotinib-pretreated and crizotinib-naive patients, respectively, and the median progression-free survival (PFS) was 13.2 months in crizotinib-pretreated patients and was not reached in crizotinib-naive patients [
17]. The favorable data from this phase I/II study supported further clinical development of brigatinib in the randomized, multicenter, phase II ALTA (
ALK in
Lung Cancer
Trial of
AP26113) study (NCT02094573) [
10]. In ALTA, treatment with brigatinib 180 mg once daily (with a 7-day lead-in at 90 mg once daily) resulted in a confirmed ORR of 57% and a median PFS of 16.7 months [
18]. The brigatinib titration dosing regimen (i.e., 180 mg once daily with a 7-day lead-in at 90 mg once daily) was selected as the recommended posology because starting treatment at the lower initial dose mitigated the risk of moderate-to-severe pulmonary adverse events that had been observed in a small subset of patients within the first 7 days after initiation of higher doses of brigatinib, while maintaining the efficacy associated with the 180-mg once-daily dose [
17,
19,
20]. The results of ALTA led to the initial accelerated approval of brigatinib in the USA for patients with crizotinib-refractory advanced
ALK-positive NSCLC in April 2017 [
21]. Subsequently, brigatinib received full approval for first-line use based on favorable data from the pivotal, open-label, randomized phase III ALTA-1L study (NCT02737501) [
20]. In ALTA-1L, brigatinib demonstrated superior efficacy against systemic and intracranial disease compared with crizotinib [
20]. At the final analysis, with a median follow-up of 40.4 months in the brigatinib arm, brigatinib continued to provide clinically meaningful improvements in efficacy (median PFS: brigatinib, 24 months; crizotinib, 11.1 months; hazard ratio, 0.48; log-rank
p < 0.0001) and acceptable tolerability compared with crizotinib [
11]. Brigatinib also has demonstrated robust clinical activity in the central nervous system. Among patients treated with 180 mg once daily (7-day lead-in at 90 mg once daily) in ALTA, independent review committee–assessed intracranial response in patients with measurable brain metastases was 67% and median intracranial PFS (iPFS) in patients with baseline brain metastases was 18.4 months. In patients treated with brigatinib in ALTA-1L, the blinded independent review committee–assessed confirmed rate of intracranial ORR (iORR) in patients with measurable baseline brain metastases was 78% and median iPFS in patients with baseline brain metastases was 24.0 months. The safety profile of brigatinib was consistent in ALTA-1L compared with ALTA, with no new safety concerns identified [
11,
22].