Brigatinib a potential standard treatment alternative for treatment-naive ALK+ NSCLC

In patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK+ NSCLC) who were ALK inhibitor-naïve, brigatinib showed superior efficacy and safety over crizotinib, according to the final results of the phase III ALTA-1L* trial presented at ELCC 2022.

Despite the superiority of the first-generation ALK inhibitor crizotinib over chemotherapy (CT) in patients with treatment-naïve advanced ALK+ NSCLC, most patients develop progressive disease within a year owing to acquired ALK resistance mutations and/or poor CNS** penetration. [N Engl J Med 2014;371:2167-2177; N Engl J Med 2013;368:2385-2394; Clin Cancer Res 2016;22:5527-5538]

Given the broad preclinical activity of the CNS-active ALK inhibitor brigatinib against ALK resistance mutations, the team sought to evaluate its performance in ALTA-1L. The initial and second interim analyses demonstrated the superiority of brigatinib over crizotinib in terms of progression-free survival (PFS). [N Engl J Med 2018;379:2027-2039; J Clin Oncol 2020;38:3592-3603]

Brigatinib continued to prevail over crizotinib in terms of PFS in the final analysis (median 24.0 vs 11.1 months; hazard ratio [HR] for disease progression or death, 0.48 [BIRC***-assessed] and median 30.8 vs 9.2 months; HR, 0.43 [investigator-assessed]; p<0.0001 for both). [ELCC 2022, abstract 29P]

Further stratification by brain metastasis (median 24.0 vs 5.6 months; HR, 0.25; p<0.0001 [with metastasis] and median 29.3 vs 15.6 months; HR, 0.62; p=0.0131 [without metastasis]) and prior CT (median 32.2 vs 11.0 months; HR, 0.45; p=0.0093 [with CT] and median 24.0 vs 11.1 months; HR, 0.50; p=0.0002 [without CT]) also favoured brigatinib over crizotinib in terms of PFS.

Brigatinib continued to demonstrate high intracranial efficacy vs crizotinib, both in the overall cohort (median 44.1 vs 21.2 months; HR, 0.44) and among those with baseline brain metastases (median 24.0 vs 5.5 months; HR, 0.29; p<0.0001 for both).

Patients on brigatinib also had significantly longer durations of response (DoR) vs those on crizotinib (median 33 vs 14 months [BIRC] and 37 vs 11 months [investigator]), as well as restricted mean DoR up to 40 months (21 vs 13 months; p<0.0001). “Patients in the brigatinib arm had an expected mean DoR 8 months longer than those [on crizotinib],” said Professor Marcello Tiseo from the University Hospital of Parma, Parma, Italy, and colleagues.

Median time to worsening of EORTC QLQ-C30^# Global Health Status was longer with brigatinib vs crizotinib (median 26.7 vs 8.3 months; HR, 0.69; p=0.047), underlining the benefit of the former vs the latter in terms of quality of life.

Despite more grade 3/4 adverse events (AEs) with brigatinib vs crizotinib (70 percent vs 56 percent), treatment discontinuation rates owing to AEs were similar (13 percent vs 9 percent). The grade 3/4 AEs tied to brigatinib were primarily due to asymptomatic elevations in blood chemistry, noted the researchers.

ALTA-1L included 275 individuals with stage IIIB/IV ALK+ NSCLC who had not previously received an ALK inhibitor, but had ≤1 prior systemic therapy for locally advanced/metastatic NSCLC. They were randomized 1:1 to receive either brigatinib 180 mg QD (with 7-day lead-in at 90 mg QD) or crizotinib 250 mg BID. Following BIRC-assessed disease progression, 47 percent of crizotinib recipients crossed over to brigatinib.

At the final analysis, overall survival (OS) in the intention-to-treat cohort was still immature (HR, 0.81; p=0.331). Among participants with baseline brain metastases, the HR for OS with brigatinib was 0.43 despite the high crossover rate (46 percent). “[This suggests] a survival benefit in patients with brain metastases who received brigatinib as the first ALK inhibitor,” said the researchers.

“[Our final results were] consistent with the two interim analyses [and] confirm the significant improvement in PFS with brigatinib vs crizotinib in ALK+ NSCLC with no new safety signals,” said Tiseo and colleagues. “These results support brigatinib as a standard treatment option for treatment-naive ALK+ NSCLC.”