Brigatinib after lorlatinib and/or chemotherapy following first-line alectinib in ALK-rearranged NSCLC: Cohort B of the WJOG11919L/ABRAID study.

8606 Background: As survival improves in ALK-rearranged NSCLC, patients increasingly receive multiple lines of therapy; however, evidence to guide later-line ALK-TKI sequencing in the third line and beyond remains limited. Brigatinib has activity against multiple ALK resistance mutations, yet data on its effectiveness after progression on first-line alectinib and subsequent lorlatinib and/or chemotherapy—and on associated plasma ctDNA biomarkers—remain scarce. Methods: WJOG11919L/ABRAID Cohort B is a prospective, multicenter observational study enrolling patients with ALK-rearranged NSCLC who received brigatinib after lorlatinib and/or chemotherapy following first-line alectinib. Effectiveness and safety were summarized descriptively. Pretreatment plasma ctDNA was analyzed with the PGDx Elio Plasma Resolve panel. The data cutoff was September 26, 2024. Results: Twenty-five patients were analyzed (median age, 64 years; all adenocarcinoma); ECOG PS was 0-1/2-3 in 22 (88.0%)/3 (12.0%). Baseline CNS metastases were present in 10 patients. After alectinib, 13 patients received lorlatinib and 14 received platinum-based chemotherapy (overlap, n=2). Median follow-up was 12.7 months. Efficacy outcomes overall and by prior lorlatinib exposure are summarized in the Table. 23 patients had discontinued brigatinib, including 21 due to PD. Pretreatment ctDNA was evaluable in 24 patients: ALK mutations were detected in 4 (including 3 with prior lorlatinib), and compound ALK mutations (G1202R/I1171M/L1204V and D1203N/L1196M) were identified in 2, both after lorlatinib. In exploratory analyses, among the 3 patients with prior lorlatinib and detectable ALK mutations, all experienced early progression or death within 10 weeks of brigatinib initiation. Pneumonitis/ILD occurred in 1 patient (4%; grade 4). No new safety signals were observed. Conclusions: Brigatinib showed clinically meaningful activity with a manageable safety profile, providing durable disease control in a subset of patients previously treated with alectinib followed by lorlatinib and/or chemotherapy. Outcomes appeared less favorable after prior lorlatinib, although some patients derived benefit. In exploratory plasma ctDNA analyses among patients with prior lorlatinib, detectable ALK mutations were associated with less favorable outcomes and should be validated in larger cohorts. Clinical trial information: UMIN000042439. Efficacy outcomes overall and by prior lorlatinib exposure. Endpoint Overall (n=25) Prior lorlatinib (n=13) No prior lorlatinib (n=12) ORR, % (95% CI) 32.0 (14.9–53.5) 30.8 (12.7–57.6) 33.3 (13.8–60.9) DCR, % (95% CI) 60.0 (38.7–78.9) 38.5 (17.7–64.5) 83.3 (55.2–95.3) mPFS, mo (95% CI) 4.8 (2.2–12.7) 2.2 (1.2–18.8) 8.9 (2.3–15.6) 12-mo PFS, % 32.0 30.8 33.3 mOS, mo (95% CI) 13.7 (7.29–NR) 10.8 (3.7–NR) 16.2 (7.1–NR) 12-mo OS, % 56.0 38.5 75.0