LAUSR

Simple Summary This analysis assesses the efficacy of brigatinib, a next-generation ALK inhibitor in ALK+ advanced non-small cell lung cancer (aNSCLC) included in the brigatinib French Early-Access Program (1 August 2016–21 January 2019), with a focus on post-brigatinib lorlatinib efficacy. With a median follow-up of 40.4 months (95% CI, 38.4–42.4), the median investigator-assessed PFS of the 183 included patients was 7.4 months (5.9–9.6) and overall survival from brigatinib initiation was 20.3 (15.6–27.6) months. For patients who received 1 (n = 23), 2 (n = 146) or 3 (n = 14) ALKi(s) before brigatinib, the median overall survival was 33 (9.7—not reached), 20.3 (15.7–28.7) and 18.1 (3.3–24.5) months, respectively. Ninety-two (50.3%) patients received one agent(s) post-brigatinib; 68 (73.9%) of them received lorlatinib: 51 (75%) immediately post-brigatinib. With a median follow-up of 29.9 months (25.7–33.1), the median overall survival from lorlatinib initiation was 14.1 months (10.3–19.2). Analysis results confirmed brigatinib effectiveness in a population of heavily pretreated ALK+ positive aNSCLC patients and the activity of lorlatinib after brigatinib. We confirm that neither the manuscript nor any parts of its content are currently under consideration or published in another journal. All authors have approved the manuscript and agree with its submission to cancers. Abstract Brigatinib is a next-generation ALK inhibitor (ALKi) that shows efficacy in ALK inhibitor naïve and post-crizotinib ALK+ advanced NSCLCs (aNSCLCs). The efficacy of brigatinib was retrospectively assessed in patients with aNSCLCs included in the brigatinib French Early-Access Program (1 August 2016–21 January 2019). The primary endpoint was investigator-assessed progression-free survival (invPFS) and the primary analysis was updated in 2021 with a longer follow-up, focused on post-brigatinib lorlatinib efficacy. Sixty-six centers included 183 patients: median age 60 ± 12.7 years; 78.3% never/former smokers; median of 3 ± 1 previous lines and 2 ± 0.5 ALKis; 37.1% ECOG PS 2 and 55.6% >3 metastatic sites. The median follow-up from brigatinib initiation was 40.4 months (95% CI 38.4–42.4). InvPFS was 7.4 months (95% CI 5.9–9.6), median duration of treatment (mDOT) was 7.3 months (95% CI 5.8–9.4) and median overall survival (mOS) was 20.3 months (95% CI 15.6–27.6). The median DOT and OS from brigatinib initiation tend to decrease with the number of ALK inhibitors used in previous lines of therapy. Based on the data collected, 92 (50.3%) patients received ≥1 agent(s) post-brigatinib and 68 (73.9%) of them received lorlatinib, with 51 (75%) immediately receiving it post-brigatinib, 12 (17.6%) receiving it after one and 5 (7.4%) after ≥2 subsequent treatments. The median follow-up was 29.9 (95% CI 25.7–33.1) months. Lorlatinib mDOT was 5.3 (95% CI 3.6–7.6) months with a median OS from lorlatinib initiation of 14.1 (95% CI 10.3–19.2) months. The results of the brigALK2 study confirm the efficacy of brigatinib in a population of heavily pretreated ALK+ aNSCLC patients and provide new data on the activity of lorlatinib after brigatinib.