Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs

•Lorlatinib had robust overall and intracranial (IC) activity against ALK+ advanced NSCLC after second-generation ALK TKIs.•Objective responses occurred independently of prior chemotherapy treatment.•Elevated IC versus extracranial ORR was observed, especially in patients with fewer treatment lines.•Competing risk analysis showed that probability first event being CNS progression lower than non-CNS progression.•Exploratory analyses alectinib, brigatinib, or ceritinib as the last TKI similar ORRs. BackgroundLorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine inhibitor (TKI), has substantial ALK-positive non-small-cell lung cancer (NSCLC). This study assessed overall, intracranial, efficacy lorlatinib progressed on TKIs.Patients methodsIn ongoing phase II (NCT01970865), treated ?1 ± were enrolled expansion cohorts (EXP) based history. Overall, antitumor per modified Response Evaluation Criteria Solid Tumors (RECIST) v1.1.ResultsOf 139 (EXP3B-5), 28 received one (EXP3B), 65 two TKIs (EXP4), 46 three (EXP5). In EXP3B-5, objective response rate (ORR) [95% confidence intervals] 39.6% (31.4-48.2), (IC-ORR) 56.1% (42.4-69.3), (EC-ORR) 36.7% (28.7-45.3), median duration (DOR) 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], progression-free survival 6.6 (5.4-7.4) months, 20.7 (16.1-30.3). EXP3B, 42.9% (24.5-62.8), IC-ORR 66.7% (29.9-92.5), EC-ORR 32.1% (15.9-52.4). EXP4 EXP5, 38.7% (29.6-48.5), 54.2% (39.2-68.6), 37.8% (28.8-47.5).ConclusionsLorlatinib clinically meaningful post-second-generation setting, elevated ORR, particularly lines therapy. Lorlatinib, TKIs. v1.1. Of (28.8-47.5). Lorlatinib