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

Abstract Background Lorlatinib, a potent, brain-penetrant, third-generation ALK tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs. Patients and methods In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial, and extracranial antitumor activity were assessed independently per modified RECIST v1.1. Results Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B–5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B−5, the ORR (95% CI) was 39.6% (31.4−48.2), intracranial ORR (IC-ORR) was 56.1% (42.4−69.3), extracranial ORR (EC-ORR) was 36.7% (28.7−45.3), median duration of response (DOR) was 9.6 months (5.6−16.7; IC-DOR, 12.4 [6.0−37.1]; EC-DOR, 9.7 [6.1−33.3]), median PFS was 6.6 (5.4−7.4) months, and median OS was 20.7 months (16.1−30.3). In EXP3B, the ORR was 42.9% (24.5−62.8), the IC-ORR was 66.7% (29.9−92.5), and the EC-ORR was 32.1% (15.9−52.4). In EXP4−5, the ORR was 38.7% (29.6−48.5), the IC-ORR was 54.2% (39.2−68.6), and the EC-ORR was 37.8% (28.8−47.5). Conclusions Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post−second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.