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

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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.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.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).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.

View the full article @ Annals of oncology : official journal of the European Society for Medical Oncology

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Authors: E Felip, A T Shaw, A Bearz, D R Camidge, B J Solomon, J R Bauman, T M Bauer, S Peters, F Toffalorio, A Abbattista, H Thurm, G Peltz, R Wiltshire, B Besse


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