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

• Published in: Annals of oncology Vol. 32; no. 5; pp. 620 - 630
• Main Authors: Felip, E., Shaw, A.T., Bearz, A., Camidge, D.R., Solomon, B.J., Bauman, J.R., Bauer, T.M., Peters, S., Toffalorio, F., Abbattista, A., Thurm, H., Peltz, G., Wiltshire, R., Besse, B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2021
• Subjects: ALK; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Humans; Lactams, Macrocyclic; Lorlatinib; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; non-small-cell lung cancer; Protein Kinase Inhibitors - therapeutic use; Receptor Protein-Tyrosine Kinases - genetics; second-generation ALK TKIs; third-generation ALK TKIs; ALK; Lorlatinib; second-generation ALK TKIs; third-generation ALK TKIs; non-small-cell lung cancer
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1016/j.annonc.2021.02.012

Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (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 Response Evaluation Criteria in Solid Tumors (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 objective response rate (ORR) [95% confidence intervals] 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 progression-free survival was 6.6 (5.4-7.4) months, and median overall survival 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 and EXP5, 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.
•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 of first event being CNS progression was lower than non-CNS progression.•Exploratory analyses of prior alectinib, brigatinib, or ceritinib as the last ALK TKI showed similar overall and IC ORRs.