Abstract
Lorlatinib achieved systemic and intracranial responses in patients with ALK- and ROS1-positive NSCLC.
Major finding: Lorlatinib achieved systemic and intracranial responses in patients with ALK- and ROS1-positive NSCLC.
Clinical relevance: Lorlatinib achieved objective responses in a proportion of heavily pretreated ALK-positive patients.
Impact: Lorlatinib may be an effective therapy for patients who have failed on available targeted therapies.
Patients with ALK- or ROS1-rearranged non–small cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitors (TKI) including the standard first-line therapy crizotinib, but resistance eventually develops. The second-generation ALK TKIs ceritinib, alectinib, and brigatinib can overcome crizotinib resistance in ALK-rearranged tumors, but next-generation inhibitors are needed when resistance inevitably develops. Lorlatinib is a third-generation reversible ATP-competitive TKI, designed to cross the blood–brain barrier, that potently and selectively targets ALK and ROS1. In preclinical studies lorlatinib had antitumor activity in a variety of ALK/ROS-positive xenograft models, including tumors with the ALK Gly1202Arg or ROS1 Gly2032Arg resistance mutations and ALK-positive intracranial tumors. Based on these findings, Shaw and colleagues enrolled 54 patients with locally advanced or metastatic NSCLC (41 with ALK rearrangements, 12 with ROS1 rearrangements, and 1 with unconfirmed ALK/ROS1 status) in a first-in-human, open-label, phase I dose-escalation study to assess the safety, maximum tolerated dose, and antitumor activity of lorlatinib. The primary endpoint was dose-limiting toxicity, and secondary endpoints included safety, pharmacokinetics, and overall response. Overall, 19 of 41 (46%) ALK-positive patients achieved an objective response (3 complete and 16 partial responses), including 11 of 26 (42%) patients who had been previously treated with two or more TKIs, including a second-generation ALK TKI. Partial responses were observed in 6 of 12 (50%) of patients with ROS1 rearrangements. Of the 24 patients with measurable central nervous system (CNS) lesions, 11 (46%) had intracranial objective responses. Lorlatinib was well tolerated and the maximum tolerated dose was not reached. One dose-limiting toxicity occurred at 200 mg, and the recommended phase II dose was selected as 100 mg daily. Collectively, these findings demonstrate that lorlatinib is well tolerated and has systemic and intracranial antitumor activity in patients with advanced ALK- or ROS1-rearranged NSCLC. Lorlatinib may be an effective therapy for ALK- or ROS1-positive patients who have relapsed on available TKIs, including patients with progressive CNS metastasis.
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