Final Overall Survival and Long-Term Safety of Lorlatinib in Patients With ALK-Positive NSCLC From the Pivotal Phase 2 Study: A Brief Report

Introduction: Lorlatinib is a potent, brain-penetrant, third-generation inhibitor of anaplastic lymphoma kinase (ALK) and ROS1 tyrosine kinases with broad coverage of ALK resistance mutations. We present the overall survival (OS) and long-term safety of lorlatinib in patients with advanced ALK-positive NSCLC from the final analyses of the pivotal phase 2 study. Methods: Adults with ALK-positive NSCLC, enrolled in expansion cohorts (EXPs) on the basis of prior therapy (EXP1-5), received lorlatinib 100 mg orally once daily in continuous 21-day cycles. The primary endpoint was the objective response rate; secondary endpoints included OS and safety. Results: Thirty patients were enrolled in EXP1 (treatment naïve), 59 in EXP2-3A (disease progression after crizotinib ± chemotherapy), 28 in EXP3B (disease progression after one second-generation ALK tyrosine kinase inhibitor [TKI] ± chemotherapy), 111 in EXP4-5 (disease progression after ≥2 ALK TKIs ± chemotherapy), and 139 in EXP3B-5 (disease progression after ≥1 ALK TKI ± chemotherapy). Median OS was not reached (NR) (95% confidence interval [CI]: NR–NR) in EXP1, NR (95% CI: 51.5–NR) in EXP2-3A, 37.4 months (95% CI: 12.3–NR) in EXP3B, 19.2 months (95% CI: 15.4–30.2) in EXP4-5, and 20.7 months (95% CI: 16.1–30.3) in EXP3B-5. All-cause adverse events leading to dose reduction were reported in 77 patients (28%), temporary treatment discontinuation in 158 patients (57%), and permanent discontinuation in 35 patients (13%). Conclusions: After a minimum follow-up of five years, final analyses from the global phase 2 study confirmed substantial activity, prolonged OS, and generally consistent safety findings with lorlatinib in treatment-naïve and previously treated patients with ALK-positive NSCLC. ClinicalTrials.gov