A randomized, open-label comparison of lorlatinib versus crizotinib as first-line treatment for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer

Abstract

Background: Lorlatinib and crizotinib are oral tyrosine kinase inhibitors with activity against ALK and ROS1 fusion proteins. Crizotinib is well tolerated and has superior efficacy compared to chemotherapy for treatment of patients (pts) with advanced ALK+ NSCLC. However, resistance to crizotinib can develop, and the central nervous system (CNS) is often a site of disease relapse. Lorlatinib is a CNS penetrant and has potent activity against de novo fusions and kinase domain resistance mutations. Lorlatinib has shown clinical activity in pts previously treated with crizotinib and other ALK inhibitors, including pts with progressive CNS metastases. This study aimed to determine if lorlatinib is superior to crizotinib in prolonging progression-free survival (PFS) in treatment-naïve pts with advanced ALK+ NSCLC and to identify candidate biomarkers predictive of clinical efficacy or treatment resistance. Trial design: This global, multicenter, open-label phase 3 study will enroll ≥280 treatment- naïve pts. Eligible pts must be aged ≥18 years, have Eastern Cooperative Oncology Group performance status of 0-2 and ≥1 measurable extracranial target lesion not previously treated with radiotherapy. Pts with asymptomatic brain metastases are eligible. Pts will be randomized (1:1) to lorlatinib 100 mg once daily or crizotinib 250 mg twice daily and stratified by presence of brain metastases (yes/no) and ethnicity (Asian/non-Asian). Treatment will continue until disease progression, pt refusal, or unacceptable toxicity. Crossover between treatment arms will not be permitted. The primary endpoint is PFS based on blinded independent central review (BICR) using RECIST v1.1. Secondary endpoints include PFS based on investigator assessment (IA), overall survival, objective response (OR) by BICR and IA, intracranial (IC) OR, IC time to progression, duration of response, time to response by BICR, tumor tissue and peripheral blood circulating free DNA biomarker assessment, safety, and pt-reported health-related outcomes.