Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion–Positive Lung Cancer

摘要: Purpose: Current standard initial therapy for advanced, ROS proto-oncogene 1, receptor tyrosine kinase fusion (ROS1)-positive (ROS1+) non–small cell lung cancer (NSCLC) is crizotinib or entrectinib. Lorlatinib, a next-generation anaplastic lymphoma kinase/ROS1 inhibitor, recently demonstrated efficacy in ROS1+ NSCLC, including crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance disease remain poorly understood. Here, we assessed to and lorlatinib. Experimental Design: Biopsies from patients with NSCLC progressing on were profiled by genetic sequencing. Results: From 55 patients, 47 post-crizotinib 32 post-lorlatinib biopsies assessed. Among 42 28 analyzed at distinct timepoints, ROS1 mutations identified 38% 46%, respectively. G2032R was the most commonly occurring mutation approximately one third cases. Additional included D2033N (2.4%) S1986F L2086F (3.6%), G2032R/L2086F G2032R/S1986F/L2086F S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference lorlatinib, crizotinib, entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, ROS1S1986F/G2032R/L2086F refractory but sensitive A patient progression received cabozantinib nearly 11 months control. lorlatinib-resistant biopsies, also MET amplification (4%), KRAS G12C NRAS MAP2K1 (4%). Conclusions: mediate more than cases, underscoring importance developing inhibitors potency against these mutations, L2086F. Continued efforts are needed elucidate ROS1-independent mechanisms.