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

作者：Jessica J. Lin, Noura J. Choudhury, Satoshi Yoda, Viola Weijia Zhu, Ted W. Johnson, Ramin Sakhtemani, Ibiayi Dagogo‐Jack, Subba Rao Digumarthy, Charlotte Lee, Andrew Do, Jennifer L H Peterson, Kylie Prutisto-Chang, Wafa Malik, Harper Hubbeling, Adam Langenbucher, Adam Jacob Schoenfeld, Christina J. Falcon, Jennifer S. Temel, Lecia Van Dam Sequist, Beow Yong Yeap, Jochen K. Lennerz, Alice Tsang Shaw, Michael S. Lawrence, Sai‐Hong Ignatius Ou, Aaron N. Hata, Alexander Edward Dela Cruz Drilon, Justin F. Gainor · 发表于：Clinical Cancer Research · 年份：2021 · DOI：10.1158/1078-0432.ccr-21-0032 · 被引用次数：144 · 研究领域：Lung Cancer Treatments and Mutations、PI3K/AKT/mTOR signaling in cancer、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Abstract 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 in crizotinib-pretreated patients. However, mechanisms of lorlatinib resistance in ROS1+ disease remain poorly understood. Here, we assessed mechanisms of resistance to crizotinib and lorlatinib. Experimental Design: Biopsies from patients with ROS1+ NSCLC progressing on crizotinib or lorlatinib were profiled by genetic sequencing. Results: From 55 patients, 47 post-crizotinib and 32 post-lorlatinib biopsies were assessed. Among 42 post-crizotinib and 28 post-lorlatinib biopsies analyzed at distinct timepoints, ROS1 mutations were identified in 38% and 46%, respectively. ROS1 G2032R was the most commonly occurring mutation in approximately one third of cases. Additional ROS1 mutations included D2033N (2.4%) and S1986F (2.4%) post-crizotinib and L2086F (3.6%), G2032R/L2086F (3.6%), G2032R/S1986F/L2086F (3.6%), and S1986F/L2000V (3.6%) post-lorlatinib. Structural modeling predicted ROS1L2086F causes steric interference to lorlatinib, crizotinib, and entrectinib, while it may accommodate cabozantinib. In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib. A patient ...