Patterns of Metastatic Spread and Mechanisms of Resistance to Crizotinib in <i>ROS1</i>-Positive Non-Small-Cell Lung Cancer.

Abstract

The ROS1 tyrosine kinase is activated through <i>ROS1</i> gene rearrangements in 1-2% of non-small cell lung cancer (NSCLC), conferring sensitivity to treatment with the ALK/ROS1/MET inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among <i>ROS1</i>-positive patients are limited. We reviewed clinical and radiographic imaging data of patients with <i>ROS1</i>- and <i>ALK</i>-positive NSCLC in order to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we also analyzed repeat biopsies from a cohort of <i>ROS1</i>-positive patients progressing on crizotinib. We identified 39 and 196 patients with advanced <i>ROS1-</i> and <i>ALK-</i>positive NSCLC, respectively. <i>ROS1</i>-positive patients had significantly lower rates of extrathoracic metastases (<i>ROS1</i> 59.0%, <i>ALK</i> 83.2%, <i>P</i>=0.002), including lower rates of brain metastases (<i>ROS1</i> 19.4%, <i>ALK</i> 39.1%; <i>P</i> = 0.033), at initial metastatic diagnosis. Despite similar overall survival between <i>ALK-</i> and <i>ROS1-</i>positive patients treated with crizotinib (median 3.0 versus 2.5 years, respectively; <i>P</i>=0.786), <i>ROS1-</i>positive patients also had a significantly lower cumulative incidence of brain metastases (34% vs. 73% at 5 years; <i>P</i><0.0001). Additionally, we identified 16 patients who underwent a total of 17 repeat biopsies following progression on crizotinib. <i>ROS1</i> resistance mutations were identified in 53% of specimens, including 9/14 (64%) non-brain metastasis specimens. <i>ROS1</i> mutations included: G2032R (41%), D2033N (6%), and S1986F (6%). Compared to <i>ALK</i> rearrangements, <i>ROS1</i> rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. <i>ROS1</i> resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, underscoring the need to develop novel ROS1 inhibitors with activity against these resistant mutants.