Figure 5.

Our approach to the treatment of advanced ROS1-rearranged lung cancer. After progression on first-line crizotinib, a repeat tumor biopsy is strongly recommended if feasible and safe, in order to determine the mechanism of crizotinib resistance. Liquid biopsy may be an alternative option if tumor biopsy is not feasible. The detection of a secondary ROS1 resistance mutation can inform the selection of next-line therapy. For example, in the case of a G2032R mutation, ROS1 inhibitors that have limited activity against G2032R based on preclinical data (see Figure 4B) should be avoided. In the absence of a ROS1 resistance mutation, options could include combination regimen trials or chemotherapy. Progression on/after crizotinib limited only to the central nervous system (CNS) may be effectively treated with a ROS1 inhibitor that has improved CNS penetration, such as entrectinib or lorlatinib. Of note, in the case of “oligoprogression” (i.e., progression in a limited number of metastatic sites) on first-line crizotinib, local ablative therapy could be considered with the continuation of crizotinib (see ref. 61).