Recent Advances in Targeting ROS1 in Lung Cancer

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Recent Advances in Targeting ROS1 in Lung Cancer Jessica J. Lin, MD, Alice T. Shaw, MD, PhD Journal of Thoracic Oncology Volume 12, Issue 11, Pages 1611-1625 (November 2017) DOI: 10.1016/j.jtho.2017.08.002 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Timeline of key advances in targeting ROS1 in lung cancer. FDA, U.S. Food and Drug Administration; ALK, anaplastic lymphoma kinase. Journal of Thoracic Oncology 2017 12, 1611-1625DOI: (10.1016/j.jtho.2017.08.002) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 ROS1 rearrangements in NSCLC. (A) Schematic representations of ROS1 fusion proteins described to date. Note that KDEL endoplasmic reticulum protein retention receptor 2 (KDELR2)-ROS1 is not shown, as the genomic structure of this fusion has not been published. Blue indicates ROS1 tyrosine kinase domain, purple indicates ROS1 transmembrane domain, and green indicates coiled-coil domain. (B) Distribution of ROS1 fusion proteins by the reported frequencies in NSCLC. Each fusion protein listed in the other category likely occurs in less than 1% of ROS1-rearranged NSCLCs, unless otherwise indicated. CD74, CD74 molecule gene; EZR, ezrin gene; SLC34A2, solute carrier family 34 member 2 gene; SDC4, syndecan 4 gene; TPM3, tropomyosin 3 gene; FIG, fused in glioblastoma gene; LIMA1, LIM domain and acting binding 1 gene; MSN, moesin gene; CCDC6, coiled-coil domain containing 6 gene; LRIG3, leucine-rich repeats and immunoglobulin-like domains 3 gene; TMEM106B, transmembrane protein 106B gene; TPD52L1, tumor protein D52 like 1 gene; CLTC, clathrin heavy chain gene. Updated/modified with permission from Gainor and Shaw.39 ©AlphaMed Press 2013 Journal of Thoracic Oncology 2017 12, 1611-1625DOI: (10.1016/j.jtho.2017.08.002) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Clinical response of a patient with ROS1 rearrangement to crizotinib. (A) Axial (top) and coronal (bottom) computed tomography images of the chest before crizotinib. (B) Axial (top) and coronal (bottom) computed tomography images of the chest after 6 weeks of crizotinib, demonstrating a dramatic improvement in the left lung mass, bilateral pulmonary nodules, and pleural effusions. Journal of Thoracic Oncology 2017 12, 1611-1625DOI: (10.1016/j.jtho.2017.08.002) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Crizotinib-resistant ROS1 mutations. (A) Crizotinib-resistant secondary ROS1 mutations reported to date, mapped on the structural data of ROS1 kinase domain (left) in complex with crizotinib (PDB:3ZBF). Analogous ALK receptor tyrosine kinase gene (ALK) resistance mutations are mapped on the anaplastic lymphoma kinase (ALK) kinase domain in complex with crizotinib (PDB:2XP2) on the right, revealing structural similarities. Note that the ALK mutation analogous to ROS1 L1951R has not been reported and is therefore not shown. (B) The activity of ROS1-directed tyrosine kinase inhibitors against known crizotinib-resistant ROS1 mutations. This table is based on the available preclinical data, not all of which have been validated in the clinic. Of note, preclinical data for the activity of lorlatinib against G2032R has been mixed (and thus indicated as ‘Yes/No’); clinical activity remains to be determined. Journal of Thoracic Oncology 2017 12, 1611-1625DOI: (10.1016/j.jtho.2017.08.002) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 5 Our approach to the treatment of advanced ROS1-rearranged lung cancer. After progression during first-line crizotinib therapy, a repeat tumor biopsy is strongly recommended if feasible and safe 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 on the basis of preclinical data (see Fig. 4B) should be avoided. In the absence of a ROS1 resistance mutation, options could include next-generation ROS1 inhibitors, combination regimen trials or chemotherapy. Progression during or after crizotinib that is limited solely 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) during first-line crizotinib, local ablative therapy could be considered with the continuation of crizotinib (see Lin et al.62). TKI, tyrosine kinase inhibitor. Journal of Thoracic Oncology 2017 12, 1611-1625DOI: (10.1016/j.jtho.2017.08.002) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions