Recent Advances in Targeting ROS1 in Lung Cancer

Abstract

ROS1 is a validated therapeutic target in NSCLC. In a phase I study, the multitargeted MET proto-oncogene, receptor tyrosine kinase/anaplastic lymphoma kinase/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs and consequently gained approval by the United States Food and Drug Administration and by the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.

Keywords: Crizotinib; Non–small cell lung cancer; ROS1 inhibitor; ROS1 rearrangement; Resistance.

Figure 1

Timeline of key advances in targeting ROS1 in lung cancer. Abbreviations: NSCLC, non-small cell lung cancer; ALK, anaplastic lymphoma kinase; FDA, Food and Drug Administration.

Figure 2

ROS1 rearrangements in non-small cell lung cancer (NSCLC). (A) Schematic representations of ROS1 fusion proteins described to date. Note that KDELR2-ROS1 is not shown, as the genomic structure of this fusion has not been published. Blue, ROS1 tyrosine kinase domain; purple, ROS1 transmembrane domain; green, coiled-coil domain. (B) Distribution of ROS1 fusion proteins by the reported frequencies in NSCLC. Each fusion protein listed under the ‘other’ category likely occurs in <1% of ROS1-rearranged NSCLCs, unless otherwise indicated. [Figure updated/modified from ref. .]

Figure 3

Clinical response of a ROS1-rearranged patient 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.

Figure 4

Crizotinib-resistant ROS1 mutations. (A) Crizotinib-resistant secondary ROS1 mutations reported to date, mapped on the structure data of ROS1 kinase domain (left) in complex with crizotinib (PDB:3ZBF). Analogous ALK resistance mutations are mapped on the ALK kinase domain in complex with crizotinib (PDB:2XP2) on the right, revealing structural similarities. Note: 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.

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).