Current state of the art on the diagnosis and the role of target therapy for treatment of ROS1-rearranged non-small cell lung cancer: a narrative review

Background and Objective: Strategies for diagnosis and treatment of oncogene-addicted non-small cell lung cancer (NSCLC) are constantly evolving. In particular, the development of novel techniques for the molecular classification of NSCLC lead to detect many molecular aberrations of therapeutic interest, even in peripheral blood, including ROS proto-oncogene 1, receptor tyrosine kinase, encoded by ROS1 gene. Currently there are few drugs targeting ROS1 and most of available data on their activity comes from non-randomized studies, considering the low incidence of ROS1 alterations. Only three drugs are registered for FDA (crizotinib, entrectinib and ceritinib), with similar safety profile; no study comparing these two drugs is available yet. Methods: This narrative review was conducted by gathering all the relevant literature in PubMed from 2007 to 2021 on evolving techniques for the molecular detection of ROS1 rearrangements and also on main mechanisms of resistance with consequent developments of more selective drugs. Research was carried out at both preclinical and clinical levels. For the preclinical part, we selected more than 50 publications on the implications of in situ laboratory and molecular biology techniques comparing these approaches; for the clinical part we collected the main publications on ROS1 rearranged oncogene-addicted NSCLC and reported international guidelines. We included data from ten phase I/II trials testing efficacy and safety of TKIs targeting ROS1 rearrangement. rearrangements and the consequent therapeutic implication in lung cancer. To this aim, we have analysed all the relevant literature in PubMed from 2007 to 2021 on evolving techniques for the molecular detection of ROS1 rearrangements and on the main mechanisms of resistance with consequent developments of more selective drugs ( Table 1 ). The PubMed database was searched principally using the keywords “Non-small cell lung cancer”, “ ROS1 rearrangements”. We excluded articles not published in English. Research was performed at both preclinical and clinical levels. For the preclinical part, we selected more than 50 publications on the implications of in situ laboratory and molecular biology techniques comparing these approaches; for the clinical part we collected the main publications on ROS1 rearranged oncogene-addicted NSCLCs and reported international guidelines. We included data from ten phase I/II trials testing efficacy and safety of TKIs targeting ROS1 rearrangement. despite the rarity of this molecular alteration, have reached important developments. The contribution of this review would be to explore the main developments on the diagnosis of ROS1 rearrangements and to identify therapeutic opportunities both those currently available in clinical practice and those not currently available but promising for the near future.