ISY8-4 - ROS1 and MET Inhibitors: new biomarkers, new frontiers

Abstract

Crizotinib is an ALK/ROS1/MET inhibitor which has been explored in a series of molecularly selected NSCLC cohorts from the earliest phase of its development and has helped to define several key sensitive subpopulations of lung cancer driven by either ROS1 or MET.ROS1 gene rearrangements are structurally similar to ALK rearrangements. As the rearrangements do not exist in the normal state, diagnostic assays focus on detecting the presence of the rearrangement predominantly through either cytogenetic or sequencing techniques. The activity of crizotinib in ROS1 positive disease is now established. However, the same issues associated with progression of ALK positive lung cancer on crizotinib - notably CNS progression and the development of acquired resistance through changes in the dominant biology of the cancer in the presence of the drug - are now informing the search for newer ROS1 inhibitors.MET is another potential oncogene, but one which can be activated in several different ways and in different clinical scenarios ranging from MET acting as a primary driver to MET acting as a secondary resistance mechanisms for another oncogene after initial benefit from a specific targeted therapy. Consequently, the challenges for effectively developing MET inhibitors in lung cancer include accurately defining both the target population and the most relevant predictive biomarker and cutpoint for determining positivity. Activity in primary driver states characterized by MET amplification, MET splice variants and MET mutations; and activity as a secondary driver in EGFR mutant disease will be discussed. Crizotinib is an ALK/ROS1/MET inhibitor which has been explored in a series of molecularly selected NSCLC cohorts from the earliest phase of its development and has helped to define several key sensitive subpopulations of lung cancer driven by either ROS1 or MET. ROS1 gene rearrangements are structurally similar to ALK rearrangements. As the rearrangements do not exist in the normal state, diagnostic assays focus on detecting the presence of the rearrangement predominantly through either cytogenetic or sequencing techniques. The activity of crizotinib in ROS1 positive disease is now established. However, the same issues associated with progression of ALK positive lung cancer on crizotinib - notably CNS progression and the development of acquired resistance through changes in the dominant biology of the cancer in the presence of the drug - are now informing the search for newer ROS1 inhibitors. MET is another potential oncogene, but one which can be activated in several different ways and in different clinical scenarios ranging from MET acting as a primary driver to MET acting as a secondary resistance mechanisms for another oncogene after initial benefit from a specific targeted therapy. Consequently, the challenges for effectively developing MET inhibitors in lung cancer include accurately defining both the target population and the most relevant predictive biomarker and cutpoint for determining positivity. Activity in primary driver states characterized by MET amplification, MET splice variants and MET mutations; and activity as a secondary driver in EGFR mutant disease will be discussed.