Progression on crizotinib can be mediated by the acquisition of ROS1 kinase domain mutations (e.g. ROS1G2032R or ROS1D2033N). Cabozantinib is a highly potent ROS1 tyrosine kinase inhibitor that has superior activity over lorlatinib against these mutations. We evaluated the activity of cabozantinib in patients with ROS1-rearranged lung cancers on a phase 2 trial.

IC50 data summarized in the heatmap shows that ROS1 F2004C, ROS1 G2032R and ROS1 L2086F are entrectinib resistant. Cabozantinib, consistent with our previous published data harbors robust activity against ROS1 G2032R and ROS1 L2086F, however cabozantinib-resistance is imposed by ROS1F2004C mutation. Gilteritinib, intriguingly, is active with IC50 ≤ 25 nM against both ROS1 F2004C and ROS1 L2086F but not ROS1 G2032R.