Biopsies from ROS1+ NSCLC patients progressing on crizotinib or lorlatinib were profiled by genetic sequencing....A patient with disease progression on crizotinib and lorlatinib and ROS1 L2086F received cabozantinib for nearly 11 months with disease control.

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.

In Ba/F3 models, ROS1L2086F, ROS1G2032R/L2086F, and ROS1S1986F/G2032R/L2086F were refractory to lorlatinib but sensitive to cabozantinib....ROS1 mutations mediate resistance to crizotinib and lorlatinib in over one-third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations including G2032R and L2086F.