ROS1 L2086F

Despite ROS1 fusion positive (ROS1+) NSCLC accounting approximately 1-2% of NSCLC, there is a dizzying list of ROS1 tyrosine kinase inhibitor (TKIs) being developed in addition to two approved ROS1 TKIs, crizotinib and entrectinib...Additionally, the less known central β-sheet 6 (Cβ6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target Cβ6 mutation.

This case builds the case for cabozantinib as an agent to overcome ROS1 L2086F resistance. It also highlights the efficacy and safety of using combination of ROS1 TKIs to overcome complex resistance patterns.

No grade greater than or equal to 4 adverse events were observed. Lorlatinib induced durable intracranial responses in patients with ROS1-rearranged NSCLC and prior isolated CNS progression on crizotinib.

No grade 5 adverse events were observed. The study was terminated early after enrollment of 16 of 22 planned patients due to the commercial availability of off-label lorlatinib.Conclusion s : The CNS-penetrant next-generation ROS1 inhibitor lorlatinib is an effective salvage therapy for patients experiencing isolated CNS progression on crizotinib.