2023 Targeted Therapies of Lung Cancer Meeting (Poster)-P1.12. Activity of Gilteritinib in Resistant ROS1 Rearranged Non-Small Cell Lung Cancer

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The document discusses the activity of gilteritinib, a targeted therapy, in ROS1 rearranged non-small cell lung cancer (NSCLC) with the L2086F mutation. ROS1 rearrangements occur in 1-2% of NSCLC cases worldwide, resulting in 10,000 to 15,000 new cases each year. The development of kinase-intrinsic mechanisms contributes to resistance to crizotinib, a commonly used treatment for ROS1 rearranged NSCLC. One recurrent mutation, ROS1 G2032R, accounts for almost half of crizotinib and lorlatinib resistance in patients. Another emerging mutation, L2086F, either alone or in combination with other resistant mutations, is increasingly seen in resistance cases.<br /><br />Current next-generation ROS1 inhibitors that target the G2032R mutation are being developed but are susceptible to developing resistance via L2086F. Cabozantinib is the only available therapy that demonstrates activity against ROS1 L2086F, but it is poorly tolerated by most patients. Therefore, there is a need for alternative well-tolerated drugs targeting ROS1 L2086F.<br /><br />The document presents in vitro assays evaluating the activity of gilteritinib in comparison to entrectinib and cabozantinib in ROS1 L2086F. The results show that gilteritinib and cabozantinib exhibit sensitivity in inhibiting ROS1 L2086F in cell viability and colony formation assays. These TKIs also demonstrate on-target inhibition of ROS1 in both wild-type and L2086F mutant cells.<br /><br />Additionally, the study includes an evaluation of gilteritinib and cabozantinib activity in a patient-derived cell line expressing the L2086F mutation. The results confirm the on-target inhibition of ROS1 and the inhibition of downstream MAPK pathway activation by gilteritinib and cabozantinib.<br /><br />Based on these findings, gilteritinib shows potential as an inhibitor of ROS1 with activity against the L2086F mutation. It may serve as a better-tolerated alternative for patients with ROS1 fusions and the L2086F mutation, who currently only have access to cabozantinib as a treatment option. Further in vivo studies are ongoing to validate these findings. The research is partially funded by the Oregon Medical Research Foundation and other grants, with no reported conflicts of interest.

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Rajat Thawani, Oregon Health & Science University, United States

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Speaker Rajat Thawani, Oregon Health & Science University, United States

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Keywords

gilteritinib

ROS1 rearranged non-small cell lung cancer

L2086F mutation

kinase-intrinsic mechanisms

crizotinib resistance

ROS1 G2032R mutation

ROS1 inhibitors

cabozantinib

entrectinib

MAPK pathway activation