Algorithme thérapeutique des cancers bronchiques non à petites cellules avec fusion ALK, ROSI et RET

Abstract

ALK (3-7%), ROS1 (1-2%), and RET (1-2%) rearrangements differ epidemiologically from other non-small cell lung cancers. They are more frequently observed in younger patients, light or never smokers, and are predominantly associated with adenocarcinoma histology. Several fusion partners have been identified for each of these genes, with some partners shared across targets. Identifying these genomic alterations at the time of initial diagnosis in advanced non-small cell lung cancer patients is essential to guide first-line treatment decisions, direct patients toward effective targeted therapies, and avoid ineffective strategies such as immune checkpoint inhibitors in monotherapy or potentially toxic treatment sequences. In patients with ALK rearrangements, lorlatinib is the first-line standard, with a 5-year progression-free survival (PFS) rate of 60% and remarkable intracranial efficacy. Post-lorlatinib resistance mechanisms in first-line therapy appear to be ALK-independent, and chemotherapy currently remains the standard second-line option. In patients previously treated with brigatinib or alectinib, secondline therapy should be guided by the identification of resistance mechanisms. Neladalkib, a fourth-generation ALK inhibitor, is currently available through an early access program. For ROSI-rearranged non-small cell lung cancers, crizotinib is the only approved targeted therapy to date, although agents such as taletrectinib and zidesamtinib (also available through early access) show promising activity. Finally, for RET-rearranged non-small cell lung cancers, selpercatinib is now the standard of care from the first-line setting, offering significant clinical benefit.