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Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management

*May 2022*

Key Points

  • NSCLCs harboring oncogenic EGFR mutations or ALK rearrangements can be effectively treated with EGFR and ALK TKIs respectively.
  • The third-generation TKI osimertinib and the ALK TKI lorlatinib are currently the most advanced and effective clinically approved agents in their respective NSCLC subsets; both agents are highly effective including against CNS metastases.
  • Resistance to third-generation EGFR or ALK TKIs can be mediated by acquired EGFR of ALK kinase-domain mutations, respectively; fourth-generation TKIs designed to overcome this on-target resistance are currently in development.
  • Off-target resistance to third-generation EGFR and ALK TKIs is more prevalent than on-target resistance and is mediated by various mechanisms, including the activation of bypass signaling or phenotypic transformation.
  • Novel approaches designed to overcome resistance beyond fourth-generation TKIs, including combination therapies, antibody drug conjugates, bispecific antibodies, and immune-directed approaches, are at various stages of clinical investigation.

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