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

Abstract

The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both ‘on-target’ mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and ‘off-target’ mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies. Patients with non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR or ALK alterations can benefit from therapies targeting these alterations, although acquired resistance to these agents is common. Third-generation inhibitors have extended the response durations of many patients with NSCLCs harbouring these alterations, albeit with differing patterns of resistance to those associated with earlier-generation agents. Here, the authors describe the mechanisms of acquired resistance to third-generation EGFR and ALK inhibitors and provide insights into future research directions in this area. Non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR mutations or ALK rearrangements can be effectively treated with EGFR and ALK tyrosine kinase inhibitors (TKIs), respectively. The third-generation EGFR 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 central nervous system metastases. Resistance to third-generation EGFR or ALK TKIs can be mediated by acquired EGFR or 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 signalling 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. Non-small-cell lung cancers (NSCLCs) harbouring oncogenic EGFR mutations or ALK rearrangements can be effectively treated with EGFR and ALK tyrosine kinase inhibitors (TKIs), respectively. The third-generation EGFR 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 central nervous system metastases. Resistance to third-generation EGFR or ALK TKIs can be mediated by acquired EGFR or 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 signalling 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.