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.

Figure 1.. Timeline of genomic discoveries and drug development in EGFR-mutant and ALK-rearranged NSCLCs.

Key events, in a. ∣ EGFR-mutant non-small-cell lung cancers (NSCLC) and b. ∣ ALK-rearranged NSCLC, including the discovery of the oncogenic drivers and gene alterations (orange), FDA approvals of tyrosine-kinase inhibitors for unselected patients (grey), approvals of therapies for biomarker-selected populations in the advanced-stage disease setting (blue), approvals for biomarker-selected populations in the adjuvant setting (green), and important ongoing trials (purple).

Figure 2.. Mechanisms of acquired resistance to osimertinib and lorlatinib in EGFR-mutant and ALK-rearranged NSCLCs, respectively.

Mechanisms of resistance to these agents can be divided into several main categories, including: a ∣ alterations that prevent inhibition of the target receptor tyrosine kinase by the tyrosine kinase inhibitor (TKI); b ∣ Activation of bypass and/or downstream signalling pathways that promote cell survival and proliferation despite adequate TKI binding; and c ∣ Changes in tumour cell lineage, such as transformation from an adenocarcinoma to a squamous cell carcinoma or small-cell lung cancer phenotype and epithelial–mesenchymal transition (EMT). Specific selected examples of these mechanisms are also provided.