exon 20 insertion mutations and mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates.

BACKGROUND AND OBJECTIVE

This review will provide an overview of and mutations in non-small-cell lung cancer (NSCLC) with a focus on recent clinical approvals.

METHODS

We obtained data from the literature in accordance with narrative review reporting guidelines.

KEY CONTENT AND FINDINGS

mutations are present in up to 15-20% of all NSCLCs; amongst these, 10% correspond to kinase domain insertions in exon 20. Structurally similar, () mutations occurs in 1-4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of exon 20 insertions occur within the loop following the regulatory C-helix and activate the kinase domain of EGFR without generating a therapeutic window to gefitinib, erlotinib, afatinib, dacomitinib or osimertinib. Mobocertinib represents a novel class of covalent EGFR inhibitors with a modest therapeutic window to these mutants and induces anti-tumor responses in a portion of patients [at 160 mg/day: response rate of <30% with duration of response (DoR) >17 months and progression-free survival (PFS) of >7 months] albeit with mucocutaneous and gastrointestinal toxicities. The bi-specific EGFR-MET antibody amivantamab-vmjw has modest but broad preclinical activity in EGFR-driven cancers and specifically for exon 20 insertion-mutated NSCLC has response rates <40% and PFS of <8.5 months at the cost of both infusion-related plus on-target toxicities. Both drugs were approved in 2021. The clinical development of kinase inhibitors for -mutated NSCLC has been thwarted by mucocutaneous/gastrointestinal toxicities that preclude a pathway for drug approval, as the case of poziotinib. However, the activation of ERBB2 has allowed for repurposing of antibody-drug conjugates (ADCs) that target ERBB2 with cytotoxic payloads. The FDA approved fam-trastuzumab deruxtecan-nxki in 2022 for NSCLC based on response rate of >55%, DoR >9 months, PFS >8 months and manageable adverse events (including cytopenias, nausea and less commonly pneumonitis). Other therapies in clinical development include sunvozertinib and zipalertinib, among others. In addition, traditional cytotoxic chemotherapy has some activity in these tumors.

CONCLUSIONS

The approvals of mobocertinib, amivantamab, and trastuzumab deruxtecan represent the first examples of precision oncology for exon 20 insertion-mutated and -mutated NSCLCs.