We obtained data from the literature in accordance with narrative review reporting guidelines.
Key Content and Findings: EGFR mutations are present in up to 15-20% of all NSCLCs; amongst these, 10% correspond to
kinase domain insertions in exon 20. Structurally similar, ERBB2 (HER2) mutations occurs in 1-4% of NSCLCs, mostly consisting of insertions or point mutations. The majority of EGFR 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 EGFR 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 ERBB2-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: