A Review on Pharmacology and Resistance Mechanisms for Sunvozertinib in EGFR Exon 20 Insertion–Mutant Non-Small Cell Lung Cancer

Abstract

Epidermal growth factor receptor exon 20 insertion mutations is a genetically and structurally distinct class of oncogenic drivers in non-small cell lung cancer, historically characterized by marked insensitivity to classical first-, second-, and third-generation tyrosine kinase inhibitors. The clinical management of this disease has radically changed following the introduction of targeted modalities specifically engineered to overcome the steric hindrance imposed by αC-helix and loop insertions within the ATP-binding cleft. Sunvozertinib is an orally bioavailable, irreversible, rationalized small-molecule tyrosine kinase inhibitor exhibiting selective, nanomolar potency against a wide spectrum of exon 20 insertion variants while preserving wild-type receptor margins. Clinical trial evaluations across the multi-cohort WU-KONG program have established confirmed objective response rates ranging from 46% to 62% in platinum-pretreated advanced disease, alongside robust intracranial activity and prolonged response duration. Regulatory approvals in China and the United States validate its role as a pivotal oral targeted option in second-line settings. Nevertheless, clinical utility is eventually challenged by acquired resistance pathways, including secondary receptor alterations such as the C797S covalent binding site disruption, MET and ERBB2 bypass amplification, downstream pathway reactivation, and histological lineage plasticity. Ongoing phase III investigations explore frontline positioning against systemic chemo-immunotherapy combinations, while companion biomarker discovery aims to define individualized treatment sequencing. Sunvozertinib provides a compelling pharmacological option that bridges long-standing unmet needs in precision thoracic oncology.