Zipalertinib (CLN-081/TAS6417): A Comprehensive Review of a Novel EGFR TKI Targeting Exon 20 Insertion Mutations in Non-Small Cell Lung Cancer

1. Introduction

1.1. Overview of Zipalertinib

Zipalertinib, also identified by the codes CLN-081 and TAS6417, represents an investigational therapeutic agent under development for specific oncological indications.[1] It is characterized as an orally available, small molecule belonging to the class of irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).[1] Chemically, its structure incorporates elements from acrylamides, amines, indolizines, pyrimidines, and quinolines.[4] The primary focus of Zipalertinib's clinical development is the treatment of non-small cell lung cancer (NSCLC) characterized by specific mutations in the EGFR gene, with a particular emphasis on exon 20 insertion (ex20ins) mutations.[1]

1.2. The Unmet Need in EGFR Exon 20 Insertion NSCLC

Mutations within the EGFR gene, typically located in exons 18 through 21, function as critical oncogenic drivers in a subset of NSCLC, predominantly adenocarcinoma. These mutations lead to constitutive activation of downstream signaling pathways, promoting cancer cell proliferation and survival.[1] While significant progress has been made with EGFR TKIs targeting common mutations (e.g., exon 19 deletions, L858R point mutation), the landscape is markedly different for patients whose tumors harbor EGFR exon 20 insertion mutations.[6]