Exploring TAS6417: A Promising EGFR Inhibitor for NSCLC with Exon 20 Insertions

Mutations in the EGFR gene are significant in NSCLC therapy as they are major disease drivers. While EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, erlotinib, and afatinib are first-line treatments for NSCLC with specific EGFR mutations, those with EGFR exon 20 insertions, the third most prevalent EGFR mutation, typically have a poor response to these therapies. TAS6417, a novel EGFR inhibitor, has been developed with the potential to effectively target exon 20 insertions without affecting the wild-type EGFR, possibly avoiding severe diarrhea associated with wild-type inhibition.

In the study, tumor growth was analyzed in athymic nude mice and rats with patient-derived xenografts (PDX) or genetically engineered cells expressing EGFR exon 20 insertions. TAS6417 showed more potent and selective inhibitory activity against EGFR with exon 20 insertions compared to the wild-type. Tumor growth was inhibited in subcutaneously implanted models at dosages of 50 mg/kg or higher, and a PDX model with an EGFR V769_D770insASV mutation exhibited tumor regression at 100 mg/kg. In rats, TAS6417 effectively inhibited tumor growth at 10 mg/kg and induced tumor shrinkage at 40 mg/kg without impacting body weight gain. Additionally, TAS6417 improved survival with good tolerability in a lung orthotopic implantation mouse model. Pharmacodynamics analysis indicated that TAS6417 suppressed EGFR signaling pathways, leading to caspase activation and increased Bim protein expression.

The results suggest that TAS6417 possesses significant antitumor activity and good tolerability in both engineered xenografts and PDX models with EGFR exon 20 insertions, indicating its potential as a therapeutic option for NSCLC patients with these specific EGFR mutations.

The research was presented by Shinichi Hasako, Miki Terasaka, and colleagues at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in 2017.