Poziotinib for EGFR Exon 20-Insertion NSCLC: Clinical Efficacy of the Phase 2 ZENITH Trial and Differential Impact of EGFR Exon 20 Insertion Location on Sensitivity

Authors

Xiuning Le
Jacqulyne P Robichaux
Monique Nilsson
R S K Vijayan
Ashwin Ravichandran
Jia Wu
Yasir Y Elamin
Lingzhi Hong
Jun Pei
Jun He
Sonia Patel
Hibiki Udagawa
Sriramvignesh Mani
Chang Woon Jang
Jeffrey M Clarke
Nishan Tchekmedyian
Jonathan W Goldman
Mark Socinski
Gajanan Bhat
Sharon Leu
Veronica Bunn
Zhenqiang Su
Sylvie Vincent
John W Lawson
Jason B Cross
John V Heymach

Publication Date

9-24-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-61817-8

PMID

40993146

PMCID

PMC12460621

PubMedCentral® Posted Date

9-24-2025

PubMedCentral® Full Text Version

Post-print

Abstract

EGFRex20 insertions (EGFRex20ins) can be classified as near- and far-loop based on the insertion location, however, the impact of location on responses to various EGFR tyrosine kinase inhibitors (TKIs) is poorly understood. In vitro studies show that afatinib, poziotinib, and zipalertinib more potently inhibited near-loop than far-loop insertions, whereas mobocertinib has similar IC50 in both groups. Molecular dynamics simulations reveal that near-loop insertions have multiple conformational states and lower transitional energy than far-loop insertions. ZENITH20 trial cohort 1 (NCT03318939) evaluates poziotinib in EGFRex20 NSCLC patients (n = 115) and demonstrates an objective response rate of 14.8% (95% Confidence Interval [CI], 8.9 to 22.6, primary endpoint of the trial). Although the study's primary efficacy endpoint was not met in the overall cohort, the exploratory analysis indicates poziotinib has superior benefit in EGFRex20 near- versus far-insertions showing greater mean tumor size reduction (-25.9% vs. -9.8%, p = 0.0014) and progression-free survival (PFS, 11.1 vs. 3.5 months, p = 0.016). In comparison, in the previously published EXCLAIM trial (NCT02716116), mobocertinib demonstrates similar activities across both groups in tumor size reduction (-38.5% vs. -34.1%, p = 0.59) and PFS (12.0 vs. 13.0 months, p = 0.99). Therefore, EGFRex20ins location differentially impacts the sensitivity of TKIs.

Keywords

Adult, Aged, Female, Humans, Male, Middle Aged, Carcinoma, Non-Small-Cell Lung, ErbB Receptors, Exons, Lung Neoplasms, Molecular Dynamics Simulation, Mutagenesis, Insertional, Piperazines, Protein Kinase Inhibitors, Pyrimidines, Quinazolines, Treatment Outcome

Published Open-Access

yes

Recommended Citation

Le, Xiuning; Robichaux, Jacqulyne P; Nilsson, Monique; et al., "Poziotinib for EGFR Exon 20-Insertion NSCLC: Clinical Efficacy of the Phase 2 ZENITH Trial and Differential Impact of EGFR Exon 20 Insertion Location on Sensitivity" (2025). Faculty, Staff and Student Publications. 5147.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5147