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

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 and John V. Heymach ()
Additional contact information
Xiuning Le: MD Anderson Cancer Center
Jacqulyne P. Robichaux: MD Anderson Cancer Center
Monique Nilsson: MD Anderson Cancer Center
R. S. K. Vijayan: MD Anderson Cancer Center
Ashwin Ravichandran: Moffett Field
Jia Wu: MD Anderson Cancer Center
Yasir Y. Elamin: MD Anderson Cancer Center
Lingzhi Hong: MD Anderson Cancer Center
Jun Pei: MD Anderson Cancer Center
Jun He: MD Anderson Cancer Center
Sonia Patel: MD Anderson Cancer Center
Hibiki Udagawa: MD Anderson Cancer Center
Sriramvignesh Mani: The University of Chicago
Chang Woon Jang: Moffett Field
Jeffrey M. Clarke: Duke University Medical Center
Nishan Tchekmedyian: City of Hope
Jonathan W. Goldman: David Geffen School of Medicine at UCLA
Mark Socinski: AdventHealth Cancer Institute
Gajanan Bhat: Spectrum Pharmaceuticals
Sharon Leu: Spectrum Pharmaceuticals
Veronica Bunn: Takeda Pharmaceutical Company
Zhenqiang Su: Takeda Pharmaceutical Company
Sylvie Vincent: Takeda Pharmaceutical Company
John W. Lawson: Moffett Field
Jason B. Cross: MD Anderson Cancer Center
John V. Heymach: MD Anderson Cancer Center

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61817-8

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