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

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 IC<sub>50</sub> 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.

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Publication Details

Journal
Nature Communications
Published
2025-09-24
DOI
https://doi.org/10.1038/s41467-025-61817-8
Citations
3
Primary Topic
Lung Cancer Treatments and Mutations
Type
article
Field-Weighted Citation Impact
4.56

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article

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

Gajanan Bhat, Jia Wu, Xiuning Le, John W. Lawson et al.
3 citations
Nature Communications
Lung Cancer Treatments and Mutations
4.56
article

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

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

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 IC<sub>50</sub> 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.

Nature CommunicationsVol. 16(1)
Ames Research Center (US), City Of Hope National Medical Center (US), The University of Texas MD Anderson Cancer Center (US), University of California, Los Angeles (US), University of Chicago (US), Florida Hospital Cancer Institute (US), City of Hope (US), Duke Medical Center (US), Takeda (United States) (US), Spectrum Pharmaceuticals (United States) (US)
National Aeronautics and Space Administration, Conquer Cancer Foundation, Damon Runyon Cancer Research Foundation, Cancer Prevention and Research Institute of Texas, American Society of Clinical Oncology, Spectrum Pharmaceuticals, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute
Openalex Percentile: Top 5%
Lung Cancer Treatments and Mutations
4.56
DOIOpen Access PDFOpenAlex
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