2. Academic Validation
  3. 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

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

  • Nat Commun. 2025 Sep 24;16(1):8358. doi: 10.1038/s41467-025-61817-8.
Xiuning Le 1,  Jacqulyne P Robichaux 1,  Monique Nilsson 1,  R S K Vijayan 2,  Ashwin Ravichandran 3,  Jia Wu 4,  Yasir Y Elamin 1,  Lingzhi Hong 1,  Jun Pei 2,  Jun He 1,  Sonia Patel 1,  Hibiki Udagawa 1,  Sriramvignesh Mani 5,  Chang Woon Jang 3,  Jeffrey M Clarke 6,  Nishan Tchekmedyian 7,  Jonathan W Goldman 8,  Mark Socinski 9,  Gajanan Bhat 10,  Sharon Leu 10,  Veronica Bunn 11,  Zhenqiang Su 11,  Sylvie Vincent 11,  John W Lawson 12,  Jason B Cross 2,  John V Heymach 13
Affiliations

Affiliations

  • 1 Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.
  • 2 Institute for Applied Cancer Science, MD Anderson Cancer Center, Houston, TX, USA.
  • 3 KBR Inc., Intelligent Systems Division, NASA Ames Research Center, Moffett Field, Mountain View, California, USA.
  • 4 Department of Imaging Physics, MD Anderson Cancer Center, Houston, TX, USA.
  • 5 Department of Chemistry, The University of Chicago, Chicago, Illinois, USA.
  • 6 Medical Oncology, Duke University Medical Center, Durham, NC, USA.
  • 7 Medical Oncology, City of Hope, Irvine, CA, USA.
  • 8 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 9 AdventHealth Cancer Institute, Orlando, Florida, USA.
  • 10 Spectrum Pharmaceuticals, Henderson, NV, USA.
  • 11 Takeda Pharmaceutical Company, Cambridge, MA, USA.
  • 12 Intelligent Systems Division, NASA Ames Research Center, Moffett Field, Mountain View, California, USA.
  • 13 Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA. jheymach@mdanderson.org.
PMID: 40993146 DOI: 10.1038/s41467-025-61817-8
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.

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