Poziotinib for EGFR exon 20-mutant NSCLC : Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its primary endpoint, with confirmed objective response rates (ORRs) of 32% and 31% by investigator and blinded independent review, respectively, with a median progression-free survival of 5.5 months. Using preclinical studies, in silico modeling, and molecular dynamics simulations, we found that poziotinib sensitivity was highly dependent on the insertion location, with near-loop insertions (amino acids A767 to P772) being more sensitive than far-loop insertions, an observation confirmed clinically with ORRs of 46% and 0% observed in near versus far-loop, respectively (p = 0.0015). Putative mechanisms of acquired resistance included EGFR T790M, MET amplifications, and epithelial-to-mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in EGFR exon 20-mutant NSCLC, although this activity is influenced by insertion location.
| Errataetall: |
CommentIn: Cancer Cell. 2022 Jul 11;40(7):705-708. - PMID 35820394 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:40 |
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| Enthalten in: |
Cancer cell - 40(2022), 7 vom: 11. Juli, Seite 754-767.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Elamin, Yasir Y [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.07.2022 Date Revised 01.07.2023 published: Print ClinicalTrials.gov: NCT03066206 CommentIn: Cancer Cell. 2022 Jul 11;40(7):705-708. - PMID 35820394 Citation Status MEDLINE |
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| doi: |
10.1016/j.ccell.2022.06.006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Poziotinib for EGFR exon 20-mutant NSCLC |b Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity |
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| 500 | |a Date Revised 01.07.2023 | ||
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| 500 | |a CommentIn: Cancer Cell. 2022 Jul 11;40(7):705-708. - PMID 35820394 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its primary endpoint, with confirmed objective response rates (ORRs) of 32% and 31% by investigator and blinded independent review, respectively, with a median progression-free survival of 5.5 months. Using preclinical studies, in silico modeling, and molecular dynamics simulations, we found that poziotinib sensitivity was highly dependent on the insertion location, with near-loop insertions (amino acids A767 to P772) being more sensitive than far-loop insertions, an observation confirmed clinically with ORRs of 46% and 0% observed in near versus far-loop, respectively (p = 0.0015). Putative mechanisms of acquired resistance included EGFR T790M, MET amplifications, and epithelial-to-mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in EGFR exon 20-mutant NSCLC, although this activity is influenced by insertion location | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a epidermal growth factor receptor | |
| 650 | 4 | |a exon 20 insertion | |
| 650 | 4 | |a non-small cell lung carcinoma | |
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