Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

Yasir Y. Elamin; Jacqulyne Ponville Robichaux; Brett W. Carter; Mehmet Altan; Hai Tran; Don L. Gibbons; Simon Heeke; Frank V. Fossella; Vincent K Lam; Xiuning Le; Marcelo V. Negrao; Monique B. Nilsson; Anisha Patel; R. S.K. Vijayan; Jason B. Cross; Jianjun Zhang; Lauren A. Byers; Charles Lu; Tina Cascone; Lei Feng; Rajyalakshmi Luthra; Francis A. San Lucas; Geeta Mantha; Mark Routbort; George Blumenschein; Anne S. Tsao; John V. Heymach

doi:10.1016/j.ccell.2022.06.006

Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

Yasir Y. Elamin, Jacqulyne Ponville Robichaux, Brett W. Carter, Mehmet Altan, Hai Tran, Don L. Gibbons, Simon Heeke, Frank V. Fossella, Vincent K Lam, Xiuning Le, Marcelo V. Negrao, Monique B. Nilsson, Anisha Patel, R. S.K. Vijayan, Jason B. Cross, Jianjun Zhang, Lauren A. Byers, Charles Lu, Tina Cascone, Lei FengRajyalakshmi Luthra, Francis A. San Lucas, Geeta Mantha, Mark Routbort, George Blumenschein, Anne S. Tsao, John V. Heymach

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Abstract

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.

Original language	English (US)
Pages (from-to)	754-767.e6
Journal	Cancer cell
Volume	40
Issue number	7
DOIs	https://doi.org/10.1016/j.ccell.2022.06.006
State	Published - Jul 11 2022

Keywords

epidermal growth factor receptor
exon 20 insertion
non-small cell lung carcinoma

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Tissue Biospecimen and Pathology Resource
Biostatistics Resource Group
Functional Proteomics Reverse Phase Protein Array Core
Bioinformatics Shared Resource
Clinical and Translational Research Center

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10.1016/j.ccell.2022.06.006

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Elamin, Y. Y., Robichaux, J. P., Carter, B. W., Altan, M., Tran, H., Gibbons, D. L., Heeke, S., Fossella, F. V., Lam, V. K., Le, X., Negrao, M. V., Nilsson, M. B., Patel, A., Vijayan, R. S. K., Cross, J. B., Zhang, J., Byers, L. A., Lu, C., Cascone, T., ... Heymach, J. V. (2022). Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity. Cancer cell, 40(7), 754-767.e6. https://doi.org/10.1016/j.ccell.2022.06.006

Elamin, YY, Robichaux, JP, Carter, BW , Altan, M , Tran, H , Gibbons, DL , Heeke, S , Fossella, FV, Lam, VK, Le, X , Negrao, MV , Nilsson, MB , Patel, A , Vijayan, RSK, Cross, JB, Zhang, J , Byers, LA, Lu, C, Cascone, T , Feng, L , Luthra, R , San Lucas, FA, Mantha, G, Routbort, M , Blumenschein, G , Tsao, AS & Heymach, JV 2022, 'Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity', Cancer cell, vol. 40, no. 7, pp. 754-767.e6. https://doi.org/10.1016/j.ccell.2022.06.006

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title = "Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity",

abstract = "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.",

keywords = "epidermal growth factor receptor, exon 20 insertion, non-small cell lung carcinoma",

author = "Elamin, {Yasir Y.} and Robichaux, {Jacqulyne Ponville} and Carter, {Brett W.} and Mehmet Altan and Hai Tran and Gibbons, {Don L.} and Simon Heeke and Fossella, {Frank V.} and Lam, {Vincent K} and Xiuning Le and Negrao, {Marcelo V.} and Nilsson, {Monique B.} and Anisha Patel and Vijayan, {R. S.K.} and Cross, {Jason B.} and Jianjun Zhang and Byers, {Lauren A.} and Charles Lu and Tina Cascone and Lei Feng and Rajyalakshmi Luthra and {San Lucas}, {Francis A.} and Geeta Mantha and Mark Routbort and George Blumenschein and Tsao, {Anne S.} and Heymach, {John V.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = jul,

day = "11",

doi = "10.1016/j.ccell.2022.06.006",

language = "English (US)",

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T2 - Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

AU - Elamin, Yasir Y.

AU - Robichaux, Jacqulyne Ponville

AU - Carter, Brett W.

AU - Altan, Mehmet

AU - Tran, Hai

AU - Gibbons, Don L.

AU - Heeke, Simon

AU - Fossella, Frank V.

AU - Lam, Vincent K

AU - Le, Xiuning

AU - Negrao, Marcelo V.

AU - Nilsson, Monique B.

AU - Patel, Anisha

AU - Vijayan, R. S.K.

AU - Cross, Jason B.

AU - Zhang, Jianjun

AU - Byers, Lauren A.

AU - Lu, Charles

AU - Cascone, Tina

AU - Feng, Lei

AU - Luthra, Rajyalakshmi

AU - San Lucas, Francis A.

AU - Mantha, Geeta

AU - Routbort, Mark

AU - Blumenschein, George

AU - Tsao, Anne S.

AU - Heymach, John V.

PY - 2022/7/11

Y1 - 2022/7/11

N2 - 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.

AB - 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.

KW - epidermal growth factor receptor

KW - exon 20 insertion

KW - non-small cell lung carcinoma

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VL - 40

SP - 754-767.e6

JO - Cancer cell

JF - Cancer cell

IS - 7

ER -

Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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