Abstract
The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.
Original language | English (US) |
---|---|
Pages (from-to) | 205-215 |
Number of pages | 11 |
Journal | Journal of Thoracic Oncology |
Volume | 16 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2021 |
Keywords
- Anti-angiogenesis
- Dual inhibition
- EGFR
- EGFR-mutant NSCLC
- NSCLC
- VEGF
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
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In: Journal of Thoracic Oncology, Vol. 16, No. 2, 02.2021, p. 205-215.
Research output: Contribution to journal › Review article › peer-review
}
TY - JOUR
T1 - Dual EGFR-VEGF Pathway Inhibition
T2 - A Promising Strategy for Patients With EGFR-Mutant NSCLC
AU - Le, Xiuning
AU - Nilsson, Monique
AU - Goldman, Jonathan
AU - Reck, Martin
AU - Nakagawa, Kazuhiko
AU - Kato, Terafumi
AU - Ares, Luis Paz
AU - Frimodt-Moller, Bente
AU - Wolff, Katharina
AU - Visseren-Grul, Carla
AU - Heymach, John V.
AU - Garon, Edward B.
N1 - Funding Information: Disclosure: Dr. Le reports receiving grants and personal fees from Eli Lilly and Boehringer Ingelheim ; and personal fees from AstraZeneca and EMD Serono outside of the submitted work. Dr. Nilsson reports receiving licensing fees from Spectrum Pharmaceuticals outside of the submitted work. Dr. Nilsson also has a patent PCT/US2019/022067 pending, and a patent PCT/US2017/062326 and U.S. Provisional Patent application numbers 62/423,732; 62/427,692; and 62/572,716, with royalties paid to the University of Texas System Board of Regents. Dr. Goldman reports receiving grants and personal fees from AstraZeneca and Genentech outside of the submitted work. Dr. Reck reports receiving personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck, Merck Sharp & Dohme, Eli Lilly, Novartis, Pfizer, and Roche outside of the submitted work. Dr. Nakagawa reports receiving institutional research funding from A2 Healthcare Corp. , AbbVie , Astellas Pharma , AstraZeneca KK, Bayer Yakuhin, Bristol-Myers Squibb , Chugai Pharma , CMIC Shift Zero KK, Daiichi Sankyo , Eisai , EPS Corporation, EPS International Co. Ltd., ICON Japan KK, IQVIA Services Japan KK, Kissei Pharmaceutical Co. Ltd., Kyowa Hakko Kirin , Eli Lilly and Company , Merck Serono, Merck Sharp & Dohme , Otsuka Pharmaceutical Co. Ltd., Parexel International Corp., Pfizer R&D Japan GK, SymBio Pharmaceuticals , Syneos Health, Taiho Pharmaceutical , and Takeda . Dr. Nakagawa reports receiving honoraria from AbbVie Inc., Astellas Pharma, AstraZeneca KK, Bayer Yakuhin Ltd., Bristol-Myers Squibb, CareNet Inc., Chugai Pharma, Daiichi Sankyo, Hisamitsu Pharmaceutical, Kyorin Medicus Shuppan Publishers Co. Ltd., Merck Biopharma Co. Ltd., Merck Sharp & Dohme KK, Nanzando Co. Ltd., Nichi-Iko Pharmaceutical Co. Ltd., Nikkei Business Publications Inc., Nippon Boehringer Ingelheim, Nippon Kayaku Co. Ltd., Novartis, Ono Pharmaceutical, Roche Diagnostics KK, Taiho Pharmaceutical, Takeda Pharmaceutical Co. Ltd., Thermo Fisher Scientific KK, Yodosha Co. Ltd., and Yomiuri Telecasting Corporation; and has also served in a consulting or advisory role with Eli Lilly Japan KK, Kyorin Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd. Dr. Kato reports receiving grants and personal fees from AbbVie , Amgen , AstraZeneca , Bristol-Myers Squibb , Chugai Pharmaceutical , Eli Lilly , Merck Biopharma, Merck Sharp & Dohme , Novartis , Ono Pharmaceutical , Pfizer , and Taiho Pharmaceutical ; personal fees from Boehringer Ingelheim, Daiichi Sankyo, F.Hoffman-La Rohe, Nippon Kayaku, Nitto Denko, Shionogi, Sumitomo Dainippon, and Takeda Pharmaceutical; and grants from Astellas , Kyorin, Kyowa-Kirin , and Regeneron outside of the submitted work. Dr. Ares reports receiving grants and personal fees from Bristol-Myers Squibb and Astra Zeneca ; personal fees from Merck Sharp & Dohme, Roche, Eli Lilly, Merck, Novartis, Angem, Incyte, Takeda, Blueprint, and Bayer; other fees from Altum Sequencing; and personal fees and other fees from Gernomica, Pharma Mar, and Ipsen outside of the submitted work. Ms. Frimodt-Moller is an employee of Eli Lilly and Company with stock holdings. Dr. Wolff is an employee of Eli Lilly and Company with stock holdings. Dr. Visseren-Grul is an employee of Eli Lilly and Company with stock holdings. Dr. Heymach has served on advisory committees for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, EMD Serono, Foundation Medicine, Hengrui Therapeutics, Genentech, GlaxoSmithKline, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Spectrum, and Takeda, and reports receiving research support from AstraZeneca , GlaxoSmithKline , and Spectrum , and has received royalties and licensing fees from Spectrum. Dr. Garon reports receiving grants from Eli Lilly during the conduct of the study; grants from Bristol-Myers Squibb , AstraZeneca , Genentech , Merck , Lovance, Neon, Dynavax, and Mirati; grants and other fees from Novartis and EMD Serono; and other fees from Dracen and GlaxoSmithKline outside of the submitted work. Funding Information: Disclosure: Dr. Le reports receiving grants and personal fees from Eli Lilly and Boehringer Ingelheim; and personal fees from AstraZeneca and EMD Serono outside of the submitted work. Dr. Nilsson reports receiving licensing fees from Spectrum Pharmaceuticals outside of the submitted work. Dr. Nilsson also has a patent PCT/US2019/022067 pending, and a patent PCT/US2017/062326 and U.S. Provisional Patent application numbers 62/423,732; 62/427,692; and 62/572,716, with royalties paid to the University of Texas System Board of Regents. Dr. Goldman reports receiving grants and personal fees from AstraZeneca and Genentech outside of the submitted work. Dr. Reck reports receiving personal fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Merck, Merck Sharp & Dohme, Eli Lilly, Novartis, Pfizer, and Roche outside of the submitted work. Dr. Nakagawa reports receiving institutional research funding from A2 Healthcare Corp., AbbVie, Astellas Pharma, AstraZeneca KK, Bayer Yakuhin, Bristol-Myers Squibb, Chugai Pharma, CMIC Shift Zero KK, Daiichi Sankyo, Eisai, EPS Corporation, EPS International Co. Ltd., ICON Japan KK, IQVIA Services Japan KK, Kissei Pharmaceutical Co. Ltd., Kyowa Hakko Kirin, Eli Lilly and Company, Merck Serono, Merck Sharp & Dohme, Otsuka Pharmaceutical Co. Ltd., Parexel International Corp., Pfizer R&D Japan GK, SymBio Pharmaceuticals, Syneos Health, Taiho Pharmaceutical, and Takeda. Dr. Nakagawa reports receiving honoraria from AbbVie Inc., Astellas Pharma, AstraZeneca KK, Bayer Yakuhin Ltd., Bristol-Myers Squibb, CareNet Inc., Chugai Pharma, Daiichi Sankyo, Hisamitsu Pharmaceutical, Kyorin Medicus Shuppan Publishers Co. Ltd., Merck Biopharma Co. Ltd., Merck Sharp & Dohme KK, Nanzando Co. Ltd., Nichi-Iko Pharmaceutical Co. Ltd., Nikkei Business Publications Inc., Nippon Boehringer Ingelheim, Nippon Kayaku Co. Ltd., Novartis, Ono Pharmaceutical, Roche Diagnostics KK, Taiho Pharmaceutical, Takeda Pharmaceutical Co. Ltd., Thermo Fisher Scientific KK, Yodosha Co. Ltd., and Yomiuri Telecasting Corporation; and has also served in a consulting or advisory role with Eli Lilly Japan KK, Kyorin Pharmaceutical Co. Ltd., Ono Pharmaceutical Co. Ltd., Pfizer Japan Inc., and Takeda Pharmaceutical Co. Ltd. Dr. Kato reports receiving grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Biopharma, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; personal fees from Boehringer Ingelheim, Daiichi Sankyo, F.Hoffman-La Rohe, Nippon Kayaku, Nitto Denko, Shionogi, Sumitomo Dainippon, and Takeda Pharmaceutical; and grants from Astellas, Kyorin, Kyowa-Kirin, and Regeneron outside of the submitted work. Dr. Ares reports receiving grants and personal fees from Bristol-Myers Squibb and Astra Zeneca; personal fees from Merck Sharp & Dohme, Roche, Eli Lilly, Merck, Novartis, Angem, Incyte, Takeda, Blueprint, and Bayer; other fees from Altum Sequencing; and personal fees and other fees from Gernomica, Pharma Mar, and Ipsen outside of the submitted work. Ms. Frimodt-Moller is an employee of Eli Lilly and Company with stock holdings. Dr. Wolff is an employee of Eli Lilly and Company with stock holdings. Dr. Visseren-Grul is an employee of Eli Lilly and Company with stock holdings. Dr. Heymach has served on advisory committees for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, EMD Serono, Foundation Medicine, Hengrui Therapeutics, Genentech, GlaxoSmithKline, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Spectrum, and Takeda, and reports receiving research support from AstraZeneca, GlaxoSmithKline, and Spectrum, and has received royalties and licensing fees from Spectrum. Dr. Garon reports receiving grants from Eli Lilly during the conduct of the study; grants from Bristol-Myers Squibb, AstraZeneca, Genentech, Merck, Lovance, Neon, Dynavax, and Mirati; grants and other fees from Novartis and EMD Serono; and other fees from Dracen and GlaxoSmithKline outside of the submitted work. Publisher Copyright: © 2020 International Association for the Study of Lung Cancer
PY - 2021/2
Y1 - 2021/2
N2 - The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.
AB - The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.
KW - Anti-angiogenesis
KW - Dual inhibition
KW - EGFR
KW - EGFR-mutant NSCLC
KW - NSCLC
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=85096103298&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096103298&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2020.10.006
DO - 10.1016/j.jtho.2020.10.006
M3 - Review article
C2 - 33096270
AN - SCOPUS:85096103298
SN - 1556-0864
VL - 16
SP - 205
EP - 215
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 2
ER -