TY - JOUR
T1 - Hype or hope – Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC?
AU - Papini, Filippo
AU - Sundaresan, Janani
AU - Leonetti, Alessandro
AU - Tiseo, Marcello
AU - Rolfo, Christian
AU - Peters, Godefridus J.
AU - Giovannetti, Elisa
N1 - Funding Information: This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) , Grant IG2017-20074 (P.I. Marcello Tiseo) and IG2020-24444 (P.I. Elisa Giovannetti), Dutch Cancer Society KWF grant# 11957 and # 13598 (P.I. Elisa Giovannetti). Funding Information: Associate Professor Elisa Giovannetti , received her M.D. and Ph.D. with full marks and honors from the University of Pisa, Italy, in 2000 and 2007, respectively. Between 2001 and 2004, she contributed to translational studies on pharmacogenetics as clinical fellow in Pharmacology in the Department of Oncology of Pisa University. Since 2006 she collaborated with the Department of Medical Oncology at VU University Medical Center (VUmc), Amsterdam, The Netherlands, to set-up a line of research on (epi)genetic determinants of drug activity and molecular mechanisms underlying chemoresistance in pancreatic and lung cancer. She was promoted to Associate Professor in 2016, and she is also working as PI of a Start-Up lab at the Fondazione Pisana per la Scienza, Pisa, Italy. Her current research interests include also the role of liquid biopsies in early diagnosis and prediction of drug activity. She is actively involved, as elected chair, in research projects within the “Pharmacology and Molecular Mechanism Group” group of the EORTC (EORTC- PAMM), as well as in the European Pancreatic Club (EPC). She successfully requested funding from the Netherlands Organization for Scientific Research (NWO, VENI grant), “Marie Curie” and COST European Initiatives (H2020-MSCA-RISE “Alise” and COST “Stratagem”), Italian Association for Research against Cancer (AIRC, Start-Up and IG grants), Cancer Center Amsterdam (CCA) Foundation, and Dutch Cancer Society (KWF). Dr. Giovannetti is author or co-author of >300 scientific publications in peer-reviewed journals, with an H-index of 55 (Google Scholar), she has been invited for >130 Selected/Invited Lectures in international meetings, seminars and webinars and she is Deputy Editor of Critical Reviews in Oncology and Hematology, Associate Editor of Cancer Chemotherapy and Pharmacology, Cellular Oncology, Cancers, and Journal of Chemotherapy. Funding Information: Dr. C. Rolfo reports roles in speaker bureaus for MSD and AstraZeneca; advisory board roles with ARCHER, Inivata, and Merck Serono; consultant roles with Mylan and Oncompass; a supported research grant from the Lung Cancer Research Foundation/Pfizer; and research support from Guardant Health and Biomark. He has also received nonfinancial research support from OncoDNA and other support from Guardant Health. Publisher Copyright: © 2021 The Author(s) Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Three generations of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) have been developed for treating advanced/metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations, while a fourth generation is undergoing preclinical assessment. Although initially effective, acquired resistance to EGFR-TKIs usually arises within a year due to the emergence of clones harboring multiple resistance mechanisms. Therefore, the combination of EGFR-TKIs with other therapeutic agents has emerged as a potential strategy to overcome resistance and improve clinical outcomes. However, results obtained so far are ambiguous and ideal therapies for patients who experience disease progression during treatment with EGFR-TKIs remain elusive. This review provides an updated landscape of EGFR-TKIs, along with a description of the mechanisms causing resistance to these drugs. Moreover, it discusses the current knowledge, limitations, and future perspective regarding the use of EGFR-TKIs in combination with other anticancer agents, supporting the need for bench-to-bedside approaches in selected populations.
AB - Three generations of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) have been developed for treating advanced/metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations, while a fourth generation is undergoing preclinical assessment. Although initially effective, acquired resistance to EGFR-TKIs usually arises within a year due to the emergence of clones harboring multiple resistance mechanisms. Therefore, the combination of EGFR-TKIs with other therapeutic agents has emerged as a potential strategy to overcome resistance and improve clinical outcomes. However, results obtained so far are ambiguous and ideal therapies for patients who experience disease progression during treatment with EGFR-TKIs remain elusive. This review provides an updated landscape of EGFR-TKIs, along with a description of the mechanisms causing resistance to these drugs. Moreover, it discusses the current knowledge, limitations, and future perspective regarding the use of EGFR-TKIs in combination with other anticancer agents, supporting the need for bench-to-bedside approaches in selected populations.
KW - EGFR
KW - EGFR-TKI
KW - NSCLC
KW - chemotherapy
KW - combination therapy
KW - targeted therapies
UR - http://www.scopus.com/inward/record.url?scp=85114220435&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.critrevonc.2021.103454
DO - https://doi.org/10.1016/j.critrevonc.2021.103454
M3 - Review article
C2 - 34455092
SN - 1040-8428
VL - 166
JO - Critical Reviews in Oncology/Hematology
JF - Critical Reviews in Oncology/Hematology
M1 - 103454
ER -