Hype or hope – Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC?

https://doi.org/10.1016/j.critrevonc.2021.103454Get rights and content
Under a Creative Commons license
open access

Abstract

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.

Keywords

NSCLC
EGFR
EGFR-TKI
combination therapy
chemotherapy
targeted therapies

Cited by (0)

Filippo Papini obtained his B.Sc. in Medical and Pharmaceutical Biotechnologies from the University of Florence (Italy) in 2017 and M.Sc. in Oncology at Vrije Universiteit Amsterdam (the Netherlands) in 2021. During his Master's, he worked on projects elucidating the effects of a novel cytidine analog for the treatment of pancreatic cancer and the role of miR-21 in driving resistance to EGFR-TKIs in non-small cell lung cancer.

Janani Sundaresan received her Bachelor’s Degree (B.Tech) in biotechnology from Anna university in 2014 and M.Sc. Degree in Biomedical Sciences from the University of Amsterdam in 2018. She is currently a Ph.D. student at the Amsterdam UMC (location VUMC), in the department of clinical chemistry. Her Master’s focus was on the behavioral relationship between pancreatic stellate cells and pancreatic adenocarcinoma.

Alessandro Leonetti, MD. Current position: Consultant at Medical Oncology Unit, University Hospital of Parma (Italy). November 2019-onwards: PhD student in Medical and Surgical Translational Sciences at University of Parma (Italy). December 2019: Specialization in Medical Oncology at University of Modena and Reggio Emilia (Italy). September 2018-February 2019: Research fellowship at Amsterdam UMC, VU university medical center, Laboratory Medical Oncology, Cancer Center Amsterdam, Amsterdam (Netherlands). October 2013: M.D. graduation at University of Sacred Hearth of Rome (Italy). Fields of interest: thoracic oncology, overcoming resistance in oncogene-addicted NSCLC. Member of European Society for Medical Oncology (ESMO), Italian Association of Medical Oncology (AIOM), Italian Oncology Group of Clinical Research (GOIRC).

Prof. Marcello Tiseo from 2005 is a Medical Oncologist at the Department of Medical Oncology of the University Hospital in Parma, Italy. Coordinator of Thoracic Oncology Disease Management Team and Head of Day Hospital of Medical Oncology Unit of University Hospital in Parma, Italy. From November 2018, Associate Professor of Medical Oncology and Director of Specialty School of Oncology, University of Parma. He is author or co-author of 295 papers in international peer-reviewed journals indexed by PubMed (H index = 43). He is a member of the Italian Association of Medical Oncology (AIOM), Italian Association of Thoracic Oncology (AIOT) and IASLC. He has served as co-ordinator of several controlled clinical trials in NSCLC, SCLC and mesothelioma at national and international level. He was or is PI or co-investigator in research programs of Italian Ministry of Health or Regional Agency, project of Italian Drug Agency (AIFA) and research projects of AIRC (Italian Association for Cancer Research).

Christian Rolfo MD, PhD, MBA, Dr.h.c. is the Associate Director of Clinical Research at the Center for Thoracic Oncology, Tisch Cancer Institute in Mount Sinai System. In addition, he is Professor of Medicine at the Division of Hematology and Oncology at Icahn School of Medicine, Mount Sinai, New York, NY, USA. From April 2018 to May 2021 he was serving as Director of Thoracic Medical Oncology and Director of Early Clinical Trials at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC), in Baltimore, Maryland, USA. In addition, he was appointed Professor of Medicine at the Division of Oncology at Maryland University, School of Medicine. Prof. Rolfo is Medical Oncologist focused in Thoracic Oncology, Drug Development and Translational Oncology. From 2012 to March 2018 he was working as Director of the Phase I - Early Clinical Trials Unit, Director of the Clinical Trials Management Program at Antwerp University Hospital, and Senior Staff member of Thoracic Oncology Cluster at Antwerp University Hospital in Belgium. In addition he was Professor of Oncology at Antwerp University in the Center for Oncological Research (CORE) in Antwerp, Belgium, Professor Rolfo graduated with a degree in medicine from the National University of Córdoba, Argentina in 1996; he then studied at the University of Milan and the National Cancer Institute of Milan, Italy, receiving European Oncology Board certification in 2003, followed by Spanish Board Certification in Medical Oncology in 2007. He obtained a PhD and Doctor Europaeus in Clinical and Experimental Oncology Research cum laude from the University of Palermo, Italy in 2009 under the direction of Professor Rosell, and a Master of Business Health Administration from the Polytechnic University of Valencia, Spain in 2010. He worked as clinical researcher in the Spanish Lung Cancer Group in Mallorca, Spain for 8 years. He is actively working on drug development and Lung cancer & Mesothelioma treatment. His research is focused in molecular oncology and Immunotherapy in Thoracic Oncology and in a pan-tumoral approach, using new techniques in liquid biopsies, specifically in exosome isolation and circulating free tumour DNA. His group identified ALK translocation in exosomes in NSCLC patients, and showed, for the first time, the videos of labeled EVs uptake by living lung cancer cells. He is currently working in the identification of new biomarkers involved in immunotherapy and TKI drug-resistance. In drug development Prof. Rolfo contributed to the development of several compounds including Erlotinib, pharmacokinetics of Olaparib, Entrectinib among several drugs in early phase. Prof. Rolfo served as an expert member of the Commission for Medicinal Products for Human Use and First in Human Drugs Commission at the Federal Agency of Health and Medicinal Products from Belgium and external expert for the European Agency of Medicine (EMA). Professor Rolfo is the Deputy Chair of the educational committee at the International Association for the Study of Lung Cancer (IASLC), served on the membership committee of ESMO, is the current vice-president of the International Society of Liquid Biopsy (ISLB) and member of the American Society of Clinical Oncology (ASCO), American Society of Clinical Research (AACR) the Oncology Latin-American Association (OLA) and other prestigious societies. He has been the recipient of numerous professional accolades, including an Honorary Doctorate by UPSJB in Peru as well Visiting Professor in Saudi Arabia, Italy and Distinguish Professor by his Alma mater University in Argentina. He has been a speaker at national and international forums in lung cancer, liquid biopsy and drug development, and has published extensively in peer-reviewed journals including New England Journal of Medicine, Lancet Oncology, Cancer Discovery, Nature Nanotechnology, Clinical Cancer Research, Annals of Oncology, and Lung Cancer among others. Prof. Rolfo is Editor in Chief of Critical Review in Oncology Hematology.

Prof. Godefridus (Frits) J Peters is currently at the Laboratory Medical Oncology, Amsterdam University Medical Centers (location VUMC) in Amsterdam, The Netherlands and at the Department of Biochemistry at the Medical University of Gdansk, Poland. He obtained a master’s degree in 1977 and PhD in 1982 at the Radboud University of Nijmegen, the Netherlands. He did post-docs at the Netherlands Cancer Institute and at the VU University in Amsterdam. He received a senior-research fellowship of the Royal Netherlands Academy of Arts and Sciences. Thereafter he was appointed as Associate Professor at the VUMC in 1992 and as full Professor in 2003, and in Gdansk as full Professor in 2019. His major research interests include pharmacology of and resistance to anticancer agents, with emphasis on antimetabolites, antifolates, platinum analogs, taxanes, anti-signaling and third-generation targeted agents, and the role of energy metabolism in cancer cells. He is (co)-author of more than 600 peer-reviewed papers in these fields with an H-index of 95 (Google Scholar). Professor Peters’ group was involved in the development of several clinically used antimetabolites and anti-signaling drugs. His current research interests also involve the role of genetic polymorphisms and epigenetics in drug metabolism and response to anticancer agents. He has been Chairman of the EORTC Pharmacology and Molecular Mechanisms Group for 6 years, of the Purine and Pyrimidine Society and is editor-in-chief and member of the editorial board for several journals, and has edited a number of books and proceedings of meetings.

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.

1

Equally contributed.