Unravelling signal escape through maintained EGFR activation in advanced non-small cell lung cancer (NSCLC): new treatment options

The discovery of activating epidermal growth factor receptor (EGFR) mutations has opened up a new era in the development of more effective treatments for patients with non-small cell lung cancer (NSCLC). However, patients with EGFR-activating mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) ultimately develop acquired resistance (AR). Among known cases of patients with AR, 70% of the mechanisms involved in the development of AR to EGFR TKI have been identified and may be categorised as either secondary EGFR mutations such as the T790M mutation, activation of bypass track signalling pathways such as MET amplification, or histologic transformation. EGFR-mutant NSCLC tumours maintain oncogenic addiction to the EGFR pathway beyond progression with EGFR TKI. Clinical strategies that can be implemented in daily clinical practice to potentially overcome this resistance and prolong the outcome in this subgroup of patients are presented.

• Publication year

  2016

• Venue

  ESMO Open

• Publication date

  2016-07-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1136/esmoopen-2016-000081PMID 27843631PMCID 5070255
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT).

  2016cited by this paper
• Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.

  2016cited by this paper
• Plasma genotyping for predicting benefit from osimertinib in patients (pts) with advanced NSCLC: 135O_PR

  2016cited by this paper
• Osimertinib Responses After Disease Progression in Patients Who Had Been Receiving Rociletinib.

  2016cited by this paper
• Randomized phase 2 trial of gefitinib with and without pemetrexed as first-line therapy in East Asian patients with advanced, epidermal growth factor receptor (EGFR) mutation-positive (mt+), nonsquamous (NS) non-small cell lung cancer (NSCLC): Translational research and interim overall survival (OS)

  2016cited by this paper
• Update to Rociletinib Data with the RECIST Confirmed Response Rate.

  2016cited by this paper
• Impact of Continuing First-Line EGFR Tyrosine Kinase Inhibitor Therapy Beyond RECIST Disease Progression in Patients with Advanced EGFR-Mutated Non-Small-Cell Lung Cancer (NSCLC): Retrospective GFPC 04-13 Study

  2016cited by this paper
• Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.

  2016cited by this paper
• First-Line Erlotinib Therapy Until and Beyond Response Evaluation Criteria in Solid Tumors Progression in Asian Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: The ASPIRATION Study.

  2016cited by this paper
• Clinical Implications of Genomic Discoveries in Lung Cancer.

  2016cited by this paper
• First‐Line Afatinib versus Chemotherapy in Patients with Non–Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases

  2016cited by this paper
• Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM).

  2016cited by this paper
• Assessment of EGFR Mutation Status in Matched Plasma and Tumor Tissue of NSCLC Patients from a Phase I Study of Rociletinib (CO-1686)

  2016cited by this paper
• Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials.

  2016cited by this paper
• BI 1482694 (HM61713), an EGFR mutant-specific inhibitor, in T790M+ NSCLC: Efficacy and safety at the RP2D.

  2016cited by this paper
• Beyond clinical trials in advanced soft tissue sarcoma: what to expect from trabectedin treatment? Foreword.

  2015cited by this paper
• Updated safety and efficacy results from phase I/II study of HM61713 in patients (pts) with EGFR mutation positive non-small cell lung cancer (NSCLC) who failed previous EGFR-tyrosine kinase inhibitor (TKI).

  2015cited by this paper
• Efficacy of chemotherapy after first-line gefitinib therapy in EGFR mutation-positive advanced non-small cell lung cancer-data from a randomized Phase III study comparing gefitinib with carboplatin plus paclitaxel (NEJ002).

  2015cited by this paper
• Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial.

  2015cited by this paper
• AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer.

  2015cited by this paper
• Delay of treatment change after objective progression on first‐line erlotinib in epidermal growth factor receptor‐mutant lung cancer

  2015cited by this paper
• Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping.

  2015cited by this paper
• Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer.

  2015cited by this paper
• Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

  2015cited by this paper
• EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291.

  2015cited by this paper
• Common EGFR-mutated subgroups (Del19/L858R) in advanced non-small-cell lung cancer: chasing better outcomes with tyrosine kinase inhibitors.

  2015cited by this paper
• Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012

  2015cited by this paper
• Phase II Trial of Gefitinib in Combination with Bevacizumab as First-Line Therapy for Advanced Non–Small Cell Lung Cancer with Activating EGFR Gene Mutations: The Okayama Lung Cancer Study Group Trial 1001

  2015cited by this paper
• Safety and tolerability results from a phase I study of MEDI4736, a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib in patients (pts) with non-small-cell lung cancer (NSCLC).

  2015influential reference
• Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M

  2015cited by this paper
• Overall survival benefits of first-line EGFR tyrosine kinase inhibitors in EGFR-mutated non-small-cell lung cancers: a systematic review and meta-analysis

  2015cited by this paper
• Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer

  2015cited by this paper
• A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non–Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

  2015cited by this paper
• Phase Ib study of afatinib plus standard-dose cetuximab in patients (pts) with advanced solid tumors.

  2015cited by this paper
• Ultra-Sensitive Detection of the Pretreatment EGFR T790M Mutation in Non–Small Cell Lung Cancer Patients with an EGFR-Activating Mutation Using Droplet Digital PCR

  2015cited by this paper
• The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies

  2015cited by this paper
• Crizotinib in ROS1-rearranged non-small-cell lung cancer.

  2015cited by this paper
• Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial

  2015cited by this paper
• Biomarker analysis of a phase II trial of cabozantinib and erlotinib in patients (pts) with EGFR-mutant NSCLC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance: A California Cancer Consortium Phase II Trial (NCI 9303).

  2015cited by this paper
• Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis.

  2015cited by this paper
• Pemetrexed Singlet Versus Nonpemetrexed-Based Platinum Doublet as Second-Line Chemotherapy after First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Failure in Non-small Cell Lung Cancer Patients with EGFR Mutations

  2015influential reference
• EGFR-TKI down-regulates PD-L1 in EGFR mutant NSCLC through inhibiting NF-κB.

  2015cited by this paper
• Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts).

  2015cited by this paper
• Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.

  2015cited by this paper
• Rociletinib in EGFR-mutated non-small-cell lung cancer.

  2015cited by this paper
• Phase I study of INC280 plus erlotinib in patients with MET expressing adenocarcinoma of the lung.

  2015cited by this paper
• Reduced chemotherapy sensitivity in EGFR-mutant lung cancer patient with frontline EGFR tyrosine kinase inhibitor.

  2014cited by this paper
• Efficacy of the Irreversible ErbB Family Blocker Afatinib in Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI)–Pretreated Non–Small-Cell Lung Cancer Patients with Brain Metastases or Leptomeningeal Disease

  2014cited by this paper
• Acquired resistance to TKIs in solid tumours: learning from lung cancer

  2014cited by this paper
• Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.

  2014cited by this paper
• The predictive role of pretreatment epidermal growth factor receptor T790M mutation on the progression-free survival of tyrosine-kinase inhibitor-treated non-small cell lung cancer patients: a meta-analysis

  2014cited by this paper
• Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs.

  2014cited by this paper
• AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer.

  2014cited by this paper
• The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.

  2014cited by this paper
• Prior EGFR tyrosine-kinase inhibitor therapy did not influence the efficacy of subsequent pemetrexed plus platinum in advanced chemonaïve patients with EGFR-mutant lung adenocarcinoma

  2014cited by this paper
• Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations.

  2014cited by this paper
• Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing.

  2014cited by this paper
• Immune checkpoint blockade: the hope for immunotherapy as a treatment of lung cancer?

  2014cited by this paper
• The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial

  2014cited by this paper
• Crizotinib in ROS1-rearranged non-small-cell lung cancer.

  2014cited by this paper
• Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial.

  2014cited by this paper
• Safety and efficacy of INC280 in combination with gefitinib (gef) in patients with EGFR-mutated (mut), MET-positive NSCLC: A single-arm phase lb/ll study.

  2014influential reference
• Safety and response with nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus erlotinib in patients (pts) with epidermal growth factor receptor mutant (EGFR MT) advanced NSCLC.

  2014influential reference
• Continued treatment with gefitinib beyond progressive disease benefits patients with activating EGFR mutations.

  2013cited by this paper
• LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both.

  2013cited by this paper
• Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.

  2013cited by this paper
• Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers

  2013cited by this paper
• Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.

  2013cited by this paper
• Clinical implications of T790M mutation in patients with acquired resistance to EGFR tyrosine kinase inhibitors.

  2013cited by this paper
• EGFR mutational status in a large series of Caucasian European NSCLC patients: data from daily practice

  2013cited by this paper
• Local Therapy with Continued EGFR Tyrosine Kinase Inhibitor Therapy as a Treatment Strategy in EGFR-Mutant Advanced Lung Cancers That Have Developed Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

  2013cited by this paper
• Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial.

  2013cited by this paper
• Rebiopsy of non–small cell lung cancer patients with acquired resistance to epidermal growth factor receptor‐tyrosine kinase inhibitor

  2013cited by this paper
• Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer.

  2013cited by this paper
• Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer.

  2013cited by this paper
• Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology

  2013cited by this paper
• Chemotherapy with Erlotinib or chemotherapy alone in advanced non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitors.

  2013cited by this paper
• Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.

  2013cited by this paper
• Local Ablative Therapy of Oligoprogressive Disease Prolongs Disease Control by Tyrosine Kinase Inhibitors in Oncogene-Addicted Non–Small-Cell Lung Cancer

  2012cited by this paper
• Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.

  2012cited by this paper
• Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

  2012cited by this paper
• Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.

  2012cited by this paper
• Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors.

  2012cited by this paper
• Hallmarks of cancer: the next generation.

  2011cited by this paper
• Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based Assay

  2011cited by this paper
• Integration of EGFR inhibitors and conventional chemotherapy in the treatment of non-small-cell lung cancer.

  2011influential reference
• Pretreatment EGFR T790M Mutation and BRCA1 mRNA Expression in Erlotinib-Treated Advanced Non–Small-Cell Lung Cancer Patients with EGFR Mutations

  2011cited by this paper
• Disease Flare after Tyrosine Kinase Inhibitor Discontinuation in Patients with EGFR-Mutant Lung Cancer and Acquired Resistance to Erlotinib or Gefitinib: Implications for Clinical Trial Design

  2011cited by this paper
• Optimization of Dosing for EGFR-Mutant Non–Small Cell Lung Cancer with Evolutionary Cancer Modeling

  2011cited by this paper
• Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in the Treatment of Epidermal Growth Factor Receptor–Mutant Non–Small Cell Lung Cancer Metastatic to the Brain

  2011cited by this paper
• Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

  2011cited by this paper
• Association of Epidermal Growth Factor Receptor Activating Mutations with Low ERCC1 Gene Expression in Non-small Cell Lung Cancer

  2010cited by this paper
• Frequent central nervous system failure after clinical benefit with epidermal growth factor receptor tyrosine kinase inhibitors in Korean patients with nonsmall‐cell lung cancer

  2010cited by this paper
• Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer: Distinct Natural History of Patients with Tumors Harboring the T790M Mutation

  2010cited by this paper
• Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

  2010cited by this paper
• Lapatinib Plus Capecitabine in Women with HER-2–Positive Advanced Breast Cancer: Final Survival Analysis of a Phase III Randomized Trial

  2010cited by this paper
• Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

  2009cited by this paper
• Screening for epidermal growth factor receptor mutations in lung cancer.

  2009cited by this paper
• F1000 highlights

  2009cited by this paper
• The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

  2008cited by this paper

• Treatment-Induced Gene Expression Changes in Metastatic Renal Cell Carcinoma: Insights from a Syngeneic Mouse Model

  2025cites this paper
• Keeping a track on leptomeningeal disease in non–small cell lung cancer: A single-institution experience with CNSideTM

  2023cites this paper
• Roles of DNA repair enzyme OGG1 in innate immunity and its significance for lung cancer

  2019cites this paper
• Targeting histone deacetylase SIRT1 selectively eradicates EGFR TKI-resistant cancer stem cells via regulation of mitochondrial oxidative phosphorylation in lung adenocarcinoma

  2019cites this paper
• Driver genes in non-small cell lung cancer: Characteristics, detection methods, and targeted therapies

  2017cites this paper
• α2,3-sialyltransferase type I regulates migration and peritoneal dissemination of ovarian cancer cells

  2017cites this paper
• Treating EGFR mutation resistance in non-small cell lung cancer – role of osimertinib

  2017cites this paper
• Adenocarcinoma of the lung: an exploration of the relationships between histopathology, molecular pathology and inflammatory markers and their relationship to patient outcomes

  2017cites this paper