Current Strategies for Treating NSCLC: From Biological Mechanisms to Clinical Treatment

Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study

(2020) Lecia V Sequist et al.   LANCET ONCOLOGY

Management of Non-small Cell Lung Cancer Patients with MET Exon 14 Skipping Mutations

(2020) Caiwen Huang et al.   CURRENT TREATMENT OPTIONS IN ONCOLOGY

SHR-A1403, a novel c-Met antibody-drug conjugate, exerts encouraging anti-tumor activity in c-Met-overexpressing models

(2019) Chang-yong Yang et al.   ACTA PHARMACOLOGICA SINICA

AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells

(2019) Hirokazu Taniguchi et al.   Nature Communications

Acquired BRAF rearrangements induce secondary resistance to EGFR therapy in EGFR-mutated lung cancers

(2019) Morana Vojnic et al.   Journal of Thoracic Oncology

A Phase Ib Study of the Combination of afatinib and ruxolitinib in EGFR mutant NSCLC with progression on EGFR-TKIs

(2019) Ji Soo Park et al.   LUNG CANCER

AXL degradation in combination with EGFR-TKI can delay and overcome acquired resistance in human non-small cell lung cancer cells

(2019) Donghwa Kim et al.   Cell Death & Disease

Sequencing of therapy following first-line afatinib in patients with EGFR mutation-positive non-small cell lung cancer

(2019) Keunchil Park et al.   LUNG CANCER

PCC0208027, a novel tyrosine kinase inhibitor, inhibits tumor growth of NSCLC by targeting EGFR and HER2 aberrations

(2019) Qiuju Dong et al.   Scientific Reports

Combination of metformin and gefitinib as first-line therapy for non-diabetic advanced NSCLC patients with EGFR mutations: A randomized, double-blind phase 2 trial

(2019) Li Li et al.   CLINICAL CANCER RESEARCH

Exon-16-skipping HER2 as a novel mechanism of osimertinib-resistance in EGFR L858R/T790M-positive non-small-cell lung cancer

(2019) Chia-Chi Hsu et al.   Journal of Thoracic Oncology

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

(2019) Yoshikane Nonagase et al.   Thoracic Cancer

Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine Kinase Inhibitors Alone in Patients With Epidermal Growth Factor Receptor–Mutated Lung Adenocarcinoma

(2019) Oscar Arrieta et al.   JAMA Oncology

CMET-22. CAPMATINIB (INC280) IN METΔEX14-MUTATED ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC): EFFICACY DATA FROM THE PHASE 2 GEOMETRY MONO-1 STUDY

(2019) Rebecca S Heist et al.   NEURO-ONCOLOGY

Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC

(2019) Suresh S. Ramalingam et al.   NEW ENGLAND JOURNAL OF MEDICINE

Blockade of AXL activation overcomes acquired resistance to EGFR tyrosine kinase inhibition in non-small cell lung cancer

(2019) Feng Wang et al.   Translational Cancer Research

Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1–2 study

(2019) Myung-Ju Ahn et al.   LANCET ONCOLOGY

CD74-ROS1 G2032R mutation transcriptionally up-regulates Twist1 in non-small cell lung cancer cells leading to increased migration, invasion, and resistance to crizotinib

(2018) Wenfeng Gou et al.   CANCER LETTERS

TargetingHER2Aberrations in Non–Small Cell Lung Cancer with Osimertinib

(2018) Shengwu Liu et al.   CLINICAL CANCER RESEARCH

Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial

(2018) Bob T. Li et al.   JOURNAL OF CLINICAL ONCOLOGY

Receptor Tyrosine Kinase fusions and BRAF kinase fusions are rare but actionable resistance mechanisms to EGFR tyrosine kinase inhibitors

(2018) Alexa B. Schrock et al.   Journal of Thoracic Oncology

First-in-Human Phase I Study of AC0010, a Mutant-Selective EGFR Inhibitor in Non–Small Cell Lung Cancer: Safety, Efficacy, and Potential Mechanism of Resistance

(2018) Yuxiang Ma et al.   Journal of Thoracic Oncology

Mechanisms of receptor tyrosine kinase activation in cancer

(2018) Zhenfang Du et al.   Molecular Cancer

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

(2018) Jean-Charles Soria et al.   NEW ENGLAND JOURNAL OF MEDICINE

Epigenetic silencing of miR-483-3p promotes acquired gefitinib resistance and EMT in EGFR-mutant NSCLC by targeting integrin β3

(2018) Jinnan Yue et al.   ONCOGENE

FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non‐Small Cell Lung Cancers HarboringBRAF V600EMutations

(2018) Lauretta Odogwu et al.   ONCOLOGIST

Use of erlotinib and thalidomide in advanced NSCLC patients with acquired resistance to erlotinib: A pilot study

(2018) Gen-He Wang et al.   PATHOLOGY RESEARCH AND PRACTICE

Increased expression of miR-641 contributes to erlotinib resistance in non-small-cell lung cancer cells by targeting NF1

(2018) Juan Chen et al.   Cancer Medicine

EGFR–TKI-Associated Interstitial Pneumonitis in Nivolumab-Treated Patients With Non–Small Cell Lung Cancer

(2018) Yasuo Oshima et al.   JAMA Oncology

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

(2018) Freddie Bray et al.   CA-A CANCER JOURNAL FOR CLINICIANS

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer

(2018) Hiroki Sato et al.   CANCER SCIENCE

CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non–Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3)

(2018) Yi-Long Wu et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor–Dysregulated Non–Small-Cell Lung Cancer

(2018) Yi-Long Wu et al.   JOURNAL OF CLINICAL ONCOLOGY

Safety analysis of an open label, randomized phase 2 study of osimertinib alone versus osimertinib plus carboplatin-pemetrexed for patients with non–small cell lung cancer (NSCLC) that progressed during prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and which harbors a T790M mutation of EGFR.

(2018) Morihito Okada et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009).

(2018) Atsushi Nakamura et al.   JOURNAL OF CLINICAL ONCOLOGY

Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI

(2018) Chien-Hui Weng et al.   ONCOGENE

1382PDPhase III study of gefitinib (G) versus gefitinib+carboplatin+pemetrexed (GCP) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009)

(2018) M Seike et al.   ANNALS OF ONCOLOGY

Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer

(2018) Mong-Wei Lin et al.   LUNG CANCER

miR-21 and KLF4 jointly augment epithelial-mesenchymal transition via the Akt/ERK1/2 pathway

(2017) Chen-Hai Liu et al.   INTERNATIONAL JOURNAL OF ONCOLOGY

Gefitinib Plus Chemotherapy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation–Positive Non–Small-Cell Lung Cancer Resistant to First-Line Gefitinib (IMPRESS): Overall Survival and Biomarker Analyses

(2017) Tony S.K. Mok et al.   JOURNAL OF CLINICAL ONCOLOGY

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

(2017) Imane Chaib et al.   JNCI-Journal of the National Cancer Institute

P3.02-042 DS-1205b, a Novel, Selective, Inhibitor of AXL, Delays the Onset of Resistance and Overcomes Acquired Resistance to EGFR-TKIs

(2017) T. Jimbo et al.   Journal of Thoracic Oncology

Modulation of Biomarker Expression by Osimertinib: Results of the Paired Tumor Biopsy Cohorts of the AURA Phase I Trial

(2017) Kenneth S. Thress et al.   Journal of Thoracic Oncology

Characteristics and Outcomes of Patients with Lung Cancer Harboring Multiple Molecular Alterations: Results from the IFCT Study Biomarkers France

(2017) Nicolas Guibert et al.   Journal of Thoracic Oncology

Inhibition of miR-23a increases the sensitivity of lung cancer stem cells to erlotinib through PTEN/PI3K/Akt pathway

(2017) Zhijun Han et al.   ONCOLOGY REPORTS

Reduced expression levels of PTEN are associated with decreased sensitivity of HCC827 cells to icotinib

(2017) Yang Zhai et al.   Oncology Letters

Concomitant EML4-ALK rearrangement and EGFR mutation in non-small cell lung cancer patients: a literature review of 100 cases

(2017) Giuseppe Lo Russo et al.   Oncotarget

Acquisition of EGFR TKI resistance and EMT phenotype is linked with activation of IGF1R/NF-κB pathway in EGFR-mutant NSCLC

(2017) Ling Li et al.   Oncotarget

Co-activation of STAT3 and YES-Associated Protein 1 (YAP1) Pathway in EGFR-Mutant NSCLC

(2017) Imane Chaib et al.   JNCI-Journal of the National Cancer Institute

Chronic treatment of non-small-cell lung cancer cells with gefitinib leads to an epigenetic loss of epithelial properties associated with reductions in microRNA-155 and -200c

(2017) Michiko Narita et al.   PLoS One

Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells

(2017) An-Fu Lee et al.   PLoS One

441O Preliminary safety and clinical activity of erlotinib plus atezolizumab from a Phase Ib study in advanced NSCLC

(2016) B.B.Y. Ma et al.   ANNALS OF ONCOLOGY

Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib

(2016) Aurelie Courtin et al.   BRITISH JOURNAL OF CANCER

Afatinib: An overview of its clinical development in non-small-cell lung cancer and other tumors

(2016) Pasqualina Giordano et al.   CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY

Synergistic effect of pacritinib with erlotinib on JAK2-mediated resistance in epidermal gowth factor receptor mutation-positive non-small cell lung Cancer

(2016) Nobuaki Ochi et al.   EXPERIMENTAL CELL RESEARCH

miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells

(2016) NOBUHIKO NISHIJIMA et al.   INTERNATIONAL JOURNAL OF ONCOLOGY

Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer

(2016) Shuhang Wang et al.   Journal of Hematology & Oncology

136O: Osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: Results from the TATTON phase Ib trial

(2016) M.-J. Ahn et al.   Journal of Thoracic Oncology

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

(2016) Keunchil Park et al.   LANCET ONCOLOGY

Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors

(2016) Yong Jia et al.   NATURE

Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition

(2016) Aaron N Hata et al.   NATURE MEDICINE

AURA3 magic reveals new standard

(2016) Lisa Hutchinson   Nature Reviews Clinical Oncology

JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors

(2016) Sizhi P. Gao et al.   Science Signaling

Intrinsic resistance to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer with activating EGFR mutations

(2016) Jun Wang et al.   OncoTargets and Therapy

Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients

(2016) Jacob J. Chabon et al.   Nature Communications

Efficacy and safety of bevacizumab plus erlotinib versus bevacizumab or erlotinib alone in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis

(2016) Shu Zhang et al.   BMJ Open

JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors

(2016) Sizhi P. Gao et al.   Science Signaling

Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902

(2015) S. Sugawara et al.   ANNALS OF ONCOLOGY

Global cancer statistics, 2012

(2015) Lindsey A. Torre et al.   CA-A CANCER JOURNAL FOR CLINICIANS

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma

(2015) Yun-Rong Zhu et al.   CANCER BIOLOGY & THERAPY

The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies

(2015) M. J. Niederst et al.   CLINICAL CANCER RESEARCH

EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs

(2015) Y. Kobayashi et al.   CLINICAL CANCER RESEARCH

Down-regulation of ERK1/2 and AKT-mediated X-ray repair cross-complement group 1 protein (XRCC1) expression by Hsp90 inhibition enhances the gefitinib-induced cytotoxicity in human lung cancer cells

(2015) Chun-Liang Tung et al.   EXPERIMENTAL CELL RESEARCH

Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells

(2015) Yongik Lee et al.   MOLECULAR CARCINOGENESIS

Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for non-small cell lung cancer cells

(2015) Zhi-hong Xu et al.   TUMOR BIOLOGY

Integrin β1-mediated acquired gefitinib resistance in non-small cell lung cancer cells occurs via the phosphoinositide 3-kinase-dependent pathway

(2015) QIN-FANG DENG et al.   Oncology Letters

Synergistic interaction between MEK inhibitor and gefitinib in EGFR-TKI-resistant human lung cancer cells

(2015) SUXIA LI et al.   Oncology Letters

Metformin Sensitizes EGFR-TKI-Resistant Human Lung Cancer Cells In Vitro and In Vivo through Inhibition of IL-6 Signaling and EMT Reversal

(2014) L. Li et al.   CLINICAL CANCER RESEARCH

The combination of irreversible EGFR TKIs and SAHA induces apoptosis and autophagy-mediated cell death to overcome acquired resistance in EGFRT790M-mutated lung cancer

(2014) Tae-Gul Lee et al.   INTERNATIONAL JOURNAL OF CANCER

Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial

(2014) Yi-Long Wu et al.   LANCET ONCOLOGY

Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression

(2014) Noemi Reguart et al.   LUNG CANCER

Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation

(2014) GEPING QU et al.   ONCOLOGY REPORTS

Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer

(2014) Hua Shen et al.   PLoS One

The HSP90 inhibitor ganetespib potentiates the antitumor activity of EGFR tyrosine kinase inhibition in mutant and wild-type non-small cell lung cancer

(2014) Donald L. Smith et al.   Targeted Oncology

Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers

(2013) H. A. Yu et al.   CLINICAL CANCER RESEARCH

Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation

(2013) Ji-Young Song et al.   INVESTIGATIONAL NEW DRUGS

KRASMutation: Should We Test for It, and Does It Matter?

(2013) Patrick J. Roberts et al.   JOURNAL OF CLINICAL ONCOLOGY

Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma WithEGFRMutations

(2013) Lecia V. Sequist et al.   JOURNAL OF CLINICAL ONCOLOGY

Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial

(2013) Yuankai Shi et al.   LANCET ONCOLOGY

The ErbB/HER family of protein-tyrosine kinases and cancer

(2013) Robert Roskoski   PHARMACOLOGICAL RESEARCH

A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop

(2013) K E Ware et al.   Oncogenesis

Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin–paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002)

(2012) A. Inoue et al.   ANNALS OF ONCOLOGY

ZEB/miR-200 feedback loop: At the crossroads of signal transduction in cancer

(2012) Louise Hill et al.   INTERNATIONAL JOURNAL OF CANCER

First-SIGNAL: First-Line Single-Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung

(2012) Ji-Youn Han et al.   JOURNAL OF CLINICAL ONCOLOGY

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

(2012) Rafael Rosell et al.   LANCET ONCOLOGY

MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib

(2012) Ming-Hung Huang et al.   Molecular Oncology

AXL and acquired resistance to EGFR inhibitors

(2012) Sophie Postel-Vinay et al.   NATURE GENETICS

Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1

(2012) K. Ohashi et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

HER2 Amplification: A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR -Mutant Lung Cancers That Lack the Second-Site EGFR T790M Mutation

(2012) Ken Takezawa et al.   Cancer Discovery

MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression

(2011) Marc D. Bullock et al.   BIOLOGY OF THE CELL

Hepatocyte Growth Factor Expression in EGFR Mutant Lung Cancer with Intrinsic and Acquired Resistance to Tyrosine Kinase Inhibitors in a Japanese Cohort

(2011) Seiji Yano et al.   Journal of Thoracic Oncology

Overcoming Erlotinib Resistance in EGFR Mutation-Positive Non-Small Cell Lung Cancer Cells by Targeting Survivin

(2011) K. Okamoto et al.   MOLECULAR CANCER THERAPEUTICS

Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors

(2011) L. V. Sequist et al.   Science Translational Medicine

Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor

(2010) D Ercan et al.   ONCOGENE

Combined Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor (EGFR) Blockade Inhibits Tumor Growth in Xenograft Models of EGFR Inhibitor Resistance

(2009) G. N. Naumov et al.   CLINICAL CANCER RESEARCH

Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancers Dependent on the Epidermal Growth Factor Receptor Pathway

(2009) Kim-Son H. Nguyen et al.   Clinical Lung Cancer

Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial

(2009) Tetsuya Mitsudomi et al.   LANCET ONCOLOGY

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M

(2009) Wenjun Zhou et al.   NATURE

Short interfering RNA directed against TWIST, a novel zinc finger transcription factor, increases A549 cell sensitivity to cisplatin via MAPK/mitochondrial pathway

(2008) Wen-Lei Zhuo et al.   BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

MicroRNA-155 Is Regulated by the Transforming Growth Factor  /Smad Pathway and Contributes to Epithelial Cell Plasticity by Targeting RhoA

(2008) W. Kong et al.   MOLECULAR AND CELLULAR BIOLOGY

Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition

(2008) Hendrik Fischer et al.   MOLECULAR CANCER THERAPEUTICS

BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models

(2008) D Li et al.   ONCOGENE

The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

(2008) C.-H. Yun et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA