Advanced Non-Small Cell Lung Cancer with Activating Epidermal Growth Factor Receptor Mutation: First Line Treatment and Beyond

Author(s): Danilo Rocco, Ciro Battiloro, Luigi Della Gravara, Cesare Gridelli*.

Journal Name: Reviews on Recent Clinical Trials

Volume 14 , Issue 2 , 2019

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Graphical Abstract:


Abstract:

Background: Lung cancer is the leading cause of cancer mortality, being responsible for more than 1.6 million deaths each year worldwide and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers; moreover, 10 to 15% of all NSCLCs harbor EGFR (epidermal growth factor receptor) activating mutations, being suitable for EGFR-Tyrosine Kinase Inhibitors (TKI) molecular targeted therapy. However, EGFR+ NSCLCs gain acquired resistance to these agents, representing one of the key challenges for modern precision oncology.

Objective: Therefore, this paper aims to provide an extensive state of the art review, alongside with hints about future perspectives.

Conclusion: To date, in the light of the data from the FLAURA study, osimertinib represents the best first-line option in NSCLC patients with EGFR activating mutations; EGFR-TKI plus chemotherapy combination therapies, even though interesting, must still be considered investigational.

Keywords: Combination therapy, EGFR, NSCLC, Osimertinib, T790M, TKI.

[1]
Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005; 353: 172-87.
[2]
Lemmon MA, and Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2010; 141: 1117-34.
[3]
Yarden Y. The EGFR family and its ligands in human cancer signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001; 37(Suppl. 4): S3-8.
[4]
Zhang Y-L, Yuan J-Q, Wang K-F, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget 2016; 7(48): 78985-93.
[5]
Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res 2015; 5(9): 2892-911.
[6]
Cho J, Choi SM, Lee J, et al. Proportion and clinical features of never-smokers with non-small cell lung cancer. Chin J Cancer 2017; 36: 20.
[7]
G da Cunha Santos, FA. Shepherd, MS Tsao EGFR mutations and lung cancer annual review of pathology. Mechanism Dis 2011; 6(1): 49-69.
[8]
Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129-39.
[9]
Noronha V, Choughule A, Patil VM, et al. Epidermal growth factor receptor exon 20 mutation in lung cancer: Types, incidence, clinical features and impact on treatment. OncoTargets Ther 2017; 10: 2903-8.
[10]
Beau-Faller M, Prim N, Ruppert AM, et al. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: A multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol 2014; 25(1): 126-31.
[http://dx.doi.org/10.1093/annonc/mdt418]
[11]
Gazdar A. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene 2009; 28(Suppl. 1): S24-31.
[12]
Joshi A, Zanwar S, Noronha V, et al. EGFR mutation in squamous cell carcinoma of the lung: does it carry the same connotation as in adenocarcinomas? OncoTargets Ther 2017; 10: 1859-63.
[13]
Gandara DR, Hammerman PS, Sos ML, et al. Squamous cell lung cancer: from tumor genomics to cancer therapeutics. Clin Cancer Res 2015; 21(10): 2236-43.
[14]
Hanna N, Johnson D, Temin S, et al. Systemic therapy for stage IV Non-Small-Cell lung cancer: American society of clinical oncology clinical practice guideline Update. J Clin Oncol 2017; 3484-515.
[15]
Masters GA, Temin S, Azzoli CG, et al. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015; 30(3): 3488-515.
[16]
Novello S, Barlesi F, Califano R, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27: v1-7.
[http://dx.doi.org/10.1093/annonc/mdw326]
[17]
Schettino C, Bareschino MA, Ricci V, et al. Erlotinib: An EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment. Expert Rev Respir Med 2008; 2(2): 167-78.
[18]
Rosell R, Carcereny E, Gervais R, et al. 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. Lancet Oncol 2012; 13(3): 239-46.
[19]
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011; 12(8): 735-42.
[20]
Giaccone G. The role of gefitinib in lung cancer treatment. Clin Cancer Res 2004; 10(12): 4233s-7s.
[21]
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947-57.
[22]
Douillard J-Y, Ostoros G, Cobo M, et al. First-line gefitinib in Caucasian EGFR mutation-positive NSCLC patients: A phase-IV, open-label, single-arm study. Br J Cancer 2014; 110(1): 55-62.
[23]
Han JY, Park K, Kim SW, et al. First-SIGNAL: First-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with adenocarcinoma of the lung. J Clin Oncol 2012; 30(10): 1122-8.
[24]
Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362(25): 2380-8.
[25]
Mitsudomi T, Morita S, Yatabe Y, et al. 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. Lancet Oncol 2010; 11(2): 121-8.
[26]
Wirth SM. Afatinib in non-small cell lung cancer. J Adv Pract Oncol 2015; 6(5): 448-55.
[27]
Nelson V, Ziehr J, Agulnik M, et al. Afatinib: Emerging next-generation tyrosine kinase inhibitor for NSCLC. OncoTargets Ther 2013; 6: 135-43.
[28]
Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012; 343: 342-50.
[29]
Sequist LV, Yang JCH, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with egfr mutations. J Clin Oncol 2013; 3327-34.
[30]
Wu YL, Zhou C, Hu CP, et al. 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. Lancet Oncol 2014; 15(2): 213-22.
[31]
Oser MG, Niederst MJ, Sequist LV, et al. Transformation from non-small-cell lung cancer to small-cell lung cancer: Molecular drivers and cells of origin. Lancet Oncol 2015; 16(4): e165-72.
[32]
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 375ra26
[33]
Dorantes-Heredia R, Ruiz-Morales JM, Cano-García F. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors. Transl Lung Cancer Res 2016; 5(4): 401-12.
[34]
Xiao D, He J. Epithelial mesenchymal transition and lung cancer. J Thorac Dis 2010; 2(3): 154-9.
[35]
Jakobsen KR, Demuth C, Sorensen BS, et al. The role of epithelial to mesenchymal transition in resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Transl Lung Cancer Res 2016; 5(2): 172-82.
[36]
Huang L, Fu L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharm Sin B 2015; 5(5): 390-401.
[37]
Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316(5827): 1039-43.
[38]
Turke AB, Zejnullahu K, Wu Y-L, et al. Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 2010; 17(1): 77-88.
[39]
Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification: A potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2012; 2(10): 922-33.
[40]
Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008; 68: 6913-21.
[41]
Li S, Li L, Zhu Y, et al. Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts. Br J Cancer 2014; 110(11): 2812-20.
[42]
Ma C, Wei S, Song Y. T790M and acquired resistance of EGFR TKI: a literature review of clinical reports. J Thorac Dis 2011; 3(1): 10-8.
[43]
Ko R, Kenmotsu H, Serizawa M, et al. Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients. BMC Cancer 2016; 16: 864.
[44]
Kuiper JL, Heideman DAM, Thunnissen E, et al. Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer 2014; 85(1): 19-24.
[45]
Saad N, Poudel A, Basnet A, et al. Epidermal growth factor receptor T790M mutation-positive metastatic non-small-cell lung cancer: focus on osimertinib (AZD9291). OncoTargets Ther 2017; 10: 1757-66.
[46]
Cross DAE, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4(9): 1046-61.
[47]
Zhang H. Osimertinib making a breakthrough in lung cancer targeted therapy. OncoTargets Ther 2016; 9: 5489-93.
[48]
Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016; 22: 5130-40.
[49]
Goss G, Tsai C-M, Shepherd F, et al. MA16.11 CNS response to osimertinib in patients with T790M-positive advanced NSCLC: Pooled data from two phase II trials. J Thorac Oncol 2017; 12(1): Suppl: S440-S441.
[50]
Yang JC, Ahn MJ, Kim DW, et al. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component. J Clin Oncol 2017 20; 35(12): 1288-96.
[51]
Goss G, Tsai CM, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): A multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2016; 17(12): 1643-52.
[52]
Ng TL, Camidge DR. AURA 3: The last word on chemotherapy as a control arm in EGFR mutant NSCLC? Ann Transl Med 2017; 5(Suppl. 1): S14.
[53]
Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018; 378: 113-25.
[54]
Milano G, Spano JP, Leyland-Jones B. EGFR-targeting drugs in combination with cytotoxic agents: From bench to bedside, a contrasted reality. BJC 2008; 99(1): 1-5.
[55]
Zhou C, Yao LD. Strategies to improve outcomes of patients with EGFR-Mutant Non-Small Cell Lung Cancer: Review of the literature. J Thorac Oncol (JTO) 2016; 11(2): 174-86.
[56]
Tabernero J. The Role of VEGF and EGFR inhibition: Implications for combining Anti-VEGF and Anti-EGFR Agents. MCR 2007; 5(3): 203-20.
[57]
Horn L, Sandler A. Epidermal growth factor receptor inhibitors and antiangiogenic agents for the treatment of non-small cell lung cancer. CCR 2009; 15(16): 5040-8.
[58]
Moya-Horno I, Viteri S, Karachaliou N, et al. Combination of immunotherapy with targeted therapies in advanced non-small cell lung cancer (NSCLC). Ther Adv Med Oncol 2018; 101758834017745012
[59]
Pilotto S, Molina-Vila MA, Karachaliou N, et al. Integrating the molecular background of targeted therapy and immunotherapy in lung cancer: A way to explore the impact of mutational landscape on tumor immunogenicity. Transl Lung Cancer Res 2015; 4(6): 721-7.
[60]
Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: The tarceva lung cancer investigation trial. J Clin Oncol 2007; 25(12): 1545-52.
[61]
Herbst RS, Prager D, Hermann R, et al. TRIBUTE: A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23(25): 5892-9.
[62]
Hirsch FR, Kabbinavar F, Eisen T, et al. A randomized, phase II, biomarker-selected study comparing erlotinib to erlotinib intercalated with chemotherapy in first-line therapy for advanced non-small-cell lung cancer. J Clin Oncol 2011; 29(26): 3567-73.
[63]
Jänne PA, Wang X, Socinski MA, et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol 2012; 30(17): 2063-9.
[64]
Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol 2013; 14(8): 777-86.
[65]
Seto T, Kato T, Nishio M, et al. 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. Lancet Oncol 2014; 15(11): 1236-44.
[66]
Yamamoto N, Seto T, Nishio M, et al. Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation-positive non-squamous non-small-cell lung cancer (NSCLC): Survival follow-up results of JO25567. J Clin Oncol 2018; suppl: abstr 9007.
[67]
Gridelli C, Rossi A, Ciardiello F, et al. BEVERLY: Rationale and design of a randomized open-label phase iii trial comparing bevacizumab plus erlotinib versus erlotinib alone as first-line treatment of patients with EGFR-Mutated advanced nonsquamous non-smallcell lung cancer. clin lung cancer. 2016; 17(5): 461-5.
[68]
La Monica S, Madeddu D, Tiseo M, et al. Combination of gefitinib and pemetrexed prevents the acquisition of tki resistance in nsclc cell lines carrying EGFR-Activating mutation. J Thorac Oncol 2016; 11(7): 1051-63.
[69]
Yoshimura N, Kudoh S, Mitsuoka S, et al. Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation. Lung Cancer 2015; 90(1): 65-70.
[70]
Cheng Y, Murakami H, Yang PC, et al. Randomized Phase II Trial of gefitinib with and without pemetrexed as first-line therapy in patients with advanced nonsquamous non-small-cell lung cancer with activating epidermal growth factor receptor mutations. J Clin Oncol 2016; 34(27): 3258-66.
[71]
Han B, Jin B, Chu T, et al. Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial. Int J Cancer 2017; 141(6): 1249-56.
[72]
Oizumi S, Sugawara S, Minato K, et al. Updated survival outcomes of NEJ005/TCOG0902: A randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations. ESMO Open 2018; 3(2)e000313
[73]
Inoue A, Hosomi Y, Maemondo M, et al. NEJ009 trial: A randomized phase III study of gefitinib (G) in combination with carboplatin (C) plus pemetrexed (P) versus G alone in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) with EGFR mutation. J Clin Oncol 2018; 32: 15. [_suppl.].
[74]
Nakamura A, Inoue A, Morita S, et al. 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). J Clin Oncol 2018; 36: 9005.
[75]
Piotrowska Z, Liu SV, Muzikansky A, et al. Safety of osimertinib plus chemotherapy in EGFR-mutant NSCLC. J Clin Oncol 2018; 36(suppl); abstr e21231.
[76]
Okada M, Tanaka K, Asahina H, et al. 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. J Clin Oncol 2018; 36e21073
[77]
Planchard D, Yu HA, Yang JCH, et al. Efficacy and safety results of ramucirumab in combination with osimertinib in advanced T790M-positive EGFR-mutant NSCLC. J Clin Oncol 2018; 26: 9053.
[78]
Ahn MJ, Sun JM, Lee SH, et al. EGFR TKI combination with immunotherapy in non-small cell lung cancer. Expert Opin Drug Saf 2017; 16(4): 465-9.


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VOLUME: 14
ISSUE: 2
Year: 2019
Page: [120 - 128]
Pages: 9
DOI: 10.2174/1574887114666181205155211
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