Generic placeholder image

Reviews on Recent Clinical Trials

Editor-in-Chief

ISSN (Print): 1574-8871
ISSN (Online): 1876-1038

Meta-Analysis

Efficacy and Safety of EGFR Inhibitors in the Treatment of EGFRPositive NSCLC Patients: A Meta-Analysis

Author(s): Amit Dang*, Sumit Dang and B.N. Vallish

Volume 16, Issue 2, 2021

Published on: 03 November, 2020

Page: [193 - 201] Pages: 9

DOI: 10.2174/1574887115999201103200248

Price: $65

Abstract

Background: We compared the response rates, survival rates, and safety profile of epidermal growth factor receptor (EGFR) inhibitors with non-targeted chemotherapy and older EGFR inhibitors when used to treat advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations.

Methods: We searched PubMed, Cochrane Central Register of Controlled Trials, and clinicaltrial.- gov for randomized controlled trials published until 11-Feb-2020. Treatment outcomes were compared between EGFR inhibitor and pooled comparator; a subgroup analysis compared outcomes between EGFR inhibitor and non-targeted chemotherapy, and between newer and older EGFR inhibitors.

Results: Twenty-one studies with 4,250 unique patients were included. Significantly higher objective response rate (ORR) (odds ratio (OR) 2.28; 95% CI 2.00-2.61), higher disease control rate (DCR) (OR 2.3; 95% CI 1.88-3.06), and longer progression-free survival (PFS) (Hazard ratio (HR) 0.56; 95% CI 0.52-0.60) were observed in the EGFR inhibitor group compared to the pooled comparator group. Subgroup analysis revealed that the ORR, DCR, and PFS were significantly higher with EGFR inhibitors than non-targeted chemotherapy, and only PFS (and not ORR and DCR) was significantly longer with newer EGFR inhibitors than the older EGFR inhibitors. Overall survival (OS) was not significantly different between EGFR inhibitors and pooled comparator (HR 0.91; 95% CI 0.83-1.00) as well as in either of the subgroup analyses. Adverse events ≥ grade 3 and treatment discontinuation were significantly higher with non-targeted chemotherapy compared to the EGFR inhibitors.

Conclusion: The benefits of prolongation of ORR, DCR, and PFS might not imply significantly improved OS after therapy with EGFR inhibitors when compared with non-targeted chemotherapy or older EGFR inhibitors.

Keywords: EGFR inhibitors, non-small cell lung cancer, EGFR mutation, overall survival, progression-free survival, metaanalysis.

Graphical Abstract

[2]
Kratzke R, Franklin MJ. Lung Cancer Epidemiology.Encyclopedia of Cancer Berlin, Heidelberg: Springer 2011; pp 1-8.[http://dx.doi.org/10.1007/978-3-642-16483-5_6893]
[3]
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61(2): 69-90.[http://dx.doi.org/10.3322/caac.20107] [PMID: 21296855]
[4]
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67(1): 7-30.[http://dx.doi.org/10.3322/caac.21387] [PMID: 28055103]
[5]
Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013; 24(9): 2371-6.[http://dx.doi.org/10.1093/annonc/mdt205] [PMID: 23723294]
[6]
Peters S, Adjei AA, Gridelli C, Reck M, Kerr K, Felip E. ESMO Guidelines Working Group. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23(Suppl. 7): vii56-64.[http://dx.doi.org/10.1093/annonc/mds226] [PMID: 22997455]
[7]
Majem M, Juan O, Insa A, et al. SEOM clinical guidelines for the treatment of non-small cell lung cancer (2018). Clin Transl Oncol 2019; 21(1): 3-17.[http://dx.doi.org/10.1007/s12094-018-1978-1] [PMID: 30446985]
[8]
Sporn MB, Todaro GJ. Autocrine secretion and malignant transformation of cells. N Engl J Med 1980; 303(15): 878-80.[http://dx.doi.org/10.1056/NEJM198010093031511] [PMID: 7412807]
[9]
Maemondo M, Inoue A, Kobayashi K, et al. North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362(25): 2380-8.[http://dx.doi.org/10.1056/NEJMoa0909530] [PMID: 20573926]
[10]
Rosell R, Carcereny E, Gervais R, et al. Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo- Cancérologie and Associazione Italiana Oncologia Toracica. 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.[http://dx.doi.org/10.1016/S1470-2045(11)70393-X] [PMID: 22285168]
[11]
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.[http://dx.doi.org/10.1016/S1470-2045(13)70604-1] [PMID: 24439929]
[12]
Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017; 18(11): 1454-66.[http://dx.doi.org/10.1016/S1470-2045(17)30608-3] [PMID: 28958502]
[13]
Mok TS, Wu Y-L, Ahn M-J, et al. AURA3 Investigators. Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. N Engl J Med 2017; 376(7): 629-40.[http://dx.doi.org/10.1056/NEJMoa1612674] [PMID: 27959700]
[14]
Pirker R, Szczesna A, von Pawel J, et al. FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2008; 26: 1006s. [Abstract].[http://dx.doi.org/10.1200/jco.2008.26.15_suppl.3]
[15]
Thatcher N, Hirsch FR, Luft AV, et al. SQUIRE Investigators. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol 2015; 16(7): 763-74.[http://dx.doi.org/10.1016/S1470-2045(15)00021-2] [PMID: 26045340]
[16]
Takeda M, Nakagawa K. First- and Second-Generation EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer? Int J Mol Sci 2019; 20(1): E146.[http://dx.doi.org/10.3390/ijms20010146] [PMID: 30609789]
[17]
Park K, Tan EH, O’Byrne K, et al. 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. Lancet Oncol 2016; 17(5): 577-89.[http://dx.doi.org/10.1016/S1470-2045(16)30033-X] [PMID: 27083334]
[18]
Soria JC, Ohe Y, Vansteenkiste J, et al. FLAURA Investigators. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small- Cell Lung Cancer. N Engl J Med 2018; 378(2): 113-25.[http://dx.doi.org/10.1056/NEJMoa1713137] [PMID: 29151359]
[19]
Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.[http://dx.doi.org/10.1136/bmj.l4898] [PMID: 31462531]
[20]
Higgins JPT, Green S, Eds. Cochrane Handbook for Systematic Reviews of Interventions Version 510 The Cochrane Collaboration 2011. updated March 2011
[22]
Ranganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: Measures of agreement. Perspect Clin Res 2017; 8(4): 187-91.[http://dx.doi.org/10.4103/picr.PICR_123_17] [PMID: 29109937]
[23]
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.[http://dx.doi.org/10.1016/S1470-2045(11)70184-X] [PMID: 21783417]
[24]
Chen G, Feng J, Zhou C, et al. Quality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC). Ann Oncol 2013; 24(6): 1615-22.[http://dx.doi.org/10.1093/annonc/mdt012] [PMID: 23456778]
[25]
Zhou C, Wu YL, Chen G, et al. Final overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802). Ann Oncol 2015; 26(9): 1877-83.[http://dx.doi.org/10.1093/annonc/mdv276] [PMID: 26141208]
[26]
Mitsudomi T, Morita S, Yatabe Y, et al. West Japan Oncology Group. 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.[http://dx.doi.org/10.1016/S1470-2045(09)70364-X] [PMID: 20022809]
[27]
Yoshioka H, Shimokawa M, Seto T, et al. Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. Ann Oncol 2019; 30(12): 1978-84.[http://dx.doi.org/10.1093/annonc/mdz399] [PMID: 31553438]
[28]
Ramalingam SS, Vansteenkiste J, Planchard D, et al. FLAURA Investigators. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020; 382(1): 41-50.[http://dx.doi.org/10.1056/NEJMoa1913662] [PMID: 31751012]
[29]
Sequist LV, Yang JC, 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; 31(27): 3327-34.[http://dx.doi.org/10.1200/JCO.2012.44.2806] [PMID: 23816960]
[30]
Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010; 28(5): 744-52.[http://dx.doi.org/10.1200/JCO.2009.24.3030] [PMID: 20038723]
[31]
Herbst RS, Redman MW, Kim ES, et al. Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study. Lancet Oncol 2018; 19(1): 101-14.[http://dx.doi.org/10.1016/S1470-2045(17)30694-0] [PMID: 29169877]
[32]
Khambata-Ford S, Harbison CT, Hart LL, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010; 28(6): 918-27.[http://dx.doi.org/10.1200/JCO.2009.25.2890] [PMID: 20100958]
[33]
Sun JM, Lee KH, Kim SW, et al. Korean Cancer Study Group. Gefitinib versus pemetrexed as second-line treatment in patients with nonsmall cell lung cancer previously treated with platinum-based chemotherapy (KCSG-LU08-01): an open-label, phase 3 trial. Cancer 2012; 118(24): 6234-42.[http://dx.doi.org/10.1002/cncr.27630] [PMID: 22674612]
[34]
Watanabe S, Yoshioka H, Sakai H, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line treatment for stage IV squamous non-small cell lung cancer: A phase 1b and randomized, open-label, multicenter, phase 2 trial in Japan. Lung Cancer 2019; 129: 55-62.[http://dx.doi.org/10.1016/j.lungcan.2019.01.005] [PMID: 30797492]
[35]
Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015; 26(9): 1883-9.[http://dx.doi.org/10.1093/annonc/mdv270] [PMID: 26105600]
[36]
Yue D, Xu S, Wang Q, et al. Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. Lancet Respir Med 2018; 6(11): 863-73.[http://dx.doi.org/10.1016/S2213-2600(18)30277-7] [PMID: 30150014]
[37]
Urata Y, Katakami N, Morita S, et al. Randomized Phase III Study Comparing Gefitinib With Erlotinib in Patients With Previously Treated Advanced Lung Adenocarcinoma: WJOG 5108L. J Clin Oncol 2016; 34(27): 3248-57.[http://dx.doi.org/10.1200/JCO.2015.63.4154] [PMID: 27022112]
[38]
Yang JJ, Zhou Q, Yan HH, et al. A phase III randomised controlled trial of erlotinib vs gefitinib in advanced non-small cell lung cancer with EGFR mutations. Br J Cancer 2017; 116(5): 568-74.[http://dx.doi.org/10.1038/bjc.2016.456] [PMID: 28103612]
[39]
Franek J, Cappelleri JC, Larkin-Kaiser KA, Wilner KD, Sandin R. Systematic review and network meta-analysis of first-line therapy for advanced EGFR-positive non-small-cell lung cancer. Future Oncol 2019; 15(24): 2857-71.[http://dx.doi.org/10.2217/fon-2019-0270] [PMID: 31298572]
[40]
Yang JC, Wu YL, Schuler M, et al. 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. Lancet Oncol 2015; 16(2): 141-51.[http://dx.doi.org/10.1016/S1470-2045(14)71173-8] [PMID: 25589191]
[41]
Lee CK, Davies L, Wu YL, et al. Gefitinib or Erlotinib vs Chemotherapy for EGFR Mutation-Positive Lung Cancer: Individual Patient Data Meta-Analysis of Overall Survival. J Natl Cancer Inst 2017; 109(6)[http://dx.doi.org/10.1093/jnci/djw279] [PMID: 28376144]
[42]
Booth CM, Tannock I. Reflections on medical oncology: 25 years of clinical trials- where have we come and where are we going? J Clin Oncol 2008; 26(1): 6-8.[http://dx.doi.org/10.1200/JCO.2007.13.8156] [PMID: 18165630]
[43]
Wilson MK, Karakasis K, Oza AM. Outcomes and endpoints in trials of cancer treatment: the past, present, and future. Lancet Oncol 2015; 16(1): e32-42.[http://dx.doi.org/10.1016/S1470-2045(14)70375-4] [PMID: 25638553]
[44]
Baker SG, Kramer BS. Surrogate endpoint analysis: an exercise in extrapolation. J Natl Cancer Inst 2013; 105(5): 316-20.[http://dx.doi.org/10.1093/jnci/djs527] [PMID: 23264679]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy