Comparative Efficacy and Safety of Osimertinib Versus First-Generation EGFR-TKIS as First-Line Treatment in Egfr-Mutated Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis
DOI:
https://doi.org/10.22159/ijap.2026v18i5.59387Keywords:
Osimertinib, EGFR-TKI, Non-small cell lung cancer, Systematic review, Meta-analysis, Progression-free survival, Overall survivalAbstract
Objective of this study was to compare the efficacy and safety of Osimertinib versus first-generation EGFR-TKIs (gefitinib, erlotinib) as first-line treatment in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) through a systematic review and meta-analysis. A systematic review was conducted following PRISMA 2020 guidelines (PROSPERO: CRD420251163356). PubMed, Embase, and Scopus were searched from inception through September 2025. Eligible studies were randomized controlled trials (RCTs) and comparative cohort studies. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Hazard ratios (HRs) and risk ratios (RRs) were pooled. Risk of bias was assessed using RoB-2 and ROBINS-I. Evidence certainty was graded using GRADE. Eight studies (3 RCTs, 5 cohort studies; N=2824) met inclusion criteria; seven studies contributed to quantitative synthesis. Osimertinib significantly improved PFS (HR=0.46; 95% CI: 0.37–0.57; p<0.001) and OS (HR=0.80; 95% CI: 0.71–0.90; p<0.001). ORR (RR=1.04; 95% CI: 0.99–1.10; p=0.12) and DCR (RR=1.03; 95% CI: 0.99–1.07; p=0.18) were comparable. Grade ≥3 AEs were significantly lower with Osimertinib (RR=0.68; 95% CI: 0.56–0.83; p<0.001). Any-grade AEs were also reduced (RR=0.92; 95% CI: 0.87–0.98; p=0.008). GRADE certainty was high for PFS, OS, Grade ≥3 AEs, and any-grade AEs, and moderate for ORR and DCR. In conclusion, Osimertinib demonstrates significant improvements in PFS and OS with a favorable safety profile compared with first-generation EGFR-TKIs, supporting guideline recommendations as the preferred first-line targeted therapy in EGFR-mutated advanced NSCLC.
References
[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-49.
[2] Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
[3] 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. Am J Cancer Res. 2015;5(9):2892-911.
[4] Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, Khoa MT, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154-62.
[5] Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 2010;277(2):301-8.
[6] Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-57.
[7] Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-8.
[8] Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the EGFR (WJTOG3405). Lancet Oncol. 2010;11(2):121-8.
[9] Wu YL, Zhou C, Liam CK, Wu G, Liu X, Zhong Z, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer (ENSURE). Lancet Oncol. 2015;16(6):610-22.
[10] Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC). Lancet Oncol. 2012;13(3):239-46.
[11] Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL). Lancet Oncol. 2011;12(8):735-42.
[12] Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19(8):2240-7.
[13] Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3(75):75ra26.
[14] Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014;4(9):1046-61.
[15] Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018;378(2):113-25.
[16] Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray JE, Ohe Y, et al. Overall survival with Osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50.
[17] Planchard D, Janne PA, Cheng Y, Yang JC, Yanagitani N, Kim SW, et al. Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med. 2023;389(21):1935-48.
[18] Lu S, Dong X, Jian H, Chen J, Chen G, Sun Y, et al. AENEAS: a randomized phase III trial of aumolertinib versus gefitinib as first-line therapy. J Clin Oncol. 2022;40(27):3162-71.
[19] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71.
[20] Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.
[21] Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.
[22] Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919.
[23] Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60.
[24] Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-34.
[25] Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck Ytter Y, Alonso Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336(7650):924-6.
[26] Cho BC, Kim DW, Park K, Lee JS, Yoo SS, Kang JH, et al. Phase II study of Osimertinib versus gefitinib as first-line treatment in patients with EGFR mutation-positive advanced NSCLC. J Thorac Oncol. 2022;17(4):567-77.
[27] Kato Y, Hosomi Y, Watanabe K, Yomota M, Kawai S, Okuma Y, et al. Real-world efficacy of Osimertinib versus first-generation EGFR-TKIs in EGFR-mutated NSCLC: a multicenter retrospective study. Lung Cancer. 2021;162:146-53.
[28] Chen Y, Zhang L, Liu W, Wang Y, Zhao J, Han B, et al. Osimertinib versus gefitinib as first-line treatment for EGFR-mutated advanced NSCLC: a real-world retrospective study. Cancer Med. 2022;11(15):2934-44.
[29] Lin CC, Shih JY, Yu CJ, Ho CC, Liao WY, Lee JH, et al. Real-world comparison of Osimertinib versus first-generation EGFR-TKIs in treatment-naive EGFR-mutant NSCLC in Taiwan. Ther Adv Med Oncol. 2023;15:17588359231164592.
[30] Park S, Kim HR, Cho BC, Kang MH, Lee GK, Kim TM, et al. Prospective cohort comparison of Osimertinib with gefitinib in treatment-naive EGFR-mutant NSCLC in Korea. J Cancer Res Clin Oncol. 2024;150(2):89-98.
[31] Mu Y, Chen X, Wang J, Li Z, Zhang Y, Liu C, et al. Comparative effectiveness of Osimertinib versus erlotinib/gefitinib in EGFR-mutated NSCLC: a propensity-matched analysis. Target Oncol. 2023;18(4):523-34.
[32] Zhao Y, Liu J, Cai X, Pan Z, Liu J, Yin W, et al. Efficacy and safety of first-line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis. BMJ. 2019;367:l5460.
[33] Holleman MS, van Tinteren H, Groen HJM, Al MJ, Uyl-de Groot CA. First-line tyrosine kinase inhibitors in EGFR mutation-positive non-small cell lung cancer: a network meta-analysis. Onco Targets Ther. 2019;12:1413-21.
[34] Passaro A, Janne PA, Mok T, Peters S. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer. 2021;2(4):377-91.
[35] Mok TS, Cheng Y, Zhou X, Lee KH, Nakagawa K, Niho S, et al. Updated overall survival in a randomized study comparing dacomitinib with gefitinib. Drugs. 2021;81(2):257-66.
[36] National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer (Version 3.2025). Available from: https://www.nccn.org/guidelines [Last accessed on 10 Sep 2025].
[37] Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, et al. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019;125(6):892-901.
[38] Shah RR, Shah DR. Safety and tolerability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in oncology. Drug Saf. 2019;42(2):181-98.
[39] Planchard D, Popat S, Kerr K, Novello S, Smit EF, Faivre Finn C, et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29 Suppl 4:iv192-237.
[40] Hanna NH, Robinson AG, Temin S, Baker S Jr, Brahmer JR, Ellis PM, et al. Therapy for stage IV non-small-cell lung cancer with driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol. 2021;39(9):1040-91.
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