|Year : 2021 | Volume
| Issue : 3 | Page : 664-670
EGFR tyrosine kinase inhibitors alone or in combination with chemotherapy for non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials
Cui-Min Zhu1, Xiang-Yao Lian1, Hong-Yan Zhang2, Lu Bai1, Wen-Jing Yun1, Ru-Han Zhao1, Qing-Shan Li1
1 Department of Oncology, Affiliated Hospital of Chengde Medical College, Chengde, China
2 Department of Oncology, China National Petroleum Corporation Central Hospital, Langfang, Hebei, China
|Date of Submission||19-Feb-2020|
|Date of Decision||13-Jul-2020|
|Date of Acceptance||15-Nov-2020|
|Date of Web Publication||9-Jul-2021|
Department of Oncology, Affiliated Hospital of Chengde Medical College, No. 36, Nanyingzi Street, Chengde, Hebei 067000
Source of Support: None, Conflict of Interest: None
Objective: The objective of this study was to perform a meta-analysis comparing the efficiency of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy to EGFR TKI treatment alone in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC).
Materials and Methods: Following keyword queries in databases and identification of randomized control trials for inclusion, hazard ratios (HRs), relative risks (RRs), and associated 95% confidence intervals (95% CIs) were determined.
Results: Ten randomized controlled trials involving 1354 participants with NSCLC were evaluated. We found that a combined approach of chemotherapy with EGFR TKIs significantly improved overall survival (OS) compared with EGFR TKI alone in our patient cohort (HR = 0.47, 95% CI = 0.31–0.72). In addition, a higher overall response rate (ORR) was found for patients who received combined treatment compared to chemotherapy alone (RR = 2.17, 95% CI = 1.51-3.12). Furthermore, concomitant use of chemotherapy with TKIs significantly improved the progression-free survival (PFS) when compared to the use of TKIs alone (HR = 0.68, 95% CI = 0.49-0.95). Moreover, there was a higher ORR among patients who received combined treatment as compared to those who were managed using TKIs only (RR=1.17, 95%CI=1.09-1.25).
Conclusion: Our meta-analysis shows that EGFR TKIs with chemotherapy confer better OS and ORR compared to either treatment alone, similarly, the combined treatment showed better PFS and ORR profiles than the use of TKI alone.
Keywords: Epidermal growth factor receptor, meta-analysis, non-small cell lung cancer, randomized controlled trials, tyrosine kinase inhibitors
|How to cite this article:|
Zhu CM, Lian XY, Zhang HY, Bai L, Yun WJ, Zhao RH, Li QS. EGFR tyrosine kinase inhibitors alone or in combination with chemotherapy for non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials. J Can Res Ther 2021;17:664-70
|How to cite this URL:|
Zhu CM, Lian XY, Zhang HY, Bai L, Yun WJ, Zhao RH, Li QS. EGFR tyrosine kinase inhibitors alone or in combination with chemotherapy for non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials. J Can Res Ther [serial online] 2021 [cited 2021 Aug 5];17:664-70. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/664/321023
| > Introduction|| |
Lung cancer is the most common malignancy with the highest mortality, particularly in women in developed countries. In China, lung cancer has the highest reported incidence (48.32/100,000) and mortality (39.27/100,000) of cancers in 2011. Non-small cell lung cancer (NSCLC) accounts for 85% of cases of lung cancer, of which nearly 46% are diagnosed at advanced or metastasized stages., Conventionally, 4–6 cycles of first-line platinum-based double chemotherapy are recommended for patients; however, efficiency is poor, with a median overall survival (OS) of ~1 year., Thus, new approaches are needed to improve clinical outcome.
Personalized treatment of lung cancer is emerging as the main player targeting lung cancer driver gene mutations using molecular targeted therapy.,,, One such biomarker is epidermal growth factor receptor (EGFR) mutation status as it is found in nearly 23% of lung adenocarcinomas, accounting for 75.3% of East Asian patient subgroups and female patients with no exposure to smoking and lack of available alternative therapeutic interventions. EGFR tyrosine kinase inhibitors (TKIs) show increased clinical efficacy and safety compared to chemotherapy as first-line therapy in patients with NSCLC and advanced EGFR mutations,,,, although their adoption in combined therapeutic regimens to improve patient prognosis has yielded mixed results. Therefore, the purpose of this meta-analysis was to obtain a more comprehensive understanding of the combined use of EGFR TKIs with chemotherapy versus EGFR TKIs alone in patients with EGFR mutation-positive NSCLC.
| > Materials and Methods|| |
Databases, including PubMed, EMBASE, and Cochrane Library, were queried using the keyword phrases “lung cancer/lung neoplasm/pulmonary cancer/pulmonary neoplasm,” “gefitinib/erlotinib/afatinib,” and “chemotherapy.” The final search was performed on February 15, 2019. There were no restrictions on language, and an examination of cross-references and reviews was performed to identify additional publications.
Our inclusion criteria were as follows: (1) study cohort consisted of patients with NSCLC and EGFR mutations; (2) the study described a randomized controlled trial (RCT); (3) comparisons were reported between EGFR TKIs with chemotherapy versus EGFR TKIs alone; (4) OS, progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR) were presented; and (5) a trial with the longest follow-up was used instead of overlapping cohort studies.
Data were extracted by two independent investigators by reviewing publications. The following was obtained from each publication: first author, publication year, trial phase, sample size per group, chemotherapy regimens, and measures of the primary endpoint (OS, PFS, ORR, and DCR).
Because of the scarcity of prognostic studies directly reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs),, logarithm of the HR and variance were determined with indirect approaches using reported HR and 95% CI if available, log-rank P values, or Kaplan–Meier survival curves. Pooled relative risks (RRs) and corresponding 95% CIs were also estimated. Heterogeneity was evaluated by Q-test. At I2 <50%, pooled HRs or RRs of studies were obtained by fixed-effects or random-effects model. For sensitivity analysis, the relative influence of studies on pooled results was estimated by omission of a single trial at a time. We evaluated publication bias by Begg's funnel plot and Egger's test. STATA 12.0 (STATA Corp., USA) was used for analysis. P < 0.05 was considered statistically significant.
| > Results|| |
We identified 411 articles, of which 357 were excluded upon reviewing the title. Next, abstracts were evaluated, and 29 full-text reports underwent thorough evaluation for inclusion in our study. Based on inclusion criteria, we identified ten publications for our study,,,,,,,,,, including 1354 patients [detailed characteristics are shown in [Table 1]]. A schematic of the selection procedure, as well as exclusion criteria, is shown in [Figure 1]. Our study cohort consists of 681 randomized patients who received EGFR TKI plus chemotherapy, 471 patients who received chemotherapy alone, and 202 patients who received EGFR TKI alone. Five studies evaluated the combined approach versus chemotherapy alone, four studies compared a combined approach to EGFR TKI alone, and one study performed comparisons between all three treatment approaches. Gemcitabine/cisplatin, gemcitabine/carboplatin, pemetrexed/carboplatin, pemetrexed/cisplatin, and docetaxel and pemetrexed alone were the chemotherapy regimens used in six studies, and gefitinib and erlotinib were the EGFR TKIs used in five studies.
Two trials evaluated OS using a combined approach of chemotherapy and EGFR TKI versus chemotherapy alone. Using a fixed-effects model, we found no significant diversity (P = 0.923, I2 = 0%). Further, pooled data indicated that combined treatment resulted in a significantly higher OS compared to chemotherapy alone in patients with EGFR mutation-positive NSCLC [HR = 0.47, 95% CI = 0.31–0.72; [Figure 2]a]. Six trials reported OS for a combined approach versus EGFR TKI alone. We found evidence of significant heterogeneity (P < 0.001, I2 = 79.1%), using a random-effects model. Pooled data showed there were no significant variations in OS between combined treatment and EGFR TKI treatment alone in patients [HR = 0.78, 95% CI = 0.48-1.27; [Figure 2]b].
|Figure 2: Forest plots of overall survival in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus (a) chemotherapy alone or (b) epidermal growth factor receptor tyrosine kinase inhibitor alone|
Click here to view
Of the four trials that evaluated a combined approach versus chemotherapy only, significant heterogeneity (P < 0.001, I2 = 91.9%) was found using a random-effects model. We found no evidence from pooled data of a difference in PFS between these approaches in patients [HR = 0.35, 95% CI = 0.11-1.10; [Figure 3]a]. For the seven studies that investigated a combined approach against EGFR TKIs only, we found using a random-effects model evidence of heterogeneity (P < 0.001, I2 = 78.2), %). Pooled data indicated that the combined treatment approach had a significantly higher PFS significantly than the sole use of TKIs in EGFR mutation-positive NSCLC subjects (HR = 0.68, 95% CI = 0.49-0.95; [Figure 3]b].
|Figure 3: Forest plots of progression-free survival in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus (a) chemotherapy alone or (b) epidermal growth factor receptor tyrosine kinase inhibitor alone|
Click here to view
Overall response rate
Two trials evaluated ORR between patients receiving a combined treatment approach versus chemotherapy alone. Using a fixed-effects model, we found no significant heterogeneity (P = 0.164, I2 = 48.3%)). We also found using pooled data that ORR was increased in patients who received a combined treatment compared with those who received chemotherapy only [RR = 2.17, 95% CI = 1.51-3.12; [Figure 4]a]. Of the seven trials that compared combined treatment with EGFR TKI alone, no significant heterogeneity (P = 0.533, I2 = 0%) was found, using a fixed-effects model. In addition, we found the ORR was superior in patients who received a combined treatment compared with those who received TKIs only (RR = 1.17, 95% CI = 1.09 - 1.25; [Figure 4]b].
|Figure 4: Forest plots of overall response rate and disease control rate in patients with epidermal growth factor receptor mutation-positive non-small cell lung cancer. Overall response rate of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus (a) chemotherapy alone or (b) epidermal growth factor receptor tyrosine kinase inhibitor alone. (c) Overall response rate of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus epidermal growth factor receptor tyrosine kinase inhibitor alone|
Click here to view
Disease control rate
DCR was determined in three studies that investigated a combined approach versus EGFR TKI alone. Using a random-effects model, significant heterogeneity (P = 0.073, I2 = 61.7%) was found in this cohort. Further, we found no evidence of a difference in DCR between treatment approaches in our pooled cohort data [RR = 1.02, 95% CI = 0.89–1.18; [Figure 4]c].
No individual trial had significant effects on overall results, indicating that the pooled data were stable [Figure 5].
|Figure 5: Sensitivity analysis examining influence of individual studies on pooled results. (a) Overall survival of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus tyrosine kinase inhibitor alone. (b) Progression-free survival of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus chemotherapy alone. (c) Progression-free survival of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus tyrosine kinase inhibitor alone|
Click here to view
Finally, the Begg's and Egger's regression tests revealed no publication bias, with symmetrical funnel plots for overall survival and progression-free survival. In all cases, p > 0.05 [Figure 6].
|Figure 6: Funnel plots for publication bias assessment. Each point represents a separate study. (a) Overall survival of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus tyrosine kinase inhibitor. (b) Progression-free survival of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus chemotherapy. (c) Progression-free survival of epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy versus tyrosine kinase inhibitor|
Click here to view
| > Discussion|| |
Our study was a meta-analysis of publications based on data from randomized trials that used a combination of chemotherapy with either gefitinib or erlotinib as an EGFR TKI in patients with EGFR mutation-positive NSCLC. We evaluated the efficiency of the combined use of an EGFR TKI with chemotherapy against either approach alone in our pooled cohort. Using OS and ORR as endpoints, our analysis revealed that a combined approach resulted in a better outcome compared with either approach used alone. The combined approach proved superior, in view of the OS and ORR, compared to using chemotherapy alone. Similarly, use of both EGFR TKIs and chemotherapy resulted in better PFS and ORR compared to the use of TKI alone. However, no significant differences were apparent with regard to the OS and DCR between the use of TKIs alone or in combination with chemotherapy.
Previously, a multicenter study of patients with nonsquamous NSCLC with no background of smoking compared a combination of pemetrexed and erlotinib with either drug alone. Subgroup analysis showed that OS was conspicuously increased using a combined treatment approach compared with either regimen alone in 24 patients with EGFR mutations, although there was no difference in PFS between subgroups. Similarly, another study compared the effect of erlotinib with paclitaxel and carboplatin against erlotinib alone in patients with advanced NSCLC as first-line therapy. No difference was found with PFS or its rate in six patients with an active EGFR mutation compared to nine patients treated with erlotinib. However, they also found better OS (P = 0.001) and ORR (P < 0.001) for the combined treatment approach compared to chemotherapy alone in their cohort of patients with NSCLC.
We identified three limitations of our meta-analysis. First, the included studies have significant heterogeneity, which may be because of the inclusion of different EGFR TKIs, chemotherapeutic regimens, and clinical characteristics of patients. Second, although HRs and 95% CIs were derived as previously proposed by Tierney et al., Kaplan–Meier curve data may not have the same precision as those obtained directly from original articles. Third, the low sample size of the RCTs evaluated inherently confers a limited dataset for our meta-analysis.
| > Conlusion|| |
Our work suggests significant improvements in the OS and ORR among patients with EGFR mutation-positive NSCLC with the use of both EGFR TKIs and chemotheraoy as opposed to the use of chemotherapy alone. Furthermore, the combined approach to treatment also yielded improvements in the PFS and ORR as compared to the use of TKI alone. We recommend larger prospective robust RCTs to further validate these observations.
Financial support and sponsorship
This study was financially supported by the Natural Science Foundation of Hebei Province (H2020406050).
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al
. Cancer statistics in China, 2015. CA Cancer J Clin 2016;66:115-32.
Felip E, Stahel RA, Pavlidis N; ESMO Guidelines Task Force. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol 2005;16 Suppl 1:i28-9.
William WN Jr., Lin HY, Lee JJ, Lippman SM, Roth JA, Kim ES. Revisiting stage IIIB and IV non-small cell lung cancer: Analysis of the surveillance, epidemiology, and end results data. Chest 2009;136:701-9.
Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, et al
. Non-small cell lung cancer, version 1.2015. J Natl Compr Canc Netw 2014;12:1738-61.
Shi Y, Sun Y, Ding C, Wang Z, Wang C, Wang Z, et al
. China experts consensus on icotinib for non-small cell lung cancer treatment (2015 version). Ann Translat Med 2015;3:260.
Bulbul A, Husain H. First-line treatment in EGFR mutant non-small cell lung cancer: Is there a best option? Front Oncol 2018;8:94.
Mountzios G. Making progress in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer by surpassing resistance: Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs). Ann Transl Med 2018;6:140.
Zhang L, Qi Y, Xing K, Qian S, Zhang P, Wu X. A novel strategy of EGFR-TKI combined chemotherapy in the treatment of human lung cancer with EGFR-sensitive mutation. Oncol Rep 2018;40:1046-54.
Sari M, Aydiner A. Rare mutations of epidermal growth factor receptor in epidermal growth factor receptor-tyrosine kinase inhibitor-naive non-small cell lung carcinoma and the response to erlotinib therapy. J Cancer Res Ther 2020;16:132-8.
Li C, Fang R, Sun Y, Han X, Li F, Gao B, et al
. Spectrum of oncogenic driver mutations in lung adenocarcinomas from East Asian never smokers. PLoS One 2011;6:e28204.
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;362:2380-8.
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, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42.
Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al
. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-34.
Yu S, Wang X, Wang X, Wu X, Xu R, Wang X, et al
. Tumor shrinkage rate as a potential marker for the prediction of long-term outcome in advanced non-small cell lung cancer treated with first-line tyrosine kinase inhibitors. J Cancer Res Ther 2019;15:1574-80.
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998;17:2815-34.
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.
Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med 1997;127:820-6.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
Hirsch FR, Kabbinavar F, Eisen T, Martins R, Schnell FM, Dziadziuszko R, 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;29:3567-73.
Janne PA, Wang X, Socinski MA, Crowford J, Stinchcombe TE, Gu L, 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;30:2063-9.
Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, Ladrera G, 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;14:777-86.
Yu H, Zhang J, Wu X, Luo Z, Wang H, Sun S, et al
. A phase II randomized trial evaluating gefitinib intercalated with pemetrexed/platinum chemotherapy or pemetrexed/platinum chemotherapy alone in unselected patients with advanced non-squamous non-small cell lung cancer. Cancer Biol Ther 2014;15:832-9.
Halmos B, Pennell NA, Fu P, Saad S, Gadgeel S, Otterson GA, et al
. Randomized Phase II Trial of erlotinib beyond progression in advanced erlotinib-responsive non-small cell lung cancer. Oncologist 2015;20:1298-303.
An C, Zhang J, Chu H, Gu C, Xiao F, Zhu F, et al
. Study of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer Harboring EGFR mutation. Pathol Oncol Res 2016;22:763-8.
Cheng Y, Murakami H, Yang PC, He J, Nakagawa K, Kang JH, 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;34:3258-66.
Han B, Jin B, Chu T, Niu Y, Dong Y, Xu J, 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;141:1249-56.
Hosomi Y, Morita S, Sugawara S, Kato T, Fukuhara T, Gemma A, et al
. Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. Journal of clinical oncology: Official journal of the American Society of Clinical Oncology 2020; 38:115-23.
Noronha V, Patil VM, Joshi A, Menon N, Chougule A, Mahajan A, et al
. Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. Journal of clinical oncology: Official journal of the American Society of Clinical Oncology 2020;38:124-36.
Lee DH, Lee JS, Kim SW, Rodrigues-Pereira J, Han B, Song XQ, et al
. Three-arm randomised controlled phase 2 study comparing pemetrexed and erlotinib to either pemetrexed or erlotinib alone as second-line treatment for never-smokers with non-squamous non-small cell lung cancer. EUR J CANCER 2013;49:3111-3121.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]