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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  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


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 Submission19-Feb-2020
Date of Decision13-Jul-2020
Date of Acceptance15-Nov-2020
Date of Web Publication9-Jul-2021

Correspondence Address:
Qing-Shan Li
Department of Oncology, Affiliated Hospital of Chengde Medical College, No. 36, Nanyingzi Street, Chengde, Hebei 067000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_195_20

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 > Abstract 


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 Jul 29];17:664-70. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/664/321023




 > Introduction Top


Lung cancer is the most common malignancy with the highest mortality, particularly in women in developed countries.[1] In China, lung cancer has the highest reported incidence (48.32/100,000) and mortality (39.27/100,000) of cancers in 2011.[2] 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.[3],[4] Conventionally, 4–6 cycles of first-line platinum-based double chemotherapy are recommended for patients;[3] however, efficiency is poor, with a median overall survival (OS) of ~1 year.[5],[6] 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.[7],[8],[9],[10] 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.[11] 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,[12],[13],[14],[15] 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 Top


Search strategy

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.

Selection criteria

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 extraction

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).

Statistical analysis

Because of the scarcity of prognostic studies directly reporting hazard ratios (HRs) and 95% confidence intervals (95% CIs),[16],[17] 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.[18] At I2 <50%, pooled HRs or RRs of studies were obtained by fixed-effects[19] or random-effects model.[20] 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.[21] STATA 12.0 (STATA Corp., USA) was used for analysis. P < 0.05 was considered statistically significant.


 > Results Top


Study characteristics

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,[22],[23],[24],[25],[26],[27],[28],[29],[30],[31] 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.
Table 1: Characteristics of the studies included in this meta-analysis

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Figure 1: Flow diagram of study inclusion

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Quantitative synthesis

Overall survival

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

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Progression-free survival

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

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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

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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].

Sensitivity analysis

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

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Publication bias

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

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 > Discussion Top


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.[32] 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.[22] 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.,[17] 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 Top


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.



 
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