Figure 1.
PRISMA flow chart of selection process to identify studies eligible for pooling.
Citation: Yongxing Li, Jianye Yang, Yufen Xu, Ming Zhang, Xiaoping Zhang, Wenyu Chen, Xiaodong Lv. A meta-analysis of the comparing of the first-generation and next-generation TKIs in the treatment of NSCLC[J]. Mathematical Biosciences and Engineering, 2019, 16(5): 5687-5696. doi: 10.3934/mbe.2019283
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Systemic chemotherapy has long been employed as the basic treatment approach for advanced-stage NSCLC. Recently, positive results achieved with somatic mutations in NSCLC have led to a growing number of treatment options on the employment of specific inhibitors. Epidermal growth factor receptor (EGFR) mutations are well known oncogenic driver mutations that comprise approximately 10-44% of lung cancer [1,2].
The first-generation, reversible, EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have improvement in response and progression-free survival relative to chemotherapy as initial therapy among patients with EGFR-mutant NSCLC [3,4,5]. However, resistance develops against all these agents after a while. Numerous genetic mutations have been identified as resistance mechanisms against EGFR-TKIs, and researchers are developing specific inhibitors against them. Among those inhibitors, second/third-generation EGFR-TKIs have gained prominence due to their improvement in effectiveness and manageable toxicity profile [6].
Distinct from the first-generation EGFR TKIs (gefitinib and erlotinib), which are reversible inhibitors that selectively target EGFR, the next-generation EGFR TKIs are irreversible binding with broad spectrum of activity. The advantages of next-generation EGFR-TKIs as first- line treatment option for NSCLC harbors activating mutations in EGFR have been already reported when compared with chemotherapy; however, until recently, when studied head-to-head comparisons with first-generation TKI, the benefits were still under debate [7,8].
Our meta-analyses were done to address this question, and identify the most efficacious drug, by assessing the efficacy and safety of first-generation EGFR TKIs and next-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.
PubMed and Embase databases were searched to identify studies. Two investigators independently performed the literature search up to September 2018.
The process was established to find all articles with the keywords: "non-small cell lung cancer" AND "first -generation EGFR-TKIs", AND "second/third -generation EGFR-TKIs", and relevant Medical Subject Heading (MeSH) terms were utilized. The reference lists of all articles that dealt with the topic of interest were also manually checked for additional relevant publications.
The eligible studies in the meta-analysis should meet the following criteria : (1) the studies are designed as random control trials (RCTs); (2) articles that enrolled NSCLC patients harboring activating mutations in EGFR; (3) articles that comparing second/third -generation EGFR-TKIs and first -generation EGFR-TKIs; (4) the outcomes of interest were efficacy (survival, tumor response) and toxicity (incidence of severe adverse effects (SAEs)), and HRs with corresponding 95% CIs were provided; If we found duplicated or overlapped data in multiple reports, we just include the one with most complete information.
Two investigators separately rated the quality of the retrieved studies. Study quality was justified using Jadad scale [9].
Two authors (Yongxing Li and Xiaodong Lv) independently extracted the following information from included studies: first author family name, year of publication, clinical trials' name, total number of cases, mean age, treatment regimen, end-point of interests. We extracted the corresponding hazard ratios (HRs) and risk ratios (RRs) to describe the strength of the association for survival (overall (OS) and progression-free survival (PFS)) and dichotomous (overall response rate (ORR) and serve adverse effect (SAE) rate) data, respectively, with corresponding 95 % confidence intervals (CIs). Disagreement was revolved by consensus.
The result is basing on the data from random control trials. The endpoints of interest in the pooled analysis were OS, PFS, ORR and SAE data, and the endpoint outcome were considered as a weighted average of individual estimate of the HR in every included study, using the inverse variance method. The statistical analyses were conducted using Review Manager version 5.3 software (Revman; The Cochrane collaboration Oxford, United Kingdom). A sensitivity analysis to be determined depending on the degree of heterogeneity across the included studies. The heterogeneity across studies was examined the I2 statistic [10]. Studies with an I2 ≥ 50% was considered to indicate moderate and high heterogeneity, I2 < 50% was considered to have low heterogeneity, respectively [11]. When there was low heterogeneity among studies, the fixed-effects model was used. Otherwise, the random effects model was used. A P value less than 0.05 was considered as statistically significant difference. The Beg test and the Egger test were conducted to evaluate publication bias.
A total of 535 studies were retrieved initially for evaluation. Based on the criteria described in the methods, 10 publications were evaluated in more detail, but some did not provide enough detail of outcomes of two approaches. Therefore, a final total of 5 RCTs including 3 clinical trials [7,8,12,13,14] evaluated the efficacy and toxicity of comparing next-generation EGFR-TKIs versus first -generation EGFR-TKIs. The search process is described in Figure 1.
All included studies in this study were based on moderate to high quality evidence. Table 1 describes the primary characteristics of the eligible studies in more detail.
| Study | Year | Clinical Trials | Treatment regimen | Patients number | Age(years) | |||
| Study arm | Comparative arm | Study arm | Comparative arm | Study arm | Comparative arm | |||
| J.-C. Soria | 2017 | FLAURA | osimertinib | gefitinib/erlotinib | 279 | 277 | 64 | 64 |
| Keunchil Park | 2016 | LUX-Lung 7 | afatinib | gefitinib | 160 | 159 | 63 | 63 |
| L. Paz-Ares | 2017 | LUX-Lung 7 | afatinib | gefitinib | 146 | 151 | / | / |
| Yi-Long Wu | 2017 | ARCHER 1050 | dacomitinib | gefitinib | 227 | 225 | 62 | 61 |
| Tony S. Mok | 2018 | ARCHER 1050 | dacomitinib | gefitinib | 227 | 225 | 62 | 61 |
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Pooling the PFS data from three trials showed that next-generation EGFR-TKIs did prolong the PFS (OR = 0.58, 95%CI = 0.45-0.75, P < ＝0.0001 compared with the first-generation EGFR-TKIs (Figure 2). While, subetaoup analyses with EGFR mutations, there are also significant differences with exon 19 deletion (OR = 0.56, 95%CI = 0.41-0.77, P = 0.0003) (Figure 3) and exon 21 (L858R) mutation (OR = 0.60, 95%CI = 0.49-0.75, P < 0.00001) (Figure 4).
Pooled data showed that the next-generation EGFR-TKIs had significantly better OS rate than first-generation group, with the pooled OR being 0.76 (95 % CI 0.65-0.90, P = 0.001) (Figure 5).
The pooling ORR data achieved advantage in the next-generation EGFR-TKIs agents (OR = 1.27, 95%CI = 1.01-1.61, P = 0.04). In other words, the next-generation EGFR-TKIs agents did increase the rate of ORR (Figure 6).
We define the grade 3-5 toxicities as SAE. Pooling the SAE data show that there is no statistical difference between the two groups (OR = 1.48, 95%CI = 0.62-3.55, P = 0.38) (Figure 7).
In the past decade, the first-generation EGFR tyrosine-kinase inhibitors (TKIs) gefitinib, erlotinib, and icotinib, have been accepted as standard-of-care first-line treatments for EGFR-mutant NSCLC patients [15]. Although remarkable results have been achieved with these TKIs, the therapeutic plateau eventually experience disease progression owing to the resistance of therapeutics [16].
The broader and more durable inhibitory profile of second/third-generation EGFR-TKIs has been postulated to be associated with improved inhibition of EGFR-dependent tumor growth compared with first-generation EGFR-TKIs [17]. While, the role of next-generation EGFR-TKIs still remains controversial. We aim to evaluate potential approaches of next-generation EGFR-TKIs agents against first-generation EGFR-TKIs.
In the current meta-analysis, there was significant benefit in survival efficacy and objective response with next-generation EGFR-TKIs than the first-generation EGFR-TKIs. The 'gatekeeper' mutation may have contributed to this improvement.
It is known that 50%-60% of patients treated with first-generation TKI acquired resistance, which was mediated by the acquisition of the 'gatekeeper' mutation T790M [18,19,20,21]. To the best of our knowledge, the second-generation EGFR-TKI, afatinib or dacomitinib, as an irreversible ErbB family blocker, is active against EGFR harboring the T790M gatekeeper mutation [22,23]. Osimertinib is an oral, third-generation, irreversible EGFR-TKI that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations, with lower activity against wild-type EGFR [24,25]. These mechanisms include the secondary mutations of the driver oncogene, and the activation of new signaling pathways other than the EGFR pathway [26,27]. Deletion at exon 19 and point mutation at exon 21 (L858R) are the most common EGFR mutations [28].
Previous studies have shown that EGFR TKIs have been particularly active in patients with the exon 19 deletion than they do with the Leu858Arg mutation [29]. However, the result is based on trials that comparing TKI versus chemotherapy rather than used TKI as a comparator. In our study, there are no differences with exon 19 deletion and exon 21 (L858R) mutation. Therefore, as the efficacy benefit with next-generation EGFR-TKIs over first-generation EGFR-TKIs would not be restricted to patients harboring exon 19 deletions only, our data support that the using of a TKI as a treatment option for an individual patient might not be based on specific EGFR mutation.
Moreover, the safety profile of both generation TKIs therapy was also evaluated in this article. We concluded that next-generation EGFR-TKIs was comparable with that of first-generation EGFR-TKIs. This result suggests that the systematically established management of adverse events used worked well to keep patients on treatment neither the next-generation EGFR-TKIs nor first -generation EGFR-TKIs. Despite higher frequencies of next-generation EGFR-TKIs, all those AEs were manageable and predictable in all included trials, indicating that proactive supportive treatment and dose modification were an adequate strategy to properly manage the expected class effects associated with EGFR inhibition.
Our results contribute to the growing evidence that supports next-generation EGFR-TKIs in EGFR mutation-positive advanced NSCLC. However, there are limitations to our study. Firstly, although the experimental methods of the included studies were similar, they were not identical, and some clinical parameters, which may have an effect on the prognosis of NSCLC patients. Therefore, heterogeneity due to varying experimental methods cannot be discounted entirely. Furthermore, though our study including the studies are all designed as random control trials (RCTs). Nevertheless, due to all included studies' retrospective nature, bias still exist, and this may impact the comparison of interested outcomes. So, it indicated that the large-scale study with greater statistical power would be imperative to compare the efficacy and safety outcomes of next-generation EGFR-TKIs and first-generation EGFR-TKIs.
In summary, our meta-analysis indicates that next-generation EGFR-TKIs are superior to the first-generation EGFR-TKIs with respect to survival and objective response in the treatment of NSCLC patients with EGFR activating mutations. And the efficacy benefits are found both in exon 19 deletion and exon 21 (L858R) mutation when comparing the next-generation EGFR-TKIs over first -generation EGFR-TKIs. We believe that these results provide additional evidence to help to inform decision-making when choosing the standard treatment option for patients with EGFR mutation- positive NSCLC.
This study was supported by the Funds from The Key Discipline of Jiaxing Respiratory Medicine Construction Project, The Early Diagnosis and Comprehensive Treatment of Lung Cancer Innovation Team Building Project, Science and technology project of Jiaxing (2015AY23016, 2016AY23086) and Talent Cultivation in Science and Technology Innovation Project of The First Hospital of Jiaxing (No. 2016-CX-04、2016-CX-05).
The authors declare that there are no actual or potential conflicts of interest in relation to this article.
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Figures(7) / Tables(1)
Yongxing Li, Jianye Yang, Yufen Xu, Ming Zhang, Xiaoping Zhang, Wenyu Chen, Xiaodong Lv. A meta-analysis of the comparing of the first-generation and next-generation TKIs in the treatment of NSCLC[J]. Mathematical Biosciences and Engineering, 2019, 16(5): 5687-5696. doi: 10.3934/mbe.2019283
| Study | Year | Clinical Trials | Treatment regimen | Patients number | Age(years) | |||
| Study arm | Comparative arm | Study arm | Comparative arm | Study arm | Comparative arm | |||
| J.-C. Soria | 2017 | FLAURA | osimertinib | gefitinib/erlotinib | 279 | 277 | 64 | 64 |
| Keunchil Park | 2016 | LUX-Lung 7 | afatinib | gefitinib | 160 | 159 | 63 | 63 |
| L. Paz-Ares | 2017 | LUX-Lung 7 | afatinib | gefitinib | 146 | 151 | / | / |
| Yi-Long Wu | 2017 | ARCHER 1050 | dacomitinib | gefitinib | 227 | 225 | 62 | 61 |
| Tony S. Mok | 2018 | ARCHER 1050 | dacomitinib | gefitinib | 227 | 225 | 62 | 61 |
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| Study | Year | Clinical Trials | Treatment regimen | Patients number | Age(years) | |||
| Study arm | Comparative arm | Study arm | Comparative arm | Study arm | Comparative arm | |||
| J.-C. Soria | 2017 | FLAURA | osimertinib | gefitinib/erlotinib | 279 | 277 | 64 | 64 |
| Keunchil Park | 2016 | LUX-Lung 7 | afatinib | gefitinib | 160 | 159 | 63 | 63 |
| L. Paz-Ares | 2017 | LUX-Lung 7 | afatinib | gefitinib | 146 | 151 | / | / |
| Yi-Long Wu | 2017 | ARCHER 1050 | dacomitinib | gefitinib | 227 | 225 | 62 | 61 |
| Tony S. Mok | 2018 | ARCHER 1050 | dacomitinib | gefitinib | 227 | 225 | 62 | 61 |
