Comparing Overall Survival Between First Generation EGFR-TKIs And Chemotherapy In Lung Cancer Patients With Del19/L858R: A Meta-analysis

BackgroundLung cancer always has the fastest increasing incidence and mortality rate in malignant tumor, nowadays it is the leading cause of cancer-related mortality worldwide. It is unfortunately that more than half of patients with lung cancer present with metastatic disease at diagnosis and few treatment choices are available for patients with advance or metastatic disease in therapy, traditional chemotherapy may be the best choice at that time. Overall survival of patients with advance or metastatic disease was about eight months after receiving traditional chemotherapy. There was limited improvement in overall survival through chemotherapy. So, to search for new drugs and new treatment model are urgent.According to the pathomorphism, lung cancer could been divided into two category:small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), NSCLC accounts for about 85% of primary lung cancers. In recent years, the greatest changes in the treatment of advanced NSCLC have been the novel molecular-target agents and the concomitant ability to personalized treatment.Genetics discoveries identified that EGFR-dependent signaling pathway has played an indispensible role in the development and progression of NSCLC, EGFR mutations could found in approximately 50% of NSCLC. Small-molecule tyrosine kinase inhibitors (TKIs), such as first generation-gefitinib and erlotinib and second generation-afatinib which targeted the EGFR-dependent pathway, have been proved effective in the clinical use for the treatment of patients with NSCLC. Nine randomized controlled trials (RCTs) enrolling patients with EGFR mutation have demonstrated that first-line EGFR-TKIs were superior to chemotherapy in terms of objective response rate (ORR) and progression-free survival (PFS). It is more exciting that the median overall survival (OS) of patient with NSCLC harboring EGFR common sensitive mutation beyond 37 months which received EGFR-TKIs in the first-line therapy. EGFR-TKIs were recommend as standard first-line treatment for advanced NSCLC patients harboring common EGFR mutation which were sensitive to EGFR-TKIs, mainly including exon 19 deletions (De119) and a point mutation in exon 21 (L858R). Although, first-line treatment of EGFR-TKIs could prolong the PFS compared with the first-line chemotherapy among patients harboring EGFR mutation, however, post hoc analysis of OS of these trials showed that there was no statistically difference between EGFR-TKIs and chemotherapy group. The prolonged PFS did not contribute to better OS and it could be attributed to crossover use of EGFR-TKIs in chemotherapy arm, meanwhile, this negative survival difference was related to limited sample size of each trial.In 2014 American Society of Clinical Oncology (ASCO) annual meeting, Yang et al shared combined OS analysis of Lux-Lung3 and Lux-Lung6 based on EGFR common mutation types (De119/L858R). Pooled analysis showed that first-line afatinib (second generation EGFR-TKIs) improved OS for patients harboring common EGFR mutation. However, mutation-based stratification analysis revealed that this OS benefit only existed in patients with Del 19. For those with L858R, there was no evidence of survival benefit, on the contrary first-line afatinib might have an inferior role in number (22.1 vs 26.9 months). This was the first time to indicate that first-line EGFR-TKIs could prolong OS and patients harboring Del19 and L858R might be two distant populations in clinical practice. Translating this to knowledge to clinical practice, first line afatinib may just recommended to patients with Del19, for it is still arguable whether EGFR-TKIs should be given as first-line treatment for L858R patients. Given those phenomena, it is needed to know whether this discrepancy existed in patients receiving first generation EGFR-TKIs such as gefitinib and erlotinib? If so the guideline recommendation of EGFR-TKIs in EGFR mutant advanced NSCLC patients should be revised.Analysis of a single study, such as IPASS or NEJ002, has showed that patients with either Dell 9 or L858R treated with first-line first generation EGFR-TKIs had no survival advantage compared with first-line chemotherapy. In that case, we may consider the survival benefit can be overshadowed by small sample size in solitary trials. Plus, we noticed that, several small studies have previously demonstrated that patients with Del19 have superiority over those with L858R, while other studies showed different results. Therefore, a pooled analysis of current available studies that including patients with Del19 and L858R may provide clinical useful instruction with respect to first-line first generation EGFR-TKIs treatment in patients harboring common EGFR mutation.ObjectiveTo clarify the difference of OS between first-line first generation EGFR-TKIs and chemotherapy in patients with either Del19 or L858R, and to directly compare OS in these two mutation groups after receiving first generation EGFR-TKIs.Methods1. Search and Selection Process1.1 Literature searchComprehensive systematic search for all relevant articles through PubMed, EMBASE and Cochrane Library (CL)) from inception to July 31,2014 without language limitation was done by two authors (Deng Wei and Lei Yuan-yuan) independently, using a combination of key words "EGFR", "epidermal growth factor receptor", "tyrosine kinase inhibitors", "EGFR-TKIs", "TKIs", "gefitinib", "erlotinib", "first generation", "mutation", "mutated", "non-small-cell lung cancer", "NSCLC". We also retrieved the meeting abstracts including ASCO annual meetings, European Society of Medical Oncology (ESMO) congresses and World Conference on Lung Cancer (WCLC) at last 5 years by hand.1.2 Literature SelectionAll randomized controlled clinical trials (RCTs) and non-RCTs (prospective without randomization and retrospective) would be screened by the following eligibility and excluded criteria.1.2.1 Eligibility criteria:1. patients involved in the study who had a diagnosis of local advanced (stage IIIB) or metastatic or recurrent disease (stageⅣ); 2. patients harboring EGFR mutation including Del19 or L858R received first generation EGFR-TKIs (gefitinib or erlotinib) for monotherapy, first-line or otherwise, and detailed number of patients of each EGFR mutation type should be available; 3). special hazard ratios (HRs) or survival curves of EGFR-TKIs compared to conventional chemotherapy for OS in patients harboring Del19 or L858R and definitive HRs or survival curves of Del19 compared to L858R for OS after EGFR-TKIs were available.1.2.2 Excluded criteria:1. all reviews, in vitro and animal experiments; 2. special number of patients harboring Dell 9 or L858R was not available; 3. EGFR-TKIs for maintenance treatment or a combination of EGFR-TKIs with chemotherapy.2. Data ExtractionData were extracted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. The RCTs were assessed by Jadad scale, and the other studies were assessed with Newcastle-Ottawa Scale (NOS). The following main items were also extracted from those included studies:publication time, author, research name and design type, therapeutic regimens, line of EGFR-TKIs treatment, number of patients harboring Del19 or L858R in the subgroup. Data of OS were extracted as HR and its 95% confidence interval (CI), and if the data could not be extracted directly, we used Engage Digitizer 4.1 soft extracted data from survival curves and calculate the HR with the validated method. Additional, during the extraction process, we conducted an assumption that there was no significant difference in the efficacy of chemotherapy for patients with Del19 and L858R and calculated the adjusted indirect comparison with the method as previously described. Briefly, the log hazard ratio (logHR) of the adjusted indirect comparison for intervention A versus B was estimated by logHRAB=logHRAC-logHRBC and its standard error for the HR was SE(logHRAB)=(?) where log HRAC presents the log HR for the direct comparison of EGFR-TKIs versus chemotherapy in patients with Del19, the log HRBC means the log HR for the direct comparison of EGFR-TKIs versus chemotherapy in patients with L858R and SE(logHRAB) was the standard error of the log HR for the direct comparison between patients harboring Del19 and patients harboring L858R who received EGFR-TKIs. Two authors conducted the assessment independently to avoid the evaluation deviation and discussed among three authors (Liu Si-yang) to resolve all discrepancies in the extraction.3. Statistical AnalysisAll analyses were performed in R3.1.2 and P values are two-tailed and less than 0.05 were considered statistical significance. The statistical heterogeneity between studies was tested with the Cochran Q test and quantified using I2 and respective 95% CI. We performed a random effect model in all analyses to calculate pooled HRs for OS with 95% CI. Publication bias was tested by Eggers funnel plot, and we performed an influential analysis to examine whether the result was consistent.Results1. Eligible studiesA total of 6645 potential records were identified in our initial search. After duplication and eligibility screening of all the titles and relevant abstracts, there remained 276 promising articles. After screening these articles included in analysis by reading the full articles and abstracts in greater detail,15 studies were included finally. In the post hoc analysis, one retrospective study used survival curve fitting out the value of HR. We excluded this one considering its inaccuracy. For the final analysis, 14 studies with 1706 patients mainly harboring EGFR common mutation (only Del19 and L858R) were included in this meta-analysis. Among them, there were 4 RCTs (EURTAC, IPASS, NEJ002 and WJTOG3405) and 10 non-RCTs.2. Analysis of heterogeneity and results of meta-analysis2.1 Comparison of first generation EGFR-TKIs versus chemotherapy in first-line setting in NSCLC patients with Del19 in terms of OS.Three RCTs (NEJ002, IPASS and EURTAC) were included into this chapter. No significant statistical heterogeneity was noted in this analysis (I2=0%, P=0.82). The pooled HRTKI/Chemo of EGFR-TKIs versus chemotherapy for NSCLC patients with Del19 was 0.82 (95%CI:0.64-1.06, P=0.14). As the results presented, there was no statistical difference in the comparison of first-line EGFR-TKIs versus conventional platinum-based doublet chemotherapy in terms of OS for patients with Del19.2.2 Comparison of first generation EGFR-TKIs versus chemotherapy in first-line setting in NSCLC patients with L858R in terms of OS.Three RCTs (NEJ002, IPASS and EURTAC) were included into this chapter. No significant statistical heterogeneity was noted in this analysis (I2=0%, P=0.47). The pooled HRTKI/Chemo of EGFR-TKIs versus chemotherapy for NSCLC patients with L858R was 1.15 (95%CI:0.85-1.56, P=0.38). As the results presented, there was no statistical difference in the comparison of first-line EGFR-TKIs versus conventional platinum-based doublet chemotherapy in terms of OS for patients with L858R.2.3 Comparison of NSCLC patients with Del19 or L858R receiving first generation EGFR-TKIs in terms of OS.All studies were divided into RCTs and other studies based on the study design, there were 4 RCTs (EURTAC, IPASS, NEJ002 and WJTOG3405) and 10 non-RCTs.2.3.1 Pooled analysis of RCTsNo significant statistical heterogeneity was noted in this analysis(I2=0%, P=0.40). The pooled HRDel19/L858R of patients with Del19 versus L858R after first-line gefitinib or erlotinib was 0.88 (95%CI:0.67-1.16, P=0.37). As the results presented, there was no statistical difference between patients with Del19 and patients with L858R in terms of OS after receiving first-line EGFR-TKIs therapy.2.3.2 Pooled analysis of non-RCTsNo significant statistical heterogeneity was noted in this analysis(I2=24.4%, P=0.22). The pooled HRDel19/L858R of patients with Del19 versus L858R after EGFR-TKIs was 0.62 (95%CI:0.47-0.81, P=0.006). As the results presented, there was statistical difference between patients with Del19 and patients with L858R in terms of OS after receiving EGFR-TKIs therapy. We performed an influential analysis reflecting the result was consistent. Moreover, we conducted subgroup analyses according to the line of EGFR-TKIs. The pooled HR.Del19/L858R of Del19 versus L858R for patients receiving first-line EGFR-TKIs therapy was 0.75 (95%CI: 0.53-1.06) with no statistical significance, whereas, the pooled HRDel19/L858R of Del19 versus L858R for patients with non-special lines of EGFR-TKIs was 0.51 (95%CI: 0.33-0.81) with a statistical significance.2.4 Publication biasThere was no publication bias for outcome measures, the Eggers funnel plot analysis presented a symmetrical appearance and the P value was 0.08.Conclusion1. In patients with Dell9, first-line first generation EGFR-TKIs demonstrated no superiority over first-line chemotherapy in terms of OS, but, there was a trend that patients with Del19 received EGFR-TKIs therapy had longer OS.2. In patients with L858R, first-line first generation EGFR-TKIs demonstrated no superiority over first-line chemotherapy in terms of OS.3. No survival difference existed between patients with Del19 and L858R receiving first-line first generation EGFR-TKIs, but, there was a trend that patients with Del19 had longer OS.