Erlotinib in patients with advanced non-small-cell lung cancer: A meta-analysis
Cite this article as: Gao H, Ding X, Wei D, Cheng P, Su X, Liu H, Aziz F, Wang D, Zhang T. Erlotinib in patients with advanced non-small-cell lung cancer: A meta-analysis. Transl Lung Cancer Res 2012;1(2):129-144. DOI: 10.3978/ j.issn.2218-6751.2012.06.01
Original Article
Erlotinib in patients with advanced non-small-cell lung cancer: A meta-analysis
Hui Gao1†, Xin Ding2†, Dong Wei1, Peng Cheng1, Xiaomei Su1, Huanyi Liu1, Fahad Aziz3, Daoyuan Wang1, Tao Zhang1
1Department of Oncology, 2Department of Neurology, PLA General Hospital of Chengdu Military Region, Chengdu 610083 PR China; 3Department of Internal Medicine, Mount Sinai School of Medicine-Jersey City Campus, Jersey City, NJ, USA
†These authors contributed equally to this work
Corresponding to: Dr Tao Zhang, MD. Department of Oncology, PLA General Hospital of Chengdu Military Region, Tianhui Town, Jinniu District, Chengdu 610083, PR China. Email: drtao.zhang@gmail.com.
Abstract
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Abstract
Introduction
Materials and methods
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Erlotinib is a potent reversible HER1/epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with single-agent activity in patients with non–small-cell lung cancer (NSCLC). In this article, we updated the evidence of erlotinib in treating advanced NSCLC by adding new results of RCTs published between January 2011 and May 2012 into a pooled analysis which had been published in 2011. Outcomes analyzed were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events. Twenty trials including 9,005 patients were identified, and six of them were recently published. As first-line therapy compared to placebo or chemotherapy, there was a similar ORR (P=0.29 and 0.42), PFS (P=0.09 and 0.25) and OS (P=0.73 and 0.49). However, for the patients with EGFR mutations, erlotinib based regimens could significantly improve ORR (P<0.01), prolong PFS (P<0.0), but did not prolong OS (P=0.22). As maintenance therapy compared with placebo, erlotinib based regimens significantly increased ORR (P<0.01), prolonged PFS (P<0.01), but did not improve OS (P=0.22). As second/ third-line therapy comparing with placebo, erlotinib based regimens also significantly increased ORR (P<0.01), prolonged PFS (P<0.01), and improved OS (P<0.01). As second/third-line therapy compared with chemotherapy, gefitinib, or vandetanib, the outcomes were similar between two arms. However, compared with PF299804, there was a decreased ORR (P=0.02), and shorten PFS (P=0.02). Meanwhile, The patients treated with erlotinib based regimens suffered from more diarrhea, rash, and less fatigue, neutropenia, and thrombocytopenia than other agent based regimens. Our meta analysis showed that erlotinib based regimens could significantly increase ORR, improve PFS as first-line maintenance therapy or second/third-line therapy comparing with placebo or PF299804.
Key words
Erlotinib; advanced non-small-cell lung cancer; meta analysis
Submitted May 07, 2012. Accepted for publication Jun 06, 2012.
DOI: 10.3978/j.issn.2218-6751.2012.06.01
Introduction
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Abstract
Introduction
Materials and methods
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Discussion
Acknowledgements
References
Lung cancer is the major cause of cancer deaths worldwide, and the majority of new cases belong to advanced non small cell lung cancer (NSCLC) catagory (1). The standard firstline treatment for advanced NSCLC is a platinum-based two-drug combination regimen (2). However, no doublet regimen has been proved superior, and survival outcomes remained poor (median survival is 7.4 to 8.1 months; 1-year survival rate is 28% to 47%) (3-5). Thus the development of more effective therapy remains challenging. The development of agents that target the epidermal growth factor receptor signal transduction pathways has provided a class of novel targeted therapeutic agents.
The epidermal growth factor receptors (EGFR) have shown to play a significant role in tumorigenesis, with up to 80% of NSCLC expressing EGFR (6,7). Overexpression of EGFR is associated with advanced disease and poor survival (8). Erlotinib (Tarceva, OSI Pharmaceuticals) is a highly potent reversible HER1/EGFR tyrosine kinase inhibitor (EGFR-TKI) that has shown significant antitumor activity in preclinical studies (9). The antitumor activity with single-agent erlotinib has been proved by phase I/ II studies in previously treated patients (10). In a large randomized, double-blind, placebo-controlled phase III trial in previously treated patients with advanced NSCLC, erlotinib significantly prolonged survival versus placebo [6.7 vs. 4.7 months; hazard ratio (HR), 0.70; P<0.001], delayed disease progression, and delayed worsening of diseaserelated symptoms (11). The most common adverse events with single-agent erlotinib consisted of mild/moderate rash and diarrhea. However, this is the only phase III trial which have shown prolonged survival with an EGFR inhibitor in advanced NSCLC. In other phase II and III trials, erlotinib based regimens did not show superior to other agent based regimens.
In 2011, We had carried out a pooled analysis of randomized controlled trials (RCTs) that compared erlotinib based regimens with other agent based regimens between January 1997 and 2011 (12). In this article, we added the results of RCTs which were recently published between January 2011 and May 2012 into the meta analysis, and updated the evidence.
Materials and methods
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Materials and methods
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Literature search
The aim of this meta analysis was to review all published and reported randomized controlled trials comparing the erlotinib based regimens with other agent based regimens. Both published and unpublished trials reported between January 1997 and May 2012 were identified through a computer-based search of the PubMed database and abstracts from the past 13 conferences of the American Society of Clinical Oncology and the past 13 conferences of the European Society for Medical Oncology. The search strategy included the following keywords variably combined: advanced or metastatic, non small cell lung cancer or NSCLC, Erlotinib or Tarceva. In addition, we searched trial registries and conference proceedings. We also examined reference lists of original articles, and contacted original trialists for possible unpublished trials. The deadline for trial inclusion was May 1, 2012.
Inclusion and exclusion criteria
The aim of this analysis was to evaluate objective response rate (ORR), progression free survival (PFS), overall survival (OS), and relevant grade 3/4 adverse events. If erlotinib (E) alone or based combination therapy was included in a randomized controlled trial (RCT), it was considered to be eligible. Inclusion criteria for the trails included: (I) patients were randomly assigned to treatment; (II) erlotinib or based combination regimen was compared to other agent or based combination regimen without confounding by other agents or interventions; and (III) only patients with diagnosis of advanced NSCLC were included. Trials with missing adequate statistical analysis information were also excluded.
Validity assessment
Assessment of the trials was carried out openly with the instrument reported by Moher et al. (13), and there was no significant difference observed among the trials. Therefore, the result of the validity assessment was not considered in this meta analysis.
Data abstraction
The following information was extracted from each report: study design, regimen details, allocated patients, cause of disease, race or ethnic group, ECOG performance status, pathological subtype, prior chemotherapy, smoking status, EGFR protein expression, median follow-up, HRs for the whole study populations, and the year of reporting. Data was independently extracted from each report by XM. Su and HY. Liu, who were blinded to each other, using a standardized data recording form. After extraction, data was reviewed and compared by T. Zhang and P. Cheng All data were checked for internal consistency, and any disagreements were resolved by discussion among the investigators. We also tried to contact principal investigators of the trials to confirm or update both published and unpublished data.
Statistical analysis
The primary endpoints in the meta analysis were OS and PFS. The secondary endpoints were ORR and adverse events. Except adverse events, all analyses were conducted on an intention-to-treat (ITT) basis, and all randomly assigned patients were included in the analyses according to the allocated treatment. We looked for heterogeneity among the trials based on standard methods (14). The DerSimonian and Laird Q statistic (Q test) was used to test for the heterogeneity among trials (15). Begg’s funnel plots (16) and Egger’s test (17) were used to detect possible publication bias. Based on the results of the Q test, we applied a random-effects model (primarily) to estimate the summary HRs, ORs and their 95% confidence intervals (CIs). If HRs or its 95% CIs could not be obtained from reports, Crude logHR and its variance were calculated according to the method proposed by Parma et al. (18). To reduce reading errors, original survival curves were digitalized and enlarged, and data extraction was based on reading off electronic coordinates for each point of interest.
All statistical analyses were conducted with Review Manager V. 5.0.23 (Nordic Cochran Centre, Copenhagen, Denmark). All statistical tests were two-sided, and P values of 0.05 were considered to be statistically significant.
Results
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Trial flow
The flow chart of our study is shown in Figure 1 (19-26). Ultimately, results of twenty randomized phase II or III trials had been published or presented at major international meetings were included in this analysis. Although we did not limit language in the process of searching, all the trials were published in English. All the twenty trials were randomized controlled trials and the results were almost based on intention to treat analysis except adverse events. There were three PIs responded to our requests of confirming update both published or unpublished data of the trials.
Figure 1 A flow chart showing the progress of trials through the review RCT, randomized controlled trials
Characteristics of the twenty trials
The characteristics of the twenty trials are listed in Table 1. Three phase III RCTs comparing with placebo as firstline therapy (27-29), two phase III and four phase II RCT comparing with chemotherapy as first-line therapy (30-35), three phase III and one phase II RCTs comparing with placebo as maintenance therapy (36-39); one phase III RCT comparing with placebo as second/third-line therapy (11), one phase III and one phase II RCTs comparing with chemotherapy as second/third-line therapy (40,41), one phase III RCT comparing with vandetanib as second/ third-line therapy (42), one phase II RCT comparing with PF299804 as second/third-line therapy (43), and one ohase II RCT comparing with Gefitinib as second/thirdline therapy (44). In total, 9,005 patients were randomized to receive erlotinib based regimens (4,620 patients) or other agent based regimens (4,385 patients). 13 patients enrolled in one trial were excluded after randomization (27). Further information about unpublished data was obtained by contacting the principal authors. No potential sources of heterogeneity including sex, age, ECOG performance status, pathological subtype, prior chemotherapy, smoking status were associated with significant differences in outcomes.
Table 1 Characteristics of the twenty trials included in this meta analysis
Author Year Publication form Design of studys Pts Chemo/Target therapy regimen Sex PS Age Stage Adenocarcinoma (%) Smoking History (%)
Gatzemeier 2007 Full text Phase III Bouble-blind 586 E 150 mg/d, per oral + G 1,250 mg/m2, d1,8 + DDP 80 mg/m2, d1, 6 cycles 78.0 99.8 60.0 99.6 38.0 -
Bouble-blind 586 Placebo + G 1,250 mg/m2, d1,8 + DDP 80 mg/m2, d1, 6 cycles 75.0 99.8 59.1 99.8 38.0 -
Herbst 2005 Full text Phase III 539 E 150 mg/d, per oral + C AUC 6, d1 + T 200 mg/m2, d1, 6 cycles 61.6 100 62.7 100 59.9 86.6
- 540 Placebo + C AUC 6, d1 + T 200 mg/m2, d1, 6 cycles 59.7 99.8 62.6 100 61.4 91.8
Lee 2010 Abstract Phase III 350 E 150 mg/d, per oral 61.0 16 77.4 100 38 95.0
- 320 Placebo 61.0 16 77.2 100 38 94.0
Rosell 2012 Full text Phase III 86 E 150 mg/d, per oral 67.0 86.0 65.0 98.0 95.0 34.0
Open-label 87 G 1,250 mg/m2,/, d1,8 (D 75 mg/m2, d1) + DDP 75 mg/m2 (C AUC 5), d1, 3 cycles 78.0 86.0 65.0 100 90.0 28.0
Zhou 2011 Full text Phase III 83 E 150 mg/d, per oral 41.0 91.0 57.0 100 88.0 28.0
Open-label 82 G 1,000 mg/m2, d1,8 + C AUC 5, d1, 4 cycles 40.0 96.0 59.0 100 86.0 31.0
Gridelli 2011 Full text Phase II 29 E 150 mg/d, per oral + S 400mg/d, per oral, bid 59.0 100 76.0 100 86.0 93.0
Open-label 31 G 1,250 mg/m2, d1,8, 6 cycles + S 400 mg/d, per oral, bid 65.0 94.0 74.0 100 81.0 90.0
Lilenbaum 2008 Full text Phase II 52 E 150 mg/d, per oral 44.0 0 51.0 100 50.0 88.0
Open-label 51 C AUC 6, d1 + T 200 mg/m2, d1, 6 cycles 55.0 0 52.0 100 63.0 92.0
Reck 2010 Abstract Phase II 144 E 150 mg/d, per oral 65.0 100 75.5 100 50.0 82.0
Open-label 140 C AUC 5, d1 + NVB 25 mg/ m2, d1,8, 6 cycles 100 76.1 99.0 49.0 86.0
Chen 2012 Full text Phase II 57 E 150 mg/d, per oral 82.5 80.7 78.1 100 63.2 79.0
Open-label 56 NVB 60 mg/m2, d1,8, 6 cycles 80.4 73.2 77.8 100 66.1 78.6
Cappuzzo 2010 Full text Phase III 438 After CT, E 150 mg/d, per 73.0 31.0 60.0 100 47.0 82.0
Double-blind 451 oral, After CT, Placebo 75.0 32.0 60.0 100 44.0 83.0
Miller 2009 Abstract Phase III 370 After CT, E 150 mg/d, per oral + B 15 mg/kg, d1, q3 wks 52.0 100 64.0 100 81.3 83.5
Bouble-blind 373 After CT, Placebo + B 15 mg/kg, d1, q3 wks 52.3 99.7 64.0 100 82.5 82.3
Mok 2010 Full text Phase II 76 E 150 mg/d, per oral, d15- 28 + G 1,250 mg /m2, d1, 8 + DDP 75 mg/m2 (C AUC 5), d1, 6 cycles 71.0 100 57.0 100 67.0 68.0
Bouble-blind 78 Placebo+G 1,250 mg/m2, d1,8 + DDP 75 mg/m2 (C AUC 5), d1, 6 cycles 69.0 100 57.5 100 67.0 64.0
Perol 2010 Abstract Phase III 155 After CT, E 150 mg/d, per oral 73 100 56.4 100 63 -
Open-label 155 After CT, Observation 73 100 59.8 100 67 -
Shepherd 2005 Full text Phase III 488 E 150 mg/d, per oral 64.5 91.4 62.0 100 50.4 73.4
Bouble-blind 243 Placebo 65.8 91.4 59.0 100 49.0 77.0
Ciuleanu 2012 Full text Phase III 203 E 150 mg/d, per oral 79.0 81.0 59.0 100 47.0 85.0
Open-label 221 D or M 72.0 79.0 59.0 100 52.0 80.0
Herbst 2007 Full text Phase II 39 E 150 mg/d, per oral+B 15 mg/kg, d1, q3 wks 43.6 100 68.0 100 82.1 84.6
Open-label 40 T 75 mg/m2, d1/M 500 mg/ m2, d1+B 15 mg/kg, d1, q3 wks 57.5 100 63.5 100 75.0 90.0
Vamvakas 2010 Abstract Phase III 166 E 150 mg/d, per oral 81.3 79.2/td> 65 100 53.6 -
Open-label 166 MTA 500 mg/m2, d1, q3 wks 82.5 81.3 66 100 56.6 -
Natale 2011 Full text Phase III 617 E 150 mg/d, per oral 64.0 88.0 61.0 100 57.0 76.0
Bouble-blind 623 V 300 mg/d, per oral 61.0 99.0 60.0 100 63.0 79.0
2010 Abstract Phase II 94 E 150 mg/d, per oral 59.6 96.8 67.0 100 64.9 78.7
Open-label 94 PF299804 45 mg/do, per oral 58.5 81.9 69.0 100 66.0 79.8
Kim 2011 Full text Phase II 48 E 150 mg/d, per oral 14.6 85.4 56.0 83.4 89.6 4.2
Open-label 48 Gefitinib 250 mg/d, per oral 14.6 85.4 60.0 87.5 91.7 8.3
All trials were phase III trials except for Gridelli’s, Lilenbaum’s, Reck’s, Mok’s, and Herbst’s trials which were designed as phase II trials. A, abstract; AUC, area under the serum concentration-time curve; B, bevacizumab; C, carboplatin; CT, chemotherapy; D, docetaxel; DDP, cisplatin; E, erlotinib; F, full text; G, gemcitabine; M, pemetrexed; NVB, vinorelbine; Pts, patients; PS, performance status; S, Sorafenib; T, paclitaxel; V, vandetanib ( a targeted drug); d, day; po, per oral; wks, weeks
Objective response rate
Seventeen trials except for Lee’s, Miller’s, and Perol’s trials reported ORR (29,37,39). The response rates ranged from 4.0% to 82.9% for the erlotinib based regimens and from <1.0% to 47.9% for the other agent based regimens (Table 2). As first-line therapy, including ten trials and 4,168 patients (erlotinib, n=2,083; other agent, n=2,058), the random-effects model pooled estimate evaluated for ORR showed a similar ORR for erlotinib based regimens (OR, 0.58; 95% CI, 0.33 to 1.01; P=0.06). However, the test for heterogeneity showed a significant difference (I2=89%, P<0.01), so we had to carry out subgroup analysis. The subgroup analysis showed a similar ORR comparing with placebo (OR, 0.90; 95% CI, 0.74 to 1.09; P=0.29), or chemotherapy (OR, 0.56; 95% CI, 0.13 to 2.31; P=0.42), but an increased ORR comparing with placebo as maintenance therapy (OR, 0.47; 95% CI, 0.31 to 0.70; P<0.01; Figure 2).
Figure 2 Response to erlotinib based regimens compared with other agent based regimens as first-line therapy. The heterogeneity test yielded a significant result (P<0.01)
Two of the six trials comparing with chemotherapy as first line therapy only enrolled the patients with EGFR mutations (32,33). So, there was a significant heterogeneity in this subgroup (I2=92%, P<0.01). For these patients, erlotinib based regimens could significantly improve the ORR than chemotherapy (OR, 0.12; 95% CI, 0.07 to 0.20; P<0.01; data not shown).
E
Table 2 Responses in the seventeen trials
Author Chemo/Targeted therapy regimen Pts with complete or partial response Randomized Pts Objective response rate (%)
Gatzemeier et al. E+G+DDP 183 580 31.5
P+G+DDP 173 579 29.9
Herbst et al. E+C+T 116 539 21.5
P+C+T 104 540 19.3
Rosell zffigure. E 50 86 58.1
G (D) + DDP (C) 13 87 14.9
Zhou et al. E 68 82 82.9
G + C 26 72 36.1
Gridelli et al.. E + S 3 29 10.3
G + S 2 31 6.5
Lilenbaum et al.. E 2 52 4.0
C+T 6 51 12.0
Reck et al.. E 10 144 6.9
C+NVB 32 140 22.9
Chen et al.. E 13 57 22.8
C+NVB 5 56 8.9
Cappuzzo et al.. After CT, E 52 438 11.9
After CT, P 24 451 5.3
Mok et al.. E+G+DDP (C) 27 76 35.5
P+G+DDP (C) 19 78 24.4
Shepherd et al.. E 38 488 7.8
P 2 243 <1
Ciuleanu et al.. E 16 203 7.9
D or M 14 221 6.3
Herbst et al.. E+B 12 39 30.8
T/M+B 16 40 40.0
Vamvakas et al..13 166 8
MTA 19 166 11.4
Natale et al. E 74 617 12.0
V 75 623 12.0
Boyer et al.. E 4 94 4.3
PF299804 16 94 17.0
Kim et al.. E 19 48 39.6
Gefitinib 23 48 47.9
B, bevacizumab; C, carboplatin; D, docetaxel; DDP, cisplatin; E, erlotinib; G, gemcitabine; M, pemetrexed; NVB, vinorelbine; P, Placebo; Pts, patients; S, Sorafenib; T, paclitaxel; V, vandetanib ( a targeted drug). Response Rate was not included in the objectives of Lee’s, Miller’s, and Perol’s studys
As second/third-line therapy including seven trials and 3,090 patients (erlotinib, n=1,655; other agent, n=1,435), the pooled estimate showed a similar ORR for erlotinib based regimens (OR, 1.11; 95% CI, 0.65 to 1.90; P=0.70). The test for heterogeneity also showed a significant difference (I2=70%, P<0.01). When compared with placebo, the subgroup analysis showed an increased ORR (OR, 0.10; 95% CI, 0.02 to 0.41; P<0.01). However, compared with chemotherapy, there was a similar ORR between two arms (OR, 1.18; 95% CI, 0.75 to 1.87; P=0.47; Figure 3).
Figure 3 Response to erlotinib based regimens compared with other agent based regimens as second/third-line therapy. The heterogeneity test yielded a significant result (P<0.01)
With respect to all efficacy outcomes, random-effect (Figure 2, 3, 4, 5, 6, 7) and fixed-effects models (data not shown) yielded virtually identical results. Neither a Begg’s funnel plot nor a rank correlation test regarding response rate indicated the existence of publication bias (Z=0.21, P=0.84). The results of Egger’ test was similar.
Figure 4 Progression-free survival with erlotinib based regimens compared to other agent based regimens as first-line therapy. The heterogeneity test yielded a significant result (P<0.01)
Figure 5 Progression-free survival with erlotinib based regimens compared to other agent based regimens as second/third-line therapy. The heterogeneity test yielded a significant result (P<0.01)
Figure 6 Overall survival with erlotinib based regimens compared to other agent based regimens as first-line therapy. The heterogeneity test did not yield a significant result (P=0.02)
Figure 7 Overall survival with erlotinib based regimens compared to other agent based regimens as second/third-line therapy. The heterogeneity test yielded a significant result (P<0.01)
Progression free survival
Ninteen trials except for Gridelli’s trial reported PFS (Table 3) (34). As first-line therapy, the random-effects model pooled estimate evaluated for PFS showed a improved PFS for erlotinib based regimens (HR, 0.73; 95% CI, 0.60 to 0.89; P<0.01). However, the test for heterogeneity showed a significant difference (I2=91%, P<0.01), so we had to carry out subgroup analysis. The pooled estimate showed a similar PFS comparing with placebo (HR, 0.93; 95% CI, 0.85 to 1.01; P=0.09), and chemotherapy (HR, 0.62; 95% CI, 0.28 to 1.40; P=0.25), but a prolonged PFS comparing with placebo as maintenance therapy (HR, 0.71; 95% CI, 0.60 to 0.83; P<0.01; Figure 4).
Table 3 Progression free survival and overall survival in the twenty trials
Author Chemo/Target therapy regimen ITT analysis Randomized Pts Median PFS (month) P Value Median OS (month) P Value
Gatzemeier et al. E+G+DDP Yes 586 5.50 0.74 10.00 0.49
P+G+DDP 586 5.80 10.90
Herbst et al. E+C+T Yes 539 5.10 0.36 10.60 0,95
P+C+T 540 4.90 10.50
Lee et al. E Yes 350 2.8 0.038 3.8 0.069
P 320 2.7 3.6
Rosell et al. E Yes 86 9.7 <0.0001 19.3 0.87
G (D) + DDP (C) 87 5.2 19.5
Zhou et al. E No 83 13.1 <0.0001 - -
G+C 82 4.6  
Gridelli et al. E+S Yes 29 3.0 - 12.6 -
G+S 31 2.0 6.6
Lilenbaum et al. E Yes 52 1.90 0.063 6.60 0.018
C+T 51 3.50 9.70
Reck et al. E No 125 2.4 0.001 7.9 0.21
C+NVB 113 4.6 8.4
Chen et al. E Yes 57 4.57 0.029 11.67 0.698
NVB 56 2.53 9.3
Cappuzzo et al. After CT, E Yes 437 2.87 <0.01 12.0 0.009
After CT, P 447 2.59 11.0
Miller et al. After CT, E+B Yes 373 4.76 0.001   -
After CT, P+B 370 3.75  
Mok et al. E+G+DDP (C) Yes 76 6.86 <0.01 17.29 0.72
P+G+DDP (C) 78 5.46 17.67
Perol et al. After CT, E No 153 2.9 0.002   -
After CT, Observation 152 1.9  
Shepherd et al. E Yes 488 2.20 <0.01 6.70 <0.01
P 243 1.80 4.70
Ciuleanu et al. E Yes 203 1.47 0.089 5.3 0.55
D or M 221 2.01 5.3
Herbst et al. E+B Yes 39 4.40 >0.05 13.70 >0.05
T/M+B 40 4.80 12.60
Vamvakas et al. E Yes 166 3.6 0.30 7.9 0.92
MTA 166 2.7 8.9
Natale et al. E Yes 617 2.08 0.72 7.8 0.83
V 623 2.64 6.9
Boyer et al. E Yes 94 1.94 0.019 - -
PF299804 94 2.89  
Kim et al. E Yes 48 3.1 0.336 - -
Gefitinib 48 4.9  
B, bevacizumab; C, carboplatin; D, docetaxel; DDP, cisplatin; E, erlotinib; G, gemcitabine; ITT, intention to treat; M, pemetrexed; MTA, Pemetrexed; P, Placebo; PFS, progression free survival; Pts, patients; S, Sorafenib; T, paclitaxel; V, vandetanib
For the patients with EGFR mutations (32,33), our analysis showed that erlotinib based regimens could significantly improve the PFS than chemotherapy (HR, 0.25; 95% CI, 0.11 to 0.56; P<0.01; data not shown).
As second/third-line therapy including seven trials, the pooled estimate showed a similar PFS for erlotinib based regimens (HR, 0.91; 95% CI, 0.77 to 1.07; P=0.25). The test for heterogeneity also showed a significant difference (I2=85%, P<0.01). The subgroup analysis showed a prolonged PFS compared with placebo (HR, 0.61; 95% CI, 0.51 to 0.73; P<0.01), but a similar PFS compared with chemotherapy (HR, 1.04; 95% CI, 0.93 to 1.16; P=0.50; Figure 5).
Neither a Begg’s funnel plot nor a rank correlation test regarding response rate indicated the existence of publication bias (Z=0.70, P=0.48). The results of Egger’ test was similar.
Overall survival
Only thirteen trials reported OS (Table 3). As first-line therapy including eight trials, the random-effects model pooled estimate evaluated for OS showed a similar OS for erlotinib based regimens (HR, 0.99; 95% CI, 0.89 to 1.22; P=0.93). The test for heterogeneity showed a significant difference (I2=57%, P=0.02). The subgroup analysis showed a similar OS compared with placebo (HR, 1.02; 95% CI, 0.92 to 1.13; P=0.73), or with chemotherapy (HR, 1.11; 95% CI, 0.82 to 1.51; P=0.49), or as maintenance therapy (HR, 0.87; 95% CI, 0.68 to 1.11; P=0.22; Figure 6).
Only one trial reported OS for the patients with EGFR mutations (32). Our analysis showed that there was a similar OS between erlotinib based regimens and chemotherapy (HR, 1.22; 95% CI, 0.89 to 1.66; P=0.22; data not shown).
As second/third-line therapy including five trials, the pooled estimate showed a similar OS for erlotinib based regimens (HR, 0.92; 95% CI, 0.78 to 1.08; P=0.31). The test for heterogeneity showed a significant difference (I2=64%, P=0.02). The subgroup analysis showed a prolonged OS compared with placebo (HR, 0.70; 95% CI, 0.58 to 0.84; P<0.01), but a similar OS compared with chemotherapy (HR, 0.99; 95% CI, 0.85 to 1.14; P=0.85). Erlotinib could also not improve OS of the patients compared with vandetanib (HR, 1.01; 95% CI, 0.89 to 1.16; P=0.85; Figure 7).
Neither a Begg’s funnel plot nor a rank correlation test regarding response rate indicated the existence of publication bias (Z=0.43, P=0.70). The results of Egger’ test was similar.
Adverse events
Ninteen trials including 8,147 patients, except Chen’ trial, provided results of adverse events (35). Reported toxicities were analyzed in only sixteen trials except for the targeted drugs containing trials (37,38) (Table 4). Grade 3/4 diarrhea (OR, 5.08; 95% CI, 3.43 to 7.52; P<0.01) and rash (OR, 19.37; 95% CI, 11.40 to 32.92; P<0.01) were significantly prominent in the erlotinib based regimens, with all intertrial variability consistent with the play of chance. However, fatigue (OR, 0.72; 95% CI, 0.55 to 0.94; P=0.02), neutropenia (OR, 0.74; 95% CI, 0.59 to 0.92; P<0.01) and thrombocytopenia (OR, 0.73; 95% CI, 0.57 to 0.93; P=0.01) were significantly decreased in the erlotinib based regimens. Compared to other agent based regimens, erlotinib based regimen did not increase the frequency of other adverse events. The heterogeneity test found no statistical significance except for thrombocytopenia.
Table 4 Adverse events in trials comparing erlotinib based regimen with other agent based regimen (grades III and IV)
Adverse events No. of evaluable trials Erlotinib based therapy Other agent based therapy OR (95% CI) P Value for Q Test
Pts with adverse events Evaluable Pts Pts with adverse events Evaluable Pts
Diarrheaa 16 149 3445 27 3182 5.08 (3.43-7.52) <0.01
Rasha 16 261 3445 8 3182 19.37 (11.40-32.92) <0.01
Fatiguea 11 105 2181 124 1916 0.72(0.55-0.94) 0.02
Neutropeniaa 11 174 2042 225 2052 0.74(0.59-0.92) <0.01
Thrombocytopeniaa 10 116 1774 153 1756 0.73(0.57-0.93) 0.01
Anemia 12 137 1810 115 1807 1.21(0.93-1.57) 0.15
Nausea/vomiting 11 112 2263 113 2000 0.96(0.73-1.26) 0.76
Anorexia 10 44 2044 31 1791 1.24 (0.78-1.97) 0.36
Arthralgia/myalgia 4 7 541 11 554 0.64(0.25-1.62) 0.35
Heterogeneity tests showed no significant results except for thrombocytopenia. OR, odds ratio; CI, confidence interval; athe result had a significant difference
Because of the significant heterogeneity (data not showen), we had to compare erlotinib with other targeted drugs respectively (Figure 5, 6, 7). Compared with gefitinib, there was a similar ORR (OR, 1.40; 95% CI, 0.62 to 3.61; P=0.41), PFS (HR, 1.26; 95% CI, 0.78 to 2.06; P=0.35), and the frequency of grade 3/4 adverse events (data not showen). Compared with vandetanib, there was a similar ORR (OR, 1.00; 95% CI, 0.71 to 1.40; P=0.98), PFS (HR, 0.98; 95.22% CI, 0.87 to 1.10; P=0.72), OS (HR, 1.01; 95.08% CI, 0.89 to 1.16; P=0.83), and the frequency of grade 3/4 adverse events (data not showen). Compared with PF299804, there was a decreased ORR (OR, 3.87; 95% CI, 1.27 to 11.81; P=0.02), and shorten PFS (HR, 0.58; 95% CI, 0.49 to 0.95; P=0.02). At the same time, erlotinib did not increase the frequency of grade 3/4 adverse events except for diarrhea (OR, 0.25; 95% CI, 0.07 to 0.91; P=0.04).
Discussion
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The epidermal growth factor receptor (EGFR) family is part of a complicated signal-transduction network that is a key to several critical cellular processes (39). Overexpression of EGFR is common in non small cell lung cancer (NSCLC) and is associated with poor survival. During the last decade, the treatment for patients with advanced NSCLC has improved as a result of the invention of novel, effective, targeting the EGFR pathway agents such as gefitinib and erlotinib. Up to now, the reports of several phase II/III trials showed inconsistent results on clinical outcomes with regard to ORR, PFS, and OS. Thus, the impact of erlotinib based regimens on the survival of advanced NSCLC patients compared with other agent based regimens remained undetermined.
In this meta analysis, we identified twenty RCT trials including 9,005 patients, and the largest accounted for 1,240 randomly assigned patients. However, because of the difference of the schedule of treatment and controlled regimens, the heterogeneity between trials was statistically significant. Thus we must explain the results with caution and we had to carry out subgroup analysis according to the schedule of treatment and controlled regimens. As first-line therapy compared to placebo or chemotherapy, there were similar PFS (P=0.09 and 0.25) and OS (P=0.73 and 0.49). However, for the patients with EGFR mutations, erlotinib based regimens could significantly improve ORR (OR, 0.12; 95% CI, 0.07 to 0.20; P<0.01), prolong PFS (HR, 0.25; 95% CI, 0.11 to 0.56; P<0.0), but not OS (HR, 1.22; 95% CI, 0.89 to 1.66; P=0.22). As maintenance therapy compared with placebo, erlotinib based regimens significantly increased ORR (OR, 0.47; 95% CI, 0.31 to 0.70; P<0.01), prolonged PFS (HR, 0.71; 95% CI, 0.60 to 0.83; P<0.01), but did not improve OS (HR, 0.87; 95% CI, 0.68 to 1.11; P=0.22). As second/third-line therapy comparing with placebo, erlotinib based regimens also significantly increased ORR (OR, 0.10; 95% CI, 0.02 to 0.41; P<0.01), prolonged PFS (HR, 0.61; 95% CI, 0.51 to 0.73; P<0.01), and improved OS (HR, 0.70; 95% CI, 0.58 to 0.84; P<0.01). However, as second/thirdline therapy compared with chemotherapy, the outcomes were similar between two arms.
As first-line therapy, from the results of this meta analysis, we found that no matter compared with placebo or chemotherapy, for the patients we did not know their status of EGFR mutations, erlotinib based regimens could not increase ORR, improve PFS and OS. However, For the patients with EGFR mutations, erlotinib based regimens could significantly improve ORR, prolong PFS, but not OS. As first line maintenance therapy, we should prefer erlotinib to placebo.
As second/third-line therapy, we should prefer erlotinib or chemotherapy to best supportive care (BSC) in some patients with good PS status. Compared with molecular targeted drugs such as gefitinib or vandetanib, there was no significant difference between two arms. However, compared with PF299804, there was a decreased ORR (OR, 3.87; 95% CI, 1.27 to 11.81; P=0.02), and shorten PFS (HR, 0.58; 95% CI, 0.49 to 0.95; P=0.02).
In the pooled analysis published in 2011, an unexpected finding was an increased incidence in anemia with the erlotinib combination (12). At that time, we found that this increase was mostly due to the result reported by Gatzemeier’s trial (27), and believed this increased incidence was just an accident and pointless. In this analysis, there was not significant difference in the incidence of anemia between erlotinib based regimens and other agent based regimens. Neither the Begg’s funnel plot for publication bias nor did the heterogeneity test yield a significant result. Because the results based on fixed effect model were similar to the results based on random effect model, we did not show the results based on fixed effect model.
However, there were still several limitations in this meta analysis. First, this analysis was based on literature abstract based (AD) data, not individual patient data (IPD). An IPD meta-analysis would give a more robust estimate of the association but have to take a long time to obtain data (45). But the analysis based on published trials is an accepted method, offers the most comprehensive insight into erlotinib based regimens as soon as possible and may help physicians and their patients worldwide to make a better informed decision regarding the most appropriate therapy. A recently reported analysis confirmed that individual patient-based (IPD) and literature abstractbased (AD) meta-analyses did not differ substantially in their outcome (46). Second, although we included twenty trials, there were only one to six trials in each subgroup. However, all the twenty trials were randomized controlled trials, and all the results except for adverse events were based on intention to treat analysis. Therefore we considered our meta analysis based on these trials is believable. Third, possible publication bias is also a potential threat in our study, though we did not detect it statistically.
In conclusion, we updated the evidence of randomized trials of erlotinib based regimens versus other agent based regimens in treating advanced NSCLC. Although there are some limitations, our findings demonstrate that erlotinib based regimens significantly increase ORR, improve PFS as first-line maintenance therapy or second/third line therapy comparing with placebo. Thus, the use of erlotinib may be a new effective therapy of treating advanced NSCLC as first-line maintenance therapy, or second/third line therapy compared with best supportive care (BSC).
Acknowledgements
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Disclosure: The authors declare no conflict of interest.
References
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References
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