Respiratory Medicine (2013) 107, 1280e1283
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SHORT COMMUNICATION
Incidence and risk of treatment-related mortality in cancer patients treated with EGFR-TKIs: A meta-analysis of 22 phase III randomized controlled trials Wei-Xiang Qi, Li-Na Tang, Ai-Na He, Yang Yao*, Zan Shen* Department of Oncology, The Sixth People’s Hospital, Shanghai Jiao Tong University, No. 600, Yishan Road, Shanghai 200233, China Received 26 January 2013; accepted 3 June 2013 Available online 28 June 2013
KEYWORDS Erlotinib; Gefitinib; EGFR-TKIs; Fatal adverse events; Cancer; Meta-analysis
Summary Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become the cornerstone in the treatment of lung cancers that harbor EGFR mutations, but also play an important role in the treatment of other lung cancers and have been investigated among various types of solid tumors. However, these drugs have been associated with an increase in the risk of potentially life-threatening adverse event, such as arterial and venous thrombotic events. We performed a meta-analysis to determine the incidence and risk of fatal adverse events (FAEs) in cancer patients treated with EGFR-TKIs. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 13,825 patients from 22 trials were included. Among patients treated with EGFR-TKIs, the overall incidence of FAEs was 1.9% (95%CI: 1.2e2.9%), and the risk of FAEs was 0.99 (95%CI: 0.70e1.41, p Z 0.97). No increase in FAEs was detected in any prespecified subgroup. Additionally, using EGFR-TKIs as salvage treatment significantly reduced the risk of FAEs when compared to the controls (RR 0.51, 95%CI: 0.29e0.87, p Z 0.013). In conclusion, this analysis suggests that the use of EGFR-TKIs does not increase the risk of FAEs in patients with advanced solid tumors, and EGFR-TKIs are safety and tolerable for cancer patients, especially for those previously treated patients. ª 2013 Elsevier Ltd. All rights reserved.
* Corresponding authors. Tel.: þ86 021 64369181 58430; fax: þ86 021 64701361. E-mail addresses:
[email protected] (Y. Yao),
[email protected] (Z. Shen). 0954-6111/$ - see front matter ª 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rmed.2013.06.005
Treatment-related mortality with EGFR-TKIs The increased understanding of tumor biology and the availability of drugs targeting key biological mechanisms required for tumor growth provide novel approaches for the treatment of cancer. One such therapeutic target is the epidermal growth factor receptor (EGFR) pathway, a critical mediator of tumor proliferation and angiogenesis [1,2]. Indeed, two small molecular agents that target the tyrosine kinase domain of the EGFR, erlotinib and gefitinib, are approved in many countries for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) as second- or third-line therapy [3e5]. And secondgeneration tyrosine kinase inhibitors, such as neratinib and afatinib, have undergone evaluation among different epithelial cancers [6e10]. In contrast with traditional chemotherapy agents, EGFR-TKIs present a favorable toxicity profile with the most frequently adverse events (AEs) being rash, diarrhea, and nausea [11e13]. However, these small-molecule TKIs have also been associated with a new set of adverse events, some of which may be potentially life threatening, such as arterial thrombosis and venous thrombosis [14e16]. Indeed, fatal adverse events (FAEs) have occasionally been reported in several clinical trials with EGFR-TKIs, although no significant and definitive data have been established. We thus conducted this metaanalysis to determine the incidence and risk of FAEs associated with the clinical use of EGFR-TKIs. Trials were selected from those published in PubMed between January 1, 1990, and December 31, 2012, with “erlotinib”, “gefitinib”, “Iressa”, “Tarceva”, “randomized controlled trial (RCT)”, and “cancer” as key words. Inclusion criteria included (1) prospective phase III RCTs evaluating EGFR-TKIs (erlotinib and gefitinib) in patients with cancer, (2) assigned participants to EGFR-TKIs or non-EGFRTKIs-containing therapy, and (3) available data on FAEs. The quality of reports of clinical trials was assessed and calculated using the 5-item Jadad scale as previously described [17]. Data abstraction was conducted independently by two investigators (Q.W.X. and S.Z.), and any discrepancy between the reviewers was resolved by consensus. The primary end point of the analysis was
Figure 1
1281 treatment emergent, non-disease-related, fatal adverse events. Adverse events were defined as per versions two or three of the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) criteria [18]. Both versions are similar in defining fatal adverse events as grade five, though version three requires attribution to specific adverse events while version two did not have such requirements. We excluded events that were reported as related to disease progression, but included all events with unspecified attribution and included events regardless of attribution to treatment provided that they were not related to disease progression. Analyses were performed by using Stata version 12.0 software and Open Meta-Analyst software version 4.16.12 (Tufts University, URL http://tuftscaes.org/open_meta/). For one study that reported zero events in the arms, we applied the classic half-integer correction to calculate the RR and variance [19]. Random effects models were used regardless of the actual inter-study heterogeneities, which were quantified using the c2-based Q statistic [20]. Individual trials were pooled and weighted by the DerSimonianeLaird method. The incidence and relative risk of FAEs were calculated for each study along with appropriate 95% confidence intervals (CIs) and p values. A two-side p less than 0.05 was considered to indicate statistical significance. We also conducted the following prespecified subgroup analyses: different tumor types, EGFR-TKIs, countries, EGFR-TKIs-based regimens, controlled therapy, and treatment strategy. Of the 650 publications identified during the initial search, 22 trials met criteria for inclusion (Supplementary Fig. 1, available online). The median Jadad score was 3 (range Z 3e5). No evidence of publication bias was detected by Begg test (p Z 0.77). A total of 13,825 patients (EGFR-TKIs, n Z 7508; non-EGFR-TKIs, n Z 6317) were included in the analysis (Supplementary Table 1, available online). In the EGFR-TKIs group, 231 patients experienced FAEs compared with 198 patients in non-EGFR-TKIs group. The summary incidence of FAEs in patients receiving EGFR-TKIs was 1.9 (95%CI: 1.2e2.9%) (Supplementary Fig. 2, available
Relative risk of fatal adverse events associated with EGFR-TKIs versus non-EGFR-TKIs therapy.
1282 Table 1 Groups
W.-X. Qi et al. Incidence and relative risk of FAEs with EGFR-TKIs according to prespecified subgroups. Studies, n
Tumor type NSCLC 19 Pancreatic cancer 1 Head and neck cancer 1 Biliary-tract cancer 1 EGFR-TKIs Erlotinib 10 Gefitinib 12 Country Asia 10 Non-Asia 12 EGFR-TKIs-based regimens Monotherapy 17 Combinations 5 Treatment strategy First-line 12 Salvage treatment 8 Maintenance 2 Controlled therapy Placebo 3 Active therapy 19 Overall 22
Fatal adverse events, n/total, n
Incidence of fatal adverse events, % (95%CI)
RR (95%CI)
p Value
EGFR-TKIs
Control
EGFR-TKIs
Control
224/6771 6/282 1/324 0/135
194/5743 0/280 4/159 0/131
2.1 (1.3e3.3) 2.1 (1.0e4.7) 0.3 (0e2.2) 0
2.1 (1.3e3.4) 0.2 (0e2.8) 2.5 (0.9e6.5) 0
1.00 (0.72e1.40) 12.91 (0.73e228.05) 0.12 (0.01e1.09) e
0.98 0.08 0.06 e
105/4373 126/3135
62/3248 136/3069
1.7 (1.0e2.9) 2.2 (1.1e4.3)
1.9 (1.2e2.9) 2.5 (1.3e4.9)
1.13 (0.72e1.78) 0.87 (0.50e1.51)
0.60 0.61
38/1724 193/5784
19/1678 179/4639
2.2 (1.4e3.5) 1.9 (1.1e3.5)
1.2 (0.6e2.4) 2.6 (1.5e4.5)
1.65 (0.98e2.78) 0.80 (0.51e1.25)
0.058 0.32
124/5306 107/2202
113/4448 85/1869
1.7 (1.1e2.7) 2.9 (1.1e7.1)
2.2 (1.5e3.3) 1.6 (0.4e6.2)
0.83 (0.54e1.29) 1.48(0.75e2.92)
0.41 0.26
191/4462 37/2744 3/302
126/3526 70/2334 2/457
2.7 (1.6e4.4) 1.4 (0.7e2.7) 1.3 (0.3e6.0)
1.8 (0.9e3.6) 2.6 (1.4e4.7) 0.6 (0.2e1.9)
1.22 (0.98e1.52) 0.51 (0.29e0.87) 1.71 (0.10e28.59)
0.08 0.013 0.71
60/1758 171/5750 231/7508
23/952 175/5365 198/6317
1.7 (0.4e7.2) 1.8 (1.1e3.0) 1.9 (1.2e2.9)
1.1 (0.2e7.0) 1.9 (1.2e3.3) 1.9 (1.2e3.0)
1.29 (0.81e2.07) 0.94 (0.63e1.41) 0.99 (0.70e1.41)
0.29 0.76 0.97
Abbreviations: NSCLC, non-small-cell lung cancer; EGFR-TKIs, epidermal growth factor receptor tyrosine kinase.
online). The relative risk of FAE for EGFR-TKIs versus nonEGFR-TKIs therapy was 0.99 (95%CI: 0.70e1.41; p Z 0.97) (Fig. 1). To better determine possible relationships between EGFR-TKIs and FAEs, we performed several exploratory subgroup analyses (Table 1). No statistically significant increase in the relative risk of FAEs with EGFRTKIs was observed according to tumor types, EGFR-TKIs, countries, EGFR-TKIs-based regimens, controlled therapy, and treatment strategy. Additionally, using EGFR-TKIs as salvage treatment significantly reduced the risk of FAEs when compared to the controls (RR 0.51, 95%CI: 0.29e0.87, p Z 0.013). Our analysis revealed a very low event rate of FAEs (1.9%) with EGFR-TKIs, Strict eligibility criteria in phase III randomized controlled trials may have contributed, at least in part, to the lower incidence of FAEs observed. Notably, this should have impacted both EGFRTKIs and non-EGFR-TKIs arms equally. Our meta-analysis was not based on individual patient data, and meta-analyses based on published data tended to overestimate treatment effects compared with individual patient data analyses. In addition, it precluded a more comprehensive analysis such as adjusting for baseline factors and other differences that existed between the trials from which the data were pooled. Therefore, the results must be interpreted cautiously, as an individual patient data-based meta-analysis would give more reliable estimation than one based on abstracted data. Another limitation was that trials reported zero FAEs in one or both arms were also included for analysis. In this setting, using random effects models and continuity corrections would
bias the results toward null. But we felt that including trials reporting zero FAEs would provide the most conservative estimate. Additionally, different treatment strategy, duration, and regimens contributed to increase the clinical heterogeneity of the meta-analysis, which made the interpretation of the meta-analysis more problematic, although we performed subgroup analysis and combined the individual trial using a random effect model. In conclusion, the present study reveals that FAEs in patients treated with EGFR-TKIs are uncommon. We do not detect an increase in the relative risk of FAEs with EGFRTKIs therapy compared with non-EGFR-TKIs therapy, and EGFR-TKIs are safety and tolerable for cancer patients, especially for those previously treated patients.
Conflicts of interest statement All authors declare that they have no potential conflicts of interests.
Funding None.
Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.rmed.2013.06.005.
Treatment-related mortality with EGFR-TKIs
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References [1] Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5: 341e54. [2] Gori B, Ricciardi S, Fulvi A, et al. New oral multitargeted antiangiogenics in non-small-cell lung cancer treatment. Future Oncol 2012;8:559e73. [3] Cohen MH, Johnson JR, Chattopadhyay S, et al. Approval summary: erlotinib maintenance therapy of advanced/metastatic non-small cell lung cancer (NSCLC). Oncologist 2010;15: 1344e51. [4] Cohen MH, Williams GA, Sridhara R, et al. United States food and drug administration drug approval summary: gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 2004;10:1212e8. [5] Cohen MH, Williams GA, Sridhara R, et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8:303e6. [6] Awada A, Dirix L, Manso Sanchez L, et al. Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy. Ann Oncol 2013;24: 109e16. [7] Ito Y, Suenaga M, Hatake K, et al. Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a phase 1 dose-escalation study. Jpn J Clin Oncol 2012;42:278e86. [8] Tsai YC, Yeh CH, Tzen KY, et al. Targeting epidermal growth factor receptor/human epidermal growth factor receptor 2 signalling pathway by a dual receptor tyrosine kinase inhibitor afatinib for radiosensitisation in murine bladder carcinoma. Eur J Cancer 2013 Apr;49(6):1458e66. [9] Schuler M, Awada A, Harter P, et al. A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer. Breast Cancer Res Treat 2012;134:1149e59. [10] Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012;13:528e38. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011;29:1059e66. Suzumura T, Kimura T, Kudoh S, et al. Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer. BMC Cancer 2012;12:568. Qi WX, Shen Z, Lin F, et al. Comparison of the efficacy and safety of EFGR tyrosine kinase inhibitor monotherapy with standard second-line chemotherapy in previously treated advanced non-small-cell lung cancer: a systematic review and meta-analysis. Asian Pac J Cancer Prev 2012;13:5177e82. Petrelli F, Cabiddu M, Borgonovo K, Barni S. Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials. Ann Oncol 2012 Jul;23(7):1672e9. Gatzemeier U, Pluzanska A, Szczesna A, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 2007;25:1545e52. Crino L, Cappuzzo F, Zatloukal P, et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, phase II study. J Clin Oncol 2008;26:4253e60. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609e13. NCI, Cancer Therapy Evaluation Program. CTC v. 2.0 and common terminology criteria for adverse events criteria V3.0 (CTCAE). Available at: http://ctep.cancer.gov/protocol Development/electronic_applications/ctc.htm. Choueiri TK, Schutz FA, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol 2010; 28:2280e5. Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol 2005;28:123e37.
