Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer_ A systematic review and meta-analysis of clinic

Lung Cancer 83 (2014) 231239Contents lists available at ScienceDirectLung Cancerjournal homepage: /locate/lungcanRisk of interstitial lung disease with getinib and erlotinib inadvanced non-small cell lung cancer: A systematic review andmeta-analysis of clinical trialsLiang Shi, Junfang Tang, Li Tong, Zhe Liu Department of Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, 101149 P.R. Chinaa r t i c l e i n f o a b s t r a c tArticle history:Received 28 July 2013Received in revised form 24 October 2013Accepted 19 November 2013Keywords:Non-small cell lung cancerGetinibErlotinibInterstitial lung diseaseRiskMeta-analysis1. IntroductionObjectives: Getinib and erlotinib are oral epidermal growth factor receptor (EGFR) tyrosine kinaseinhibitors (TKIs) widely used in advanced non-small cell lung cancer (NSCLC). Interstitial lung disease(ILD) events have been described with these agents, although the overall risk remains unclear. We per-formed a systematic review and meta-analysis to determine the incidence and the relative risk (RR)associated with the use of getinib and erlotinib.Materials and methods: PubMed databases were searched for articles published from January 2000 toOctober 2012, and abstracts presented at the American Society of Clinical Oncology and the EuropeanSociety of Medical Oncology meetings held between 2000 and 2012 were searched for relevant studies.Eligible studies included randomized controlled trials with getinib and erlotinib in advanced NSCLCpatients. Summary incidence rates, relative risks, and 95% CIs were calculated using xed-effects orrandom-effects models, depending on the heterogeneity of the included studies.Results: 15,618 patients from 29 randomized controlled trials were selected for this meta-analysis. Theoverall incidence for all-grade ILD events was 1.2% (95% CI, 0.91.6%) among patients receiving getiniband erlotinib, with a mortality of 22.8% (95% CI, 14.631.0%). Compared with controls, the RR of all-gradeILD events associated with getinib and erlotinib was 1.53 (95% CI, 1.132.08; P = 0.006) using a xed-effects model. The RR of fatal ILD events associated with EGFR TKIs treatment was 1.96 (95% CI, 1.033.72,P = 0.041) compared with control patients. The analysis was also stratied for drug type, study location,treatment arm, and treatment line, but no signicant differences in RRs were observed.Conclusion: Treatment with EGFR TKIs getinib and erlotinib is associated with a signicant increase inthe risk of developing both all-grade and fatal ILD events in advanced NSCLC. 2013 Elsevier Ireland Ltd. All rights reserved.the frontline setting for selected patients with active EGFR mutation4.In the last decade, getinib and erlotinib, which are orally active,small molecules, selective and reversible epidermal growth factorreceptor (EGFR) tyrosine kinase inhibitors (TKIs), have been exten-sively developed in non-small cell lung cancer (NSCLC). Based onthe results of two multicenter phase II studies 1,2, getinib wasrst approved for the treatment of advanced NSCLC in Japan in2002, and erlotinib was approved by the FDA in 2004 for the treat-ment of patients with relapsed NSCLC 3. Although these agentshave modest clinical benets after one or two chemotherapy regi-mens treatment in unselected patients with advanced NSCLC, anemerging and potentially more elegant strategy is to move them to Corresponding author. Tel.: +86 10 89509323; fax: +86 10 89500153.E-mail address: (Z. Liu).0169-5002/$ see front matter 2013 Elsevier Ireland Ltd. All rights reserved./10.1016/j.lungcan.2013.11.016In clinical trials and expanded access programs (EAPs), the mainreported adverse events of getinib and erlotinib are skin rash,diarrhea, and nausea, which are usually well tolerated. The rstcase of ILD associated with getinib has been reported in a ran-domized double-blind phase 2 trial 5. Reported incidence of ILDevents in patients treated with getinib or erlotinib varied sub-stantially among trials. In a phase II study by Niho et al. in patientswith NSCLC, four (10.0%) of the 40 patients who received getinibdeveloped ILD events 6, however, in a large-scale phase IV studyof erlotinib, the reported incidence of ILD was less than1.0% 7.Importantly, patients with NSCLC who experience ILD events dur-ing the course of therapy have worse prognosis and an increasedrisk of death 8. Additionally, no signicant association betweengetinib or erlotinib and ILD events has been shown in any ran-domized controlled clinical trial to date.232 L. Shi et al. / Lung Cancer 83 (2014) 231239We propose that those studies were not powered sufciently For the meta-analyses, both the xed-effects model (weightedto show a signicantly increased risk due to the low incidence of with inverse variance) and the random-effects model were consid-ILD events. Therefore, we have done a systematic review of the ered. The latter was calculated using the method of DerSimonianpublished articles and abstracts presented at major oncologic meet- and Laird, which considers both within-study and between-studyings, and pooled relevant randomized controlled clinical trials for variation 13. For each meta-analysis, statistical heterogeneitya meta-analysis to determine the risk of ILD events associated with among studies included in the meta-analysis was rst assessedgetinib and erlotinib treatment. using Cochranes Q statistic, and inconsistency was quantied withthe I2 statistic 14. If the P value was less than 0.1, the assumption of2. Methods homogeneity was deemed invalid; in this case, we reported sum-mary estimates from the random-effects models. Otherwise, the2.1. Selection of studies xed-effects model was reported. For three-arm studies 1517,we combined arms included EGFR TKIs to create a single pair-wiseAn independent review of PubMed citations from January 2000to October 27, 2012, was conducted. Key words included in thesearch were “human studies,” “clinical trial,” “NSCLC”, “geti-nib”, “ZD1839”, “Iressa”, “erlotinib”, “OSI 774”, and “Tarceva”.The search was limited to articles published in English.Abstracts and virtual meeting presentations containing the sameterms from the American Society of Clinical Oncology (ASCO;) and the European Society of Medical Oncol-ogy (ESMO; ) conferences held betweenJanuary 2000 and October 27, 2012, were also searched to identifyrelevant clinical trials. We reviewed each publication, and only themost recent or complete report of clinical trial was included whenduplicate publications were identied. The updated manufacturerspackage inserts of approved agents (getinib and erlotinib) alsowere reviewed to identify relevant information 9,10.comparison.To explore the possible reasons for any observed hetero-geneity, we also conducted the following prespecied subgroupanalyses: drug type (getinib versus erlotinib), study location(Japanese versus non-Japanese in Asian versus non-Asian), treat-ment arm (three group: comparing EGFR TKI plus chemotherapywith chemotherapy, comparing EGFR TKI only with chemotherapy,and comparing EGFR TKI only with placebo), and treatment line(rst versus non-rst). All subgroup analyses followed the samemeta-analysis procedure. Finally, potential publication bias wasevaluated through Beggs funnel plots to examine relative sym-metry of individual study estimates around the overall estimate,and with both the Beggs and Eggers tests 18,19. A two-tailedP value of less than 0.05 was considered statistically signi-cant.The following adverse outcomes were considered as ILD eventsand were included in the analyses: interstitial lung disease, ILD-like 3. Resultsevents, ILD-type events, pneumonitis, and interstitial pneumonia.Clinical trials that met the following criteria were chosen for anal- 3.1. Population characteristicsysis: prospective phase II and III trials; randomized clinical trialsin patients with advanced NSCLC, patients assigned to treatment Our search yielded a total of 496 potentially relevant studieswith getinib or erlotinib, and safety data available for ILD. Phase with getinib or erlotinib. The selection process and reasons forI, EAPs, and single-arm phase II trials were excluded due to their exclusion are detailed in Fig. 1. Finally, a total of 29 randomizedlack of control groups. The quality of included trials was assessed trials were included in the meta-analysis. These trials repre-and calculated using the seven-item Jadad scale including random- sented 17 studies with getinib 15,16,2034, 12 with erlotinibization, double-blinding, and withdrawals as previously described 17,3545.11. All included trials involved randomized treatment allocation.Fifty-nine percent of included studies were open label with mod-2.2. Data extraction erate Jadad score (score 3), whereas the remaining 41% of includedData abstraction was conducted independently by two inves-studies were double blind with highest Jadad score (score 5).The baseline characteristics of each trial are summarized intigators (L.Shi and J.F. Tang) according to the Preferred Reporting Table 1. A total of 15,618 patients were available for the meta-Items for Systematic Reviews and Meta-Analyses (PRISMA) state- analysis. All patients were included for the incidence and RR ofment 12, and any discrepancies between reviewers were resolved all-grade ILD events analyses (9569 for getinib trials and 6049by consensus. ILD events in these studies were assessed and for erlotinib trials). For deaths as a result of ILD events analysis,recorded according to the National Cancer Institutes common tox- there were 6437 patients for getinib trials and 5171 patients foricity criteria (version 2.0 or 3.0; ), which has erlotinib trials after excluded three trials without related descrip-been widely adopted in cancer clinical trials. For each study, the tion 29,34,40.following information was extracted: rst authors name, year ofpublication, study location, trial phase, treatment line, treatment 3.2. Incidence of ILD eventsarms including doses and dosing schedules used, number of partic-ipants evaluable for safety prole, median age, median treatment For the incidence analysis of all-grade ILD events, a total ofduration, toxicity data of interest including the number of all-grade 8609 patients were considered for incidence analysis. By usingILD, number of deaths attributed to ILD. a random-effects model (heterogeneity test: Q = 65.22; I2 = 57.1%;P =70 years) withstage iiib/iv non-small cell lung cancer. J Thorac Oncol 2011;6:156977.Begg CB, Mazumdar M. Operating characteristics of a rank correlation test forpulmonary brosis, age, performance status, gender, smoking his- publication bias. Biometrics 1994;50:1088101.tory, lung cancer histology, and the mutational status of EGFR, arenot possible in this analysis.1920Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected bya simple, graphical test. BMJ 1997;315:62934.Han JY, Park K, Kim SW, Lee DH, Kim HY, Kim HT, et al. First-signal: rst-linesingle-agent iressa versus gemcitabine and cisplatin trial in never-smokers5. Conclusion 21 with adenocarcinoma of the lung. J Clin Oncol 2012;30:11228.Zhang L, Ma S, Song X, Han B, Cheng Y, Huang C, et al. Getinib versus placeboOur study has shown that small-molecule EGFR TKIs getinib as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (inform; C-tong 0804): a multicentre, double-blindand erlotinib are associated with a signicantly increased risk ofdeveloping both all-grade and fatal ILD events in advanced NSCLC.It is imperative for physicians and patients to recognize the risk.22randomised phase 3 trial. Lancet Oncol 2012;13:46675.Sun JM, Lee KH, Kim SW, Lee DH, Min YJ, Yun HJ, et al. Getinib versuspemetrexed as second-line treatment in patients with nonsmall cell lung can-cer previously treated with platinum-based chemotherapy (kcsg-lu08-01): anFuture studies are needed to investigate the prevention and man-agement of ILD events associated with EGFR TKIs getinib anderlotinib.23open-label, phase 3 trial. Cancer 2012;118:623442.Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Get-inib or chemotherapy for non-small-cell lung cancer with mutated egfr. N EnglJ Med 2010;362:23808.24 Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Geti-Conict of interest nib versus cisplatin plus docetaxel in patients with non-small-cell lung cancerharbouring mutations of the epidermal growth factor receptor (wjtog3405):The authors have declared no conicts of interest. 25an open label, randomised phase 3 trial. Lancet Oncol 2010;11:1218.Takeda K, Hida T, Sato T, Ando M, Seto T, Satouchi M, et al. Randomized phaseiii trial of platinum-doublet chemotherapy followed by getinib comparedAppendix A. Supplementary data with continued platinum-doublet chemotherapy in japanese patients withadvanced non-small-cell lung cancer: results of a west japan thoracic oncologygroup trial (wjtog0203). J Clin Oncol 2010;28:75360.Supplementary data associated with this article can befound, in the online version, at /10.1016/j.lungcan.26 Lee DH, Park K, Kim JH, Lee JS, Shin SW, Kang JH, et al. Randomized phaseiii trial of getinib versus docetaxel in non-small cell lung cancer patientswho have previously received platinum-based chemotherapy. Clin Cancer Res2013.11.016. 2010;16:130714.27 Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Geti-References nib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med2009;361:94757.28 Goss G, Ferry D, Wierzbicki R, Laurie SA, Thompson J, Biesma B, et al. Random-1 Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. ized phase ii study of getinib compared with placebo in chemotherapy-naiveMulti-institutional randomized phase ii trial of getinib for previously treatedpatients with advanced non-small-cell lung cancer (the ideal 1 trial) cor-rected. J Clin Oncol 2003;21:223746. 29patients with advanced non-small-cell lung cancer and poor performance sta-tus. J Clin Oncol 2009;27:225360.Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Getinib versus2 Kris MG, Natale RB, Herbst RS, Lynch TJ, Prager D, Belani CP, et al. Efcacy of docetaxel in previously treated non-small-cell lung cancer (interest): a ran-getinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, domised phase iii trial. Lancet 2008;372:180918.L. Shi et al. / Lung Cancer 83 (2014) 231239 23930 Maruyama R, Nishiwaki Y, Tamura T, Yamamoto N, Tsuboi M, NakagawaK, et al. Phase iii study, v-15-32, of getinib versus docetaxel in previ-ously treated japanese patients with non-small-cell lung cancer. J Clin Oncol2008;26:424452.31 Crino L, Cappuzzo F, Zatloukal P, Reck M, Pesek M, Thompson JC, et al. Geti-nib versus vinorelbine in chemotherapy-naive elderly patients with advancednon-small-cell lung cancer (invite): a randomized, phase ii study. J Clin Oncol2008;26:425360.32 Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, Ung YC, et al. Phase iii trialof maintenance getinib or placebo after concurrent chemoradiotherapy anddocetaxelconsolidationininoperablestageiiinon-small-celllungcancer:swogs0023. J Clin Oncol 2008;26:24506.33 Cufer T, Vrdoljak E, Gaafar R, Erensoy I, Pemberton K. Phase ii, open-label,randomized study (sign) of single-agent getinib (iressa) or docetaxel assecond-line therapy in patients with advanced (stage iiib or iv) non-small-celllung cancer. Anticancer Drugs 2006;17:4019.34 Thatcher N, Chang A, Parikh P, Rodrigues PJ, Ciuleanu T, von Pawel J, et al. Get-inib plus best supportive care in previously treated patients with refractoryadvanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (iressa survival evaluation in lung cancer). Lancet2005;366:152737.35 Mok T, Wu YL, Thongprasert S, Yu C, Zhang L, Ladrera GE, et al. A ran-domized placebo-controlled phase iii study of intercalated erlotinib withgemcitabine/platinum in rst-line advanced non-small cell lung cancer (nsclc):fastact-ii. J Clin Oncol 2012;30:15s (suppl; abstr 7519).36 Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versuschemotherapy as rst-line treatment for patients with advanced egfrmutation-positive non-small-cell lung cancer (optimal, ctong-0802): a mul-ticentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:73542.37 Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al.Erlotinib versus standard chemotherapy as rst-line treatment for europeanpatients with advanced egfr mutation-positive non-small-cell lung cancer(eurtac): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol2012;13:23946.38 Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, HillenbachC, et al. Efcacy and safety of erlotinib versus chemotherapy in second-linetreatment of patients with advanced, non-small-cell lung cancer with poorprognosis (titan): a randomised multicentre, open-label, phase 3 study. LancetOncol 2012;13:3008.39 Lee SM, Khan I, Upadhyay S, Lewanski C, Falk S, Skailes G, et al. First-lineerlotinib in patients with advanced non-small-cell lung cancer unsuitable4041424344454647484950for chemotherapy (topical): a double-blind, placebo-controlled, phase 3 trial.Lancet Oncol 2012;13:116170.Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, et al.Erlotinib as maintenance treatment in advanced non-small-cell lung cancer:a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol2010;11:5219.Mok TS, Wu YL, Yu CJ, Zhou C, Chen YM, Zhang L, et al. Randomized,placebo-controlled,