培美曲塞联合铂类

A Randomized Phase II Study of Pemetrexed in Combination With Cisplatin or Carboplatin as First-Line Therapy for Patients With LocallyAdvanced or Metastatic Non–Small-CellLung CancerWolfgang H.W.Schuette,1Andreas Gröschel,2Martin Sebastian,3Stefan Andreas,4 Thomas Müller,5Folker Schneller,6Sylvia Guetz,7Corinna Eschbach,8 Sabine Bohnet,9Monika I.Leschinger,10Martin Reck11AbstractA phase II randomized study of pemetrexed combined with cisplatin or carboplatin asfirst-line treatment forstage IIIB/IV non–small-cell lung cancer.Sixty-five patients were randomized to each arm.The results of the 6-month progression-free survival rate,median overall survival,and safety analyses demonstrated efficacy and tolerability of pemetrexed in combination with cisplatin or carboplatin asfirst-line therapy for patients with advanced non–small-cell lung cancer.Background:Pemetrexed plus cisplatin was approved forfirst-line treatment of non–small-cell lung cancer(NSCLC) in patients with nonsquamous histology after initiation of this study.This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin asfirst-line treatments for stage IIIB/IV NSCLC.Patients and Methods: The patients were randomized(1:1)to2parallel arms:pemetrexed(500mg/m2)plus cisplatin(75mg/m2)or pemetrexed(500mg/m2)plus carboplatin(area under the curve6)day1every3weeks(maximum,6cycles).Progression-free survival(PFS)was the primary objective;secondary objectives included overall survival(OS),1-year survival,and safety.Results:Sixty-five patients were randomized to each treatment arm.The patients treated with pemetrexed plus cisplatin had a median age of64years and were predominantly men(42[64.6%])with nonsquamous histology(53[81.5%]),stage IV(61[92.4%])disease,and a performance status of0(40[61.5%]).Median PFS was6.0months,6-month PFS rate was50.5%,median OS was11.7months,and1-year survival rate was47.5%.Drug-related grade3/4toxicities included neutropenia(11[16.9%]),anemia(5[7.7%]),thrombocytopenia(2[3.1%]), and nausea(3[4.6%]).Patients treated with pemetrexed plus carboplatin had a median age of63years,were predominantly men(46[70.8%])with nonsquamous histology(52[80.0%]),stage IV(58[86.6%])disease,and a performance status of0(45[69.2%]).The median PFS was4.7months,the6-month PFS rate was34.9%,median OS was8.9months,and1-year survival rate was39.2%.Drug-related grade3/4toxicities included neutropenia1Department of Internal Medicine II,Hospital Martha-Maria,Halle-Dölau,Halle, Germany2Pneumology,Internal Medicine V,University Hospital of the Saarland,Homburg/ Saar,Germany3Department of Hematology,Oncology and Pneumology,University Medical Center, Mainz,Germany4Lung Clinic,Center of Pneumology,Immenhausen,Germany5Hospital Hofheim,Kliniken des Main-Taunus Kreises GmbH,Krankenhaus Hofheim Klinik f.Pneumologie u.Allgemeine Innere Medizin,Hofheim am Taunus,Germany6Policlinic of the‘Klinikum rechts der Isar,’Technical University Munich,Munich,Germany 7Robert-Koch Clinic Leipzig,Leipzig,Germany 8Department of Pneumology,Asklepios Clinic Harburg,Hamburg,Germany9Medical Clinic III,University Hospital Schleswig-Holstein,Campus Luebeck,Luebeck,Germany10Medical Department,Lilly Germany GmbH,Bad Homburg,Germany11Department of Pneumology and Thoracic Surgery,Hospital Grosshansdorf,Grosshansdorf, GermanySubmitted:Jun26,2012;Revised:Sep28,2012;Accepted:Oct8,2012;Epub:Jan16,2013Address for correspondence:Wolfgang H.W.Schuette,MD,Martha-Maria Krankenhaus,Halle-Dölau gGmbH,Röntgenstrasse1,D-06120Halle/Saale,GermanyE-mail contact:wolfgang.schuette@martha-maria.deOriginal StudyClinical Lung Cancer May20132151525-7304/$-see frontmatter©2013Elsevier Inc.All rights reserved. /10.1016/j.cllc.2012.10.001(17[26.2%]),thrombocytopenia(11[16.9%]),anemia(7[10.8%]),and nausea(5[7.7%]).Conclusions:Both the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonst-rated efficacy and tolerability asfirst-line therapy in patients with advanced NSCLC.: NCT00402051.Clinical Lung Cancer,Vol.14,No.3,215-23©2013Elsevier Inc.All rights reserved.Keywords:First-line treatment,Nonsquamous histology,Pemetrexed,Platinum combinations,Stage IIIB/IV non–small-celllung cancerIntroductionApproximately85%of lung cancer cases are classified as non–small-cell lung cancer(NSCLC),with more than40%of patients presenting with locally advanced or metastatic disease atfirst diag-nosis.1,2Potent agents and therapeutic strategies have been devel-oped during the past decade;however,there remains a vast unmet medical need for more treatment options for advanced NSCLC. Pemetrexed,a multitargeted antifolate,has demonstrated superior efficacy with a tolerable safety profile in patients with nonsquamous NSCLC compared with conventional chemotherapy,as afirst-line therapy in combination with cisplatin3,4and as a single-agent main-tenance therapy4,5and second-line treatment6;pemetrexed plus cis-platin is also approved as afirst-line treatment for malignant pleural mesothelioma.4,7In advanced(stage IIIB or IV)NSCLC,doublet combinations of chemotherapeutic agents with platinum com-pounds are reference regimens.8When this study was initiated,piv-otal phase III pemetrexed studies offirst-line and maintenance ther-apy for patients with advanced NSCLC were underway.3,5In phase II studies of patients with NSCLC who were chemother-apy naive,pemetrexed combined with cisplatin or carboplatin has shown efficacy consistent with that of other platinum doublets.9-12 Previous studies of docetaxel,paclitaxel,gemcitabine,vindesine,and etoposide have indicated that both cisplatin and carboplatin doublets are efficacious13-18;and recent results from a phase III study of1350 patients with advanced NSCLC showed carboplatin area under the curve(AUC)6is noninferior to cisplatin80mg/m2when combined with gemcitabine,which suggests that treatment is efficacious with either carboplatin or cisplatin.19However,published meta-analyses favor agents combined with cisplatin.20,21Results of2phase II stud-ies11,12suggest that pemetrexed plus carboplatin is a tolerable and efficaciousfirst-line treatment regimen for patients with advanced NSCLC.Thus,it seemed worthwhile to evaluate the safety and effi-cacy of pemetrexed combined with either cisplatin or carboplatin. The primary objective of this phase II study was to evaluate the PFS for patients with advanced NSCLC afterfirst-line treatment with pemetrexed plus cisplatin or pemetrexed plus carboplatin. Patients and MethodsPatientsPatients were included if they were at least18years old and che-motherapy naive,with stage IIIB or IV NSCLC,at least1measurable lesion per the RECIST(Response Evaluation Criteria in Solid Tu-mors),22adequate organ function,an Eastern Cooperative Oncology Group PS of0or1,23and no serious concomitant systemic disorder. Patients with NSCLC of all histologies were included in this trial because data on the differential efficacy of pemetrexed in patients with nonsquamous histology,which resulted in the current pem-etrexed label(excluding patients with squamous histology),were not available at the time this study was clinically active.Exclusion criteria included significant cardiovascular disease,symptomatic central ner-vous system metastases,and uncontrolled third-spacefluid retention. Patients were also excluded if they were unable to interrupt non-steroidal anti-inflammatory drug use or were unable or unwilling to take folic acid and vitamin B12supplementation or corticosteroids as prophylaxis.The protocol was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.All the patients provided written informed consent before enrollment. Study Design and Treatment PlanThis was a2-arm,randomized,noncomparative,parallel-group, open-label,phase II multicenter study of pemetrexed(Alimta®,Eli Lilly and Company,Indianapolis,IN),asfirst-line therapy com-bined with either cisplatin or carboplatin in patients with stage IIIB or IV NSCLC.The primary objective was to assess PFS;median PFS and the PFS rate at6months were tested independently for each treatment arm.Secondary endpoints included OS,1-year survival rate,objective tumor response rate(ORR),and safety.Patients were randomly assigned(1:1)to a treatment arm by a centralized,com-puter-generated random sequence by using block randomization and an interactive voice response system.Randomization was stratified by stage of disease(IIIB vs.IV).Although there is no comparison of the 2arms,randomization does ensure that there is some consistency in the arms and also allows for a standard endpoint from which to measure OS and PFS.Patients receivedfirst-line treatment with ei-ther pemetrexed500mg/m2plus cisplatin75mg/m2(pemetrexed plus cisplatin)or pemetrexed500mg/m2plus carboplatin AUC6 (pemetrexed plus carboplatin)on day1of each21-day cycle for a maximum of6cycles(unless early disease progression,treatment intolerability,or any other reason required early discontinuation). Carboplatin dose AUC6is calculated based on the Calvert formula.24All the patients received vitamin supplementation,which con-sisted of oral folic acid(350-1000␮g)daily and1vitamin B12injec-tion(1000␮g)every9weeks,starting1week before thefirst dose and continuing until3weeks after the last dose of the study treat-ment.Dexamethasone(4mg orally twice daily,or equivalent)pro-phylaxis was administered the day before,the day of,and the day after each pemetrexed administration.Pre-and posthydration to re-duce cisplatin-caused nephrotoxicity was required.After a dose ad-justment,the patients received the reduced dose for the remainder ofPemetrexed Therapy Non-Small Cell Lung Cancer 216Clinical Lung Cancer May2013the study.The patients were allowed to receive concomitant support-ive care,granulocyte colony-stimulating factors and erythropoietic agents,according to the American Society of Clinical Oncology guidelines.25Baseline and Treatment AssessmentsBaseline patient evaluations included medical history,physical ex-amination,blood chemistry and hematology tests,and tumor mea-surements.The patients received follow-up assessments at the begin-ning of each cycle and were routinely monitored.PFS was defined as the time from randomization to the date of progressive disease or death of any cause.OS was defined as the time from randomization to the date of death of any cause.Tumor response was evaluated by using the RECIST every other cycle until treatment discontinuation. Follow-up was scheduled for6weeks after discontinuation and every 3months thereafter for up to1year.Safety evaluation included dose delays,reductions,and the assessment of grade3/4toxicities.Toxic-ity was assessed according to Common Toxicity Criteria for Adverse Events,version3.0.26Statistical AnalysesAll patients who received at least1dose of a study drug were included in the efficacy and safety analyses.The study was designed to indepen-dently test each hypothesis by treatment arm,and no comparisons be-tween treatment arms were done.The sample size calculation assumed that PFS time follows an exponential distribution and that130patients (65patients in each treatment arm)were to be enrolled.Each treatment group required53events to provide90%power to reject the null hy-pothesis(a median PFS of3.0months on each separate arm)at a2-sided significance level of.05.The Kaplan-Meier method27was used to esti-mate medians for time-to-event parameters and95%confidence inter-vals(CI)were calculated.Preplanned exploratory analyses were also con-ducted for patients with squamous and nonsquamous NSCLC histology.The histologic subtypes of NSCLC were reported by investi-gators in the following categories:adenocarcinoma,large cell carcinoma, squamous cell carcinoma,mixed-cell carcinoma,bronchoalveolar,and other NSCLC/not otherwise specified.There was no central review of pathology.ResultsPatient CharacteristicsThis study was conducted at15sites in Germany from November 2006to April2009.Of133patients randomized,130white patients (65per arm)received study treatment(Figure1).The patients treated with pemetrexed plus cisplatin had a median age of64years and were predominantly men(42[64.6%]),smokers(56[86.2%]) with nonsquamous histology(53[81.5%]),stage IV disease(61 [92.4%]),and a PS of0(40[61.5%]).The patients treated with pemetrexed plus carboplatin had a median age of63years and were predominantly men(46[70.8%]),smokers(58[89.2%])with nons-quamous histology(52[80.0%]),stage IV disease(58[86.6%]),and a PS of0(45[69.2%]).Baseline patient and disease characteristics are shown in Table1.Drug AdministrationAll the patients completed at least1cycle of treatment.The pa-tients treated with pemetrexed plus cisplatin were administered a mean of4.3cycles,and a median of4cycles(range,1-6);43%(nϭ28)completed the planned maximum of6cycles.There were3dose reductions,and no patient required more than1dose reduction. Adverse events(AE)caused dose delays in16(24.6%)of patients.The median relative dose intensity was98.2%for pemetrexed and97.8%for cisplatin.Progressive disease was the main reason for treat-ment discontinuation before study completion(nϭ13[20.0%]);11 (16.9%)patients discontinued due to AEs(Figure1).The patients treated with pemetrexed plus carboplatin were administered a meanof4.6cycles and a median of6cycles(range,1-6);49%(nϭ32) completed the planned maximum of6cycles.There were15dose reductions,and no patient required more than1dose reduction.AEs caused dose delays in19(29.2%)of patients.The median relativedose intensity was98.6%for pemetrexed and96.3%for carboplatin. Progressive disease was the main reason for treatment discontinua-tion before study completion(nϭ20[30.8%]);4(6.2%)patients discontinued due to AEs(Figure1).EfficacyPemetrexed Plus Cisplatin.For patients administered pemetrexedplus cisplatin,the6-and12-month PFS rates were50.5%(95%CI,36.6%-62.8%)and4.2%(95%CI,0.8%-12.7%),respectively(Ta-ble2).The median PFS time was6.0months(95%CI,4.6-7.1 months).The6-and12-month OS rates were77.7%(95%CI,65.2%-86.1%)and47.5%(95%CI,34.5%-59.4%),respectively. Median OS time was11.7months(95%CI,9.2-14.9months)andthe ORR was32.3%;47.7%of patients had stable disease.Efficacy parameters for patients treated with pemetrexed plus cisplatin werealso evaluated by histology(Table2).The6-month PFS rate for patients with nonsquamous histology(nϭ53,81.5%)was55.3% (95%CI,39.4%-68.6%);for patients with squamous histology(nϭ12[18.5%]),the rate was31.3%(95%CI,8.4%-57.8%).The median PFS time was6.4months(95%CI,4.7-7.5months)for patients with nonsquamous histology and4.5months(95%CI,1.6-6.4months)for patients with squamous histology.Kaplan-Meier curves for PFS for both the overall population and patientswith nonsquamous histology are shown in Figure2A,and OS levelsfor those same populations are shown in Figure2B.Pemetrexed Plus Carboplatin.For patients administered pem-etrexed plus carboplatin,the6-and12-month PFS rates were34.9% (95%CI,22.9%-47.2%)and1.9%(95%CI,0.2%-9.0%),respec-tively(Table2).The median PFS time was4.7months(95%CI,3.4-5.7months).The6-and12-month OS rates were60.4%(95%CI,47.3%,-71.2%)and39.2%(95%CI,27.2%-51.1%),respec-tively.The median OS time was8.9months(95%CI,6.0-12.2 months),and the ORR was20.0%;49.2%of patients had stable disease.Efficacy parameters for patients treated with pemetrexed plus carboplatin were also evaluated by histology(Table2).The6-monthPFS rate for patients with nonsquamous histology(nϭ52[80.0%])was34.9%(95%CI,21.5%-48.6%);for patients with squamous histology(nϭ13[20.0%]),the rate was35.2%(95%CI,11.2%-60.7%).The median PFS time was4.7months(95%CI,2.9-5.9 months)for patients with nonsquamous histology and4.6months (95%CI,3.4-6.3months)for patients with squamous histology. Kaplan-Meier curves for PFS for both the overall population andWolfgang H.W.Schuette et alClinical Lung Cancer May2013217patients with nonsquamous histology are shown in Figure3A,and OS levels for those same populations are shown in Figure3B. SafetyPemetrexed Plus Cisplatin.For patients treated with pemetrexed plus cisplatin,the most commonly reported drug-related grade3/4 hematologic toxicity was neutropenia(11patients[16.9%]).Grade4 neutropenia was reported in1patient;10patients had grade3neu-tropenia.Other drug-related grade3hematologic toxicities included anemia(5patients[7.7%])and thrombocytopenia(2patients [3.1%]).No other grade4hematologic toxicities were reported nor was febrile neutropenia observed(Table3).The most commonly reported drug-related nonhematologic toxicities were grade3nausea (3patients[4.6%]),followed by vomiting and fatigue(2patients each[3.1%])(Table3).Seven(10.8%)patients received at least1 transfusion of packed red blood cells.One death(from multiple organ failure)occurred that was considered related to the study drug. Pemetrexed Plus Carboplatin.For patients treated with pemetrexed plus carboplatin,the most commonly reported drug-related grade 3/4hematologic toxicity was neutropenia(17patients[26.2%]). Other drug-related grade3/4hematologic toxicities included throm-bocytopenia(11patients[16.9%])and anemia(7patients[10.8%]) (Table3).Febrile neutropenia was not observed.The most com-monly reported nonhematologic toxicities were grade3nausea(5 patients[7.7%]),followed by fatigue,anorexia,and urinary tract infection(2patients each[3.1%])(Table3).Sixteen(24.6%)pa-tients received at least1transfusion of packed red blood cells;4also received thrombocytes.Two deaths(from hemorrhage and pancyto-penia)occurred that were considered related to the study drug. DiscussionThe6-month PFS rate for patients in this study treated with pem-etrexed plus cisplatin was50.5%,with a median PFS of6.0months, which exceeded the protocol-defined null hypothesis of a median PFS of3.0months.Based on the statistical premise of the study, pemetrexed plus cisplatin showed a clear advantage over best sup-portive care and demonstrated efficacy results that were similar to or better than other published results for cisplatin-based chemotherapy1Abbreviations:PemϩCarbϭpemetrexed plus carboplatin;PemϩCisϭpemetrexed plus cisplatin.Pemetrexed Therapy Non-Small Cell Lung Cancer 218Clinical Lung Cancer May2013ties(only1patient had grade4neutropenia).The rates were similar to grade3/4toxicities reported for other patients with advancedNSCLC treated with pemetrexed plus cisplatin3;thrombocytopenia in4.1%,anemia in5.6%,and neutropenia in15.1%of patients. Nonhematologic toxicities for these patients were also infrequent and mild by comparison with other published studies.Ardizzoni et al20reported grade3/4nausea and vomiting in18%,neurotoxicity in12%,and nephrotoxicity in1.5%of patients.Scagliotti et al3 reported grade3/4fatigue in6.7%,vomiting in6.1%,and febrile neutropenia in1.3%of patients.In our study,the most commonly reported nonhematologic drug-related toxicities were grade3nausea (4.6%)followed by grade3vomiting and fatigue(each3.1%).Therewas1drug-related death on the pemetrexed plus cisplatin arm. Scagliotti et al3,6reported that,in patients with nonsquamous NSCLC,histology is predictive of the improved efficacy of pem-etrexed and that this pemetrexed treatment effect was consistent forthese patients in3different lines of therapy and3different studies.In addition,Ardizzoni et al20reported superior survival in patients with nonsquamous histology who were treated with cisplatin-based ther-apy compared with those treated with carboplatin-base therapy(haz-Abbreviations:OSϭoverall survival;PFSϭprogression-free survival.Wolfgang H.W.Schuette et alClinical Lung Cancer May2013219ard ratio1.12[95%CI,1.01-1.23]).In our study,efficacy parame-ters for patients treated with pemetrexed plus cisplatin were also evaluated by histology,and a similar treatment effect was observed. The6-month PFS rate,median PFS,and median OS all favored pemetrexed plus cisplatin treatment for patients with nonsquamous histology.The design of this study may be considered a limitation because it was neither designed nor powered to perform a direct comparison of21.00.80.60.40.20.0051015PFS (mo)2025301.00.80.60.40.20.0051015Survival time (mo)202530Pem+Cis (full analysis), n = 51; median, 6.0 mo (95% CI, 4.6-7.1 mo) Pem+Cis (nonsquamous), n = 41; median, 6.4 mo (95% CI, 4.7-7.5 mo)Pem+Cis (full analysis), n = 41; median, 11.7 mo (95% CI, 9.2-14.9 mo) Pem+Cis (nonsquamous), n = 34; median, 11.9 mo (95% CI, 9.4-15.2)Abbreviation:PemϩCisϭpemetrexed plus cisplatin.Figure3Kaplan-Meier Curves for Pemetrexed Plus Carboplatin for Overall and Nonsquamous Populations.(A)Progression-free Survival.(B)Overall Survival1.00.80.60.40.20.0051015PFS (mo)2025301.00.80.60.40.20.0051015Survival time (mo)202530Pem+Carbo (full analysis), n = 56; median, 4.7 mo (95% CI, 3.4-5.7 mo) Pem+Carbo (nonsquamous), n = 45; median, 4.7 mo (95% CI, 2.9-5.9 mo)Pem+Carbo (full analysis), n = 51; median 8.9 mo (95% CI, 6.0-12.2 mo) Pem+Carbo (nonsquamous), n = 41; median, 8.5 mo (95% CI, 6.0-13.3 mo)Abbreviation:PemϩCarboϭpemetrexed plus carboplatin.Pemetrexed Therapy Non-Small Cell Lung Cancer 220Clinical Lung Cancer May2013the results of the2arms.Another limitation was the number of patients with squamous cell histology in the study.Published studies of advanced NSCLC have included approximately26%to33%(95 to242,respectively)of patients with squamous histology.6Our study reported18%to20%(12to13,respectively)of patients with squamous histology.This sample of patients with squamous histol-ogy may be too small to draw meaningful conclusions.The6-month PFS rate for patients in this study treated with pem-etrexed plus carboplatin was34.9%,with a median PFS of4.7 months,which exceeded the protocol-defined null hypothesis of a median PFS of3.0months.The pemetrexed plus carboplatin arm demonstrated efficacy results similar to other published studies of carboplatin-based doublet and triplet chemotherapy for patients with advanced NSCLC.These studies reported median PFS times of 4.5to6.2months,median OS of7.3to17.3months,1-year survival rates of34%to51%,and ORRs of32%to37%.28-31The meta-analysis by Ardizzoni et al20reviewed1479patients from9random-ized studies treated withfirst-line carboplatin-based chemotherapy for NSCLC and reported a median OS of8.4months,a1-year survival rate of34%,and an ORR of24%.In our study,the patients treated with pemetrexed plus carboplatin showed a median OS time of8.9months,a1-year survival rate of39.2%,and an ORR of 20.0%.Toxicities reported for patients treated with pemetrexed plus car-boplatin in our study also compared favorably with published results, although58(86.6%)of patients had stage IV disease,20(30.8%) patients had a PS of1,and the median age was63years.Ardizzoni et al20reported that,for patients treated with carboplatin-based che-motherapy,higher percentages of drug-related grade3/4anemia (13%)and neutropenia(53%)and similar values for thrombocyto-penia(12%)than our study observed for patients treated with pem-etrexed plus carboplatin:(anemia:nϭ7[10.8%],neutropenia:nϭ17[26.2%],and thrombocytopenia:nϭ11[16.9%]).Our results were similar to those grade3/4drug-related toxicities reported for patients treated with pemetrexed plus carboplatin in other stud-ies12,30-32(anemia[2.0%-12.3%],neutropenia[21%-33.0%],and thrombocytopenia[2.0%-23.7%]).Nonhematologic toxicities for these patients were also infrequent in comparison with other published studies.Ardizzoni et al20re-ported grade3/4nausea and vomiting in8%,neurotoxicity in11%, and nephrotoxicity in0.5%of patients,and others reported fatigue in4%to13%,nausea or vomiting in2%to3%,and febrile neutro-penia in8%of patients.12,31,32In our study,the most commonly reported drug-related nonhematologic toxicities for patients treated with pemetrexed plus carboplatin were grade3/4nausea(nϭ5 [7.7%])followed by grade3/4fatigue,anorexia,and urinary tract infection(nϭ2each[3.1%]).There were2study-drug–related deaths in the pemetrexed plus carboplatin arm.In another combination therapy study,BTOG2(British Thoracic Oncology Group Trial),a randomized,3-arm,phase III trial19with 1363patients,gemcitabine was combined with2doses of cisplatin and was compared with gemcitabine combined with carboplatin in advanced NSCLC.The response rate reported for gemcitabine combined with cisplatin80mg/m2was33%,and,for carboplatin AUC6,it was28%.The median survival was reported as9.5 months(cisplatin)and10.0months(carboplatin).One study conclusion suggested that carboplatin was not inferior to cisplatin when treated in combination with gemcitabine in patients with advanced NSCLC.Although the study was not designed to compare arms,and com-parative analyses were not performed,overall,the pemetrexed-plus-cisplatin arm revealed more favorable efficacy results,including efficacy according to histology.The median relative dose intensity was comparably high for both treatment regimens;however,the median number of cycles received was lower in the pemetrexed plus cisplatin group(4vs.6),whereas the mean number of cycles was similar(4.3vs.4.6).Toxicities considered related to the study drug were reported more frequently in the pemetrexed plus carboplatin group,as were deaths(2vs.1).ConclusionWe concluded that both the pemetrexed plus cisplatin and the pemetrexed plus carboplatin regimens met the study’s primary objective,and the results complement the existing published data regarding the administration of these regimens asfirst-line treat-ments for patients with advanced NSCLC.Both of these regimens demonstrated efficacy and tolerability for patients in this setting.3a Grade3/4toxicities inՆ2(3%)patients in at least1treatment arm.b One patient had grade4neutropenia;all other toxicities were grade3.Wolfgang H.W.Schuette et alClinical Lung Cancer May2013221The patients treated with pemetrexed plus cisplatin showed a differential treatment effect in patients with nonsquamous NSCLC,which is consistent with previously published data and which supports the consideration of histology when making treat-ment decisions.Overall,the efficacy and toxicity observed fa-vored pemetrexed plus cisplatin therapy,and the regimen should be considered when selectingfirst-line treatment for patients with advanced NSCLC and good PS.Clinical Practice Points●In advanced(stage IIIB or IV)NSCLC,doublet combinations of chemotherapeutic agents with platinum compounds are reference regimens.In phase II studies of patients with NSCLC who were chemotherapy naive,pemetrexed combined with cisplatin or car-boplatin has shown efficacy consistent with that of other platinum doublets.●In this phase II study,patients with advanced NSCLC treated with pemetrexed plus cisplatin had a6-month PFS rate of50.5%,a median PFS of6.0months,a median OS of11.7months,a1-year survival rate of47.5%,and an ORR of32.3%.Drug-related grade 3/4toxicities for this regimen included neutropenia(nϭ11 [16.9%]),anemia(nϭ5[7.7%]),thrombocytopenia(nϭ2 [3.1%]),and nausea(nϭ3[4.6%]).In addition,efficacy param-eters for patients treated with pemetrexed plus cisplatin were also evaluated by histology,and a similar treatment effect was ob-served.The6-month PFS rate,median PFS,and median OS all favored pemetrexed plus cisplatin treatment for patients with nonsquamous histology.Also in this phase II study,patients with advanced NSCLC who were treated with pemetrexed plus carbo-platin had a6-month PFS rate of34.9%,a median PFS of4.7 months,a median OS time of8.9months,a1-year survival rate of 39.2%,and an ORR of20.0%.Drug-related grade3/4toxicities for this regimen included neutropenia(nϭ17[26.2%]),throm-bocytopenia(nϭ11[16.9%]),anemia(nϭ7[10.8%]),and nausea(nϭ5[7.7%]).●Both of these regimens demonstrated efficacy and tolerability for patients with advanced NSCLC.Overall,the efficacy and toxicity observed favored pemetrexed plus cisplatin therapy,and the regi-men should be considered when selectingfirst-line treatment for patients with advanced NSCLC and good PS. AcknowledgmentsThe authors are indebted to all study investigators for their contribution to data acquisition and patient care.The authors thank Patrick Peterson and Victoria Soldatenkova(Eli Lilly and Company),Anne-Laure Michel(formerly with Open Group, Paris),and Accovion for statistics support.The authors also thank Patti Moore(Eli Lilly and Company)for medical writing support and Svetlana Dominguez(Eli Lilly and Company)for editorial support.This study(H3E-SB-S109)was sponsored by Eli Lilly and Company.DisclosureW.Schuette is an advisory board member for Eli Lilly and Company,Roche,AstraZeneca,and Amgen.A.Groschel is a consultant for Eli Lilly and Company;M.Sebastian is an advisory board member and receives honoraria from Eli Lilly and Com-pany.S.Andreas receives honoraria from Eli Lilly and Company, Roche,and GlaxoSmithKline,and is an advisory board member for GlaxoSmithKline.T.Mueller and C.Eschbach are advisory board members for Eli Lilly and Company;M.Leschinger is an employee and has stock ownership in Eli Lilly and Company.M. 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