Pemetrexed: Its Promise in Treating Non–Small-Cell Lung Cancer

ABSTRACT: The use of chemotherapy in the treatment of early and advancednon–small-cell lung cancer (NSCLC) has increased during the pastdecade. One of the main reasons for the increased acceptance of chemotherapyis the development of several new cytotoxic agents with aunique mechanism(s) of action and high single-agent activity, combinedwith a favorable toxicity profile. Pemetrexed (Alimta) is a novelantifolate that inhibits several enzymes involved in DNA synthesis(thymidylate synthase [TS], dihydrofolate reductase [DHFR], andglycinamide ribonucleotide formyltransferase [GARFT]). Pemetrexed’stoxicity is markedly reduced by folic acid and vitamin B12 supplementation.The compound has been studied extensively in various tumor types,including NSCLC. In NSCLC, pemetrexed at 500 mg/m2, every 3 weeks,given IV over 10 minutes, has shown promising activity, and can safelybe administrated with vitamin supplementation. After registration,single-agent pemetrexed will certainly add to the chemotherapeuticoptions available for pretreated patients and will most likely changesignificantly chemotherapy prescriptions in second-line chemotherapy.In first-line chemotherapy, the role of platinum-based and -free combinationdoublet chemotherapy with pemetrexed still needs to be defined.Phase II data indicate high efficacy combined with favorabletoxicity for pemetrexed in combination with cisplatin, carboplatin(Paraplatin), oxaliplatin (Eloxatin), gemcitabine (Gemzar), andvinorelbine (Navelbine). This review summarizes the clinical experienceobtained thus far during the early clinical development ofpemetrexed in NSCLC.

Lung cancer, the most commontype of cancer in men, has increasedits incidence in womenover the past decade. Lung cancer isthe major cause of cancer-relateddeath in both North America and Europe,and approximately 75% of lungcancers are non-small-cell lung cancers(NSCLC).[1] NSCLC treatmentvaries according to patient tumor stageat time of diagnosis. Many patientsreceive multimodality treatment consistingof various combinations of surgery,radiotherapy, and chemotherapy.In early-stage (nonmetastatic)NSCLC, combination chemotherapyis being clinically assessed as an integralpart of multimodality treatmentregimens, either as neoadjuvant (inductive,preoperative) or adjuvant(postoperative) chemotherapy, or inpatients who are inoperable as concurrentor sequential radiochemotherapy.[2]In advanced (locally advanced ormetastatic) NSCLC, combination chemotherapycontaining platinum compoundsis an important component ofpalliative therapy, since combinationchemotherapy improves survival, providessymptom relief, and improves quality of life when compared withbest supportive care alone.[3] Aschemotherapy gains wider acceptanceas a part of the initial treatment inadvanced and early-stage NSCLC, theneed for an effective second-line chemotherapygrows. This is particularly true because increasing numbers ofpatients receive combined-modalitytherapy for early-stage NSCLC thatincludes chemotherapy, and they maybe candidates for second-line treatmentat the time of disease progressionor relapse.

Preclinical and EarlyClinical DevelopmentPemetrexed (Alimta) is a novelantifolate (N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl ]-benzoyl]-Lglutamicacid) distinguished by aunique 6-5-fused pyrrolo [2,3-d] pyrimidinenucleus that differs from themore common core structures of otherantifolates that have 6-6-fused pteridineor quinazoline rings (Figure1).[4] Pemetrexed gains entry to thecell via the reduced folate carrier, andit is an excellent substrate for folylpolyglutamatesynthase once localized,with the highest affinity of anyantifolate. Polyglutamation traps pemetrexedand enhances its intracellularretention. The parent drug is polyglutamated90- to 195-fold more efficientthan methotrexate and 6- to13-fold more efficient than the antipurineantifolate (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol).[5] The increased cellular retentionof pemetrexed forms may explainthe success of the 3-weekadministration schedule.Pemetrexed inhibits multiple enzymetargets involved in both pyrimidineand purine synthesis, includingat least thymidylate synthase, dihydrofolatereductase, aminoimidazolecarboxamide ribonucleotide formyltransferase,and glycinamide ribonucleotideformyltransferase.[6] Thesetargets are related to the cytotoxicityof pemetrexed, as both thymidine and hypoxanthine are required to circumventpemetrexed-induced cellulardeath.[7] Severe, unpredictable, andoccasionally fatal myelosuppressionand gastrointestinal toxicities havebeen associated with antifolate agents.Data accumulated in the past few yearssuggest that plasma homocysteine isa sensitive measure of the functionalfolate status, and under conditions offolate deprivation, plasma homocysteinelevels increase. Vitamin B₁₂ andB₆ deficiencies can also result in highhomocysteine levels.Data from early pemetrexed trialssuggest that an elevated plasma homocysteineconcentration was indicativeof preclinical folate deficiency,and resulted in a more severe toxicityprofile that typically included thrombocytopenia,neutropenia, severe diarrhea,and mucositis. Therefore, allpatients enrolled in pemetrexed clinicaltrials over the past 2 to 3 yearsreceived folic acid and vitamin B₁₂supplementation as follows: oral folicacid at 350 to 1,000 μg administeredat least 5 continuous days prior topemetrexed and continuing throughouttherapy. Vitamin B₁₂ at 1,000 μgwas administered intramuscularly withfolic acid and repeated every 9 weekswhile the patient was on study (Figure2). Moreover, current data fromVogelzang et al indicate that supplementaluse of vitamins can amelioratesome of the severe drug-induced toxicityeffects resulting in improvedsafety profile and efficacy for thisdrug.[8]Pemetrexed is currently under clinicalinvestigation for a variety of solidtumors, including NSCLC. Giventhe important role of systemic chemotherapyfor the treatment of earlyand advanced NSCLC, pemetrexedhas been tested in various doses andseveral combinations in the first- andsecond-line therapy settings.Single-Agent Activity in NSCLCInitial phase II study results demonstratethat pemetrexed has singleagentactivity in chemonaive andchemotherapy-pretreated patients.Two trials of single-agent pemetrexedwere undertaken in previously untreatedpatients.[9,10] In Clarke et al's Australian/South African study,[10]all patients (n = 59) were treated withpemetrexed at 600 mg/m². Among 57evaluable patients, overall responserate was 16% (9 partial remissions),median time to progression was 4.4months, median duration of responsewas 4.9 months, median survival was7.2 months, and 1-year survival ratewas 32%.In the Canadian trial (n = 33) ofRusthoven and coworkers,[9] patientsinitially received pemetrexed at 600mg/m² IV for 10 minutes every 3weeks. However, after three patientswere treated on this dose, it was reducedto 500 mg/m² IV due to toxicity.Four of 33 patients assessable fortoxicity (13.3%) developed febrileneutropenia and 13 patients (39%)grade 3/4 neutropenia; four patientsexperienced grade 4 thrombocytopenia.The main nonhematologic toxicity(> grade 2) was skin rash andlethargy. Use of prophylactic dexamethasonefor 3 days starting the daybefore pemetrexed significantly reducedskin toxicity both in frequencyand severity.In 30 patients evaluable for response,a partial response was obtainedin 23% of the patients, mediantime to progression was 3.8 months,median duration of response was 3.1months, median survival was 9.2months, and 1-year survival rate was25%.In chemotherapy-pretreated patientswith advanced NSCLC, Smit etal conducted a large phase II trial ofpemetrexed as second-line treatmentin Europe and Australia.[11] Patientswith stage IIIB or IV NSCLC wereeligible for accrual if they had relapsedduring or within 3 months ofprior chemotherapy. Patients with aperformance status of 2 were not enrolled.Pemetrexed was administeredas a 10-minute IV infusion at a doseof 500 mg/m² every 3 days. Dexamethasone4 mg was taken twice perday orally on the day before, the dayof, and the day after each dose ofpemetrexed. Leucovorin administrationwas recommended for any patientswho experienced grade 4neutropenia, grade 4 thrombocytopenia,or grade 3/4 mucositis. Antiemeticmedication was given according to standard recommendations. Vitaminsupplementation was not used.

Out of 79 patients considered evaluablefor efficacy, 44 had progressivedisease during or shortly after platinum-containing therapy and 35 hadprogressive disease during or shortlyafter a non-platinum-containing regimen.Six patients had partial responsesand one patient had a completeresponse, for an overall response rateof 8.9%. A total of 25 patients (31.6%)achieved stable disease and 30 patients(38%) had progressive disease.Median duration of response was 6.8months, median survival time was 5.7months, and median time to progressionwas 2 months (Table 1).Based on these favorable results,Hanna et al reported the results of thelargest phase III prospective randomizedtrial ever conducted in secondlineNSCLC (n = 571). In thisregistration trial, investigators comparedpemetrexed with the widely acceptedstandard treatment docetaxel(Taxotere).[12] In the trial, 288 patientswere randomized to receive a1-hour infusion of docetaxel at75 mg/m² on day 1 every 3 weeks.The remaining 283 patients receiveda 10-minute infusion of pemetrexedat 500 mg/m² on day 1 every 3 weeks.Patients in both arms of the study received prophylactic dexamethasone;only patients in the pemetrexed armreceived folic acid and vitamin B₁₂supplementation. The study was designedto demonstrate an 80% chanceof superiority. The primary study endpoint was survival; the secondary endpoints were tumor response rate, progression-free survival, and toxicity.The results can be summarized asfollows: pemetrexed and docetaxelhave similar efficacy demonstrated forresponse rates (9.1% vs 8.8%), mediansurvival (8.3 months vs 7.9 months;Figure 3), and progression-free survival(2.9 months each). The one-yearsurvival rate was 29.7% for each arm.Pemetrexed had a more favorable hematologictoxicity profile when comparedwith docetaxel. Severe neutropenia(grade 3/4) was seen in 5.3%for the pemetrexed arm and 40.2%for the docetaxel arm (P < .001). Thedifference in the incidence of febrileneutropenia and subsequent hospitalizationsbetween the pemetrexed anddocetaxel arms was also statistically significant (febrile neutropenia: pemetrexed1.9%; docetaxel 12.7%; P < .001 [Table 2]; hospitalizations becauseof febrile neutropenia: pemetrexed1.5%; docetaxel 13.4%; P < .001). Patients on pemetrexed also requiredsignificantly less granulocytecolony-stimulating factor (G-CSF)than patients on docetaxel (2.6% vs19.2%; P < .001) (Table 3).

In light of these magnitudes of significantdifference compared to docetaxel,the authors concluded thatpemetrexed possesses a more favorabletoxicity profile than docetaxel,and is an effective second-line agentin NSCLC.Pemetrexed in CombinationPemetrexed is an attractive candidatefor combination therapy, due toits unique mechanism of action andshort infusion time. A number of differentcombination therapies havebeen investigated, eg, with gemcitabine(Gemzar), irinotecan (Camptosar),fluorouracil (5-FU), orpaclitaxel.Pemetrexed/Cisplatin
Our German/Austrian study wasthe first phase II study of pemetrexed/cisplatin completed in advancedNSCLC.[13] The dose and schedule selected for the study were based onthe experience reported by Thodtmannand collegues in their clinical/pharmacokineticphase I study of pemetrexedplus cisplatin.[14] Thus, allpatients received pemetrexed at 500mg/m² IV over 10 minutes, followedby cisplatin at 75 mg/m² 30 minuteslater; treatment was preferably administeredon an outpatient basis every21 days. Cisplatin administration andpre- and posthydration were performedaccording to local policy. Patientsalso received dexamethasone at4 mg orally twice per day on the daybefore, the day of, and the day afterpemetrexed administration. Antiemeticmedications were administered accordingto standard. Vitaminsupplementation was not used, andG-CSF was not recommended routinely.A total of 36 chemotherapynaivepatients were enrolled (allevaluable for response).Fourteen (39%) patients achievedpartial remission, and 17 (47%) patientshad stable disease as their bestresponse. The median duration of responsewas 10.4 months, with 75% ofpatients having response duration exceeding9 months. The median timeto progression was 6.3 months, 56%of patients remained progression-freeat 6 months, 36% at 9 months, and33% at 1 year, respectively. The mediansurvival was 10.9 months, andthe 1-year survival percentage was50%. Twenty-one (59%) patients experiencedgrade 3/4 granulocytopeniawithout fever or infection. Four(11%) and six (17%) patients experiencedgrade 3 anemia and grade 3/4thrombocytopenia, respectively. Nonhematologictoxicity included grade3 nausea in two (6%) patients, andgrades 3/4 diarrhea in one (3%) patienteach. One patient each experiencedgrade 4 alanine aminotransferase(ALT), grade 3 bilirubin,and grade 3 aspartate aminotransferase(AST) elevations.Shepherd and colleagues of the NationalCancer Institute of Canada ClinicalTrials Group used an identical studydesign in the second phase II study ofpemetrexed and cisplatin (n = 31).[15]Out of 29 patients evaluable for response,13 (45%) obtained a partialresponse. Median duration of response was 6.1 months, median time to progressionwas 5.8 months, median survivaltime was 8.9 months, and 1-yearsurvival rate was 49%, respectively.Grade 3/4 anemia was observed in 5/1patients, and grade 3/4 granulocytopeniain 7/4 patients, respectively. Grade3 nausea and emesis occurred in onlytwo patients, grade 3/4 diarrhea in 3patients, and two patients had grade 3motor neuropathy.It is fair to conclude that thesephase II studies demonstrate that pemetrexed/cisplatin is effective and welltolerated.Response rates obtained arealmost twice as high as single-agentpemetrexed and are comparable to theresponse rates shown by other newdrugs, which have been tested in combinationwith cisplatin. The outpatientfeasibility provided by the short infusiontime of pemetrexed and the treatmentschedule of once every 3 weeksfurther enhances the convenience ofthis regimen.Pemetrexed/Carboplatin
For the carboplatin (Paraplatin)/pemetrexed combination, the phase IIrecommended study dose is pemetrexedat 500 mg/m² and carboplatinat an area under the concentrationtimecurve (AUC) of 5, given in 3-week intervals with both drugsadministered on day 1.[16] A recentphase II trial from Scagliotti et al indicatedthat pemetrexed/carboplatin iseffective and well tolerated as frontlinechemotherapy in patients with locallyadvanced NSCLC (n = 80).[17]In this study, 39 patients in the pemetrexed/carboplatin arm (arm A) receivedpemetrexed at 500 mg/m² andcarboplatin at AUC 6 on day 1 of a21-day cycle for up to six cycles oftherapy. (Arm B consisted of 41 patientsreceiving pemetrexed at500 mg/m² plus oxaliplatin [Eloxatin]at 120 mg/m².) Vitamins and dexamethasonewere provided perpemetrexed therapy.The confirmed response rate was33% (vs 27% for arm B), with stable disease reported for 41% (vs 44%) ofpatients, respectively. Neither time todisease progression nor survival datahave been reported yet.

For the pemetrexed/carboplatinarm, the main grade 3/4 hematologictoxicity included neutropenia (26%)and thrombocytopenia (18%). Mainnonhematologic toxicities consisted ofgrade 3 fatigue (8%) and stomatitis(32.6%). In the pemetrexed/oxaliplatinarm, no grade 4 hematologictoxicities were reported, with grade 3neutropenia (5%), thrombocytopenia(2%), and anemia (2%). Main nonhematologictoxicities were grade 3vomiting (7%), neuropathy (2%), diarrhea(2%), and hypersensitivity reactions(2%).Another phase II study (n = 50) byZinner et al used pemetrexed at 500mg/m² administered on day 1 followedby carboplatin at AUC 6 given on day1, every 3 weeks, for six cycles.[18]The overall response rate was 28%,with a median time to progression of4.8 months. Five patients (10%) hadgrade 3/4 nonhematologic toxicity,with mild alopecia and sensory neuropathy.Two patients had grade 3thrombocytopenia and 15 experiencedgrade 3/4 neutropenia.Pemetrexed/Gemcitabine
Both the suggested preclinical synergyand the documented efficacy inadvanced NSCLC provided the rationaleto investigate pemetrexed andgemcitabine (Gemzar) in combination.Adjei et al identified a dose for phaseII studies as gemcitabine at 1,250 mg/m² days 1 and 8 and pemetrexed at500 mg/m² (90 minutes after gemcitabine)on day 8, every 3 weeks.[19]Based on the phase I combination trialresults (objective responses obtainedin three NSCLC patients),Ettinger and coworkers initiated amulticenter phase II trial combiningpemetrexed and gemcitabine inchemonaive patients with stage IIIB/IV NSCLC (n = 60).[20]The dose and schedule was gemcitabineat 1,250 mg/m² as a 30-minuteIV infusion on days 1 and 8 and pemetrexedat 500 mg/m² as a 10-minuteIV infusion, 90 minutes after gemcitabine,on day 8 every 3 weeks withprophylactic dexamethasone. Vitaminsupplementation with folic acid andvitamin B₁₂ was initiated after the trialbegan due to pemetrexed-related toxicity.The data so far indicate thatpemetrexed/gemcitabine is active andpossesses a comparable toxicity pro-file to other relevant doublets.Out of 54 patients evaluable forresponse, 9 (17%) had a partial response,with 29 (54%) with stable disease.Median progression-freesurvival was 4.9 months, median overallsurvival 11.3 months, and 1-yearsurvival 44%. Median duration of responsewas 3.3 months. The observedgrade 3/4 hematologic toxicities in 60patients evaluable for toxicity wereneutropenia in 29%/34% of the patients,neutropenic fever in 13%/2%,thrombocytopenia in 5%/0%, and anemiain 12%/0% of the patients. Reportedgrade 3/4 nonhematologictoxicities reported were AST/ALT elevationsin 16/21%, diarrhea in 3/2%,fatigue in 23/0%, and skin rash in3/0% of patients.Pemetrexed/Vinorelbine
Clarke et al conducted a phase IIstudy to determine the response rateof the platinum-free combinationpemetrexed/vinorelbine (Navelbine)in the first-line treatment of advancedNSCLC.[21] Patients received pemetrexedat 500 mg/m² day 1 and vinorelbineat 30 mg/m² days 1 and 8 asa 10-minute IV infusion every 3weeks. Folic acid and vitamin B₁₂ supplementationwere given to reduce thehematologic toxicities noted in previouspemetrexed studies.Efficacy and toxicity results werereported for 34 of the 36 enrolledpatients. Grade 4 hematologic toxicitiesincluded neutropenia in 15 patientsand leukopenia in six. Grade3/4 nonhematologic toxicities includedfatigue (n = 7), dyspnea (5), nausea(3), and stomatitis (1). Twopatients discontinued treatment dueto toxicity (neutropenic sepsis, stomatitis)and one discontinued due tofatigue. Twelve patients achieved apartial remission and eight patientshad stable disease. The authors concludedthat pemetrexed in combinationwith vinorelbine is well toleratedand has promising activity.ConclusionsIn non-small-cell lung cancer,pemetrexed has shown promising activityand can safely be administered as either a single-agent or in combinationfor first- and second-line chemotherapy.Pemetrexed's toxicityprofile improves significantly with theconcomitant administration of dexamethasone,vitamin B₁₂, and folic acid.In second-line chemotherapy, singleagentpemetrexed may be a candidateto replace docetaxel as a standardtreatment because of lower toxicityand increased patient feasibility. Forfirst-line chemotherapy, the role ofplatinum-based and platinum-freepemetrexed combinations still needsto be defined in randomized phase IIIstudies. However, phase II data indicatehigh efficacy with favorable toxicityprofile for pemetrexed combinedwith cisplatin, carboplatin, oxaliplatin,gemcitabine, and vinorelbine.

Disclosures:

Dr. Manegold hascooperated in clinical studies with, acted as ascientific advisor for, and received speakerhonoraria and scientific grants from Eli Lilly.

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