Pemetrexed Equivalent to Docetaxel for Recurrent NSCLC Patients

November 1, 2003

This special “annual highlights” supplement to Oncology News International is acompilation of major advances in the management of lung cancer during 2003, asreported in ONI. Guest editor Dr. Roy Herbst comments on the reports includedherein and discusses advances in the clinical management of lung cancer, with afocus on developments in targeted therapy, new combinations, adjuvant therapy,induction therapy, and what to watch for in 2004.

CHICAGO-For patientswith advanced, recurrent non-smallcelllung cancer (NSCLC), outcomeswith the multitargeted antifolatepemetrexed (Alimta) are comparableto those with docetaxel (Taxotere),and toxicity is less, according to a randomized,multicenter study presentedat the 39th Annual Meeting of theAmerican Society of Clinical Oncology(ASCO) (abstract 2503). The studyis the largest phase III clinical trial toevaluate the effectiveness of secondlinetherapies in NSCLC.Pemetrexed benefits were similarto docetaxel in terms of response rates,progression-free survival, median survival,and overall survival. At ASCOlast year, a major clinical trial demonstratedthe drug's efficacy in mesotheliomaas well. Phase III trials presentedat ASCO in 2002 and 2003 of pemetrexedin combination with cisplatin(Platinol) for treatment of mesotheliomaare under review by the FDA,and the drug is available to mesotheliomapatients as part of an expandedaccessprogram."Before Taxotere, we had no agentthat was proven to prolong life forpatients with recurrent NSCLC. Now,with these data on Alimta, we haveobserved a survival advantage, just aswe have with Taxotere, but with fewerside effects," said lead investigatorNasser Hanna, MD, assistant professorof medicine, Indiana UniversityCancer Center. "Pemetrexed may soonreplace docetaxel as the treatment ofchoice for some patients with recurrentnon-small-cell lung cancer."Pemetrexed interferes with the productionof folic acid, which is essentialfor normal cell growth but can fuelcancer growth. Interrupting folic acidsynthesis also blocks activity of threekey enzymes necessary for cell division.By contrast, the first generationof antifolates (eg, 5-fluorouracil andmethotrexate) are specific for only oneenzyme and do not disrupt multiplepathways, as pemetrexed does.Study ResultsDr. Hanna reported results in 571previously treated NSCLC patients(75% stage IV) randomized to docetaxel75 mg/m2 on day 1 of a 21-daycycle or pemetrexed 500 mg/m2 onday 1 of a 21-day cycle, supplementedwith vitamin B12 and folic acid.The study's primary end point,median survival, was similar betweenthe two arms: 8.3 months with pemetrexedand 7.9 months with docetaxel.One-year overall survival was 29.7%with either treatment.Objective responses were seen in9.1% of patients receiving pemetrexedand 8.8% receiving docetaxel, whilestable disease was achieved in 46% ofpatients in each arm. Progression-freesurvival was 2.9 months in each group."As a clinician, I look at the survivalcurve and the sample size, and I feelvery comfortable saying these drugsare clinically equivalent," Dr. Hannaconcluded.While the drugs were clinicallyequivalent, pemetrexed was better tolerated,producing significantly less sesevereneutropenia (with and withoutfever), alopecia, and peripheral neuropathy.Pemetrexed patients also requiredsignificantly fewer hospitalizationsfor adverse events or febrileneutropenia and had significantly lessneed for G-CSF (Neupogen) support.Pemetrexed was more likely to produceelevated alanine transaminase,although this condition was transient."This study shows pemetrexed is abetter-tolerated and comparably activeoption for second-line NSCLCtreatment. How applicable are the results?We are desperate for new options,and pemetrexed appears to bethe next agent," said Vincent Miller,MD, medical oncologist at MemorialSloan-Kettering Cancer Center.Pemetrexedin MesotheliomaDr. Nicholas Vogelzang and colleaguesat the University of ChicagoCancer Research Center previously reportedthe results of a pivotal phase IIIstudy in 434 patients with malignantpleural mesothelioma, showing thatpemetrexed plus cisplatin significantlyimproved survival time comparedwith cisplatin alone (median 12.1months vs 9.3 months) (J Clin Oncol21:2629-2630, 2003).At ASCO 2003 (abstract 2602),James T. Symanowski, PhD, senior researchscientist, Lilly Research Laboratories,Indianapolis, described theprognostic variables impacting survival,derived from a multiple regressionanalysis of the trial.Use of the pemetrexed combinationvs single-agent cisplatin was themain factor in improved survival, witha hazard ratio (HR) of 0.77 in theunivariate analysis and 0.70 in the multivariateanalysis. Other factors signif-icantly associated with improved prognosiswere vitamin supplementation,good performance status, and epithelialsubtype (HR 0.36). Poor survivalwas associated with advanced diseasestage, elevations in white blood cellcounts, and increased cystathionine.Additional analysis from the pivotalphase III trial, also reported at ASCO2003, found quality-of-life parametersto be better with the pemetrexed/cisplatin combination (abstract 2496).The differentiation in quality of lifeand symptoms occurred rapidly (withinthe first three cycles), reaching significancein most parameters by week15, reported Richard Gralla, MD, president,New York Lung Cancer Alliance,New York City.