FDA Approves Alimta as Second-Line Tx

ROCKVILLE, Maryland-The FDA has granted acceleratedapproval to Eli Lilly's Alimta(pemetrexed for injection) for thetreatment of locally advanced or metastaticnon-small-cell lung cancer(NSCLC) in previously treated patients.The agent was approved earlierin 2004 for use in combination withcisplatin (Platinol) for the treatmentof malignant pleural mesothelioma(see report on page 19).The FDA accelerated approval isbased on Alimta's activity and favorablesafety profile as evidenced in aphase III trial in the second-line settingcomparing Alimta with docetaxel(Taxotere). In July, the study was thebasis for a unanimous recommendationfor accelerated approval by theFDA's Oncologic Drugs AdvisoryCommittee (ODAC). A companywhose drug enters the market withaccelerated approval must conductpostmarketing clinical trials to confirmthe agent's safety and efficacy.Alimta disrupts folate-dependentmetabolic processes essential for atumor's rapid growth-specificallythree enzymes: thymidylate synthase,dihydrofolate reductase, and glycinamideribonucleotide formyltransferase.The antifolate drug isconverted to polyglutamate forms intumor cells, which results in a prolongeddrug action in malignancells. "Activity is seen across a widespectrum of scientific tumor models,"Roy Herbst, MD, PhD, chief of thoraciconcology, MD. Anderson CancerCenter, told ODAC members atthe July meeting.Pivotal TrialLilly's pivotal study, designatedJMEI, involved 571 patients in a randomized,controlled, unblinded trialof Alimta and docetaxel, the standardsecond-line treatment, carried out at135 sites in 23 countries (J Clin Oncol22:1589-1597, 2004). Approximately21% of the participants receivedtreatment in the United States. Thetrial's primary endpoint was overallsurvival.Study enrollment began on March20, 2001, and ended on February 6,2002. Researchers randomized 283patients to receive Alimta 500 mg/m²intravenously on day 1 of each 21-daycycle, plus 350 to 1,000 μg of oralfolic acid daily, 1,000 μg of vitaminB12 every 9 weeks, and dexamethasone.The remaining 288 participantswere assigned to receive 75 mg/m²of docetaxel intravenously on day 1of each 3-week cycle, plus dexamethasone.Among the Alimta-treated patients,85 (32%) crossed over todocetaxel therapy after tumor progression,a finding whose meaning becamea point of contention betweenthe sponsor and the FDA's reviewersat the ODAC meeting.The unblinding of the JMEI analysisdata sets occurred on January 30,2003. According to both the sponsorand the FDA review team, there wasno significant difference in survival,(the primary endpoint) between thetwo arms of the study, the primaryendpoint, nor in response, progressionfreesurvival, or time to disease progression.Among the patients actuallytreated (264 with Alimta and 274 withdocetaxel), 9.1% of the Alimta groupand 8.8% of the docetaxel arm responded, and 45.8% of the Alimta patientsand 46.4% of the docetaxelgroup showed stable disease."Notice the fact that over 50% ofthe patients had either a major responseor stable disease in this trial,"said Richard J. Gralla, MD, immediatepast president of the MultinationalAssociation of Supportive Care inCancer (MASCC), who spoke on behalfof Lilly at the ODAC meeting.Among the treated patients, researchersfound no statistically significantdifference in on-study deathsbetween the two groups, 11.7% in theAlimta group and 14.5% in thedocetaxel arm regardless of cause, orin drug-related deaths, 1.1% vs 1.8%.However, a significant difference wasseen in the percentage of drug-relateddeaths among patients who sufferedone or more significant adverseevents, 10.2% in the Alimta arm, comparedwith 23.9% in the docetaxelgroup (P < .001).JMEI researchers did find significantdifferences favoring Alimta inseveral grade 3-4 adverse eventsamong the treated patients. These includedneutropenia, 5.3% vs 40.2%for the docetaxel group; febrile neutropenia,1.9% vs 12.7%; and infectionwith grade 3-4 neutropenia, 0.0%≤ 5.8% (all P ≤ .001). Amongnonlaboratory grade 3-4 toxicities,diarrhea occurred in 0.4% of theAlimta group and 4.0% in thedocetaxel arm (P ≤ .006), and for allgrades of alopecia, the respective numberswere 11.3% vs 42.4% (P ≤ .001)."Because all the efficacy parameterswere equivalent, much of the clinicalbenefit of Alimta relates to thetoxicity, and so the toxicity analysisbecomes important," said Paul A.Bunn, Jr., MD, director, University ofColorado Cancer Center, and a coprincipalinvestigator, who presentedthe JMEI efficacy data.Issue of NoninferiorityODAC members found themselvesgrappling with the issues of whetherAlimta met FDA's criteria for a noninferiordrug and whether it had a morefavorable toxicity profile thandocetaxel.FDA medical officer Martin H.Cohen, MD, argued that Alimta failedto meet the noninferiority test for tworeasons. First, the one small historicalstudy available (104 patients) fordocetaxel made it impossible for FDAto precisely estimate the survivaleffect of docetaxel in this setting. Second,the 32% crossover of Alimtapatients to docetaxel after tumor progressionconfounded the comparisonof survival between the two drugs, asdid the fact that only 139 Alimta patientsreceived no poststudy chemotherapy,compared with 169 in thedocetaxel group. "The 30-patient differencebetween the two treatmentarms might be important because patientson both study arms who didnot receive poststudy chemotherapyhad shorter median survival," Dr.Cohen said.After discussion, ODAC membersvoted on three questions put to themby the FDA relating to Alimta. By avote of 13 to 0, the committee foundthat Alimta had a more favorable toxicityprofile than docetaxel. It also voted13 to 0 that Alimta's toxicity profileand the supporting efficacy datashowing noninferiority outweighedthe uncertainty about a possible lossof survival effect that might resultfrom Alimta. FDA officials describedthis decision as a vote recommendingaccelerated approval for Alimta. Finally,ODAC members voted 8 to 5that the drug did not warrant fullapproval.