FDA Approves Alimta/Cisplatin for Malignant Pleural Mesothelioma

ROCKVILLE, Maryland-TheU.S. Food and Drug Administration(FDA) has approved Eli Lilly's Alimta(pemetrexed disodium for injection)in combination with cisplatin(Platinol) for the treatment of malignantpleural mesothelioma in patientswho are not candidates for curativesurgery. Alimta, received priority reviewand is the first agent approvedfor the treatment of the asbestos-relateddisease. The FDA's action followsmore than 3 decades of efforts todevelop an effective chemotherapy formalignant pleural mesothelioma."For the first time ever, we haveproof that a chemotherapeutic regimenhelps patients with malignantpleural mesothelioma live longer,"said Claude Denham, MD, a studycoinvestigator for U.S. Oncology.Alimta disrupts folate-dependentmetabolic processes essential for thetumor's rapid growth-specificallythree enzymes: thymidylate synthase,dihydrofolate reductase, and glycinamideribonucleotide formyltransferase.It is converted to polyglutamateforms in tumor cells, which resultsin a prolonged drug action inmalignant cells.Pivotal StudyThe FDA granted marketing approvalto Alimta on the basis of amulticenter, randomized, single-blindstudy in 448 patients with malignantpleural mesothelioma from 19 countrieswho had not been treated previouslywith chemotherapy. Patients'ages ranged from 19 to 85; 81.5% weremale, and 46% had stage IV disease.Study participants received eitherAlimta plus cisplatin (226) or cisplatinalone (222). Alimta was given intravenouslyfor 10 minutes at 500 mg/m².This was followed about 30 minuteslater by a 2-hour infusion of cisplatinat 75 mg/m². Both doses are listed inthe Alimta labeling.Prophylactic Folic Acid/B12After treating 112 patients, the researcherschanged the study protocolto require that all participants receivesupplemental folic acid and vitaminB12, to reduce hematologic and gastrointestinal(GI) side effects.Among the 448 patients in thestudy, median overall survival was 12.1months for the Alimta-treated patientsvs 9.3 months for the cisplatin-onlyarm, a- 30% increase with Alimta.At 1 year, 50.3% of Alimta-treatedpatients were alive, vs 38% treatedwith cisplatin alone. There was alsoimprovement in lung function (forcedvital capacity) on the Alimta/cisplatinarm, vs the cisplatin-only arm.Among the 331 patients who receivedthe full folic acid and B12 supplementation,the median overall survivalwas 13.3 months in the Alimtagroup vs 10.0 months in the cisplatinonlyarm.Among the fully supplemented patients,the Alimta-treated arm receiveda median of six cycles of treatment vsfour cycles for cisplatin only. Patientswho received no supplementationcompleted a median of two cycles ineach arm. Adverse events among thefully supplemented participants consistentlyoccurred more often in theAlimta-group than in the cisplatinonlypatients. For example, the ratesfor all stages of hematologic problemswere significantly higher for the treatmentgroup vs the control group-neutropenia, 58% vs 16%; leukopenia,55% vs 20%; anemia, 33% vs 14%;and thrombocytopenia, 27% vs 10%."Complete blood cell counts, includingplatelet counts, should be performedon patients receiving Alimta,"the labeling cautions.ToxicityAmong the fully supplemented patients,the most common adverse reactionsfor the Alimta arm vs thecisplatin-only group were, respectively:nausea, 84% vs 79%; fatigue, 80%vs 74%; dyspnea, 66% vs 62%; vomiting,58% vs 52%; constipation, 44%vs 39%; chest pain, 40% vs 30%; anorexia,35% vs 25%; stomatitis/pharyngitis,28% vs 9%; and diarrheawithout colostomy, 26% vs 16%. Skinrash occurred more often in patientsnot pretreated with a corticosteroid,dexamethasone.The drug's labeling warns that physicianstreating patients with Alimtamust instruct them "to take folic acidand vitamin B12 as a prophylacticmeasure to reduce treatment-relatedhematologic and GI toxicity." It alsostates that patients should receive thedrug only under the supervision of aphysician experienced in the use ofantineoplastic agents. Patients withkidney impairment should notreceive Alimta therapy. Patientsshould inform their doctors if theyare taking nonsteroidal anti-inflammatorydrugs (NSAIDs).Physicians worldwide diagnose between10,000 and 15,000 new cases ofmalignant pleural mesothelioma thecancer annually, about 2,000 of themin the United States. The incidencerate for the cancer, which develops inthe inner lining of the chest cavity, hasbeen increasing. At diagnosis, mostpatients have progressed to an advancedstage where neither surgery norradiation offers benefit.