FDA Approves Alimta/Cisplatin for Malignant Mesothelioma

ROCKVILLE, Maryland—The Food and Drug Administration (FDA) has approved Eli Lilly’s Alimta (peme-trexed disodium for injection) in combination with cisplatin (Platinol) for the treatment of malignant pleural mesotheli-oma in patients who are not candidates for curative surgery. Alimta, an orphan drug, received priority review and is the first agent approved for the treatment of the asbestos-related disease. The FDA’s action follows more than 3 decades of efforts to develop an effective chemotherapy for malignant pleural mesothelioma.

Physicians worldwide diagnose between 10,000 and 15,000 new cases of the cancer annually, about 2,000 of them in the United States. The incidence rate for the cancer, which develops in the inner lining of the chest cavity, has been in-creasing. At diagnosis, most people who develop the disease have progressed to an advanced stage where neither surgery nor radiation offers a treatment option.

"For the first time ever, we have proof that a chemotherapeutic regimen helps patients with malignant pleural mesothelioma live longer," said Claude Denham, MD, a study coinvestigator for U.S. Oncology and a medical oncologist with Texas Oncology in Dallas.

Alimta disrupts folate-dependent metabolic processes essential for the tumor’s rapid growth—specifically three enzymes: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. The antifolate drug is converted to polyglutamate forms in tumor cells, which results in a prolonged drug action in malignant cells.

The FDA granted marketing approval to Alimta on the basis of a multicenter, randomized, single-blind study in 448 patients with malignant pleural mesothelioma from 19 countries who had not been treated previously with chemotherapy. Patients’ ages ranged from 19 to 85; 81.5% were male, and 46% had stage IV disease.

Study participants received either Alimta plus cisplatin (226) or cisplatin alone (222). Alimta was given intrave-nously for 10 minutes at a dose of 500 mg/m^2. This treatment was followed about 30 minutes later by a 2-hour infusion of cisplatin at 75 mg/m². Both doses are listed in the Alimta labeling.

After treating 112 patients, the researchers changed the study protocol to require that all participants receive supplemental folic acid and vitamin B₁₂, to reduce hematologic and gastrointestinal (GI) side effects.

Among the 448 patients in the study, median overall survival was 12.1 months for the Alimta-treated patients vs 9.3 months for the cisplatin-only arm, a 30% increase with Alimta. At 1 year, 50.3% of Alimta-treated patients were alive, compared with 38% treated with cisplatin alone. In addition, there was an improvement in lung function (forced vital capacity) on the Alimta/cisplatin arm, compared with the cisplatin-only arm.

Among the 331 patients who received the full folic acid and B₁₂ supplementation, the median overall survival was 13.3 months in the Alimta group vs 10.0 months in the cisplatin-only arm.

Among the fully supplemented patients, the Alimta-treated arm received a median of six cycles of treatment vs four cycles for cisplatin only. Patients who received no supplementation completed a median of two cycles in each arm.

Adverse Events

Adverse events among the fully supplemented participants consistently occurred more often in the Alimta-group than in the cisplatin-only patients. For example, the rates for all stages of hematologic problems were significantly higher for the treatment group 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, including platelet counts, should be performed on patients receiving Alimta," the labeling cautions.

Among the fully supplemented patients, the most common adverse reactions for the Alimta arm vs the cisplatin-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 diarrhea without colostomy, 26% vs 16%. Skin rash occurred more often in patients who did not receive pretreatment with a corticosteroid such as dexamethasone.

The drug’s labeling warns that physicians treating patients with Alimta must instruct them "to take folic acid and vita-min B₁₂ as a prophylactic measure to reduce treatment-related hematologic and GI toxicity." It also states that patients should receive the drug only under the supervision of a physician experienced in the use of antineoplastic agents. Patients with kidney impairment should not receive Alimta therapy. Patients should inform their doctors if they are taking nonsteroidal anti-inflammatory drugs (NSAIDs).

In a press release, Eli Lilly said that it has submitted a New Drug Application to the FDA for the use of single-agent Alimta in the second-line treatment of non-small-cell lung cancer (NSCLC). The agent is also being evaluated as first-line treatment of NSCLC, and in cancers of the pancreas, colon, and breast.