FDA Approval for Pemetrexed Disodium
- Approved for maintenance treatment of non-squamous non-small cell lung cancer
- Approved for non-squamous non-small cell lung cancer
- Approved for malignant pleural mesothelioma
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.
Maintenance Treatment of Non-Squamous Non-Small Cell Lung Cancer
On July 2, 2009, the U. S. Food and Drug Administration (FDA) approved pemetrexed disodium injection (Alimta®, made by Eli Lilly and Company) for maintenance treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. This approval is the third approved indication for pemetrexed in locally advanced or metastatic non-squamous non-small cell lung cancer. Pemetrexed is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.
A double-blind study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care was conducted in patients with non-small cell lung cancer whose disease had not progressed following 4 cycles of platinum-based doublet induction chemotherapy. The study was designed to demonstrate superior progression-free survival and overall survival (OS) of Alimta treatment over placebo. The FDA-specified primary study objective was OS.
Pemetrexed, 500 mg/m2, was administered as an intravenous infusion over 10 minutes on day 1 of each 21-day cycle until disease progression. Folic acid, vitamin B12, and a corticosteroid were also given to all patients to reduce pemetrexed toxicity.
The median OS for patients in the intent-to-treat (ITT) group was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo [hazard ratio (HR) of 0.79 (95 percent CI: 0.65 to 0.95, p=0.012)]. Median OS was 15.5 months versus 10.3 months for patients with non-squamous non-small cell lung cancer receiving pemetrexed and placebo, respectively [HR of 0.70 (95 percent CI: 0.56 to 0.88)]. The median OS in patients with squamous cell non-small cell lung cancer receiving pemetrexed was 9.9 months versus 10.8 months for those receiving placebo [HR of 1.07 (95 percent CI: 0.77 to 1.50)].
A statistically significant improvement in progression-free survival (PFS) for the ITT patient population receiving pemetrexed maintenance therapy compared to placebo was observed. The median PFS was 4.0 months for the pemetrexed-treated patients compared to 2.0 months for the placebo-treated patients [HR of 0.60 (95 percent CI: 0.49 to 0.73, p < 0.00001)]. A treatment-by-histology interaction was also observed for PFS. In patients with non-squamous non-small cell lung cancer, PFS was 4.4 months for those receiving pemetrexed and 1.8 months for those receiving placebo [HR of 0.47 (95 percent CI: 0.37 to 0.60)]. In patients with squamous cell non-small cell lung cancer, PFS was 2.4 months for those reciving pemetrexed versus 2.5 months for those receiving placebo [HR of 1.03 (95 percent CI: 0.71 to 1.49)].
The safety results for patients treated with pemetrexed are consistent with the known safety profile of single-agent pemetrexed previously described in product labeling. The most common (>5 percent) adverse reactions in patients receiving pemetrexed were hematologic toxicity, increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash.
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On September 26, 2008, the U.S. Food and Drug Administration (FDA) approved pemetrexed disodium for injection for use in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Pemetrexed is not indicated for treatment of patients with squamous cell lung carcinoma.
The FDA had initially granted accelerated approval on August 19, 2004, to pemetrexed disodium for injection as a single agent for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after prior chemotherapy. Later studies led the FDA to revise its information to indicate that single-agent pemetrexed is not indicated in patients with squamous cell lung cancer after prior chemotherapy
A multicenter, randomized, open-label study in 1,725 patients with stage IIIb/IV NSCLC who had not received prior chemotherapy was conducted to compare overall survival following treatment with pemetrexed plus cisplatin (AC) to gemcitabine plus cisplatin (GC). The median survival was 10.3 months in the AC arm and 10.3 months in the GC arm [adjusted hazard ratio 0.94 (95 percent CI: 0.84, 1.05)]. The median progression-free survival was 4.8 and 5.1 months for the AC and GC arms, respectively [adjusted hazard ratio 1.04 (95 percent CI: 0.94, 1.15)]. The overall response rates were 27.1 percent and 24.7 percent for the AC and GC arms, respectively.
A pre-specified analysis of the impact of NSCLC histology on overall survival was conducted in this trial. Clinically relevant differences in survival according to histology were observed. In the non-squamous cell NSCLC subgroup the median survival was 11.0 and 10.1 months in the AC and GC groups, respectively [unadjusted hazard ratio 0.84 (95 percent CI: 0.74, 0.96)].
However, in the squamous cell histology subgroup the median survival was 9.4 versus 10.8 months in the AC and GC groups, respectively [unadjusted hazard ratio 1.22 (95 percent CI: 0.99, 1.50)].
This unfavorable effect on overall survival associated with squamous cell histology observed with pemetrexed was also noted in a retrospective analysis of the single-agent trial of pemetrexed versus docetaxel in patients with stage III/ IV NSCLC after prior chemotherapy. Single-agent pemetrexed was approved in 2004 for this more heavily treated lung cancer population. Current product labeling has been revised to recommend that pemetrexed is also not indicated in patients with squamous cell lung cancer after prior chemotherapy.
The most common (>20 percent) adverse reactions in patients receiving pemetrexed plus cisplatin in NSCLC were nausea (56 percent), fatigue (43 percent), vomiting (40 percent), anemia (33 percent), neutropenia (29 percent), anorexia (27 percent), and constipation (21 percent).
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On February 4, 2004, the FDA approved pemetrexed disodium for injection (Alimta®, made by Eli Lilly and Company) in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are not otherwise candidates for curative surgery.
Safety and efficacy were demonstrated in one multicenter, randomized trial in 456 patients comparing the combination of pemetrexed disodium and cisplatin with cisplatin alone. Supplementation with vitamin B12 and folic acid was instituted during the trial to decrease adverse effects. Subsequently, all patients, including previously enrolled patients, were given vitamin supplementation.
In an analysis of all patients who were randomized and treated, the combination of pemetrexed disodium and cisplatin was associated with a statistically significant improvement in survival compared to cisplatin alone. The median survivals were 12.1 versus 9.3 months, respectively (p = 0.020). This superiority in the combination arm was also demonstrated in the fully vitamin supplemented subgroup. The median survivals were 13.3 and 10.0 months in the combination and cisplatin alone groups, respectively (p = 0.051).
The principal adverse effects of the pemetrexed disodium plus cisplatin regimen were myelosuppression (in which the bone marrow produces fewer blood cells), fatigue, nausea, vomiting, and dyspnea (difficulty breathing). Most Grade 3/4 adverse effects were significantly reduced by vitamin supplementation without any efficacy decrement.
Pemetrexed disodium, 500 mg/m2, was diluted in 100 mL normal saline and administered as a 10-minute intravenous infusion. Approximately 30 minutes after pemetrexed disodium administration, cisplatin, 75 mg/m2 over 2 hours, was administered. Both drugs were given every 21 days.
Folic acid, 350 to 1000 micrograms orally, was given daily, beginning 1 to 3 weeks prior to the first chemotherapy dose and continued daily for one to three weeks after treatment discontinuation. A vitamin B12 injection, 1000 micrograms intramuscularly, was administered one to three weeks before the first chemotherapy dose and repeated approximately every nine weeks until treatment discontinuation.
Dexamethasone 4 mg (or an equivalent corticosteroid) twice daily was administered orally for skin rash prophylaxis to all patients one day prior to, on the day of, and one day after each dose of pemetrexed disodium.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.