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On July 2, 2009, the U. S. Food and Drug Administration (FDA) approved pemetrexed injection (Alimta Injection, Eli Lilly and Company) for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer 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 nonsquamous 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 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 of Alimta over placebo. The FDA-specified primary study objective was overall survival (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.
There were 663 randomized patients (pemetrexed arm = 441 patients; placebo arm = 222 patients). Treatments were well balanced with respect to the baseline disease characteristics and randomization factors. The majority of patients had ECOG Performance Status (PS) of 1 (60.2%) and stage IV disease (80.8%). Adenocarcinoma (49.6%) was the predominant histologic subtype, followed by squamous cell histology (27.3%).
The median OS for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo [hazard ratio (HR) of 0.79 (95% CI: 0.65 to 0.95, p=0.012)]. Median OS was 15.5 months versus 10.3 months for patients with nonsquamous histologies receiving pemetrexed and placebo, respectively [HR of 0.70 (95% CI: 0.56 to 0.88)]. The median OS in patients with squamous histology receiving pemetrexed was 9.9 months versus 10.8 months for those receiving placebo [HR of 1.07 (95% CI: 0.77 to 1.50)].
A significant improvement in 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 patients in the placebo arm [HR of 0.60 (95% CI: 0.49 to 0.73, p < 0.00001)]. A treatment-by-histology interaction was also observed for PFS. The PFS for patients with nonsquamous histologies receiving pemetrexed versus placebo was 4.4 months and 1.8 months, respectively [HR of 0.47 (95% CI: 0.37 to 0.60)]. The PFS for pemetrexed therapy in patients with squamous cell histology was 2.4 months versus 2.5 months for placebo treatment [HR of 1.03 (95% 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%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy and skin rash.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021462s021lbl.pdf