ROCKVILLE, Maryland- The FDA has granted accelerated approval to Eli Lilly's Alimta (pemetrexed for injection) for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in previously treated patients. The agent was approved earlier in 2004 for use in combination with cisplatin(Drug information on cisplatin) (Platinol) for the treatment of malignant pleural mesothelioma (see report on page 19). The FDA accelerated approval is based on Alimta's activity and favorable safety profile as evidenced in a phase III trial in the second-line setting comparing Alimta with docetaxel(Drug information on docetaxel) (Taxotere). In July, the study was the basis for a unanimous recommendation for accelerated approval by the FDA's Oncologic Drugs Advisory Committee (ODAC). A company whose drug enters the market with accelerated approval must conduct postmarketing clinical trials to confirm the agent's safety and efficacy. Alimta disrupts folate-dependent metabolic processes essential for a 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 malignan cells. "Activity is seen across a wide spectrum of scientific tumor models," Roy Herbst, MD, PhD, chief of thoracic oncology, MD. Anderson Cancer Center, told ODAC members at the July meeting. Pivotal Trial Lilly's pivotal study, designated JMEI, involved 571 patients in a randomized, controlled, unblinded trial of Alimta and docetaxel, the standard second-line treatment, carried out at 135 sites in 23 countries (J Clin Oncol 22:1589-1597, 2004). Approximately 21% of the participants received treatment in the United States. The trial's primary endpoint was overall survival. Study enrollment began on March 20, 2001, and ended on February 6, 2002. Researchers randomized 283 patients to receive Alimta 500 mg/m2 intravenously on day 1 of each 21-day cycle, plus 350 to 1,000 μg of oral folic acid(Drug information on folic acid) daily, 1,000 μg of vitamin B12 every 9 weeks, and dexamethasone(Drug information on dexamethasone). The remaining 288 participants were assigned to receive 75 mg/m2 of docetaxel intravenously on day 1 of each 3-week cycle, plus dexamethasone. Among the Alimta-treated patients, 85 (32%) crossed over to docetaxel therapy after tumor progression, a finding whose meaning became a point of contention between the sponsor and the FDA's reviewers at the ODAC meeting. The unblinding of the JMEI analysis data sets occurred on January 30, 2003. According to both the sponsor and the FDA review team, there was no significant difference in survival, (the primary endpoint) between the two arms of the study, the primary endpoint, nor in response, progressionfree survival, or time to disease progression. Among the patients actually treated (264 with Alimta and 274 with docetaxel), 9.1% of the Alimta group and 8.8% of the docetaxel arm responded, and 45.8% of the Alimta patients and 46.4% of the docetaxel group showed stable disease. "Notice the fact that over 50% of the patients had either a major response or stable disease in this trial," said Richard J. Gralla, MD, immediate past president of the Multinational Association of Supportive Care in Cancer (MASCC), who spoke on behalf of Lilly at the ODAC meeting. Among the treated patients, researchers found no statistically significant difference in on-study deaths between the two groups, 11.7% in the Alimta group and 14.5% in the docetaxel arm regardless of cause, or in drug-related deaths, 1.1% vs 1.8%. However, a significant difference was seen in the percentage of drug-related deaths among patients who suffered one or more significant adverse events, 10.2% in the Alimta arm, compared with 23.9% in the docetaxel group (P < .001). JMEI researchers did find significant differences favoring Alimta in several grade 3-4 adverse events among the treated patients. These included neutropenia, 5.3% vs 40.2% for the docetaxel group; febrile neutropenia, 1.9% vs 12.7%; and infection with grade 3-4 neutropenia, 0.0% ≤ 5.8% (all P ≤ .001). Among nonlaboratory grade 3-4 toxicities, diarrhea occurred in 0.4% of the Alimta group and 4.0% in the docetaxel arm (P ≤ .006), and for all grades of alopecia, the respective numbers were 11.3% vs 42.4% (P ≤ .001). "Because all the efficacy parameters were equivalent, much of the clinical benefit of Alimta relates to the toxicity, and so the toxicity analysis becomes important," said Paul A. Bunn, Jr., MD, director, University of Colorado Cancer Center, and a coprincipal investigator, who presented the JMEI efficacy data. Issue of Noninferiority ODAC members found themselves grappling with the issues of whether Alimta met FDA's criteria for a noninferior drug and whether it had a more favorable toxicity profile than docetaxel. FDA medical officer Martin H. Cohen, MD, argued that Alimta failed to meet the noninferiority test for two reasons. First, the one small historical study available (104 patients) for docetaxel made it impossible for FDA to precisely estimate the survival effect of docetaxel in this setting. Second, the 32% crossover of Alimta patients to docetaxel after tumor progression confounded the comparison of survival between the two drugs, as did the fact that only 139 Alimta patients received no poststudy chemotherapy, compared with 169 in the docetaxel group. "The 30-patient difference between the two treatment arms might be important because patients on both study arms who did not receive poststudy chemotherapy had shorter median survival," Dr. Cohen said. After discussion, ODAC members voted on three questions put to them by the FDA relating to Alimta. By a vote of 13 to 0, the committee found that Alimta had a more favorable toxicity profile than docetaxel. It also voted 13 to 0 that Alimta's toxicity profile and the supporting efficacy data showing noninferiority outweighed the uncertainty about a possible loss of survival effect that might result from Alimta. FDA officials described this decision as a vote recommending accelerated approval for Alimta. Finally, ODAC members voted 8 to 5 that the drug did not warrant full approval.