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Pemetrexed Equivalent to Docetaxel for Recurrent NSCLC Patients

Pemetrexed Equivalent to Docetaxel for Recurrent NSCLC Patients

CHICAGO-For patients with advanced, recurrent non-smallcell lung cancer (NSCLC), outcomes with the multitargeted antifolate pemetrexed (Alimta) are comparable to those with docetaxel (Taxotere),and toxicity is less, according to a randomized, multicenter study presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO) (abstract 2503). The study is the largest phase III clinical trial to evaluate the effectiveness of secondline therapies in NSCLC. Pemetrexed benefits were similar to docetaxel in terms of response rates, progression-free survival, median survival, and overall survival. At ASCO last year, a major clinical trial demonstrated the drug's efficacy in mesothelioma as well. Phase III trials presented at ASCO in 2002 and 2003 of pemetrexed in combination with cisplatin (Platinol) for treatment of mesothelioma are under review by the FDA, and the drug is available to mesothelioma patients as part of an expandedaccess program. "Before Taxotere, we had no agent that was proven to prolong life for patients with recurrent NSCLC. Now, with these data on Alimta, we have observed a survival advantage, just as we have with Taxotere, but with fewer side effects," said lead investigator Nasser Hanna, MD, assistant professor of medicine, Indiana University Cancer Center. "Pemetrexed may soon replace docetaxel as the treatment of choice for some patients with recurrent non-small-cell lung cancer." Pemetrexed interferes with the production of folic acid, which is essential for normal cell growth but can fuel cancer growth. Interrupting folic acid synthesis also blocks activity of three key enzymes necessary for cell division. By contrast, the first generation of antifolates (eg, 5-fluorouracil and methotrexate) are specific for only one enzyme and do not disrupt multiple pathways, as pemetrexed does. Study Results Dr. Hanna reported results in 571 previously treated NSCLC patients (75% stage IV) randomized to docetaxel 75 mg/m2 on day 1 of a 21-day cycle or pemetrexed 500 mg/m2 on day 1 of a 21-day cycle, supplemented with vitamin B12 and folic acid. The study's primary end point, median survival, was similar between the two arms: 8.3 months with pemetrexed and 7.9 months with docetaxel. One-year overall survival was 29.7% with either treatment. Objective responses were seen in 9.1% of patients receiving pemetrexed and 8.8% receiving docetaxel, while stable disease was achieved in 46% of patients in each arm. Progression-free survival was 2.9 months in each group. "As a clinician, I look at the survival curve and the sample size, and I feel very comfortable saying these drugs are clinically equivalent," Dr. Hanna concluded. While the drugs were clinically equivalent, pemetrexed was better tolerated, producing significantly less sesevere neutropenia (with and without fever), alopecia, and peripheral neuropathy. Pemetrexed patients also required significantly fewer hospitalizations for adverse events or febrile neutropenia and had significantly less need for G-CSF (Neupogen) support. Pemetrexed was more likely to produce elevated alanine transaminase, although this condition was transient. "This study shows pemetrexed is a better-tolerated and comparably active option for second-line NSCLC treatment. How applicable are the results? We are desperate for new options, and pemetrexed appears to be the next agent," said Vincent Miller, MD, medical oncologist at Memorial Sloan-Kettering Cancer Center. Pemetrexed in Mesothelioma Dr. Nicholas Vogelzang and colleagues at the University of Chicago Cancer Research Center previously reported the results of a pivotal phase III study in 434 patients with malignant pleural mesothelioma, showing that pemetrexed plus cisplatin significantly improved survival time compared with cisplatin alone (median 12.1 months vs 9.3 months) (J Clin Oncol 21:2629-2630, 2003). At ASCO 2003 (abstract 2602), James T. Symanowski, PhD, senior research scientist, Lilly Research Laboratories, Indianapolis, described the prognostic variables impacting survival, derived from a multiple regression analysis of the trial. Use of the pemetrexed combination vs single-agent cisplatin was the main factor in improved survival, with a hazard ratio (HR) of 0.77 in the univariate analysis and 0.70 in the multivariate analysis. Other factors signif-icantly associated with improved prognosis were vitamin supplementation, good performance status, and epithelial subtype (HR 0.36). Poor survival was associated with advanced disease stage, elevations in white blood cell counts, and increased cystathionine. Additional analysis from the pivotal phase III trial, also reported at ASCO 2003, found quality-of-life parameters to be better with the pemetrexed/ cisplatin combination (abstract 2496). The differentiation in quality of life and symptoms occurred rapidly (within the first three cycles), reaching significance in most parameters by week 15, reported Richard Gralla, MD, president, New York Lung Cancer Alliance, New York City.

 
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