CHICAGO -- Increasing the dose of pemetrexed (Alimta) to 900 mg/m 2 did not improve outcome for patients with advanced non-small cell lung cancer (NSCLC), but did slightly increase toxicity, researchers found.
CHICAGO, June 8 -- Increasing the dose of pemetrexed to 900 mg/m2 did not improve outcome for patients with advanced non-small cell lung cancer (NSCLC), but did slightly increase toxicity, researchers found.
The approved dose of pemetrexed is 500 mg/m2, but that dose was approved without vitamin supplementation said Michael Cullen, M.D., of Queen Elizabeth Hospital in Birmingham, England.
When it was discovered that supplementation with vitamin B-2 and folic acid could increase the maximum tolerated dose to 900 mg/m2, it seemed reasonable to test the higher dose, he said at the American Society of Clinical Oncology meeting here.
But in a phase III trial that randomized 588 patients to standard or high dose, Dr. Cullen and colleagues found no "evidence of a benefit for high dose pemetrexed. Median survival was 2.6 months with the standard dose versus 2.8 months with high dose pemetrexed (P=0.893)."
Future trials should be conducted at the 500 mg/m2 dose, Dr. Cullen said.
The partial response rate was 7.1% at standard dose and 4.3% with high dose pemetrexed. About half of all patients in both arms achieved stable disease, he said.
All patients in the trial had failed at least one platinum-based regimen, he said. The average age of patients was 62 and two-thirds of the patients were men.
About 75% of patients had stage IV disease and the majority were performance status 0 to 1 at study entry, but 12% to 13% of patients were performance status 2 at baseline.
Whichever dose patients received, the pemetrexed was given in short infusions every 21 days. An average of three cycles was completed in each arm.
Grade 3/4 neutropenia developed in 3.4% of the patients in the low dose arm versus 7.9% percent of patients in the high dose arm. The rate of drug-related hospitalization was 10.8% in the low dose arm versus 15.8% in the high dose arm.
Study discussant Thomas J. Lynch Jr., M.D., of Massachusetts General Hospital in Boston, said they were somewhat surprising, because he and others had assumed that the high dose regimen would demonstrate benefit, especially because vitamin supplementation had been shown to significantly reduce both bone marrow and gastrointestinal toxicity.
One possible explanation, he said, is that "at 500 mg the targets [of pemetrexed] are saturated or it may be possible that 500 mg is maximal transport [of pemetrexed]."
Another possibility, he noted, is that "we are using too much vitamin B," which effectively impairs the mechanism of pemetrexed -- a drug that is an antifolate that works by targeting three key enzymes, dehydrofolate, GARFT, and thymedilate synthase.