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
"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.
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
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.
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
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.