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Lung Cancer Home Page
NCI's gateway for information about lung cancer.
Malignant Mesothelioma Home Page
NCI's gateway for information about malignant mesothelioma.
Drug Information Summaries
NCI's drug information summaries provide consumer-friendly information about certain drugs that are approved by the U.S. Food and Drug Administration (FDA) to treat cancer or conditions related to cancer.
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FDA Approval for Pemetrexed DisodiumBrand
name(s): Alimta®
Full
prescribing information is available, including clinical
trial information, safety, dosing, drug-drug interactions and
contraindications.
Non-Squamous
Non-Small Cell Lung Cancer
On September 26, 2008, the U.S. Food and Drug Administration
(FDA)
approved pemetrexed disodium for injection
for use in combination with cisplatin therapy for the initial treatment
of patients with locally advanced or metastatic non-squamous non-small
cell lung cancer (NSCLC). Pemetrexed is not indicated for treatment of
patients with squamous cell lung carcinoma.
The FDA had initially granted accelerated approval on
August 19, 2004, to
pemetrexed disodium for injection as a single agent for the treatment
of patients with locally advanced or metastatic non-small cell lung
cancer after prior chemotherapy. Later studies led the FDA to
revise its information to indicate that
single-agent pemetrexed is not indicated in patients with squamous cell
lung cancer after prior chemotherapy
A multicenter, randomized, open-label study in 1,725 patients
with stage IIIb/IV NSCLC who had not received prior chemotherapy was
conducted to compare overall survival following treatment with
pemetrexed plus cisplatin (AC) to gemcitabine plus cisplatin (GC). The
median survival was 10.3 months in the AC arm and 10.3 months in the GC
arm [adjusted hazard ratio 0.94 (95 percent CI: 0.84, 1.05)]. The
median progression-free survival was 4.8 and 5.1 months for the AC and
GC arms, respectively [adjusted hazard ratio 1.04 (95 percent CI: 0.94,
1.15)]. The overall response rates were 27.1 percent and 24.7 percent
for the AC and GC arms, respectively.
A pre-specified analysis of the impact of NSCLC histology on
overall survival was conducted in this trial. Clinically relevant
differences in survival according to histology were observed. In the
non-squamous cell NSCLC subgroup the median survival was 11.0 and 10.1
months in the AC and GC groups, respectively [unadjusted hazard ratio
0.84 (95 percent CI: 0.74, 0.96)].
However, in the squamous cell histology subgroup the median
survival was 9.4 versus 10.8 months in the AC and GC groups,
respectively [unadjusted hazard ratio 1.22 (95 percent CI: 0.99, 1.50)].
This
unfavorable effect on overall survival associated with squamous cell
histology observed with pemetrexed was also noted in a retrospective
analysis of the single-agent trial of pemetrexed versus docetaxel in
patients with stage III/ IV NSCLC after prior chemotherapy.
Single-agent pemetrexed was approved in 2004 for this more heavily
treated lung cancer population. Current product labeling has been
revised to recommend that pemetrexed is also not indicated in patients
with squamous cell lung cancer after prior chemotherapy.
The most common (>20 percent) adverse reactions in
patients receiving pemetrexed plus cisplatin in NSCLC were nausea (56
percent), fatigue (43 percent), vomiting (40 percent), anemia (33
percent), neutropenia (29 percent), anorexia (27 percent), and
constipation (21 percent).
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Malignant
Pleural Mesothelioma
On February 4, 2004, the FDA approved
pemetrexed disodium for injection (Alimta®, made by Eli Lilly and
Company) in combination with cisplatin for the
treatment of patients with malignant pleural mesothelioma
whose disease is either unresectable or who are not otherwise
candidates for curative surgery.
Safety and efficacy were demonstrated in one multicenter, randomized trial in
456 patients comparing the combination of pemetrexed disodium and
cisplatin with cisplatin alone. Supplementation with vitamin B12 and
folic acid was instituted during the trial to decrease adverse effects.
Subsequently, all patients, including previously enrolled patients,
were given vitamin supplementation.
In an analysis of all patients who were randomized and
treated, the combination of pemetrexed disodium and cisplatin was
associated with a statistically significant
improvement in survival compared to cisplatin alone. The median survivals were
12.1 versus 9.3 months, respectively (p = 0.020). This superiority in
the combination arm was also demonstrated in the fully vitamin
supplemented subgroup. The median survivals were 13.3 and 10.0 months
in the combination and cisplatin alone groups, respectively (p = 0.051).
The principal adverse effects of the pemetrexed disodium plus
cisplatin regimen were myelosuppression (in which the bone marrow
produces fewer blood cells), fatigue, nausea, vomiting, and dyspnea
(difficulty breathing). Most Grade 3/4 adverse effects were
significantly reduced by vitamin supplementation without any efficacy
decrement.
Pemetrexed disodium, 500 mg/m2, was diluted in 100 mL normal
saline and administered as a 10-minute intravenous infusion.
Approximately 30 minutes after pemetrexed disodium administration,
cisplatin, 75 mg/m2 over 2 hours, was administered. Both drugs were
given every 21 days.
Folic acid, 350 to 1000 micrograms orally, was given daily,
beginning 1 to 3 weeks prior to the first chemotherapy dose and
continued daily for one to three weeks after treatment discontinuation.
A vitamin B12 injection, 1000 micrograms intramuscularly, was
administered one to three weeks before the first chemotherapy dose and
repeated approximately every nine weeks until treatment discontinuation.
Dexamethasone 4 mg (or an equivalent corticosteroid) twice
daily was administered orally for skin rash prophylaxis to all
patients one day prior to, on the day of, and one day after each dose
of pemetrexed disodium.
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This summary was provided
by Richard Pazdur, M.D., director of the FDA's Division of Oncology
Drug Products, or Patricia Keegan, M.D., director of the FDA's Division
of Clinical Trials Design and Analysis.
The FDA is the division of the U.S. Department of Health and
Human Services charged with ensuring the safety and effectiveness of
new drugs and other products. (See "Understanding
the Approval Process for New Cancer Treatments.") The FDA's
mission is to promote and protect the public health by helping safe and
effective products to reach the market in a timely way, and monitoring
products for continued safety after they are in use.
For further information related to oncology drug approvals, regulatory
information and other oncology resources, please refer to the FDA's Oncology Tools
Web site.
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