Cancer Medications : Alimta, Aromasin

by National Cancer Institute

(Page 2 of 18)

Alimta

On February 4, 2004, the FDA approved pemetrexed 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 Alimta 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 Alimta 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 Alimta 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.

Alimta, 500 mg/m2, was diluted in 100 mL normal saline and administered as a 10-minute intravenous infusion. Approximately 30 minutes after Alimta 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 Alimta dose.

Alimta® for NSCLC

On August 19, 2004, the FDA granted accelerated approval to pemetrexed for injection (Alimta®, made by Eli Lilly and Company) as a single agent for the treatment of patients with locally advanced or metastatic nonsmall cell lung cancer after prior chemotherapy.

Safety and efficacy were demonstrated in one multi-center, randomized trial in 571 patients comparing single-agent Alimta versus docetaxel. Alimta, 500 mg/m2 intravenously, was administered over 10 minutes on day 1 of each 21-day cycle. Patients receiving Alimta also received dexamethasone for skin rash prophylaxis and vitamin B12 and folic acid supplementation.

The primary efficacy endpoint was survival. Alimta failed to demonstrate superior survival compared to docetaxel. Non-inferiority for overall survival could not be demonstrated because there was only one small historical study (total 104 patients) from which to estimate docetaxel's survival effect. A meta-analysis of multiple historical studies is usually required for this survival effect estimation. In addition, comparison of the survival effect in the current randomized trial was confounded by a 32% crossover rate of Alimta patients to docetaxel after tumor progression. The median survival time was 8.3 months for Alimta-treated patients and 7.9 months for docetaxel-treated patients. Secondary efficacy endpoints included response rate (Alimta 9.1%, docetaxel 8.8%), progression-free survival (Alimta and docetaxel, medians 2.9 months) and time-to-progressive disease (Alimta, median 3.4 months; docetaxel, median 3.5 months).

Alimta has a more favorable safety profile than docetaxel. Alimta caused less neutropenia, febrile neutropenia, neutropenic infections and need for granulocyte/macrophage colony stimulating factors. Alimta causes less severe alopecia. Elevation of hepatic transaminases was more frequent with Alimta than docetaxel. Accelerated approval was based on the improved safety profile and effects on surrogate endpoints.

As a condition of accelerated approval, Eli Lilly and Company is required to conduct additional studies to demonstrate a clinical benefit, such as increased survival or improved disease-related symptoms.

Aromasin

On October 5, 2005, the FDA approved exemestane tablets (Aromasin®, a product of Pfizer Inc.) for adjuvant treatment of postmenopausal women with estrogen receptor positive early breast cancer who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy.

Safety and efficacy were evaluated in the Intergroup Exemestane Study (IES), a double-blind, multicenter, international clinical trial in postmenopausal women with early stage breast cancer who had received two to three years of adjuvant tamoxifen. Four thousand seven hundred and twenty four patients in the intention-to-treat population were randomly assigned to either continue tamoxifen (20-30 mg/day) or switch to exemestane (25 mg/day) to complete a total of five years of adjuvant hormonal therapy.

Approval was based on an analysis of disease-free survival (DFS), defined as the time from randomization to the development of local or distant recurrence, contralateral breast cancer (cancer in the other breast), or death from any cause. After a median duration of randomized therapy of 27 months and with a median duration of follow-up of 34.5 months, DFS was significantly improved in patients who switched to exemestane compared to those who continued tamoxifen (HR=0.69, 95 percent CI: 0.58-0.82, p<0.0001).

In the hormone receptor-positive subpopulation representing about 85 percent of the trial patients, DFS was significantly improved (HR=0.65, 95 percent CI: 0.53-0.79, p=0.00001) in the exemestane arm compared to the tamoxifen arm. Overall survival was not significantly different in the two arms.

The most common adverse events on the IES that occurred more frequently on the exemestane arm included hot flashes, fatigue, arthralgia (joint pain), headache, insomnia (difficulty sleeping), increased sweating, hypertension (high blood pressure), and dizziness. Cardiac ischemic events (heart problems) occurred in 1.6 percent of patients in the exemestane arm of the IES compared to 0.6 percent of patients in the tamoxifen arm.

Changes in bone mineral density (BMD) were evaluated in a substudy of the IES and in a supporting safety study (027), which compared the effects of two years of exemestane to placebo. Mean decreases in BMD of the lumbar spine and femoral neck were more pronounced with exemestane than with either tamoxifen or placebo. On the IES, osteoporosis was reported in 4.6 percent of patients treated with exemestane compared to 2.8 percent of patients receiving tamoxifen.

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