International Approvals: Evoltra, Sutent, Femara

Yael Waknine

June 05, 2006

June 5, 2006 — The European Commission has approved clofarabine for the treatment of refractory acute lymphoblastic leukemia in pediatric patients; Health Canada has approved sunitinib malate capsules for the treatment of refractory gastrointestinal stromal tumors; and the Scottish Medicines Consortium has approved a new indication for letrozole tablets, allowing their use in the adjuvant treatment of postmenopausal women with hormone receptor–positive early breast cancer.


Clofarabine (Evoltra) for Pediatric ALL in EU


On May 31, the European Commission granted marketing authorization for clofarabine intravenous infusion ( Evoltra
, made by Bioenvision, Inc) for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients who have relapsed or are refractory to at least 2 prior regimens and for whom there is no treatment option expected to yield a durable response. The approval extends to all 25 member states of the European Union (EU).

According to a company news release, patients with multiple relapsed or refractory leukemia have a low response rate and a very poor prognosis, with a median survival of approximately 8 to 10 weeks.

In contrast, data from the pivotal clinical study upon which the approval was based showed that clofarabine induced a response in 30% of children, yielding a median survival of 66.6 weeks and allowing them the opportunity to achieve a cure via bone marrow transplant.

Clofarabine was previously approved for this indication by the US Food and Drug Administration ( Clolar
, made by Genzyme Corporation under license from Bioenvision). Other potential indications under investigation include acute myeloid leukemia, psoriasis, and autoimmune diseases.


Sunitinib Malate Capsules (Sutent) for GIST in Canada


On May 26, Health Canada approved sunitinib malate capsules ( Sutent
, made by Pfizer Canada, Inc) for the treatment of gastrointestinal stromal tumor (GIST) after disease progression while receiving or intolerance to imatinib mesylate ( Gleevec
, made by Novartis Pharmaceuticals Corporation).

In Canada, advanced GIST is currently treated with surgery followed by imatinib therapy. According to a company news release, many patients who undergo surgery eventually develop recurrent or metastatic disease for which treatment options are limited. Sunitinib is an oral multikinase inhibitor that represents a new therapeutic option, targeting several receptor tyrosine kinases that are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer.

The drug's approval was based on a review of data from an international, randomized, double-blind, placebo-controlled trial (n = 312) showing that sunitinib therapy significantly improved the median time to tumor progression (27.3 vs 6.4 weeks; P
< .0001) and progression-free survival (24.1 vs 6.0 weeks; P
< .0001).

The most commonly reported adverse events included fatigue, diarrhea, nausea, stomatitis, altered taste, skin abnormalities, hypertension, and bleeding. Discontinuation rates were similar in the active treatment and placebo groups (9% vs 8%).

Sunitinib is available in 12.5-, 25-, and 50-mg capsules. The recommended dose for GIST is 50 mg once daily on a schedule of 4 weeks on treatment followed by 2 weeks off. Dose increases or reductions in 12.5-mg increments are recommended based on individual safety and tolerability.

Sunitinib was previously approved by the US Food and Drug Administration in January 2006 for the treatment of GIST and metastatic renal cell carcinoma.

Letrozole (Femara) for Adjuvant Treatment of Early Breast Cancer in Scotland


On May 8, the Scottish Medicines Consortium approved a new indication for letrozole ( Femara
tablets, made by Novartis AG), allowing its use in the adjuvant treatment of postmenopausal women with hormone receptor–positive early breast cancer.

The approval was based on a review of data from a randomized, double-blind, phase 3 trial (BIG 1-98) in more than 8000 women, which showed that adjuvant use of letrozole reduced the risk for breast cancer recurrence by an additional 19% compared with tamoxifen ( P
= .003).

In 2 subgroups of women at greater risk for recurrence, the benefit of letrozole vs tamoxifen therapy was even more pronounced. Compared with tamoxifen, letrozole further decreased recurrence by 29% and 30% among women whose cancer had spread to the lymph nodes at time of diagnosis and those who had received prior chemotherapy, respectively.

In addition, treatment with letrozole reduced the overall risk for distant metastases by 27% compared with tamoxifen. This finding is clinically significant in that disease-free survival is considered a surrogate end point for overall survival.

In the adjuvant setting, increases from normal baseline total cholesterol levels to levels 1.5 times the upper limit of normal occurred in 5.4% of patients in the letrozole group compared with 1.2% of those receiving tamoxifen, and lipid-lowering medication was required in 18% of those receiving letrozole vs 12% of those receiving tamoxifen.

Commonly reported adverse effects were generally mild to moderate in both groups and included hot flashes (33.7% vs 38.0%), joint pain (21.1% vs 13.4%), night sweats (14.1% vs 16.4%), and weight gain (10.7% vs 12.9%). Other adverse events included fractures (5.7% vs 4%), myocardial infarction (0.6% vs 0.4%), endometrial cancer (0.2% vs 0.4%), second malignancies (1.9% vs 2.4%), and thromboembolic events (1.2% vs 2.8%).

Letrozole was previously approved for this indication by the US Food and Drug Administration. It is also approved in the United States and Scotland for use in postmenopausal women as first-line therapy for advanced breast cancer; extended adjuvant therapy for early invasive breast cancer after prior adjuvant tamoxifen therapy; and the treatment of advanced breast cancer that has progressed after anti-estrogen therapy. In other countries, letrozole is also indicated as neoadjuvant therapy for localized hormone receptor–positive breast cancer.

Reviewed by Gary D. Vogin, MD


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