FDA Oks Torisel for Renal Cell Ca

ROCKVILLE, Maryland—Torisel has become the third drug in 18 months to win FDA approval for the treatment of advanced renal cell carcinoma. Torisel (temsirolimus, Wyeth Pharmaceuticals) received its marketing approval on the basis of data from a phase III clinical trial showing increased survival with single-agent Torisel, compared with interferon-alfa, which was the standard at the time the study was designed. Wyeth expects to make Torisel available to patients this month.

FDA approved Nexavar (sorafenib, Bayer Pharmaceuticals) in December 2005 for the same cancer indication on the basis of delayed disease progression, and Sutent (sunitinib, Pfizer) in January 2006 based on durable response rate. Later data showed Sutent delayed tumor progression.

"Temsirolimus is the first drug to demonstrate a significant increase in overall survival for patients with the most aggressive form of kidney cancer, providing us with a new and much needed option for treatment," said Gary Hudes, MD, director of the genitourinary malignancies program at Fox Chase Cancer Center, and lead investigator of the phase III trial (N Engl J Med 356:2271-2281, 2007).

Temsirolimus binds to the intracellular protein FKBP-12, and the protein-drug complex inhibits the activity of mTOR (the mammalian target of rapamycin), a key protein in the regulation of cell proliferation, growth, and survival. In vitro studies with cancer cells have shown that mTOR inhibition blocks the translation of genes that regulate the cell cycle and reduces the levels of some growth factors involved in angiogenesis.

Study Results

Wyeth submitted a phase III, multicenter, randomized, open-label study of 626 patients with untreated advanced renal cell carcinoma—both clear-cell and non-clear-cell histologies—to support its New Drug Application. Patients ranged in age from 23 to 86 years (mean, 59 years); 69% were male; 91% were white; 76% had undergone prior nephrectomy.

Participants were randomized to receive interferon-alfa only (n = 207), Torisel alone at 25 mg weekly (n = 209), or a combination of Torisel 15 mg and interferon-alfa (n = 210). Of the intention-to-treat patients, 616 underwent therapy.

The Torisel-only patients had a significant 49% improvement in overall survival—defined as the time from randomization to death—a median of 10.9 months vs 7.3 months for the interferon-only group (P = .0078). "This is a modest improvement in survival [3.6 months], but the patients in the study had the most advanced tumors," Dr. Hudes said.

Median survival for the Torisel/interferon combination was 8.4 months, a nonsignificant difference, compared with interferon alone. Dr. Hudes said that this finding could be explained by the lower dose of temsirolimus given to patients on combination therapy. The Torisel-alone patients also had a significant advantage in median progression-free survival, 5.5 months vs 3.1 months for interferon alone (P = .0001), and showed a trend toward a better overall response rate.

Temsirolimus was better tolerated than interferon. Fewer patients treated with temsirolimus had grade 3-4 side effects, compared with those given interferon alone or the combination. The most common side effects associated with temsirolimus were asthenia, anemia, nausea, dyspnea, and rash. As part of a postmarketing commitment, Wyeth has agreed to submit two completed study reports and data sets: one on a thorough QT prolongation study and one on an ongoing hepatic impairment study.