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Survival Benefit from mTOR Inhibition in Advanced Kidney Cancer

Compared with interferon, temsirolimus improved overall survival in patients with metastatic renal-cell carcinoma.

After years of limited therapeutic options for patients with advanced renal-cell carcinoma, several new drugs have emerged. Sunitinib and sorafenib are multi-targeted tyrosine kinase inhibitors that have been approved by the FDA for treating advanced kidney cancer (see Journal Watch Oncology and Hematology Jan 10 2007, first and second summaries). Temsirolimus (CCI-779) inhibits the mammalian target of rapamycin (mTOR) kinase. Disruption of mTOR signaling suppresses production of proteins that regulate angiogenesis, which has been long recognized as a therapeutic target in renal-cell carcinoma. Early studies of temsirolimus demonstrated clinically important activity in renal cancer, and the combination of temsirolimus and interferon is both safe and active.

An international group of investigators randomized 626 patients with newly diagnosed, poor-prognosis, metastatic renal-cell carcinoma to receive intravenous temsirolimus (25 mg weekly), subcutaneous interferon- (3 million U [escalating to 18 million U] three times weekly), or combination therapy (15-mg temsirolimus weekly plus 3 million U [escalating to 6 million U] interferon- three times weekly). The primary endpoint was overall survival in patients who received either of the two temsirolimus-containing regimens compared with that in patients who received interferon alone.

Compared with patients who received interferon alone, those who received only temsirolimus had longer overall survival and progression-free survival (P<0.001). In the combination-therapy group, overall survival was similar to that in the interferon-alone group. Median survival times for the temsirolimus group, the combination-therapy group, and the interferon group were 10.9, 8.4, and 7.3 months, respectively. Asthenia was more common among patients who received interferon (alone or in combination); rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group. Overall, fewer serious adverse events occurred in the temsirolimus group than in the interferon group or the combination-therapy group (P=0.02).

Comment: Median overall survival among patients with poor-prognosis renal cancer is 4 to 8 months. The results of this trial show that, compared with interferon, single-agent temsirolimus improves overall survival by several months — a clinically relevant difference. The potential for a more substantial effect on the survival of patients with low- or intermediate-risk disease remains an open issue. Temsirolimus is tolerated relatively well, but, unlike sunitinib and sorafenib, is administered parenterally. The optimal sequencing of these three agents (as well as the possible addition of bevacizumab to the mix of approved agents for renal cancer) will require prospective evaluation.

— Robert Dreicer, MD, MS, FACP

Published in Journal Watch Oncology and Hematology May 30, 2007

Citation(s):

Hudes G et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007 May 31; 356:2271-81.

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