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Everolimus in metastatic renal cell carcinoma after treatment with VEGF-targeted therapies

Treatment with Everolimus ( Afinitor ) prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma who have experienced treatment failure on other regimens.

Everolimus is an oral drug which inhibits an intracellular signalling pathway responsible for regulating cell metabolism, growth, and division. Abnormal functioning of signalling pathways is thought to contribute to many cancers, and is particularly relevant to kidney cancers. Until recently, metastatic kidney cancer was considered a cancer with a poor outlook, with limited treatment options. The recent advent of Sunitinib ( Sutent ) and Sorafenib ( Nexavar ), which target another receptor ( the VEGF receptor ) has seen improved progression-free survival ( PFS ) and overall survival; but for the relatively new group of patients who have failed on these new treatments, there is a high unmet need for new therapies.

Robert Motzer, Memorial Sloan-Kettering Cancer Center, New York, and colleagues did a randomised controlled phase III trial to test the efficacy of Everolimus in these patients.

Patients with metastatic kidney cancer whose disease had progressed on Sunitinib, Sorafenib, or both, were randomly assigned in a 2:1 ratio to receive Everolimus 10 mg once daily ( 272 patients ) or placebo ( 138 ), in conjunction with best supportive care. The primary endpoint was progression-free survival, and the study was designed to end after 290 progression events.

The researchers found that results of the second interim analysis showed a significant difference in efficacy favouring the Everolimus arm; thus the trial was stopped after 191 progression events as it was not ethical to continue without providing Everolimus to all patients.
Progression events were observed in 101 of 272 ( 37% ) in the Everolimus group and 90 of 138 ( 65% ) in the placebo group; analysis showed that patients in the Everolimus group were less than one third as likely to experience disease progression as those in the placebo group.
Median progression-free survival was more than twice as long in the Everolimus group compared with placebo ( 4 vs 1.9 months ).

Adverse events were more common in the Everolimus group versus placebo; stomatitis ( 40% v 8% ); rash ( 25% v 4% ); and fatigue ( 20% v 16% ), were the most common adverse events reported but were mostly mild or moderate in severity. Pneumonitis ( any grade ) was detected in 22 patients in the Everolimus group, of whom eight had pneumonitis of grade 3 severity.

According to Authors, On the basis of the results of this trial, Everolimus should now be considered as the standard-of-care in patients with metastatic renal cell carcinoma whose disease has progressed after treatment with VEGF-targeted therapies.

Source: Lancet, 2008