Everolimus in Patients with Cytokine-Pretreated mRCC

ROBERT A FIGLIN, MD: Dr Amato and colleagues reported in Cancer the results of a Phase II study with the daily regimen of an oral mTOR inhibitor everolimus — now commercially available for the treatment of renal cell carcinoma — with patients experiencing disease progression after up-front TKI therapy with either sorafenib or sunitinib.

Dr Amato studied these patients prior to everolimus becoming commercially available. They enrolled 41 patients and evaluated the efficacy of everolimus in this setting. Most of the patients had MSKCC intermediate performance status, and approximately one third of the patients had a good performance status.

One notable aspect of this study that is helpful is that the majority of patients had received prior cytokine therapy and had not received prior VEGF-targeted therapy. Why is that important? Currently, everolimus is indicated by the NCCN guidelines as treatment for such patients after disease progression or intolerance to targeted agents, such as sorafenib and sunitinib. So this provides a window into how everolimus might have activity in patients who have not received prior targeted therapy but had received prior cytokine-based therapy or in patients who had not received any prior therapy at all.

The authors demonstrate, as we would have expected, no complete responses, a 6.5 percent partial response rate and, by independent assessment, approximately 75 percent of patients experienced stable disease. That’s consistent with our observations about mTOR inhibition, with which the overall response rates are quite low but the absence of progression is quite high. This study thus demonstrates that everolimus may have a benefit in patients who have not received prior cytokine therapy, and this will certainly be evaluated in up-front clinical trials.

Dr Amato discusses the progression-free and overall survival. I believe that in the era of targeted therapy, it’s not prudent to consider these results in a predictive way because this was a single-institution clinical trial with a small number of patients. We now have large Phase III trials with which to understand the benefits of agents such as everolimus in patients with metastatic renal cell carcinoma.

The toxicity profile was comparable to what we experience with everolimus, although Dr Amato did point out that approximately 18 percent of patients had Grade III pneumonitis. This underscores our understanding that mTOR inhibitors have a spectrum of toxicity that is different from the TKIs and one must watch for hypercholesterolemia, hyperlipidemia, hyperglycemia and pneumonitis associated with these agents that are not found with the VEGF TKIs.

In this study Dr Amato demonstrates that everolimus has clinical activity in a small number of patients with previously untreated or cytokine-refractory metastatic clear cell carcinoma, and in this setting, everolimus might be an appropriate choice.

Some of the current clinical trials that are underway with these mTOR inhibitors in the clinic are comparisons of combination therapy — temsirolimus or everolimus with bevacizumab compared to bevacizumab and interferon in the previously untreated population. These studies may help us to understand how to use these targeted agents in the up-front setting for these patients.

Dr Figlin is Acting Cancer Center Director, Arthur and Rosalie Kaplan Professor of Medical Oncology as well as Chair of the Division of Medical Oncology and Experimental Therapeutics at the City of Hope National Medical Center/Beckman Research Institute in addition to Associate Director for Clinical Research at the City of Hope Comprehensive Cancer Center in Duarte, California.