I am thrilled to see that GRACE has expanded their scope to include metastatic kidney kidney cancer – quite honestly, there couldn’t be a better time. In the 1990’s, the big dilemma we faced was a lack of therapies. Beyond interleukin-2 and interferon, we didn’t have much – standard chemotherapy really doesn’t work well in the vast majority of patients with this disease. In the mid-2000’s, everything changed. Now we have an expanding arsenal of therapies with which to fight kidney cancer. I generally divide these therapies into two categories – (1) mTOR inhibitors and (2) VEGF pathway inhibitors. These terms refer broadly to the way in which these drugs attack the cancer cell. There are two mTOR inhibitors that have been FDA-approved (temsirolimus and everolimus), and five VEGF pathway inhibitors (sunitinib [Sutent], sorafenib [Nexavar], pazopanib [Votrient], axitinib [Inlyta] and bevacizumab [Avastin]). Today, when a patient is diagnosed, we typically move through these agents sequentially. It’s not unusual for me to see patients that have been exposed to every one of these therapies. The question always arises – why not simply combine these therapies? It’s an excellent thought, and it’s one that kidney cancer investigators have struggled with for a long time. Unfortunately, to date, we haven’t found a combination that is both safe and effective.
The efforts began with attempts to combine VEGF pathway inhibitors with one another. These efforts were sometimes disastrous. For instance, the combination of sunitinib with bevacizumab led to a rare condition with blood clots in small capillaries and vessels called thrombotic microangiopathy (TMA); this can sometimes be associated with profound anemia and kidney failure. After learning that VEGF pathway inhibitors may not be ideal in combination with eachother, efforts turned to combining VEGF pathway inhibitors with mTOR inhibitors. Though not all VEGF inhibitors combine well with mTOR inhibitors, we did learn that the VEGF pathway inhibitor bevacizumab could be combined with the mTOR inhibitors (temsirolimus or everolimus) relatively safely.
Building on this initial experience, there was a study presented by Dr. Bernard Escudier at the American Society of Clincial Oncology meeting in 2010 (it’s been more recently published in the journal Lancet Oncology). In this study (termed the “TORAVA” trial), 171 patients with metastatic kidney cancer received either bevacizumab with interferon (the standard way to give the drug), bevacizumab with temsirolimus, or sunitinib. Patients getting bevacizumab with temsirolimus didn’t appear to tolerate the regimen well, and many had to come off due to toxicity. In terms of effectiveness, bevacizumab with temsirolimus was outperformed by bevacizumab with interferon. This was perceived as the first blow to combinations of VEGF pathway inhibitors and mTOR inhibitors.