Combining Second-Line Targeted Therapies for Advanced Kidney Cancer
Name of the Trial
Phase III Randomized Study of Everolimus with Versus without Bevacizumab in Patients with Advanced Renal Cell Carcinoma that Progressed after First-line Treatment with Tyrosine Kinase Inhibitors (CALGB-90802). See the protocol summary.
Dr. George K. Philips, Georgetown-Lombardi Comprehensive Cancer Center and Cancer and Leukemia Group B
Why This Trial Is Important
Renal cell carcinoma (RCC) accounts for nearly 3 percent of all yearly cancer diagnoses in the United States. Once thought to be a single disease, several distinct subtypes are now recognized, including clear cell, papillary/chromophilic, chromophobic, and collecting duct carcinomas. Each of these subtypes has a unique genetic basis and susceptibility to targeted therapies. Nevertheless, some RCC tumors may have features of more than one subtype.
Standard treatment for localized RCC includes surgical removal of part or all of the affected kidney, the adjacent adrenal gland, and nearby lymph nodes. Up to 30 percent of patients, however, have metastases at the time of diagnosis, and another 30 percent of those treated for localized disease will relapse. Since RCC is known to be resistant to standard chemotherapy drugs, patients must rely on alternative systemic therapies.
Until the middle of the last decade, biological therapy with high-dose interleukin-2 or interferon, both of which have substantial toxicities, was the only option available to patients with advanced RCC, and only a small percentage of patients had a positive response to these treatments. In 2004, researchers showed that clear cell RCC tumors respond to the tyrosine kinase inhibitor (TKI) sorafenib and, subsequently, to other TKIs, including sunitinib and pazopanib. However, after initially responding to TKIs, RCC tumors began to develop resistance to the drugs, necessitating the identification of new second-line therapies.
In 2009, the FDA approved everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, and interferon-alpha plus bevacizumab (Avastin), an anti-VEGF monoclonal antibody, for the treatment of advanced RCC. These treatments were shown separately in randomized clinical trials to increase progression-free survival but not overall survival.
The goal of this new clinical trial is to determine whether using everolimus and bevacizumab in combination will improve the overall survival of patients with RCC whose disease has progressed on TKIs. The trial is accepting participants who have metastatic RCC with some component of clear cell disease, have cancer that has progressed after treatment with at least one prior TKI, and have not been previously treated with a VEGF-binding agent or an mTOR inhibitor. Participants will take oral everolimus once a day and be randomly assigned to receive either intravenous bevacizumab or a placebo twice a month. Doctors will monitor the participants to determine whether the combined treatment helps extend overall survival and progression-free survival and to evaluate the toxicity of the combination.
“This trial is an example of a sequential hit to an angiogenesis pathway,” said Dr. Philips. “One is the mTOR inhibitor blocking the production of its downstream target VEGF, and the other, bevacizumab, hammering down the actual VEGF levels. Essentially, it is a two-pronged attack to reduce VEGF levels as much as possible.
“There is a vacuum in what to do for kidney cancer patients after failure of a first-line TKI,” he continued. “We want to move this field forward and have some good data to base clinical decisions on and to know that we are improving the outcome of patients with kidney cancer.”