Treatment of Advanced Renal Cell Carcinoma

Daniel J. George, MD

The treatment of advanced renal cell carcinoma (RCC) remains a major challenge for clinicians. However, according Daniel J. George, MD, director of Genitourinary Oncology, Duke Cancer Institute, the progress being made in understanding RCC tumor biology is already helping us to discover better, more effective treatments.

Using Current Treatments More Effectively

“We now know that RCC is not one single entity, but a complex set of heterogeneous tumors, each defined by distinct genetic abnormalities, histopathological characteristics, and natural histories. Even within clear cell RCC, the most common type of kidney cancer, we’re recognizing through genomic studies and protein analyses that we’re really dealing with distinct subgroups.” The fact that these subgroups have different molecular features has direct implications for treatment.Better understanding of the molecular pathways involved in the development of RCC has led to the selection of important therapeutic targets such as the vascular endothelial growth factor (VEGF), and the mTOR (mammalian target of rapamycin) pathways.

George notes that the VEGF receptor tyrosine kinase inhibitors (TKIs) pazopanib, axitinib, sunitinib, sorafenib, and bevacizumab have well-established therapeutic effects in patients that extend from shrinking tumors, to delaying progression, to improving survival in the context of that delayed progression. “In our latest studies looking at frontline TKIs, the median survival for patients has improved from 20 months to about 30 months due in part to the benefits of sequential treatments.”

A study recently published inThe New England Journal of Medicineprovided evidence for using pazopanib in the frontline setting, thus adding to the physician’s therapeutic armamentarium. In the COMPARZ trial, pazopanib was compared with sunitinib, the current standard treatment for RCC in a population of 1110 treatment-naïve patients with clear-cell, metastatic RCC. The trial showed that these two drugs had similar efficacy but that their side-effect profiles were different. Overall, the trial suggests that both drugs are safe and effective first-line therapies. “This study offers the best perspective to date of how these therapies differ from one another with regards to side effects,” said George.

There is growing evidence that using more than one line of VEGF/TKI is advantageous, and that speaks to the benefit of sequential uses of these drugs, George said. “We have lots of examples where patients respond even better in the second-line setting than they did upfront. Importantly, the point is that these drugs are not identical; they’re not simply ‘me, too’ drugs. They have different pharmacokinetics, clearance, metabolism; they have different degrees of side effects that are shared across this class of agents, and in all likelihood they have differences in the effectiveness or efficacy in patients due to the differences in the drugs themselves.”

Another therapeutic point sometimes missed, notes George, is that there is a second class of agents that has activity in this disease, the mTOR inhibitors temsirolimus and everolimus. “The mTOR inhibitors work by a different mechanism; they inhibit a critical intracellular protein within the tumor cell that slows the growth or progression of the disease,” George said. “Temsirolimus is very specific in its function. It doesn’t block any other protein in the body. When we use temsirolimus upfront as a single agent in a population of untreated patients with really aggressive metastatic disease, we see a dramatic improvement in overall survival. On average, these patients from the time of diagnosis have an expected survival of about 7 months. However, temsirolimus extends that survival to almost 11 months.” In addition, George said, temsirolimus has a different side-effect profile than the VEGF/TKIs, and has been tolerated at near full dose, even in a symptomatic population of patients. “Temsirolimus is a well-tolerated drug with a real clinical benefit, and community physicians should not fear using it to treat patients with aggressive disease.”

Jeffrey A. Sosman, MD on Immune Response in RCC

Sosman is the director of the Melanoma and Tumor Immunotherapy Program at Vanderbilt University School of Medicine.

New Therapeutic Developments in RCC

The other drug in this class, everolimus, an oral mTOR inhibitor, also has clinical benefit. “Everolimus delays progression in patients who have relapsed on one or more of the VEGF receptor TKIs. This is in many respects a complementary strategy to the VEGF receptor TKIs, and for these more rapidly-growing tumors, we can see a real clinical benefit from this class of agents,” George said.Vaccine

Ongoing clinical trials are studying immunotherapeutic agents for advanced RCC, some of which have very disparate mechanisms. “We’ve known for decades that RCC is particularly sensitive to reactivation of the immune system. Tolerance is when the immune system no longer recognizes the cancer as dangerous and is an important part of kidney cancer progression. When our immune systems overcome that tolerance and re-engage in fighting the cancer, we can see some dramatic effects. Historically, that’s using high doses of a natural compound, interleukin-2, in order to passively activate the immune system. Now, there are more active ways of re-engaging the immune system. We can, for example, create a tumor vaccine from patients who are undergoing a nephrectomy. There’s one important pivotal study—the Autologous Dendritic Cell Immunotherapy (AGS-003) Plus Standard Treatment of Advanced Renal Cell Carcinoma (RCC) or ADAPT—currently in phase III, where patients are randomized to either receive sunitinib or sunitinib plus the tumor vaccine (AGS-003). This may result in a significant change in the progression of this disease. That’s what the study is hoping to show,” said George.

Immune Checkpoint Inhibitor

A second important immunotherapy study, notes George, is the study of nivolumab, now in phase III development. “Nivolumab is the most advanced agent of PD-1-targeting cancer immunotherapies,” George said. “The drug works by blocking the protein PD-1, which is a receptor on the surface of the T-cell, the immune cells that fight and kill cancer. PD-1, when it’s activated, shuts off the T-cell. It’s the ‘snooze button’ for T-cells. Tumors can activate that snooze button by expressing the PD-1 ligand. This antibody prevents that from happening and allows those T-cells to re-engage, to ‘wake up,’ if you will. This is associated with a fairly dramatic and durable treatment response in about one-third of patients. This agent is being studied now in an advanced population of patients who have failed a VEGF receptor TKI and are going on that agent or everolimus, the mTOR inhibitor. This is a really important study that’s going on right now.”

VEGFR2/MET Inhibitor