New Treatments Changing the Management of Renal Cell Carcinoma

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Advances in detecting and targeting genetic signatures are opening up new avenues of treatment along with new immunotherapies.
Advances in detecting and targeting genetic signatures are opening up new avenues of treatment along with new immunotherapies.

While the U.S. Food and Drug Administration's approval of nivolumab for the treatment of metastatic renal cell carcinoma (RCC) in November marked a milestone in RCC care, it was just one of several significant advances that have occurred over the past year.1

Advances in detecting and targeting genetic signatures are opening up new avenues of treatment along with new immunotherapies.

Many oncologists are encouraged by a growing body of scientific evidence showing that agents for treating other tumors may be beneficial in combating RCC. Richard Pazdur, MD, who is the director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, announced the approval of nivolumab and noted that it is an extended indication.

It was already approved for treating melanoma and non-small cell lung cancer. He said the new approval for treating RCC demonstrates how immune therapies can benefit patients across a wide range of tumors. Nivolumab, which targets the cellular pathway PD-1/PD-L1, may be one of several new agents changing the treatment paradigm in the coming months.

He said this agent is one of 2 therapies to demonstrate an ability to extend survival in patients with RCC. Dr Pazdur said temsirolimus, which was approved in 2007, was the only other FDA-approved therapy that has demonstrated improvement in overall survival in RCC.

“Two new drugs have shown improved progression free survival (PFS) after 1 or 2 lines with anti-vascular endothelial growth factor (VEGF) therapies: c-met/VEGF inhibitor cabozantinib and anti-PD-1 antibody nivolumab, which also showed improved median survival in comparison to everolimus,” said Igor Puzanov, MD, who is an associate professor of medicine (hematology/oncology) and the clinical director of renal cancer at Vanderbilt-Ingram Cancer Center in Nashville, TN.

“Nivolumab has become a new standard for patients who progressed on 1 or 2 VEGF inhibitors such as sunitinib and axitinib. We are now very quickly exploring the checkpoint inhibitor combination ipilimumab/nivolumab as well as anti-PDL-1/anti-VEGF atezolizumab/bevacizumab combinations in the first-line setting.”

Attacking RCC in a New Way

Immunotherapy approaches are being tested in patients with both metastatic disease and localized disease. This summer, patients were enrolled in a novel immunotherapy trial involving AGS-003, an autologous dendritic-cell-based immunotherapy designed to induce a memory T-cell response specific to each patient's unique tumor antigens, said Thomas Schwaab, MD, PhD, who is the principle investigator in the trial, as well as an associate professor of oncology in the departments of Urology and Immunology at Roswell Park Cancer Institute in Buffalo, NY. AGS-003 has shown promise in metastatic disease and is now being tested in localized disease.

In this trial, 10 patients are being treated with AGS-003 before nephrectomy in order to assess immune system response and tumor effects. Schwaab said the goal is to develop a treatment that will interrupt tumor progression before it can metastasize. He said that while there is a great deal of optimism, there is also reason for caution. He noted that new studies have confirmed that RCC is a very heterogeneous disease.

“We don't know how the immunotherapies will work yet. They are looking good for melanoma but I would caution that kidney cancer is different than other cancers,” Dr Schwaab said in an interview with Cancer Therapy Advisor.

Dr Puzanov agreed that there are several types of RCC that are only now being subtyped based on their genomic signatures. Investigators at Rutgers Cancer Institute of New Jersey published a study in the journal Cell Reports that identified an entirely new way of identifying and potentially treating patients with kidney tumors.2

The findings from this study suggest that inhibiting mitochondria with agents such as metformin may have anti-cancer activity in a variety of cancers.

The Rutgers researchers sequenced 11 benign human renal oncocytoma samples. Renal oncocytoma in general is not cancerous.

However, it has the ability to become malignant. The samples were characterized based on chromosome loss and the researchers designated type-1 as having no chromosome loss. Type-2 included those samples having a specific chromosome loss. The investigators concluded that type-2 oncocytomas with chromosome loss may progress to the subtype of malignant kidney cancer known as eosinophilic chromophobe RCC.

“There are no new modalities for localized RCC and surgery remains the best option with enrollment in an adjuvant clinical trial afterwards. We are currently exploring everolimus versus placebo in an adjuvant trial run by the Eastern Cooperative Oncology Group and will soon open a trial with the anti PD-1 agent nivolumab for these patients,” Dr Pazanov told Cancer Therapy Advisor.

Statins May Be Beneficial

Earlier this year, researchers at Vanderbilt University reported in Urologic Oncology that patients being treated with statins at the time of surgery for RCC had improved overall survival and disease-specific survival.3

The study suggested a 38% reduction in the risk of death as well as a 52% reduction in the risk of disease-specific death for patients taking statins.

The authors found the 3-year overall survival for patients taking statins at the time of surgery was 83.1% but only 77.3% for nonusers. The 3-year disease-specific survival was 90.9% for statin users compared to 83.5% for nonusers. The results were consistent in an analysis of patients whose disease had not metastasized.

Ajjai Alva, MD, who is a clinical assistant professor of hematology/oncology at the University of Michigan Health System in Ann Arbor, MI, said the large phase 3 randomized, double-blind, RCC trial EVEREST (SWOG 0931) testing everolimus in the adjuvant setting is nearing completion of accrual. He said it is hoped that the results will be different from the prior negative adjuvant trials with sunitinib, sorafenib, and pazopanib.

“The next development has been double immunotherapy of nivolumab and ipilimumab versus sunitinib. The trial in the first-line setting is completing accrual. Results should be coming in a few years,” Dr Alva told Cancer Therapy Advisor.

“It is indeed a new era and immunotherapy works in metastatic RCC, but we still have a long, long way to go. For one, we are not curing anyone. The overall response rate for nivolumab as a single agent is only 25%. The next challenge is how to increase this with immunopotentiators.”

Dr Alva said questions remain over which stage is ideal for starting immunopotentiators and how best to sequence them. Mayer Fishman, MD, PhD, who is a senior member of the Genitourinary Oncology Program at Moffitt Cancer Center, in Tampa, FL, said clinicians in the coming year may have several new treatment approaches to offer patients with RCC.

“Another trial with the combination of ipilimumab and nivolumab compared to sunitinib has completed accrual for first-line patients. The results may impact first-line therapy choices in 2017,” Dr Fishman told Cancer Therapy Advisor. “Interest in this type of immunotherapy also continues with pembrolizumab and avelumab starting kidney cancer pivotal trial programs.”

References

  1. U.S. Food and Drug Association. FDA approves Opdivo to treat advanced form of kidney cancer [news release]. http://1.usa.gov/1PWB9aE. Accessed December 22, 2015.  
  2. Joshi S, Tolkunov D, Aviv H, et al. The genomic landscape of renal oncocytoma identifies a metabolic barrier to tumorigenesis. Cell Reports. 2015;13(9):1895-1908.
  3. Kaffenberger SD, Lin-Tsai O, Stratton KL, et al. Statin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma. Urol Oncol. 2015;33(1):21.e11-e17. 

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