Two drugs have shown in clinical trials led by Memorial Sloan Kettering medical oncologist and kidney cancer expert Robert J. Motzer that they improve outcomes in patients with advanced renal cell carcinoma (RCC). The drugs, nivolumab (Opdivo®) and cabozantinib, have also both been granted breakthrough status by the US Food and Drug Administration (FDA) for the treatment of advanced RCC. The FDA introduced the breakthrough therapy designation in 2012 to speed the development and review of drugs for serious or life-threatening conditions.
RCC is the most common form of kidney cancer, with more than 330,000 patients diagnosed and more than 140,000 deaths worldwide annually. It’s also particularly aggressive: Approximately 30 percent of patients have metastatic disease at the time of diagnosis — which means the cancer has already spread to other organs — and about one-third of treated patients whose disease is confined to the kidney will relapse.
Renal cell carcinoma is the most common form of kidney cancer.
The current standard of care for metastatic or advanced RCC has been treatment with a drug called everolimus (Afinitor®). Part of a class of drugs known as mTOR inhibitors, it works by slowing the growth and spread of certain cancers and has been used in patients in whom the disease has metastasized or relapsed after treatment with other drugs.
Now, an international, multicenter phase III clinical trial led by Dr. Motzer has shown that nivolumab improves overall survival in previously treated patients with advanced RCC. The trial was published online in the New England Journal of Medicine (NEJM) on September 25 and results were presented at the European Cancer Congress 2015 in Vienna, Austria, on September 26.
In the trial, patients with advanced RCC had a median overall survival rate of approximately two years with nivolumab, compared with an overall survival rate of about 19 months with everolimus. The drug works by interfering with a molecular brake known as a PD-1 checkpoint inhibitor that prevents the body’s immune system from attacking tumors.
“Although everolimus and other agents have changed the therapeutic landscape for this disease, the treatments offer only limited overall survival,” says Dr. Motzer. “Renal cell carcinoma is a disease that is crying out for new and novel treatment strategies, and this trial has produced practice-changing results in a cancer that is highly resistant to other therapies.”
An Additional Study, Additional Promise
In another study led in part by Dr. Motzer, cabozantinib improved progression-free survival (PFS) in patients with advanced RCC when compared with everolimus. (PFS is the length of time during and/or after treatment that a patient lives with a disease but it does not get worse.)
The study, published in NEJM on September 26 and also presented at the European Cancer Congress, was a randomized phase II clinical trial in patients with RCC whose disease had progressed despite treatment with at least one VEGFR-targeted therapy.
VEGF — vascular endothelial growth factor — is a signaling protein that stimulates the growth of blood vessels. Solid cancers can’t grow without an adequate blood supply, so the recruitment of blood vessels to a tumor is a key step in tumor growth and spread. Tumors expressing VEGF acquire the ability to grow and metastasize. VEGF-targeted therapies inhibit either VEGF or VEGF receptors (VEGFR).
Cabozantinib — a VEGFR inhibitor— reduced the rate of disease progression or death by 42 percent compared with everolimus. Everolimus was used as a comparison because it’s the standard treatment for patients who have progressed after receiving a VEGFR-targeted therapy. In addition to VEGFR, cabozantinib targets tyrosine kinases MET and AXL, which are believed to be important in RCC, particularly in resistant tumors.
“Over the past ten years, we have made considerable progress against advanced kidney cancers with the development of targeted drugs in phase III trials led by MSK,” says Dr. Motzer. “The phase III trials of nivolumab and cabozantinib established an improved outcome over standard treatment with everolimus in resistant tumors, and pending regulatory approval will provide two new treatment options. Both of these new drugs will contribute to the progress we’re making against this malignancy.”