A NEW DRUG APPROVED FOR RENAL CANCER (AFINITOR)-BEWARE OF PNEUMONITIS

Everolimus (Afinitor) Approved for Refractory Renal Cell Carcinoma

On March 30, the FDA approved everolimus 5- and 10-mg tablets (Afinitor, Novartis Pharmaceuticals Corp) for the treatment of advanced renal cell carcinoma after failure of treatment with sunitinib (Sutent, Pfizer, Inc) or sorafenib (Nexavar, Bayer Healthcare AG).

Everolimus potently inhibits the molecular target of rapamycin, a critical downstream effector of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, thereby inhibiting cell cycle progression, cell growth, and proliferation.

"This approval provides a new and useful tool for treating advanced renal cell carcinoma, representing an important step forward in managing this disease," said Robert J. Motzer, MD, in a company news release. "New treatment options are vital to help us continue to offer patients with advanced kidney cancer new ways to battle their difficult-to-treat disease. Based on clinical trial data, this option should be considered when sunitinib or sorafenib fail."

Dr. Motzer is an attending physician at Memorial Sloan-Kettering Cancer Center in New York and principal investigator of the Renal Cell Cancer Treatment With Oral RAD001 Given Daily trial (n = 416), which served as the basis for the FDA's approval.

Results of the study showed that treatment with 10 mg/day everolimus more than doubled the time to tumor growth or to death (4.9 vs 1.9 months) and decreased the risk for disease or death by 67% (hazard ratio = 0.33; 95% confidence interval [CI], 0.25 – 0.43, P < .0001). After 10 months of treatment, about 25% of patients still had no tumor growth.

The most frequently reported adverse events related to treatment with everolimus (incidence ≥ 20%) were stomatitis, asthenia, diarrhea, poor appetite, fluid buildup in the extremities, dyspnea, coughing, nausea, vomiting, rash, and fever.

Laboratory tests of blood samples determined that 50% or more patients experienced anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine levels. Renal function, blood glucose, lipids, and hematological parameters should be evaluated before initiating treatment with everolimus and periodically thereafter.

Potentially serious adverse reactions include noninfectious pneumonitis and infections for which patients should be monitored carefully and treated as needed, the FDA warns, noting that temporary dose reductions and/or interruption or discontinuation of therapy may be warranted. Live vaccinations and close contact with those who have received live vaccines should be avoided during treatment with everolimus.

Concomitant use of strong or moderate CYP3A4 or P-glycoprotein inhibitors should be avoided in patients receiving everolimus therapy; dose increases are recommended for coadministered strong CYP3A4 inducers.

Everolimus, marketed as Certican (Novartis Pharmaceuticals), previously was approved in the European Union for the prevention of organ rejection in heart and kidney transplant recipients. Applications currently under investigation in phase 3 trials include multiple cancer types (neuroendocrine, breast, and gastric), tuberous sclerosis complex, and non-Hodgkin's lymphoma.

Sunitinib and sorafenib are multiple kinase inhibitors indicated for the primary treatment of advanced renal cell carcinoma; sunitinib is also approved to treat gastrointestinal stromal tumors, and sorafenib may be used for unresectable hepatocellular carcinoma.