Everolimus (Afinitor®) Licensed in UK for Advanced Kidney Cancer Patients After Failure of First Line Vascular Targeted Therapy

Everolimus (Afinitor®, Novartis AG, Basel, Switzerland) has recently been licensed in the United Kingdom for the treatment of advanced kidney cancer after failure of treatments which prevent the growth of the tumor’s blood vessels, which is essential for the cancer to survive. The European Commission (EC) approved everolimus for this use on 3rd August 2009 for patients with advanced kidney cancer whose disease progressed on or after treatment with VEGF-targeted therapy.

Everolimus belongs to a class of drugs called kinase inhibitors, which interfere with cell communication, preventing tumor growth. The drug is intended for those patients with advanced renal cell cancer who have already tried another kinase inhibitor, sunitinib (Sutent, Pfizer Inc., New York, USA) or sorafenib (Nexavar, Bayer HealthCare AG, Leverkusen, Germany).

Mechanism of Action
While sunitinib and sorafenib are multiple kinase inhibitors (acting on a number of cellular targets), everolimus works by blocking a specific protein known as the mammalian target of rapamycin or mTOR, a protein that acts as a central regulator of tumor cell division, blood vessel growth and cell metabolism.

A clinical trial studying the safety and effectiveness of everolimus was discontinued after an interim analysis showed that, in patients receiving the drug, the growth or spread of the tumor was delayed when compared to patients who did not receive the drug. In addition, disease progression was delayed approximately five months in half of the patients who received everolimus. In contrast, disease progression was delayed two months in patients who did not receive the drug.

The most frequent adverse reactions in the trial (occurring in at least 20 percent of patients) included inflammation in the mouth, loss of strength, diarrhea, poor appetite, fluid buildup in the extremities, shortness of breath, coughing, nausea, vomiting, rash, and fever. Laboratory tests of blood samples determined that at least half of all patients experienced anemia, low white blood counts, high cholesterol and high triglycerides and high blood sugar.

Patients with advanced renal cell cancer have limited options once tumors progress after first line standard therapy. Now, phase III trials show that everolimus more than doubles the median time without tumor growth and reduces the risk of disease worsening or death by 67% compared with placebo.

Prior to this date, there were no licensed treatment options in the United Kingdom for advanced renal cell carcinoma patients whose cancer progressed while on or after treatment with these targeted therapies.

Incidence
Advanced renal cell carcinoma, the most common type of kidney cancer, accounts for approximately 2% of all new cancers. In the UK, the incidence of kidney cancer is increasing, due in part to obesity and smoking.

Renal cell cancer originates in the lining of the small tubules in the kidney that filter waste products from the blood. The cancer is resistant to such standard treatments as radiation therapy and chemotherapy, and the initial treatment for most patients is surgical removal of the kidney. If the cancer is confined to the kidney, the five-year survival rate is 60 to 70 percent. However, if left untreated, the tumor can spread to neighboring lymph nodes and eventually to other organs, considerably reducing the survival rate.

"I am delighted that there is now a proven treatment option available to people living with advanced kidney cancer in the UK, who have progressed after treatment with a targeted therapy. The availability of Afinitor is an important step in ensuring this population of poor prognosis patients have the potential to control their disease even further," said Tim Eisen, Professor of Medical Oncology at the University of Cambridge.

Expert consensus opinion, recently published in a review article in the British Journal of Hospital Medicine, has been updated to recommend everolimus as a Second-Line Therapy treatment option for advanced kidney cancer therapy after progression on targeted therapies.

Data that led to the European approval show that everolimus, when compared with placebo, more than doubled the median time without tumor growth or death in patients with advanced kidney cancer whose disease progressed following prior vascular targeted therapy (4.9 vs. 1.9 months). The data showed the reduction of the risk of disease progression or death by 67% based on the primary endpoint of progression-free survival (PFS) (hazard ratio=0.33 with 95% confidence interval 0.25 to 0.43; P<0.001.>

Every year there are 7,000 newly diagnosed cases of kidney cancer which also causes around 3,700 deaths a year," said Pat Hanlon, Kidney Cancer UK. "While many of these cancer patients will be diagnosed early and undergo surgery to cure them, 40% of patients will be diagnosed in the advanced stages when prognosis is extremely poor and the cancer is notoriously difficult to treat."

James Whale, Founder of The James Whale Fund for Kidney Cancer, adds: "We at the Fund are pleased everolimus has been granted a license in the UK as, given the poor prognosis of kidney cancer, it is critical for people living with the disease to have access to life-extending treatments. This has been proven to provide benefit to kidney cancer patients, enabling them to spend precious time with family and friends."

The U.S. Food and Drug Administration (FDA) approved everolimus oral tablets for the treatment of patients with advanced kidney cancer whose disease has progressed after treatment with other cancer therapies in March 2009. Following the approval in the US National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines in Oncology™ for Kidney Cancer to reflect th eFDA approval of everolimus.

For more information:

• Afinitor® website (for non-US healthcare professionals)
• Afinitor® website (for US healthcare professionals)
• EPARs for Authorised Medicinal Products for Human Use
• Escudier, B et al. 72O - Phase III Randomised Trial of Everolimus (RAD001) vs Placebo in Metastatic Renal Cell Carcinoma. Presented at the European Society for Medical Oncology (ESMO) 33rd Congress, Stockholm, Sweden on 16 September 2008
• Escudier B, Kataja V; ESMO Guidelines Working Group. Renal cell carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009 May;20 Suppl 4:81-2.
• Motzer RJ, Escudier B, Oudard S, Hutson TE, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008 Aug 9;372(9637):449-56. Epub 2008 Jul 22.
• Nathan P, Wagstaff J, Porfiri E, Powles T, Eisen T. UK Guidelines for the Systemic Treatment of Renal Cell Carcinoma. Br J Hosp Med (Lond). 2009 May;70(5):284-6. Review.
• Eisen T, Oudard S, Szczylik C, Gravis G, et al; TARGET Study Group. Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst. 2008 Oct 15;100(20):1454-63. Epub 2008 Oct 7.
• McLaughlin JK, Lipworth L, Tarone RE. Epidemiologic aspects of renal cell carcinoma.
  Semin Oncol. 2006 Oct;33(5):527-33. Review.
• Motzer RJ, Agarwal N, Beard C, Bolger GB, et al. NCCN clinical practice guidelines in oncology: kidney cancer. J Natl Compr Canc Netw. 2009 Jun;7(6):618-30.
• Highlights of the NCCN 13th Annual Conference: Clinical Practice Guidelines & Quality Cancer Care™, published as a supplement to The Oncology Report: The mTOR pathway as a new target.