Sorafenib (Nexavar®) Significantly Improves the Length of Time Before Breast Cancer Worsens: Results From First, Large Randomized Trial

Approximately 30 studies evaluating the use of sorafenib (Nexavar®, Bayer Healthcare Pharmaceuticals/Onyx Pharmaceuticals)tablets across tumor types – as a single agent or in combination with other therapies – were presented at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin.

“The presentations at the ECCO/ESMO conference continue to build on our large body of data in unresectable liver cancer and advanced kidney cancer where sorafenib has a proven track record,” said Dimitris Voliotis, Vice President, Global Clinical Development Oncology. “Additionally, we are very enthusiastic about the presented Phase 2 studies evaluating the safety and efficacy of sorafenbib in other tumor types, including breast and thyroid cancers.”

One of the first of a series of trials to investigate the use of sorafenib – a targeted anti-cancer drug – for the treatment of advanced breast cancer has found that if it is combined with the chemotherapy drug, capecitabine (Xeloda®, Roche, Basel, Switzerland), it makes a significant difference to the time women live without their disease worsening.

Principal investigator of the study, Professor José Baselga told his audience: “This is the first, large, randomized study that demonstrates significant clinical activity of sorafenib in breast cancer when given in combination with chemotherapy. Our results showed that patients who received sorafenib plus capecitabine had a 74% percent improvement in the time they lived without their disease worsening compared to those who received the chemotherapy alone. This is a very positive study and the magnitude of the benefit is such that it suggests that this agent will be an important addition to our therapeutic armory in breast cancer.”

Sorafenib is a potent multi-kinase inhibitor, which works by interfering with the growth of cancer cells and slowing the growth of new blood vessels within the tumor. Until now, it has only been used in the treatment of kidney and liver cancer.

Prof Baselga, who is head of the oncology department at Vall d’Hebron University Hospital (Barcelona, Spain), president of ESMO (European Society for Medical Oncology) and a member of the ECCO (European CanCer Organization) executive committee, and his colleagues in Spain, France and Brazil enrolled 229 patients with locally advanced or metastatic breast cancer in the double-blind, randomized phase II clinical trial between June 2007 and December 2008. They randomized the patients to receive capecitabine (1000 mg/m2 pill taken twice daily for 14 of every 21 days) and a placebo (114 women), or capecitabine and sorafenib (400 mg pill taken twice daily continuously) for 115 women.

The very first results from the trial only became available in time for the ECCO 15 – ESMO 34 congress, and they show that the average progression free survival (the time that elapses without the cancer getting worse) was 6.4 months for women on capecitabine and sorafenib compared to 4.1 months for women taking the placebo. It is too early for data on overall survival to be available. The only death that occurred was in the placebo arm of the trial, attributed to the effect of capecitabine. The number of patients discontinuing treatment due to adverse side-effects was nine (8%) in the placebo arm and 15 (13.4%) in the sorafenib arm of the trial.

Prof Baselga said: “The regimen was tolerable and the side-effects were mostly manageable. No new or unexpected side effects were observed with this combination. The fact that this treatment could be taken orally may represent a unique and convenient treatment option for patients with breast cancer.

“This trial is an example of good academia and industry partnership. It was designed and conducted by the Spanish breast cooperative group SOLTI with the participation also of Brazilian and French groups. The trial was fully supported by Onyx and Bayer. Based on the encouraging data from this trial so far, Onyx and Bayer are evaluating various strategies for sorafenib in breast cancer.

“This trial is the first of a series of randomized phase II studies with sorafenib that are currently underway in breast cancer. Based on our results, we believe that the drug shows considerable promise for the treatment of the disease.”

For more information:

• Jose Baselga, M.D., Vall d'Hebron University Hospital in Barcelona, Spain. A double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients (pts) with locally advanced (adv) or metastatic (met) breast cancer (BC). Late-breaking abstract 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1

Other trial results:

Hepatocellular Carcinoma

• Jean-Luc Raoul, M.D., Centre Eugène Marquis, Rennes, France. Effect of Macroscopic Vascular Invasion (MVI), Extrahepatic Spread (EHS), and ECOG Performance Status (ECOG PS) on Outcome in Patients with Advanced Hepatocellular Carcinoma (HCC) Treated with Sorafenib: Analysis of Two Phase 3, Randomized Double-Blind Trials. Abstract 6621, Poster 309, Wednesday, September 23, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Josep Llovet, M.D., Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain. Efficacy and Safety of Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC): Collective Results from the Phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Asia-Pacific (AP) Trials. Abstract 6519, Poster 13, Tuesday, September 22, 2009, 8 a.m. – 11 a.m., Poster Discussion, 11:15 a.m. – 12:15 p.m., Central Lobby (Outside Hall 3)

Renal Cell Carcinoma

• Joachim Beck, M.D., Johannes-Gutenberg-Universität III. Medizinische Klinik, Mainz, Germany. Final Analysis of a Large Open-label, Noncomparative, Phase 3 Study of Sorafenib in European Patients with Advanced RCC (EU-ARCCS). Abstract 7137, Poster 150, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Hideyuki Akaza, M.D., Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan. Efficacy and Safety of Long-term Use of Sorafenib: Final Report of a Phase II Trial of Sorafenib in Japanese Patients with Unresectable/Metastatic Renal Cell Carcinoma. Abstract 7147, Poster 160, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Ronald M. Bukowski, M.D., Cleveland Clinic Taussig Cancer Center, Cleveland, OH. Efficacy and Safety of Sorafenib in Patients with Advanced Clear-Cell Renal-Cell Carcinoma (RCC) with Bone Metastases: Results from the Phase III TARGET Study Abstract 7130, Poster 143, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Dirk Jäger, M.D., National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. PREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with Nexavar) Global Non-interventional Study: First interim results. Abstract 7128, Poster 141, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1

Thyroid Cancer

• Marcia Brose, M.D., Ph.D. Department of Medicine, Division of Hematology/Oncology and Department of Otorhinolaryngology: Head and Neck Surgery, Abrahamson Cancer Center of the University of Pennsylvania, Philadelphia, PA, U.S.A. Completion of a Phase II study of sorafenib for advanced thyroid cancer. Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 11 a.m. – 1:00 p.m. Hall 14.1

Highlights of Prescribing Information:

• Sorafenib (Nexavar ®)
• Capecitabine (Xeloda®)

Also read these Pubmed Abstracts:

• Higgins MJ, Forastiere A, Marur S. New directions in the systemic treatment of metastatic thyroid cancer. Oncology (Williston Park). 2009 Aug;23(9):768-75.
• Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs. 2009 Aug;20(7):616-24.
• Hill KL Jr, Lipson AC, Sheehan JM. Brain magnetic resonance imaging changes after sorafenib and sunitinib chemotherapy in patients with advanced renal cell and breast carcinoma. J Neurosurg. 2009 Sep;111(3):497-503.
  Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I. Tyrosine kinase blockers: new hope for successful cancer therapy Anticancer Agents Med Chem. 2009 Jan;9(1):66-76. Review.
• Schraml C, Schwenzer NF, Martirosian P, Bitzer M, et al. Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol. 2009 Oct;193(4):W301-7.
• Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):367-72.

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.