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.

A Novel Targeted Multi-Mechanistic Oncolytic Poxvirus Targets Refractory Hepatocellular Carcinoma (HCC)

JX-594, a novel, first-in-class, targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell cycle abnormalities and EGFR/ ras pathway activation, may be uniquely suited to treat cancers.

The EGF pathway is a validated pathway and targeted by marketed pharmaceuticals such as cetuximab (Erbitux®, ImClone Systems Incorporated, Branchburg, NJ 08876, Bristol-Myers Squibb Company, Princeton, NJ 08543 and Merck KGaA, Darmstadt, Germany), which is indicated for the treatment of patients with metastasized colorectal cancer whose tumor expresses a protein called an Epidermal Growth Factor Receptor (EGFR), and gefitinib (Iressa®, AstraZeneca Pharmaceuticals, London, United Kingdom), which is indecated for continued treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum based and docetaxel chemotherapies.

In many cancers EGFR is often inappropriately activated, leading to uncontrolled cell growth. JX-594 is designed to blocks tumor growth and induce tumor regression. The compound, which is currently in Phase II trials, treats patients with advanced, primary liver cancer refractory to standard therapies. In this trial, patients are randomized to receive treatment at one of two dose levels. The 30-patient, multi-national trial is being conducted at clinical sites in the United States, South Korea and Canada.

An engineered virus
Viruses have been engineered for cancer therapy in a variety of ways. Approaches include non-replicating gene therapy vectors, cancer vaccines and oncolytic viruses, but the clinical efficacy of these approaches has been limited by multiple factors. However, a new therapeutic class of oncolytic poxviruses, which includes JX-594, has recently been developed that combines targeted and armed approaches for treating cancer. Although holding much promise for clinical treatment of many cancers, oncolytic viruses general lack of systemic delivery, and insufficient tumor cell killing, so far, limited their usefulness.

In a phase I trial, researchers have now shown that products from this therapeutic class can systemically target cancers in a highly selective and potent fashion using a multi-pronged mechanism of action. Furthermore, efficacy and safety of JX-594 was shown in patients with diverse cancer types in three Phase I trials.

Commenting on the potential of the trial, David H. Kirn, M.D., President and Chief Executive Officer of Jennerex Biotherapeutics (One Market Street, Spear Tower, Suite 2260, San Francisco, CA 94105), a clinical-stage biopharmaceutical company focused on the development and commercialization of first-in-class, breakthrough targeted oncolytic products for cancer and currently involved in the development of JX-594, said: 'We're very excited to have this trial open and enrolling with our lead product, JX-594, which has the potential to revolutionize the treatment of the more than 10,000 patients each year who develop liver cancer in the U.S. alone. The numbers of patients with liver cancer in the EU, Japan and Asia are even higher. These desperate patients represent a huge unmet medical need since few effective therapies are available for them.'

'We have already treated four patients with JX-594 in Korea and are anxious to see the efficacy of JX-594 in these late stage liver cancer patients,' said B.G. Rhee, Ph.D., Executive Vice President of Korea Green Cross Corporation (227, Kugal-ri, Kihung-up, Yong-in, Kyonggi-do 449-900, South Korea), a biotechnology company developing several vaccines and therapeutic proteins, who is developing the new compound in collaboration with Jennerex.

RECIST-criteria
The primary objective for the phase II trial is to study the efficacy of treatment with JX-594 at two different dose levels in preventing tumor progression, as measured by modified RECIST criteria, at eight weeks from initiation of treatment in patients with unresectable primary hepatocellular carcinoma. In addition, safety and tolerability, as well as tumor response and progression-free survival, of JX-594 administered at the two dose levels will be evaluated. Up to 30 total patients will be treated.

A new therapeutic approach
The new compound uses a vaccinia viruses that has been engineered to target, attack and eradicate cancer. Unlike 'vectors' or 'vaccines', JX-594 replicates in cancer cells, leading to cancer cell destruction. As a result of this uniek mechanism of action, JX-594 is able to infect and eradicate other tumor cells both locally and in distant sites in the body. The cycle of JX-594 replication, cancer cell destruction, release and spread is then repeated. Normal, healthy, cells are not affected by JX-594 resulting in safety and tolerability.

Poxvirus offers an uniek Mechanism of Action
The comound is activated by genetic pathways that are critical to the vast majority of human cancers, including common solid tumors such as lung, colon, prostate, breast, pancreas and melanoma. They employ a novel primary mechanism-of-action that is effective even against cancers that are resistant to standard therapies such as chemotherapy, small molecule tyrosine kinase inhibitors, antibodies and radiotherapy. Simultaneously, a therapeutic cascade is initiated by product replication resulting in tumor vasculature shutdown and anti-tumoral immune attack.

The poxvirus strain backbone of JX-594 has been used safely in millions of people as part of a worldwide vaccination program. This strain naturally targets cancer cells due to common genetic defects in cancer cells. JX-594 was engineered to enhance this natural safety and cancer-selectivity by deleting its thymidine kinase (TK) gene, thus making it dependent on the cellular TK expressed at persistently high levels in cancer cells. To enhance product efficacy, JX-594 is also engineered to express the GM-CSF (hGM-CSF) protein. GM-CSF complements the cancer cell lysis work of the product candidate, leading to a cascade of events resulting in tumor necrosis, tumor vasculature shutdown and an anti-tumoral immune attack.

Based on the results so far, researcher believe that JX-594 holds promise as an i.v.-delivered, targeted virotherapeutic.

For additional information, please read:

• Kirn DH, Thorne SH. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat Rev Cancer. 2009 Jan;9(1):64-71
• Liu TC, Hwang T, Park BH, Bell J, Kirn DH. The targeted oncolytic poxvirus JX-594 demonstrates antitumoral, antivascular, and anti-HBV activities in patients with hepatocellular carcinoma. Mol Ther. 2008 Sep;16(9):1637-42. Epub 2008 Jul 15
• Park BH, Hwang T, Liu TC, Sze DY, et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol. 2008 Jun;9(6):533-42. Epub 2008 May 19.
• Alemany R. A smart move against cancer for vaccinia virus. Lancet Oncol. 2008 Jun;9(6):507-8
• Kim JH, Oh JY, Park BH, Lee DE, et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol Ther. 2006 Sep;14(3):361-70
• Kirn DH, Wang Y, LeBoeuf F, Bell J, Thorne SH. Targeting of interferon-beta to produce a specific, multi-mechanistic oncolytic vaccinia virus. PLoS Med. 2007 Dec;4(12):e353
• Guo ZS, Bartlett DL. Vaccinia as a vector for gene delivery. Expert Opin Biol Ther. 2004 Jun;4(6):901-17
• McCart JA, Ward JM, Lee J, Hu Y. Systemic cancer therapy with a tumor-selective vaccinia virus mutant lacking thymidine kinase and vaccinia growth factor genes. Cancer Res. 2001 Dec 15;61(24):8751-7.

Also see:

• JX-594, Mode of Action (how does it work)