NEJM Publishes Nexavar® (sorafenib) Study Demonstrating Major Improvement In Overall Survival In Patients With Advanced Hepatocellular Carcinoma

Main Category: Liver Disease / Hepatitis
Also Included In: Cancer / Oncology;  Clinical Trials / Drug Trials
Article Date: 25 Jul 2008 - 3:00 PDT

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The New England Journal of Medicine (NEJM) has today published the results of the Sorafenib HCC Assessment Randomized Protocol (SHARP) Phase 3 trial in which Nexavar® (sorafenib) tablets demonstrated that "survival rates at 1 year were 44% in the sorafenib group and 33% in the placebo group. This significant survival benefit represents a 31% relative reduction in the risk of death"1

HCC is the most common form of liver cancer accounting for 80-90 percent of all primary liver tumours.2 'Primary' liver cancer is when the cancer begins in the liver and this type of cancer is relatively rare in the UK. Each year there are approximately 2,800 new cases of primary liver cancer diagnosed in the UK and every year the disease is responsible for causing around 2,800 deaths.3

"For the first time we have unequivocal evidence of a treatment that significantly improves the survival of patients with advanced hepatocellular carcinoma. Moreover, our clinical experience since completion of the trial corroborates that this treatment is clearly effective in maintaining quality of life as well as prolonging it." said Dr Daniel Palmer, Senior Lecturer in Medical Oncology, University of Birmingham, UK. He continued: "We are now presented with opportunities, but also challenges, to further improve the care of patients with this disease. The opportunities are provided by sorafenib serving as a strong foundation upon which to build so that, through further research, more people may achieve longer term benefits. Key challenges are to find ways of identifying, in advance, those patients most likely to benefit from this treatment and, in the UK, to ensure that equitable access to the drug can be achieved for all those for whom this treatment is indicated."

Based on the strength of the SHARP data, sorafenib was approved by the EMEA in October 2007 and is licensed for the treatment of patients with HCC.4

"The number of cases of primary liver cancer in the UK continues to rise, fuelled by current lifestyles and the increasing prevalence of hepatitis B and C infections, which can lead to the development of liver cancer," commented Alison Rogers, Chief Executive of the British Liver Trust. "We are encouraged to see a drug treatment which delivers survival benefit for patients diagnosed with advanced liver cancer, offering them the chance to spend invaluable additional time with loved ones."

Primary liver cancer is the sixth most common cancer worldwide, and the third leading cause of cancer-related deaths globally.5 Primary liver cancer disproportionately affects men, giving a male: female ratio of around 3:2.6 The prognosis for patients diagnosed with primary liver cancer is often poor as the disease typically does not cause symptoms until the cancer is in its later stages.7

The international Phase 3 double-blind, placebo-controlled Sorafenib HCC Assessment Randomized Protocol (SHARP) trial evaluated 602 primary liver cancer patients who had no prior systemic therapy.1

Median overall survival was 10.7 months for patients who received Nexavar compared to 7.9 months for patients who received placebo (HR=0.69; p<0.001).1 There was no difference in time to symptomatic progression between patient groups, based on a patient-reported assessment questionnaire.

Median time to tumour progression was 5.5 months with Nexavar versus 2.8 months with placebo (HR=0.58; p=<0.001). No indication of imbalances was observed with regard to serious adverse events (SAEs) rates between the Nexavar and placebo-treated groups. The most commonly observed serious adverse events in patients receiving Nexavar were diarrhea and hand-foot-skin reaction.

"The SHARP study has identified Nexavar as the only systemic treatment proven to increase survival in patients with hepatocellular carcinoma (HCC). As such, it has already become established as the standard of care across much of Europe - but notably, not in the UK. Despite many applications to PCTs by Consultant Oncologists in recent months, most patients in the NHS have been refused funding on grounds of cost." said Philip Ashman, Business Unit Head of Bayer Schering Pharma Oncology in the UK. "According to recent studies, the UK ranks 15th in Europe for cancer survival8 and despite all the rhetoric about wishing to address this, the UK is once again among the slowest countries to adopt innovation that is proven to extend life for cancer patients."

Glossary:

Hepatocellular carcinoma (HCC) - The most common form of primary liver cancer.
Systemic therapy - A drug which when administered affects the whole body and not just part of it.
Overall Survival (OS) - The time that a patient continues to live after randomisation.
Unresectable - Not capable of being removed by surgery
Renal Cell Carcinoma (RCC) - The most common type of kidney cancer in adults
EMEA - European Medicines Agency. Responsible for the scientific evaluation of applications for European marketing authorisation for medicinal products (centralised procedure).

About sorafenib:

Sorafenib was approved by the EMEA in October 2007 and licensed for the treatment of patients with hepatocellular carcinoma (HCC).4

The licence for sorafenib was based on data from the Phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial which demonstrated that sorafenib improved overall survival by 44 percent in patients with advanced HCC (HR=0.69; p=0.0006) versus best supportive care alone.1 The most commonly observed (occurring in >5% of subjects) adverse reactions (CTC-Grade 3) were diarrhoea and hand-foot skin reaction. The incidence of Grade 4 adverse reactions is less than 1%.9 The primary endpoints of the study included overall survival (OS) and time to symptomatic progression in patients administered sorafenib versus those who received placebo. Secondary endpoints included time to progression, disease control rate and safety.

Sorafenib differentiated mechanism

Sorafenib targets both the tumour cell and tumour vasculature. In preclinical studies, sorafenib has been shown to target kinases known to be involved in both cell proliferation (growth) and angiogenesis (blood supply) - two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR-2, VEGFR-3, PDGFR-B, c-KIT, FLT-3 1 and RET10. Preclinical models have also demonstrated that the Raf/MEK/ERK pathway has a role in HCC.11

Kidney cancer:

Sorafenib was first approved by the EMEA in July 2006. Sorafenib is approved in the UK for the treatment of patients with advanced renal cell carcinoma (the most common form of kidney cancer), who have failed prior interleukin-2 or interferon-alpha based therapy, or are considered unsuitable for such therapy. Prior to EMEA approval of sorafenib, there had not been any new classes of licensed kidney cancer treatment in Europe for over 10 years.

Bayer Schering Pharma

Bayer Schering Pharma is a leading, worldwide speciality pharmaceutical company. Its research and business activities are focussed on the fields of oncology, haematology & cardiology, diagnostic imaging, primary care, specialised therapeutics and women's healthcare. With innovative products and using new ideas, Bayer Schering Pharma aims to make a contribution to medical progress and strives to improve the quality of life of patients - a factor of particular importance in Oncology.

Bayer Schering Pharma's portfolio of oncological products includes treatments for both solid and haematological malignancies. Intensive research is ongoing as Bayer Schering Pharma strives to discover and advance therapeutic solutions for the benefit of all cancer patients.

Nexavar® (sorafenib) tablets is a registered trademark of Bayer Pharmaceuticals Corporation.

References

1. Sorafenib in advanced Hepatocellular Carcinoma. J. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, J. Raoul, S. Zeuzem, M. Poulin-Costello, M. Moscovici, D. Voliotis, J. Bruix, For the SHARP Investigators Study Group. N Eng J Med 2008;359:378-90
2. Wilson JF. "Liver Cancer on the Rise." Ann Int Med, 2005; 142(12):1029-32. 3. Cancer Research UK http://info.cancerresearchuk.org/cancerstats/types/liver/?a=5441
4. Electronic Medicines Compendium http://emc.medicines.org.uk/
5. Parkin DM et al. Global Cancer Statistics, 2002 CA Cancer J Clin 2005; 55:74-108
6. Cancer Research UK http://info.cancerresearchuk.org/cancerstats/types/liver/incidence/
7. Cancer Backup http://www.cancerbackup.org.uk/Cancertype/Liver/Primarylivercancer
8. A global comparison regarding patient access to cancer drugs Jönsson B, Wilking N. Ann Oncol (2007) 18(Suppl. 3). 72. (Annals of Oncology)
9 Nexavar (sorafenib) Summary of Product Characteristics, Bayer HealthCare AG, 2007.
10. BAY 43-9006 inhibition of oncogenic RET mutants. Carlomagno, F. et al, J Natl Cancer Inst 2006; 98:326-34
11. Liu, L, Y. Cao, et al. Cancer Res, 2006; 66(24):11851-8

Source:
www.bayerscheringpharma.co.uk