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Approval Of Votrient® (Pazopanib) Provides First Oral Targeted Cancer Therapy For Patients With Selective Advanced Soft Tissue Sarcomas

From today, patients in the UK with certain types of (STS) could benefit from the first oral therapy for advanced stages of the disease. The European Medicines Agency (EMA) has approved Votrient® () for the treatment of adult patients with selective subtypes of advanced STS who have received prior chemotherapy for metastatic disease or who have progressed within 12 months after (neo) adjuvant therapy. Efficacy and safety have only been established in certain STS histological tumour subtypes*.1

“I am delighted that we will now have another systemic treatment option for patients with soft tissue . This is a welcome and much needed addition to the treatments currently available and good news for patients,” said , Head of Sarcoma Unit and Professor of Cancer Pharmacology, , London.

STS are a rare group of cancers that develop in the supporting or connective tissues of the body such as muscle, nerves, cartilage, blood vessels and fat.2 Approximately 600 patients present with advanced STS in the UK each year and the prognosis for these patients is very poor.3,4 From diagnosis of advanced disease, median survival is around 12 months5 and 5-year survival rates are less than 20%.6

The approval for pazopanib in advanced STS is based on the results of the pivotal, randomised, double-blind, placebo controlled, multi-centre, Phase III study called PALETTE (PAzopanib expLorEd in sofT TissuE sarcoma).7 PALETTE evaluated the efficacy and tolerability of pazopanib in 369 patients with certain subtypes of advanced STS who had previously received chemotherapy.7

Pazopanib significantly increased the time that patients remained progression-free compared with placebo (median progression-free survival [PFS]: 4.6 months vs.1.6 months; p<0.001).1Fifty percent of patients who received pazopanib showed some degree of tumour shrinkage versus 12% of patients in the placebo arm. Pazopanib also doubled the percentage of patients who experienced stabilisation of their disease compared with placebo (54% vs. 27%).8

Erik van Snippenberg, General Manager, GlaxoSmithKline (GSK) UK commented: “The unmet need in cancer treatment remains significant and with cancer incidence and mortality set to double over the next 20 years, GSK is committed to supporting the research and development of innovative new medicines for rare cancers such as STS.”

In England, pazopanib for advanced STS will not be subject to a NICE Single Technology Appraisal due to the small patient population. Funding will be considered at a local level and could include applications for Cancer Drugs Fund (CDF) monies. Reviews by the reimbursement bodies in Scotland and Wales are planned to take place during the second half of 2012.

Pazopanib has a well-characterised and manageable adverse event (AE) profile in advanced STS. The most common AEs observed with pazopanib treatment (experienced by ≥30% of patients) were fatigue, diarrhoea, nausea, weight decrease, hypertension, decreased appetite, hair colour changes and vomiting. The majority of events were mild to moderate (grade 1 or 2).1,8 Please refer to the Summary of Product Characteristics for further information on the safety profile and special warnings/precautions associated with pazopanib.1

Detailed information on the use of and its safety profile are described in the Summary of Product Characteristics, which will be published on the EMA website, together with the European Public Assessment Report (EPAR), and in the Community Register of Medicinal Products on the European Commission’s website.

PALETTE study (PAzopanib ExpLorEd in SofT-TissuE sarcoma)

  • The PALETTE study (VEG110727) is the first phase III trial to evaluate the effectiveness of a treatment for advanced STS in patients who have received prior anthracycline chemotherapy.
  • The study was conducted in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group.7 Patients were randomised on a 2:1 basis to receive either pazopanib 800mg once daily (n=246) or placebo (n=123).8
  • Pazopanib significantly increased median progression-free survival (PFS) compared with placebo (4.6 months vs. 1.6 months, p<0.001), by independent radiology assessment. This represents a 65% reduction in the risk of progression for patients on pazopanib compared with placebo (HR 0.35).1
  • This PFS benefit was consistent across the subtypes of STS studied (leiomyosarcoma; synovial sarcoma; and “other” eligible subtypes).1,8
  • Median overall survival (OS) was 12.6 months in the pazopanib arm versus 10.7 months in the placebo arm (p=0.256).1 Administration of post-study anti-cancer therapy may have impacted the translation of the PFS benefit to OS.7
  • There were no statistically significant or clinically important differences between pazopanib and placebo in the global health status/quality of life scores (measured through to week 12), indicating that pazopanib did not adversely affect patients’ overall quality of life relative to placebo up to 12 weeks of treatment. However, there were differences between treatment groups in mean change from baseline in several symptom scales: fatigue, nausea, vomiting, diarrhoea, and appetite loss were worse in the pazopanib arm consistent with its AE profile.8
  • The safety profile of pazopanib is manageable with monitoring and interventions (such as dose modification) as appropriate. AEs identified in this advanced STS population that had not previously been seen in advanced RCC patients were myocardial dysfunction, venous thromboembolic events and pneumothorax;1 it should be noted that patients with advanced pre-treated STS may be predisposed to these toxicities.8 Please refer to the pazopanib Summary of Product Characteristics for further information.

About STS

  • STS is a rare disease accounting for approximately 1% of all adult cancers.4
  • It is also a diverse group of tumours with more than 50 subtypes recognised by the World Health Organisation.4,10
  • The most common subtypes include leiomyosarcoma, malignant fibrous histiocytoma, and liposarcoma.11,12
  • STS can occur almost anywhere in the body, but is most common in the upper and lower limbs (~50-60%), trunk/thorax (~20%), retroperitoneum (~15%) and head/neck (<10%).4,13
  • For patients with localised STS, surgery followed by post-operative radiotherapy is the standard treatment.5
  • Approximately half of all STS patients with intermediate or high-grade tumours develop advanced disease requiring systemic treatment.5
  • Chemotherapy with an anthracycline, such as doxorubicin, is the standard first-line treatment for advanced STS.5
  • Until now, options approved for second and later line treatment of advanced STS have been limited and there is no recognised standard therapy.5 The chemotherapies used are supported only by phase II data and their use is limited by their toxicities.14

Source

1. GlaxoSmithKline. Votrient (pazopanib) Summary of Product Characteristics, August 2012.

2. Sarcoma UK. What is sarcoma?

3. National Institute for Health and Clinical Excellence. Costing statement: trabectedin for the treatment of advanced soft tissue sarcoma. London: NICE; February 2010.

4. Schoffski P. Pazopanib in the treatment of soft tissue sarcoma. Expert Rev Anticancer Ther 2012; 12 (6): 711-723.

5. Grimer R, Judson I, Peake D and Seddon B. Guidelines for the management of soft tissue sarcomas. Sarcoma, Volume 2010, Article ID 506182, 15 pages doi:10.1155/2010/506182.

6. Abraham JA, Baldini EH, Butrynski JE. Management of adult soft-tissue sarcoma of the extremities and trunk. Expert Rev. Anticancer Ther 2010; 10(2): 233-248.

7. Van der Graaf WTA, Blay JY, Chawla S, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879-86.

8. Votrient (pazopanib) tablets. FDA Oncology Drug Advisory Committee Briefing Document, March 2012.

9. Pazopanib versus sunitinib in the treatment of locally advanced and/or metastatic renal cell carcinoma (COMPARZ).

10. Fletcher C, et al. Pathology and Genetics of Tumours of Soft Tissue and Bone. World Health Organization Classification of Tumours. 2002.

11.Wibmer C, Leithner A, Zielonke N, Sperl M, Windhager R. Increasing incidence rates of soft tissue sarcomas? A population-based epidemiologic study and literature review. Ann Oncol 2010; 21: 1106-1111.

12.Toro JR, Travis LB, Wu HJ, et al. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program. Int J Cancer 2006; 119: 2922-2930.

13.Mendenhall WM, Indelicato DJ, Scarborough MT, et al. The management of adult soft tissue sarcomas. Am J Clin Oncol 2009; 32: 436-442.

14.Wesolowski R. Budd GT. Use of chemotherapy for patients with bone and soft tissue sarcomas. Cleveland J Med 2010; 77 (suppl. 1): S23-S26.