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Contact: Kirsten Mason
kirsten.mason@toniclc.com
44-077-969-55353
ECCO-the European CanCer Organisation

ECCO 13 - Sunitinib prolongs survival in GIST patients after imatinib mesylate failure

Paris, France, Thursday 3 November 2005 - Updated results from a Phase III trial presented at the 13th European Cancer Conference (ECCO) show that sunitinib (SU11248) prolongs both progression-free and overall survival in patients with progressive metastatic and/or unresectable GIST whose disease has failed to respond to the standard therapy - imatinib mesylate.

This study was a double-blind, placebo-controlled, international, multicentre, Phase III trial involving 312 patients with GIST whose cancer had progressed despite previous treatment with imatinib mesylate. Failure of imatinib mesylate therapy was either the result of resistance or intolerance. Sunitinib treatment was in a repeated 6-week cycle consisting of a 50 mg capsule once daily for 4 weeks, followed by a 2-week break.

Results from the first planned interim analysis of this trial, disclosed at ECCO 13, demonstrate a 4-fold increase in the average time to progression (TTP) with sunitinib treatment, as compared to placebo. The estimated median TTP was 6.3 months with sunitinib, versus 1.5 months for placebo. Overall survival (OS) has also been estimated to be significantly greater with sunitinib therapy, although the average OS survival point has not yet been reached in either the sunitinib or placebo treatment arm.

Overall, treatment with sunitinib was well tolerated with fatigue, diarrhoea, nausea, sore mouth and skin discolouration proving to be the most common non-haematological side effects. Adverse events were generally mild to moderate and no severe effects (grade 4) were noted during the course of the study.

Dr George Demetri from the Dana-Farber Cancer Institute and Harvard Medical School, USA summarised: "These results from our global collaborative team provide important confirmatory evidence that documents the significant efficacy and acceptable tolerability of sunitinib (SU11248) in patients with metastatic GIST whose disease was resistant to imatinib, or those who experienced unacceptable side effects from imatinib. Before sunitinib, there was no therapy of proven value for such patients, and this trial shows that sunitinib has documented benefits"

Sunitinib is a mulitargeted drug which inhibits a number of important tyrosine kinase enzymes to exert antiangiogenic and antitumour effects.

According to Dr Demetri the study will have a considerable impact on future treatments, "The development of sunitinib (SU11248) has proceeded exceptionally fast, with the first GIST patient having started the drug in 2002, and now completion of a global Phase III clinical trial to confirm the benefits in 2005. This timeline represents the future of truly effective, targeted therapies which home in on the molecular causes of cancer. Once these targets are neutralised by effective new drugs, the benefits in terms of treating cancers such as GIST can be documented. The results of this trial will change therapy for GIST patients worldwide by introducing a new and effective agent into the physicians' therapeutic armamentarium. We have much to learn about the patients who benefit the most from SU11248 therapy, and we are already working to expand and enhance the ability to manage GIST patients using this new agent alone or in combination therapies."

He continued to comment, "The trial that we have performed shows that patients will benefit by control of GIST even in the absence of tumour shrinkage. SU11248 can stabilise the disease and prevent worsening, which translates into disease control and longer survival for GIST patients whose disease is resistant to imatinib."

Gastrointestinal stromal tumours (GISTs) are an extremely rare type of soft tissue sarcoma that arise from cells of the stroma, the connective tissue that supports the digestive organs. About 60% of GISTs occur in the stomach, but they can appear anywhere along the length of the digestive system from the oesophagus to the anus.

About Gastrointestinal Stromal tumours (GIST)

Gastrointestinal stromal tumours (GISTs) belong to a group of cancers called soft tissue sarcomas. They are cancers that develop in the supporting or connective tissues of the body i.e. muscle, fat, nerves, blood vessels, bone and cartilage. GISTs are a rare type of soft tissue sarcoma and 60% occur in the stomach, but they can occur anywhere along the length of the digestive system from the oesophagus to the anus.

There are over 170,000 cases of stomach cancer in Europe each year and it is the cause of just under 140,000 deaths annually.1 GISTs usually affect middle-aged and older patients with a median age of 50 to 60 years. They are rare before the age of 40 and very rare in children.3

The exact causes of GIST are unknown but research indicates that most GIST cells have an enzyme disorder relating to the tyrosine kinase enzyme. This enzyme is responsible for sending signals inside cells to stimulate growth and cell division. It may be associated with a family history but usually occurs spontaneously in the population.1

As with all cancers, GISTs are staged and graded before treatment is commenced. Stage 1 is considered localised and Stage 4 is when the tumours have become invasive and spread to other parts of the body.

Until relatively recently, treatment was mainly surgery and chemotherapy which had limited success. Newer therapies such as imatinib mesylate and sunitinib which interfere with growth factors and signal transduction proteins (tyrosine kinase inhibitors) are offering patients alternatives and prolonging patient survival.

###

1 www.cancerbacup.org.uk
2 Boyle, P. Cancer incidence and mortality in Europe, 2004. International Agency for Research on Cancer. 2004, p.483
3 Chandu de Silva, M V & Reid, R. Gastrointestinal stromal tumours (GIST), February 2005, Orphanet encyclopedia

For further information please contact:
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For any enquiries after Thursday 3rd November 2005, please contact:
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Abstract: 716
GI - GIST tumours
Sunitinib malate (SU11248) prolongs progression-free and overall survival for GIST patients after failure of imatinib mesylate therapy: update of a phase III trial
G. Demetri1, A. van Oosterom2, C. Garrett3, M. Blackstein4, M. Shah5, J. Verweij6, G. McArthur7, I. Judson8, C. Baum9, P. Casali10
1Dana-Farber Cancer Institute, Boston, USA
2UZ Gasthuisberg, Leuven, Belgium
3H. Lee Moffitt Cancer Center, Tampa, USA
4Mount Sinai Hospital and the University of Toronto, Toronto, Canada
5Ohio State University, Columbus, USA
6Erasmus Medical Center, Rotterdam, The Netherlands
7Peter MacCallum Cancer Center, East Melbourne, Australia
8Royal Marsden Hospital, Sutton, United Kingdom
9Pfizer Inc., La Jolla, USA
10Istituto Nazionale Tumouri, Milan, Italy

Background:
Sunitinib (SU) is an oral multitargeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, RET and FLT-3 with antiangiogenic and antitumour activities. This study assessed the efficacy and safety of SU in patients (pts) with progressive metastatic and/or unresectable GIST following failure of prior imatinib mesylate (IM) therapy due to resistance or intolerance.

Patients and methods:
In this double-blind, placebo-controlled, international, multicentre, phase III trial, 312 pts with documented progression of GIST despite previous IM therapy were randomised 2:1 to receive SU (n=207) or placebo (n=105). SU was administered as 50 mg capsules once daily for 4 weeks, followed by a 2-week break, in repetitive 6 week cycles. Pts in the placebo arm were offered the opportunity to receive open-label SU if RECIST-defined disease progression occurred. The primary study endpoint was time to progression (TTP). Secondary endpoints included overall survival (OS), response rates, time to tumour response, duration of response, functional status and clinical benefit-related parameters (McGill Pain Questionnaire, investigator-rated changes in severity of signs and symptoms and other pt-reported outcomes) as well as tolerability and safety assessments.

Results:
SU therapy resulted in a >4-fold increase in median TTP compared with placebo (HR 0.335, P<0.00001) at the first planned interim analysis for efficacy. Estimated median TTP was 6.3 months with SU vs. 1.5 months with placebo. SU improved the TTP in pts with either primary or secondary resistance to IM. SU was also associated with significantly greater estimated OS (HR 0.491; P=0.00674). The median OS has not yet been reached in either treatment arm. A total of 59 pts in the placebo group crossed over following disease progression to receive SU, with 10% subsequently exhibiting a partial response as assessed by investigators. SU therapy was well tolerated overall, with the most common non-haematologic adverse effects (AEs) being fatigue, diarrhoea, nausea, sore mouth and skin discolouration. AEs were generally mild to moderate (grade 1 or 2), and there were no grade 4 events during the study.

Conclusions:
SU was associated with significant efficacy and acceptable tolerability in this large-scale international phase III trial of GIST pts resistant to or intolerant of IM therapy.



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