Novartis announced that, in record time, the European Commission (EC) has issued approval for the breakthrough drug Glivec (imatinib) for the treatment of patients with Kit (CD 117)-positive unresectable (inoperable) and/or metastatic malignant gastrointestinal stromal tumours (GISTs).
The approval follows a positive recommendation by the EU's Committee for Proprietary Medicine (CPMP) in February 2002. It is the second EC approval for Glivec in seven months: the first, on 7 November 2001, was as an oral therapy for the treatment of adult patients with Philadelphia (Bcr-Abl) chromosome-positive chronic myeloid leukemia (CML) in chronic phase after failure of interferon-alpha therapy, or in accelerated phase or blast crisis.
"Patients with GISTs have traditionally had very limited treatment options, so we are especially pleased that authorities are recognising the value of Glivec in treating this life-threatening cancer," said Daniel Vasella, MD, chairman and CEO of Novartis. "Glivec has already had a significant impact on the lives of people with CML and GISTs, and we are continuing to study it in other cancers to determine if it has the potential to help patients, either alone or in combination with other therapies."
GISTs are the most common malignant form of sarcoma that arise in the gastrointestinal tract. Worldwide, there are approximately 12 000 new cases each year. The incidence is highest in people 30-60 years of age. Historically, GISTs have been very difficult to treat due to their resistance to treatment with available chemotherapy and radiation therapy.
For patients with metastatic or unresectable disease, GISTs were an incurable malignancy with a median survival of 20 months and, with local recurrence, a median survival of 9-12 months. Until now, surgery has been the only treatment option, resulting essentially in palliation of the disease.
The EC approval for the GIST indication is supported by data from an open-label, multinational study conducted in 147 patients with Kit (CD117) positive unresectable and/or metastatic malignant GISTs. Patients were randomised to receive either 400 mg or 600 mg of Glivec daily until remission. The overall response rate was 40 per cent, based on confirmed partial responses and stable disease at the time of the data cut-off for the submission.
Data which have emerged since the submission for approval were presented in May 2002 at the 38th annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA. The data showed that in this study, more than 60 per cent of patients with GIST achieved confirmed partial response to Glivec, and an additional 20% attained some degree of tumour shrinkage or stablisation of their disease. The data also revealed that at a median follow-up of 15 months, 73 per cent of patients remained on the study.
Glivec, a signal transduction inhibitor, is one of the first cancer drugs to be developed using rational drug design, based on an understanding of how some cancer cells are generated and exhibit unrestrained growth. Glivec targets the activity of specific enzymes called tyrosine kinases that play an important role within certain cancer cells. The activity of a tyrosine kinase known as Kit, a receptor that is the product of a gene called c-kit, is very often mutated and is known to drive the growth and division of most GISTs.
The U.S. Food and Drug Administration (FDA) was the first to approve Glivec for the GIST indication, for which it was designated as an Orphan Drug, on 1 February 2002. Glivec also is approved for the GIST indication in Switzerland, where it was approved on 15 April 2002. To date, Novartis has received marketing clearance for Glivec for the CML indication worldwide.
Although the majority of patients had adverse events reported at least once during this trial, most events were mild to moderate in severity and included nausea, diarrhoea, periorbital oedema, muscle cramps, fatigue, headache and skin rash. About 23 per cent of the patients had severe drug-related side effects that included low white blood cell counts, tumour haemorrhage and abdominal pain. In the GIST trial submitted for registration, drug was discontinued for adverse events in 13 patients (9% of patients).
In this clinical trial, the most common adverse events were oedema, nausea, diarrhoea, abdominal pain, muscle cramps, fatigue and rash. In this trial, seven patients (5%) were reported to have gastrointestinal bleeds and/or intra tumoural bleeds. Gastrointestinal tumour sites may have been the source of GI bleeds. Glivec is contraindicated in patients with known hypersensitivity to imatinib or any of its excipients. Women of childbearing potential should be advised to avoid becoming pregnant while taking Glivec.
In most countries where Glivec is approved, it is indicated for the treatment of patients with Philadelphia chromosome-positive CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.