Novartis seeks U.S. OK to use Gleevec on GIST

Approval would mean first treatment option beyond surgery for GIST

BASEL, Switzerland — Novartis announced Oct. 19 that it has asked the U.S. Food and Drug Administration for approval to market Gleevec for the treatment of patients with unresectable (inoperable) and/or metastatic gastrointestinal stromal tumor.

GISTs are the most common malignant form of sarcoma arising in the gastrointestinal tract. Historically, GISTs have been very difficult to treat due to their high resistance to traditional chemotherapy and radiation therapy. For patients with metastatic or unresectable disease, GISTs represent an incurable malignancy with a median survival of approximately 10 to 12 months.

Until now, surgery has been the only treatment option, resulting in essentially palliation of this disease. There are approximately 12,000 new cases each year of malignant GIST worldwide.

“GISTs are very difficult to treat and there are very few options beyond surgery for these patients,” said Dr. David Parkinson, vice president of clinical research for Novartis Oncology. “Gleevec is extremely active against the molecular abnormality that helps trigger GISTs, and Novartis believes it represents a significant advance in overall treatment of the disease.”

Last May, the Food and Drug Administration approved Gleevec for the treatment of patients with chronic myeloid leukemia just 10 weeks after Novartis filed its application for approval — the fastest approval of any cancer drug.

The effectiveness of Gleevec in CML is based on overall hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit such as improvement in disease-related symptoms or increased survival.

Gleevec (known as Glivec outside the U.S.) is currently approved for marketing in more than 30 countries. Gleevec received a positive recommendation by the European Union’s Committee for Proprietary Medicinal Products in July, and an approval by the European Commission is anticipated shortly.

Novartis sought FDA approval to use Gleevec on GIST based on data from a Phase II, open-label, multinational study conducted in 147 patients with unresectable or metastatic malignant GIST. Patients were randomized to receive either 400 mg or 600 mg of Gleevec daily for up to 24 months. The overall response rate is 40 percent based on confirmed partial responses at the time of the data cut-off for the submission. An additional 32 percent of patients in this study achieved a clinically significant reduction in tumor size. Only 12 percent of patients experienced disease progressed in the study.

Gleevec has been well tolerated in patients with GIST. Although almost all patients reported an adverse reaction at least once during the trial, only a very small percentage had these recorded as either grade 3 or 4 in severity. Five patients (3.4 percent) withdrew from the study due to adverse events. In this clinical trial, the most common adverse events were nausea, diarrhea, periorbital edema, fatigue, muscle cramps, abdominal pain, dermatitis, vomiting, flatulence, lower limb edema, nasopharyngitis, insomnia, back pain and pyrexia. There is no long-term safety data on Gleevec treatment.

Gleevec is one of the first cancer drugs to be developed using rational drug design, based on an understanding of how some cancer cells work. Gleevec targets the activity of certain enzymes called tyrosine kinases that play an important role within certain cancer cells. The activity of one of these tyrosine kinases, known as c-kit, is thought to drive the growth and division of most GISTs.

Novartis, based in Basel, Switzerland, is a world leader in health care with about 70,000 employees in more than 140 countries. In 2000, Novartis had $17.2 billion (U.S.) in sales and a net income of $3.9 billion. Some $2.4 billion was spent on research and development.