FDA Approves Gleevec for Use in Inoperable or Metastatic GISTs

March 1, 2002

ROCKVILLE, Maryland-The Food and Drug Administration (FDA) has approved the use of Gleevec (imatinib mesylate, Novartis) for the treatment of c-kit-positive inoperable and metastatic malignant gastrointestinal stromal tumors (GISTs).

ROCKVILLE, Maryland—The Food and Drug Administration (FDA) has approved the use of Gleevec (imatinib mesylate, Novartis) for the treatment of c-kit-positive inoperable and metastatic malignant gastrointestinal stromal tumors (GISTs).

The FDA granted marketing approval on the basis of objective response to Gleevec that was established in a phase II study of 147 GIST patients, 38% of whom showed a partial response to treatment with the oral medication. Gleevec was originally approved on May 10, 2001, for the treatment of three stages of chronic myeloid leukemia (CML)—myeloid blast crisis, accelerated, and chronic.

"This is the first time we have seen such encouraging results in a drug used to combat GISTs," said George Demetri, MD, of the Dana-Farber Cancer Institute, who led the open-label, international study. "Gleevec represents the most major advance to date for a patient population that has had no alternative other than surgery for treating this resistant disease."

GISTs are the most common form of gastrointestinal tract sarcoma and affect an estimated 2,000 to 5,000 people in the United States. Patients with unresectable or metastatic GISTs have been considered incurable and essentially untreat-able, with a median survival of about 10 to 12 months.

In the study reviewed by the FDA, researchers randomized 147 patients to receive either 400 mg or 600 mg of Gleevec daily for up to 24 months. Although none of the participants had a complete response to the oral medication, 56 patients—33% of the 400-mg arm and 43% of the 600-mg group—had a partial response, defined as a reduction in tumor size of 50% or more. None of the patients in the study had been followed long enough to determine a meaningful response duration.

Most patients experienced an adverse side effect at least once while taking Gleevec, but most of the events were mild or modest in severity.

The most common events were edema, nausea, vomiting, diarrhea, abdominal pain, liver toxicity, neutropenia, thrombocytopenia, muscle cramps, skin rash, and fatigue.

Twelve patients (8%), six in each arm, were taken off the drug because of adverse effects, and seven patients (5%)
suffered either GI and/or intratumoral bleeding that required red blood cell transfusions.

Gleevec is a signal transduction inhibitor that blocks the activities of abnormal tyrosine kinases involved in the growth of some cancers. The enzymes are mostly confined to specific types of cancer cells, and, thus, Gleevec causes little damage to normal cells.

Bcr-Abl, c-kit, and PDG-F

CML results from a reciprocal translocation between chromosome 9 and 12, which produces the Philadelphia chromosome. The translocation causes production of an abnormal protein designated Bcr-Abl, which, in turn, leads to an uncontrolled proliferation of white blood cells. Gleevec prevents the enzyme from functioning.

In GIST, Gleevec blocks another enzyme, called c-kit, which drives the growth and division of most GI stromal tumors. C-kit also plays a role in small-cell lung cancer. Another tyrosine kinase, PDG-F, is active in gliomas, prostate cancer, and soft-tissue sarcoma.

FDA granted marketing approval for Gleevec’s use in treating GIST under its accelerated approval and orphan drug regulations. Accelerated approval stipulates that Novartis must conduct further studies to determine whether the drug provides actual clinical benefit.