High Rate of Durable Responses With Imatinib in GIST Patients

ORLANDO—In a phase II study, 63% of patients with unresectable and/or metastatic gastrointestinal stromal tumors (GISTs) responded to treatment with imatinib mesylate (Gleevec), and after a median of 15 months of follow-up, 73% of patients remain in the study, Margaret von Mehren, MD, reported at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 1608). Results at 9 months of follow-up were recently published (N Engl J Med 347:472-478, 2002).

GISTs are the most common mesenchymal tumor of the gut. Most arise in the stomach, and they are characterized by the expression of the KIT tyrosine kinase receptor, the product of the C-KIT proto-oncogene. Dr. von Mehren, a medical oncologist at Fox Chase Cancer Center, said that GISTs are resistant to standard systemic agents. Surgery is used for initial therapy. Conventional chemotherapy has a 5% response rate in recurrent/metastatic disease.

Imatinib mesylate is an ATP binding inhibitor that blocks the activity of tyrosine kinase. It has been shown to be safe and highly effective in patients with chronic myelogenous leukemia (CML) and GISTs at 400 to 600 mg daily. Dr. von Mehren said that studies evaluating doses of 800 mg in GIST are ongoing.

Between July 2000 and April 2001, 147 patients with metastatic and/or unresec-table GISTs with expression of KIT were enrolled. The median age was 54. Most patients had previous surgery, and more than half had prior systemic chemotherapy. Patients were randomized to 400 mg or 600 mg of imatinib once daily. Patients receiving the 400 mg dose were eligible to cross over to 600 mg at the time of tumor progression. Patients remained on study until disease progression (at 600 mg for crossover patients).

Dr. von Mehren said that the drug was well tolerated, with only about 20% of patients experiencing serious drug-related side effects.

"Of note, we did not observe any thrombocytopenia and had a less than 10% incidence of neutropenia. This is in contrast to the phase I study in patients with CML, where there was a 6% incidence of grade 3-4 thrombocytopenia and neutropenia at doses of 350 to 500 mg, and a 24% incidence at doses of 600 to 1,000 mg," Dr. von Mehren said.

A few patients had grade 3-4 GI bleeding localized to a tumor mass. These bleeding episodes were associated with tumor response in some patients and with irritation of the gut in others. "This contrasts with the patients who had CML, where there was only one report of a gastric hemorrhage," Dr. von Mehren said.

Response Rate

The overall response rate was 63%, with no complete responses. There was no difference in response rate between the two doses. An additional 20% of patients had stable disease, and only 12% of patients had progressive disease. Seven patients (5%) were not evaluable.

"With a median follow-up of 15 months, the median survival has not been reached, and there is no difference in survival between the 400 and 600 mg doses. This compares favorably with a series from Memorial Sloan-Kettering that reported a median survival of less than 12 months in patients unable to have resection of recurrent or metastatic disease," Dr. von Mehren said. Median time to treatment failure was 72 weeks, but Dr. von Mehren emphasized that this needs to be confirmed with longer follow-up.

Among the initial responders, 18% have progressed, with similar numbers in each treatment group. "In the majority of these patients who progressed, we have seen regrowth in a few sites of disease, with all other sites of disease remaining stable. This suggests a different mechanism of resistance than that observed in CML," Dr. von Mehren said.

When asked about how long patients might stay on treatment Dr. von Mehren said, "As investigators, we feel that as long as a patient is benefiting, we should continue. This drug may not work forever in all patients. In some patients who have an area that is progressing but most of their disease is stable, surgery to remove the area that is progressing may be feasible, with continuing imatinib for the remainder of the disease."

Discussant Robert S. Benjamin, MD, chairman of Sarcoma Medical Oncology, M.D. Anderson Cancer Center, said the study highlights were the 63% response rate and the 12% progression rate. However, he pointed out that the survival curve at 60 weeks was based on only 30 patients, and only 3 patients at 80 weeks.

"It’s somewhat disturbing that there are a few relapses at 72 weeks. Certainly that curve may flatten out as the patients progress and we have more data," he said. In comparison, European data for conventional treatment presented last year showed that at 4 months, 70% of patients had progressed.