Trials Support Efficacy of Imatinib Mesylate for GIST Patients But Disagree on Optimal Dose

CHICAGO—According to two parallel phase III clinical trials in the United States, Europe, and Asia, imatinib mesylate (Gleevec) is highly active in the treatment of gastrointestinal stromal tumors (GISTs). The optimal dose of the drug nevertheless is still unclear. While the safety profile was more favorable with a 400 mg/d dose than an 800 mg/d dose in both studies, the efficacy of the two doses diverged. In the US trial, progression-free survival was similar among patients who received 400 mg or 800 mg of imatinib. In the European trial, the 800-mg dose produced significantly improved progression-free survival.

"There might be an advantage with the lower dose in some patients, or perhaps 600 mg may be better than 400 mg," said Karen Antman, MD, professor of medicine and pharmacology, Columbia University, who commented on the studies at the 39th Annual Meeting of the American Society of Clinical Oncology.

The two studies were designed in tandem to assess the effect of 400 and 800 mg/d of imatinib on patients with advanced GISTs, documented expression of KIT receptor tyrosine kinase, and performance status of 0 to 3. Patients started on the 400-mg dose could crossover to the higher dose at the time of relapse, and patients on the higher dose could switch to the lower dose at any time in the presence of grade 3 toxicity.

US Trial

The US trial enrolled 746 patients from 57 institutions between December 2000 and September 2001 (abstract 3271). At the time of analysis in March 2003, 436 patients (65%) remained on the study protocol.

Confirmed response rates were identical for the two arms at 37%. When unconfirmed responses were included, the rates were 49% for the lower dose and 48% for the higher dose.

Estimates of overall and disease-free survival were essentially equivalent for patients in both arms of the study. Among 360 patients who received 400 mg of imatinib, overall survival at 12 months was 86%; among 356 patients who received 800 mg, 1-year survival was 85%. Disease-free survival at 1 year was 71% for the 400-mg group and 70% for the 800-mg treatment arm.

"I would caution that these are early data. We don’t have any data on a significant number of patients, and obviously most patients have not completed follow-up, so this is a preliminary report," said Robert S. Benjamin, MD, director of the Sarcoma Center at M.D. Anderson Cancer Center. Principal investigator was George Demetri, MD, director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School.

Dr. Benjamin noted that in previous data from EORTC (the GI leiomyosarcoma group), median time to progression with first-line chemotherapy (single agents or combinations) was 3 months, and only 10% of patients were free of progression at 12 months. "Contrast that with the fact that the median progression-free survival has not been reached in 71% of patients in this study at 12 months," he said.

Dr. Benjamin concluded that "there was no apparent advantage in the efficacy of 800 mg/d over 400 mg/d. I emphasize ‘apparent’ because we don’t yet have the final analysis." There was increased toxicity with 800 mg, which is not surprising, he added.

Although data were not available on the crossover effect, "the fact that almost half the patients on crossover are still on the study protocol suggests that crossover may be possible," Dr. Benjamin commented.

European/Asian Study

The European and Asian study enrolled 946 patients at 56 centers in 13 countries between February 2001 and February 2002 (abstract 3272). At the time of analysis, 1-year data were available on 87% of patients. The median follow-up was 17 months, and the maximum follow-up was 24 months, said Jaap Verweij, MD, PhD, professor of experimental chemotherapy, Department of Oncology, Rotterdam Cancer Institute, The Netherlands.

Unlike the American study, the international trial detected a significant difference in progression-free survival for patients in the 800-mg treatment arm, with a hazard ratio of .78.

The international study also had some crossover data: 117 patients (67%) crossed over to the higher dose. Some of these patients received the higher dose for as long as 18 months, which suggests they may have benefited from the higher dose. Otherwise, they would not have made it to 18 months, Dr. Verweij noted. "There is a suggestion that there is a subset of patients who may benefit from increasing the dose," he said.

The median time to response in the international study was approximately 4 months. However, some patients did not achieve a response for up to 12 months.

The safety data, which were similar to the findings from the US study, showed that the 800-mg dose was more toxic than the 400-mg dose. However, the majority of side effects were mild to moderate, Dr. Verweij said. The number of grade 3-4 toxicities was minimal. Anemia was common in both arms. Although thrombocytopenia occurred, it never reached grade 3-4.

The response rate in both arms of the international study was approximately 50%. Dr. Verweij concluded, consequently, that "for neoadjuvant studies that are currently being designed, the 400-mg dose is just as good as the 800-mg dose, with an optimal duration of treatment before surgery of 4 to 6 months."