CHICAGOAccording 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
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.
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
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