High-Dose Imatinib Improves Survival in Gastrointestinal Stromal Tumors

Yael Waknine

September 24, 2004

Sept. 24, 2004 — A dose of 400 mg imatinib twice daily improves progression-free survival while inducing the same response and adverse event rate as a once-daily 400-mg dose in the treatment of metastatic gastrointestinal stromal tumors (GIST), according to the results of a randomized, phase III trial published in the Sept. 25 issue of The Lancet.

"GIST are a subgroup of soft-tissue sarcomas...[that] are insensitive to conventional chemotherapy and are generally characterized by a gain-of-function mutation of the KIT receptor and, occasionally, of the platelet-derived growth factor receptor α," write Jaap Verweij, MD, from the Department of Medical Oncology at Erasmus University Medical Centre in Rotterdam, the Netherlands, and colleagues of the European Organization for Research and Treatment of Cancer (EORTC). Imatinib is a competitive inhibitor of the tyrosine kinase domains of these and other receptors.

Imatinib is approved worldwide for use in GIST, according to the authors, and its clinical activity has been confirmed both in an EORTC phase I study, in which the maximal dose was 400 mg per day, and in phase II studies with doses of 400 mg to 800 mg daily.

In the EORTC 62005 trial, to explore the possibility of a dose-dependent relationship of response and progression-free survival, the investigators randomized 946 patients with GIST to receive 400 mg imatinib either once (n = 473) or twice (n = 473) daily. Patients administered the 400-mg daily dose were allowed to cross over to the twice-daily regimen upon disease progression.

Results at a median follow-up of about two years (median, 760 days) showed that 56% of those receiving imatinib once daily had progressed compared with 50% of those receiving twice-daily doses, with an estimated hazard ratio of 0.82 (95% confidence interval, 0.69 - 0.98; P = .026).

Adverse events were mild but frequent and occurred at a similar rate in both groups (99%). The most common events included anemia, granulocytopenia, edema, fatigue, nausea, pleuritic pain, diarrhea, and rash.

"[M]ost side effects happened early in the course of treatment, similar to our observations in the phase II study," the authors write. "This reduced frequency and intensity of side-effects contrasts with usual experience with conventional cytotoxic drugs...[a] possible explanation could be enhanced drug clearance over time, which leads to a reduction in exposure."

Patients receiving the twice-daily regimen required more dose reductions (60% vs. 16%) and treatment interruptions (64% vs. 40%) compared with those receiving the once-daily regimen.

"Despite the increased need for dose reduction in the group allocated imatinib 400 mg twice a day, these patients still received a higher dose of treatment throughout the treatment period compared with individuals assigned the once daily regimen," the authors note.

Length of time to best response was a median of 107 days (range, 58-172 days), with complete response achieved in 5% of patients. Partial response was achieved in 47% of patients, and 32% had stable disease. No difference was noted in response induction rates between regimens.

"[I]f the aim of treatment is response induction, a daily dose of 400 mg given for 4-6 months seems to be sufficient," the authors advise. "However, in patients with widespread metastatic disease, the prolonged progression-free survival achieved with 400 mg twice daily might lead some to favor this regimen."

Investigators for the EORTC 62005 study received honoraria and study grants from Novartis. One investigator received a grant from the Australasian Gastrointestinal Trials Group.

In an accompanying editorial, Yoichi Kitamura, MD, and Kazuhiko Hayashi, MD, from the Department of Surgery at the Institute of Gastroenterology, Tokyo Women's Medical University, Japan, concur with the authors' advice.

"In a recent report on a subset analysis of the crossover test in EORTC 62005, response rates and median time to progression after crossover were 33% and 81 days, respectively.... [Twenty-three percent] of the patients were still being treated 1 year after the crossover," the editorialists point out.

Noting that a lower proportion of patients needed dose reductions due to adverse events following the crossover, Drs. Kitamura and Hayashi point out, "Although it is unclear whether increased daily dose or extended administration affected all of these results, some patients with progressive disease despite 400 mg once daily might benefit from a higher dose of imatinib."

The authors add that further investigation is needed into whether fewer adverse effects could be achieved "by making use of the reduction in drug clearance over time — eg. with a starting dose of 400 mg daily followed by a stepwise dose escalation to 400 mg twice a day."

Lancet. 2004;364:1101-1102, 1127-1134

Reviewed by Gary D. Vogin, MD

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