3 Years versus 1 Year of Imatinib Treatment in Patients with GISTs

Chicago—Patients with high-risk gastrointestinal stromal tumors (GISTs) who received imatinib for 3 years after undergoing surgery had significantly improved overall survival and recurrence-free survival compared with patients who took 1 year of treatment with the drug. Heikki Joensuu, MD, the lead author of the prospective, open-label, multicenter, randomized phase 3 trial, presented the results during the plenary session at the ASCO meeting. Dr. Joensuu said there is an approximate GIST incidence of 10 cases per million per year. High-risk GIST consists of >5-cm tumors with a high cell proliferation rate and is associated with a ≥50% risk of recurrence within the first 5 years after undergoing surgery.

The standard therapy for patients who have an operable GIST is 1 year of imatinib, which inhibits the tyrosine kinases frequently mutated in GIST. Approximately 85% of patients respond to imatinib, and partial remission or stable disease lasts a median of 2 years. However, Dr. Joensuu said these findings may change the standard of care for patients who are at a high risk for GIST relapse. “This data is compelling,” Dr. Joensuu said. “I would not be surprised if [the standard of care guidelines] change to 3 years of imatinib.” From February 2004 to September 2008, researchers enrolled 400 patients with histologically diagnosed, c-kit receptor tyrosine kinase–positive GIST who were at high risk for recurrence. The authors defined high-risk patients as those with a tumor diameter >10 cm; a tumor mitosis count >10 as measured on 50 high-power fields of the microscope; a tumor diameter >5 cm and tumor mitosis count >5 as measured on 50 high-power fields of the microscope; or if the tumor ruptured spontaneously or at surgery. Exclusion criteria included patients with inoperable, recurrent, or metastatic GIST; age <18 years; an Eastern Cooperative Oncology Group performance status score >2; >12 weeks between the surgery and date of study entry; and clinically significant cardiac, hepatic, renal, or bone marrow disease.

Between February 2004 and September 2009, patients were randomized in 24 centers in a 1:1 ratio to receive 400 mg (4 tablets) of imatinib with food for 12 or 36 months. The dose was reduced to 300 mg when a grade 3 or 4 nonhematologic toxicity occurred or when a grade 2 nonhematologic or grade 3 or 4 hematologic toxicity recurred. Three patients were excluded because of a lack of consent from the intent-to-treat population, which consisted of patients who signed informed consent. The groups were well balanced: the median age was 61 years, and approximately 51% of patients were male. The 5-year recurrence-free survival was the primary end point and was higher in the 3-year imatinib group (65.5% vs 47.9%; hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.32-0.65; P<.0001) compared with the 1-year group. The authors defined recurrence-free survival as the time from randomization to GIST recurrence or death. Dr. Joensuu said subgroup analyses also favored the 3-year imatinib group. In addition, the 5-year overall survival for the 3-year imatinib group was 92.0% compared with 81.7% in the 1-year imatinib group (HR, 0.45; 95% CI, 0.22-0.89; P=.019). The median follow-up time was 54 months for recurrence-free survival and overall survival. All but 2 patients experienced an adverse event (AE). In the 3-year group, 65 patients had a grade 3 or 4 AE compared with 39 in the 1-year group (P=.006). There were no statistically significant differences in cardiac events or the development of second cancers. Dr. Joensuu said the treatment was well tolerated, with the most frequent side effects including anemia, eye lid swelling, fatigue, nausea, and muscle cramps. He said most side effects were mild. In the 3-year imatinib group, 13.7% of patients discontinued treatment because of an AE compared with 7.7% in the 1-year imatinib group.