The study, published March 28 in the Journal of the American Medical Association, supports the US Food and Drug Administration’s (FDA) recent decision to approve expanded use of imatinib for up to 36 months after surgery for adult patients with KIT-positive GIST at high-risk for recurrent disease.
In an accompanying commentary in JAMA, Dr. Charles D. Blanke of the University of British Columbia and British Columbia Cancer Agency in Vancouver says this trial establishes three years of 400 mg of imatinib per day as the “new standard of care” for postoperative treatment of patients with resected high-risk GISTs. “Some clinicians will use imatinib for a longer period, perhaps choosing to treat patients indefinitely,” he notes.
In their paper, Dr. Heikki Joensuu, of the Helsinki University Central Hospital in Finland and colleagues point out that up to 80% of GISTs harbor an activating mutation in the KIT oncogene. Adjuvant imatinib given for one year after resection of KIT-positive GIST prolongs recurrence-free survival but its effect on survival is unknown. GIST often recurs during the first years following discontinuation of adjuvant imatinib, suggesting that one year of administration may be too short a time period and that a longer treatment period might have benefits.
To investigate, the researchers compared one year and three years of adjuvant imatinib (400 mg per day), started within 12 weeks of resection of KIT-positive GIST. There were 200 patients in each arm; all patients were deemed to be at high-risk for GIST recurrence.
Five-year recurrence-free survival rates were higher with three years than the one year of treatment (65.6% vs 47.9%); the hazard ratio was 0.46 (p<0.001).
The difference in overall survival was also statistically significant in favor of longer treatment. The 5-year overall survival rate was 92.0% with three years of treatment compared with 81.7% with one year (hazard ratio 0.45; p=0.02). “These figures are very favorable compared to historical series that date back to the pre-imatinib era,” Dr. Joensuu told Reuters Health by email.
He also noted that this is “the first randomized trial to report an overall survival benefit associated with an oral tyrosine kinase inhibitor administered as adjuvant treatment in human cancer.”
The researchers note in their report, however, that the study was not powered for overall survival and the effect on overall survival was based on a relatively small number of deaths. They are continuing to follow the patients to confirm the overall survival benefit.
Imatinib was generally well tolerated, but 25.8% of patients in the 36-month group and 12.6% in the 12-month group discontinued the drug for a reason other than GIST recurrence. The reasons were adverse effect, patient preference, tumor histology not GIST, and other or unspecified reason. Almost all study patients experienced at least one adverse event, most were graded mild in severity.
Echoing Dr. Blanke’s statement, Dr. Joensuu said: “Three years of imatinib should now be considered the standard of care for most patients whose GIST has been removed by surgery and who are estimated to have a high risk for GIST coming back.”
The study was funded in part by Novartis Oncology. Several of the authors on the study have financial relationships with Novartis. Dr. Blanke has received support for travel from Novartis.
JAMA 2012; 307:1265-1272,1312-1314.