Three Years of Adjuvant Imatinib May Be the New Standard of Care for High-risk Patients with GIST
Extended treatment with imatinib for 3 years after surgery provides high-risk patients with gastrointestinal stromal tumors (GIST) improved recurrence-free survival and overall survival compared with standard 12-month therapy with adjuvant imatinib.
|Final results of the SSGXVIII/AIO study established 3-year therapy with imatinib as the gold standard according to presenter Heikki Joensuu, MD.
These results, the final analysis of the SSGXVIII/AIO study (Abstract LBA1), were presented at Sunday’s Plenary Session by Heikki Joensuu, MD, of the Helsinki University Central Hospital, Finland. The SSGXVIII/AIO study was designed to determine whether 3 years of continuous treatment with adjuvant imatinib would provide significant clinical benefits for high-risk patients with operable GIST compared with the current standard of care. Imatinib was given orally at a daily dosage of 400 mg.
In this open-label, multicenter, randomized phase III study, 400 patients with KIT-positive GIST received imatinib for 12 months (200 patients) or 36 months (200 patients) following surgery. Recurrence-free survival was the primary endpoint.
Although patients with operable, metastatic GIST were initially enrolled in the study, the protocol was later amended to exclude patients with advanced disease based on an observation in a different study, which showed that patients with advanced GIST experienced disease recurrence following cessation of active treatment.
After 54 months of follow-up, data in the intent-to-treat population indicated that patients who received GIST for 36 months were 54% less likely to experience recurrence (hazard ratio [HR]: 0.46; 95% CI [0.32, 0.65]; p < 0.0001) compared with patients who received imatinib for 12 months.
Sub-group analyses indicated that recurrence-free survival advantage was seen in patients on extended therapy regardless of age, sex, tumor site, tumor size, and tumor rupture. In addition, patients receiving extended treatment with imatinib for 36 months were 55% less likely to experience death (HR: 0.45; 95% CI [0.22, 0.89]; p = 0.019). Ninety-two percent of those who received imatinib for 36 months were alive at 5 years, compared with 81.7% of those who received the drug for 12 months.
"The survival rate in this study was very high compared with historical survival rates. Also, this may be the first targeted agent used in the adjuvant setting for a prolonged period," said Dr. Joensuu. "This study means that treatment with imatinib for 36 months is likely to replace 12-month therapy with imatinib as the new standard of care."
In discussing the study, Charles D. Blanke, MD, of the University of British Columbia and the British Columbia Cancer Agency, agreed with Dr. Joensuu’s assessment.
"Three-year therapy with imatinib is now the new gold standard. Data from this study along with data from other trials might suggest that even longer treatment would be better," Dr. Blanke told ASCO Daily News.
In this regard, PERSIST5 is a phase II study that will provide guidance for continuous treatment with imatinib for 5 years. However, Dr. Blanke noted that, although lifelong treatment with imatinib might be attractive, it remains unproven.
Issues Related to Extended Treatment with Imatinib
Dr. Blanke’s discussion addressed which patients may derive the greatest clinical benefit from extended treatment with imatinib. Dr. Joensuu reported that patients included in the study were at high risk for relapse, based on a 2002 classification scheme. Dr. Blanke suggested that oncologists use more precise tools to generate a numerical risk of relapse for individual patients, rather than just place them in broad, descriptive categories.
"Based on current definitions, the risk of recurrence for patients on the study was probably between 34% and 100%," Dr. Blanke said. "Within risk categories, higher- and lower-risk patients enjoy the same benefits of longer-term therapy. We can thus apply SSGXVIII’s results to patients at roughly a 1-in-3 or greater chance of recurrence. [The question is] should we?"
He indicated that expert panels are likely to discuss what actual cancer recurrence risk would trigger extended adjuvant imatinib therapy. In clinical practice, it would be the responsibility of the individual oncologist and might be dependent on third-party reimbursement.
Dr. Blanke also discussed whether patients would be compliant with extended therapy in the postoperative setting. In the study, 36% of patients in the 3-year arm discontinued therapy early. Although a small percentage (7%) was due to disease recurrence, most discontinuations were associated with adverse events or other reasons.
Dr. Blanke speculated that in the long-term treatment setting, any low-grade adverse events may not be tolerable in the absence of visible disease. Dr. Blanke remarked that, in light of the high discontinuation rate, it was quite remarkable that the study still provided improved clinical outcomes for high-risk patients with GIST.
Finally, Dr. Blanke indicated that it would be difficult to study adjuvant imatinib for multiple, longer durations. He suggested that we apply lessons from the laboratory, including future biomarker studies, which may provide additional insights into post-operative imatinib therapy.
While cautioning that extended adjuvant treatment with GIST does not equate to a cure, he concluded that "the overall survival advantage demonstrated [in the study] means we cannot try to 'catch up' later in the advanced disease setting."