Final analysis of a collaborative intergroup study confirmed the efficacy of adjuvant treatment with imatinib in patients with localized gastrointestinal stromal tumor (GIST) in terms of prolonged relapse-free survival. In the high-risk subgroup, there was a trend toward a better long-term imatinib failure–free survival. According to a report by Casali et al published in Annals of Oncology, these results support current standard treatment with adjuvant imatinib for 3 years in patients with GIST and a significant risk of relapse.
Study Details
This collaborative, randomized study of adjuvant imatinib was launched in 2004. The study team included all patients with GIST and an intermediate or high risk of relapse, following the consensus classification used at the time. When designing the study, the investigators believed that a benefit in relapse-free survival was more than likely and decided that a meaningful benefit would have been in place only if it resulted in an increase in the cure rate, or, at least, in a substantial delay of relapses, provided no decrease in the time to progression was to occur when rechallenging relapsing patients with imatinib. Therefore, they chose overall survival as the study primary endpoint.
However, at a planned interim analysis in March 2009, the study Independent Data Monitoring Committee concluded that keeping overall survival as the primary endpoint would be incompatible with a reasonable duration of the study. The study team then decided another primary endpoint, imatinib failure–free survival, as an estimate of the time to resistance to imatinib, defined as a survival interval to the date of switching to an alternate tyrosine kinase inhibitor at any time during or following the adjuvant period.
The interim analysis was published in 2015, while continuing the study follow-up to the planned final analysis that is now reported. It is a randomized, open-label, multicenter phase III study performed at 112 hospitals in 12 countries.
Patients were randomly assigned to receive 2 years of imatinib at 400 mg daily or no further therapy after surgery.
Long-Term Follow-up
In total, 908 patients were randomly assigned between January 2005 and October 2008 (454 patients to imatinib and 454 patients to observation), but 835 patients were eligible. With a median follow-up of 9.1 years, 5-year imatinib failure–free survival was 87% and 10-year imatinib failure–free survival was 75% in the imatinib arm vs 83% and 74% in the control arm (hazard ratio [HR] = 0.87, 95.7% confidence interval [CI] = 0.65–1.15, P = .31).
Relapse-free survival was 70% vs 63% at 5 years and 63% vs 61% at 10 years (HR = 0.71, 95% CI = 0.57–0.89, P = .002). Overall survival was 93% vs 92% at 5 years and 80% vs 78% at 10 years (HR = 0.88, 95% CI = 0.65–1.21, P = .43). Among 526 patients with high-risk GIST by local pathology, 10-year imatinib failure–free survival and relapse-free survival rates were 69% vs 61% and 48% vs 43%, respectively.
For both overall survival and its potential surrogate defined in this study as imatinib failure–free survival, the data did not show an effect in favor of adjuvant treatment with imatinib overall, but a trend was observed in the high-risk cohort. The authors concluded that although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supportive for the results reported by a Scandinavian/German study, showing a sustained small but significant long-term overall survival benefit in high-risk patients with GIST treated with 3 years of adjuvant imatinib, and may attenuate a mismatch between relapse-free and overall survival that undoubtedly marks the efficacy of adjuvant targeted therapy in GIST.
Accompanying Editorial
In an accompanying editorial, authors cited the results from the three randomized studies that suggest that careful patient selection for adjuvant imatinib is of critical importance, and that administration of adjuvant imatinib for a long enough duration is likely needed.
Currently, 3 years of adjuvant imatinib remains the standard of care for patients who are at high-risk for GIST recurrence, despite macroscopically complete surgery, and who have a GIST mutational status that suggests sensitivity to imatinib. However, evaluation of the safety and efficacy of adjuvant imatinib of duration longer than 3 years remains a high priority, and two such studies are currently ongoing.
Disclosure: The collaborative intergroup study—conducted by EORTC Soft Tissue and Bone Sarcoma Group, the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas—was supported by the EORTC Charitable Trust. Supporting funding was received from Novartis. For full disclosures of the study authors, visit annalsofoncology.org.
