In 2004, we started an inter-group randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk GIST patients. Interim analyses results were published in 2015 upon recommendation from an independent data review committee. We now report on the final outcome of the study.
This was a randomized, open label, multicenter phase III trial performed at 112 hospitals in 12 countries. Patients were randomized to 2 years (yrs) of imatinib, 400 mg daily, or no further therapy after surgery. The primary end-point was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary end-points. Adjusting for the interim analyses, results on IFFS will be assessed on a 4.3% significance levels; for the other endpoints 5% was used.
908 patients were randomized between December 2004 and October 2008, 454 to imatinib and 454 to observation. 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm (HR = 0.87, 95.7% CI [0.65; 1.15], p = 0.31); RFS was 70% versus 63% at 5 years and 63% vs 61% at 10 years, (HR = 0.71, 95% CI [0.57; 0.89], p = 0.002); OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years (HR = 0.88, 95% CI [0.65; 1.21], p = 0.43). Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43% respectively.
With 9.1 years of follow-up, a trend toward better long-term IFFS and RFS in Imatinib treated patients was observed in the high risk subgroup. Although not statistically significant, this trend is consistent with the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high risk GIST patients treated with 3 years adjuvant Imatinib. On the contrary our study discourages the use of Imatinib in patients affected by low risk (as per current standards) GIST, as long term IFFS and RFS are superimposable.
Clinical trial identification
EUDRACT 2004-001810-16, NCT00103168
Legal entity responsible for the study
P.G. Casali: Research funds (institution): Amgen, Bayer, Eli Lilly, Daiichi Sankyo, Epizyme, Novartis, Pharmamar. Advisory: Bayer, Blueprint, Eisai, EliLilly, Merck SD, Merck Serono, Nektar Therapeutics, Novartis, Pfizer, Pharmamar. Honoraria: Bayer, Novartis, Pfizer, Pharmamar. A. Le Cesne: Pharmamar, Lilly, Pfizer, Novartis, Amgen Honoraria, myself, compensated. P. Rutkowski: Novartis, BMS, Roche, MSD, GSK, Amgen. P. Hohenberger: Honoraria, consultation fees and research support from Novartis. H. Gelderblom: My institution (LUMC) received study grants form Novartis. D. Goldstein: Research grants to institution, Pfizer, Amgen, Celgene, unremunerated advisory - Celgene, Shire, Pfizer, Bayer. A. Gronchi: Honoraria and compensation for advisory boards from Novartis honoraria from Pfizer compensation for advisory boards from Bayer. J. Zalcberg: Research support from Novartis and Bayer. J-Y. Blay: Research support and honoraria from Novartis, GSK, Bayer, Roche. All other authors have declared no conflicts of interest.