Dose effect of imatinib (IM) in patients (pts) with metastatic GIST - Phase III Sarcoma Group Study S0033

Abstract

9005 Background: Although IM induces high rates of objective responses and durable disease control in patients (pts) with metastatic GIST, the potential impact of dose on clinical outcomes remains uncertain.At ASCO 2003, this trial reported no differences in progression-free or overall survival between two initial dose levels of IM. The outcomes of pts who crossed over to the higher dose arm are now reported. Methods: Phase III trial in pts with metastatic GIST randomized to one of two dose levels (400 mg vs. 800 mg) of IM daily. The primary aim was to assess the impact of Imatinib dose on overall survival. Pts whose disease progressed on the lower dose were considered to cross over to receive the higher dose IM therapy. Results: As of December 9, 2003, 320 of the initial 746 pts (43%) remain on study. Median follow-up among the 527 surviving pts is now 768 days (range 70–1029); median overall survival has still not been reached for either arm of the trial. Survival estimates at 2 years are 78% (95% confidence interval 73–82%) for the IM 400 arm vs. 73% (95% CI 68–77%) for the IM 800 arm. Progression-free survival at 2 years is estimated at 50% (95% CI 45–55%) vs. 53% (95% CI 47%–58%) (p>0.05) for the 400 vs. 800 mg arms, respectively. 164 pts with initial dose of 400/d have had progression of disease; 88/164 pts with progression at the lower dose have crossed over to the 800/d IM therapy. Median follow-up on crossover therapy is 307 days (range 1–852 d). Following crossover, 5 of 68 evaluable pts (7%) have demonstrated PR and an additional 20 pts (29%) have achieved stable disease. Median progression-free survival and overall survival following crossover are 4 months and 19 months, respectively. Conclusions: This multicenter study continues to demonstrate no significant differences between these two dose levels of IM while supporting the durable survival benefits of this agent in pts with metastatic GIST. The clinical benefit of dose escalation to 800 mg after progression on 400 is unclear, although a subset of pts have had objective benefit with continued IM dosing. Future studies should define the optimal management of GIST pts following limited progression on IM therapy. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis; Pfizer Novartis Novartis; Pfizer