Incidence and reasons for dose modification of standard-dose vs. high-dose imatinib mesylate (IM) in the Phase III Intergroup Study S0033 of patients (pts) with unresectable or metastatic gastrointestinal stromal tumor (GIST)

Abstract

9032 Background: IM benefits the majority of patients with metastatic GIST. Study S0033 aims to evaluate differences between two initial dose levels of IM (400 vs. 800 mg/day), with the crossover possible for pts on lower dose to increase dose in case of disease progression. Dose delays and reductions were required for defined toxicities. The present analysis was performed to analyze the incidence and reasons for dose modification in each arm on this multicenter trial. Methods: The dataset of S0033 (746 pts randomized) was analyzed; recorded dose levels of IM were tabulated and reasons for dose modifications assessed. Results: 350 eligible pts enrolled at 400 mg/day with information on dose modifications available on 335 pts. 126 (62%) had at least one dose delay and 34 (10%) had at least one dose reduction, due most commonly to rash, edema, and GI bleeding. 353 eligible pts enrolled at 800 mg/day IM, 337 with full dosing information. 189 (56%) had at least one dose delay and 148 (44%) had at least one dose reduction, due to edema, nausea, and fatigue. Of the subset of 112 eligible pts who eventually crossed over to higher dose IM due to PD, 108 had complete dosing information available prior to crossover: 33 (31%) had at least one dose delay and 6 (6%) had at least one dose reduction while on the lower dose IM, primarily for edema, GI bleeding, or nausea. Following crossover, in 77 pts with complete dosing information, 18 (23%) had at least one dose delay and 12 (16%) had at least one dose reduction, due to edema and rash. Conclusions: IM can be given safely in a multicenter study, although reductions in dose intensity were common. It is possible that management of toxicities could have been accomplished safely without the stringent dose reductions required by the protocol rules. Crossover to high dose IM was feasible with low incidence of required dose modifications. Further analyses of correlations between dose modifications and clinical outcomes (PFS, OS) are in progress. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis