Continuous daily dosing (CDD) of sunitinib (SU) in pts with advanced GIST: Updated efficacy, safety, PK and pharmacodynamic analysis

Abstract

10554 Background: SU is an oral multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, FLT3, CSF-1R and RET, approved multinationally for the treatment of advanced imatinib (IM)-resistant/intolerant GIST on an intermittent dosing schedule comprising 4 wk on 50 mg/d followed by 2 wk off treatment. The safety and efficacy of SU 37.5 mg CDD in pts with GIST after IM failure were evaluated in this phase II study. Methods: In this open-label, multicenter trial, pts were randomized either to morning (AM) or evening SU dosing. The primary endpoint was clinical benefit rate (CBR; % of pts with RECIST-defined CR, PR or SD ≥24 wk). Secondary endpoints included PFS, OS, ORR, safety/tolerability, PK parameters and plasma concentrations of potential biomarkers. Results: 60/61 randomized pts (30/arm) received CDD of SU. As of Dec. 2007, pts had started a median of 11 28-d treatment cycles (range 1–24). 24 pts had completed 1 y of study treatment, and 37 had discontinued. To date, the overall CBR is 55%, including 7 pts (12%) with PRs. Median PFS overall is 32 wk (95% CI 25–48). With 60% of pts still alive, median OS is estimated to be 88 wk (95% CI 68-NA). The most common treatment-emergent (all- causality) non-hematologic Aes of any grade were diarrhea (45%), abdominal pain (42%) and asthenia (38%). Grade 3/4 hematologic laboratory abnormalities included reduced levels of neutrophils (12%), hemoglobin (12%) and platelets (3%). Dose reduction to 25 mg due to Aes occurred in 14 pts (23%). Sunitinib CDD achieved constant drug exposure with no unexpected accumulation. 23 pts on AM dosing had plasma samples taken at ≥2 timepoints during treatment. Analysis of VEGF, soluble (s)VEGFR-2, sVEGFR-3 and sKIT concentrations in these samples supported a persistent pharmacodynamic effect of SU with CDD, without the concentration rebound observed during off-treatment periods with intermittent dosing. Preliminary analyses suggested a correlation between OS and decreases in plasma sKIT after the first 3 cycles, and particularly after cycle 5 (n=17; P=0.007). Conclusions: CDD of SU appears to be a safe and potentially effective dosing strategy for pts with GIST after IM failure. CDD is associated with constant drug exposure and a persistent pharmacodynamic effect. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer GlaxoSmithKline, Infinity, MedImmune, Novartis, Pfizer, PharmaMar, Roche, sanofi-aventis Pfizer GlaxoSmithKline, Novartis, Pfizer, PharmaMar, Roche, SigmaTau Infinity, Janssen-Cilag, Novartis, Pfizer, SigmaTau Infinity, Novartis, Pfizer Novartis, PharmaMar