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

2008; Lippincott Williams & Wilkins; Volume: 26; Issue: 15_suppl Linguagem: Inglês

10.1200/jco.2008.26.15_suppl.10554

1527-7755

Suzanne George, Jean‐Yves Blay, Paolo G. Casali, Axel Le Cesne, S. E. DePrimo, Charles S. Harmon, Calvin Law, Vanessa Tassell, Charles M. Baum, George D. Demetri,

Platelet Disorders and Treatments

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