In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 3600-3600
Abstract:
3600 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for RAS wild-type (WT) mCRC. Limited data suggest a correlation between Cet clearance and progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts with KRAS WT mCRC who participated in the randomized phase III NCIC CO.20 trial. Methods: Standard Cet doses ± brivanib (Briv) were administered. Intermittent blood samples were obtained, and analyzed by ELISA for Cet. Pop-pK analysis was conducted to estimate Cet clearance. Pts were divided into quartiles according to clearance parameters to evaluate exposure-outcome with overall survival (OS), PFS, response rate (RR), and toxicity. Results: Blood samples were available from 703 pts. Cet clearance was best described as a one-compartment model with a saturable elimination (defined by V max and K m ). Mean values (± standard deviation) were 5.6 ± 1.4 L for V, 10.5 ± 2.8 mg/h for V max , and 403.1 ± 2.0 mg/L for K m . V max and K m were significantly associated with OS, but not PFS or RR. Median OS for pts in the highest quartile of V max was 7.8 versus (vs.) 11.6 ms for pts in the lowest V max quartile (HR 1.12, 95% confidence interval (CI) 1.05-1.20, p 〈 0.001). In the highest K m quartile, median OS was 11.6 vs. 7.6 ms in the lowest K m quartile (HR 0.89, 95% CI 0.83-0.96, p= 0.001). Pts with the lowest clearance parameters (lowest V max and highest K m ) had significantly longer OS (11.6 ms) compared to pts with the highest clearance (highest V max and lowest K m ) (7.6 ms) (HR 0.67, 95% CI 0.53-0.83, p 〈 0.001). Overall incidences of grade 3/4 toxicity were not associated with Cet clearance. However, pts with the lowest clearance parameters had more frequent grade 3 diarrhea (OR 0.23, p= 0.005). Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with lower Cet clearance have significantly improved OS and increased likelihood of grade 3 diarrhea. Further studies are needed to identify individual patient factors associated with Cet clearance, and to optimize Cet dosing based on individual pk assessments.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2017.35.15_suppl.3600
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2017
detail.hit.zdb_id:
2005181-5
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