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DDMODEL00000107: Girard_2013_oncology_cetuximab_TGI

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Drug-disease model of tumor size and overall survival in metastatic colorectal cancer patients treated with cetuximab administered weekly or every second week. P. Girard, T. Brodowicz, A. Kovar, B. Brockhaus, M. Zühlsdorf, M. Schlichting, A. Munafo, R. Esser, E. Van Cutsem, J. Tabernero European Journal of Cancer, Volume 49 Supplement 2, 09/2013
PharmML (0.6.1)
  • Drug-disease model of tumor size and overall survival in metastatic colorectal cancer patients treated with cetuximab administered weekly or every second week.
  • P.Girard, T. Brodowicz, A. Kovar, B. Brockhaus, M. Zühlsdorf, M. Schlichting, A. Munafo, R. Esser, E. Van Cutsem, J. Tabernero
  • Euroean Journal of Cancer, 6/2016, Volume 49
  • Merck Institute for Pharmacometrics, Lausanne (Switzerland) Medical university of Vienna, Vienna (Austria) Merck KGaA, Darmstadt (Germany) University hospital Gathuisberg, Leuven (Belgium) Vall d'Hebron University Hospital, Barcelona (Spain)
  • Background: Cetuximab, administered in a standard weekly regimen (q1w) with first-line chemotherapy (CT) can improve tumor response and overall survival (OS) in metastatic colorectal cancer (mCRC) pts. Cetuximab (400 or 500 mg/m2) every second week (q2w) was safely administered with reported activity in mCRC pts. Tumor size (response) and OS were further studied in a drug-disease model. Material and Methods: A pharmacokinetic (PK)-disease model of tumor size was constructed (using NONMEM7.2) in a pooled analysis of mCRC pts from the 502 (EVEREST, second-line CT + cetuximab q1w) study, and 045 and CECOG/CORE.1.2.002 (CORE) studies (both first-line CT with either cetuximab q1w or q2w). The model estimated changes in tumor size from baseline for early tumor shrinkage (ETS, % change in tumor size at wk 8) and time to tumor (re)growth (TTG, time to smallest tumor size). Covariates were examined including the effects of cetuximab q1w and q2w regimens. ETS and TTG were tested as predictors of OS using Cox models. Results: 369 pts from the 3 studies provided 3821 PK, 2053 tumor size and 233 death observations. Tumor size model fit was very good. Excluding study 502 (irinotecan-refractory pts), covariate analysis identified study (baseline tumor size was 32% lower in the CORE study; p < 0.01) and KRAS status (treatment was 43% less effective in KRAS mutated tumors; p < 0.01) as significant. TTG (p = 0.12) and ETS (p = 0.28) were not markedly different between the q2w and q1w regimens, were positively correlated (Spearman’s rho=0.64), and were identified as individual predictors of OS. For ETS and TTG, pts were grouped by low (L), intermediate (I), and high (H) terciles. In pts with KRAS wild-type tumors, OS was longer in the H-TTG (27 to 118 wk, median OS 31.4 mth) vs L-TTG group (0 to 11 wk, median OS 15.1 mth), or H-ETS (?66 to ?22%, median OS 25.9 mth) vs L-ETS group (?9 to +2%, median OS 12.8 mth). In a Cox model excluding study 502 (n = 215, death=93), ECOG PS grouped as fully active or restrictive activity (RA, p = 0.038), TTG (p < 0.001) and baseline tumor size (p < 0.001) were independent predictors of OS. In a model including ETS, ECOG PS RA (p = 0.0044), ETS (p = 0.013) and baseline tumor size (p = 0.0055) were independent predictors of OS. Treatment regimen was not significant. Conclusions: In this analysis changes in tumor size from baseline and OS were not significantly modified by the cetuximab dosing regimen in mCRC pts. The model identified TTG and ETS as predictors of OS
Nadia Terranova, Kheizurane_ElMekki
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  • Model owner: Nadia Terranova
  • Submitted: Dec 11, 2015 4:57:30 PM
  • Last Modified: Jul 22, 2016 5:32:49 PM
Revisions
  • Version: 9 public model Download this version
    • Submitted on: Jul 22, 2016 5:32:49 PM
    • Submitted by: Nadia Terranova
    • With comment: Updated model annotations.
  • Version: 7 public model Download this version
    • Submitted on: Jul 22, 2016 5:02:05 PM
    • Submitted by: Nadia Terranova
    • With comment: Updated model annotations.
  • Version: 4 public model Download this version
    • Submitted on: Dec 11, 2015 4:57:30 PM
    • Submitted by: Kheizurane_ElMekki
    • With comment: Edited model metadata online.
 
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