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Clinical Trial
. 2019 Jun;85(6):1357-1366.
doi: 10.1111/bcp.13907. Epub 2019 Apr 13.

Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients

Félicien Le Louedec  1   2 , Catherine Alix-Panabières  3 , Thierry Lafont  1   2 , Ben C Allal  1   2 , Renaud Garrel  4 , Laurence Digue  5 , Joël Guigay  6   7 , Didier Cupissol  8 , Jean-Pierre Delord  2   9 , Benjamin Lallemant  10 , Marc Alfonsi  11 , Karine Aubry  12 , Martine Mazel  3 , François Becher  13 , Françoise Perriard  14 , Etienne Chatelut  1   2 , Fabienne Thomas  1   2
Affiliations
Clinical Trial

Cetuximab pharmacokinetic/pharmacodynamics relationships in advanced head and neck carcinoma patients

Félicien Le Louedec et al. Br J Clin Pharmacol. 2019 Jun.

Abstract

Aims: Cetuximab associated with cisplatin and 5-fluorouracil is used to treat patients with inoperable or metastatic head and neck squamous cell carcinomas (HNSCC) up until disease progression or unacceptable toxicities. To date, no biomarkers of efficacy are available to select patients who will benefit from treatment.

Methods: An ancillary pharmacokinetics (PK) exploration was performed in the context of a prospective study investigating circulating-tumour cells vs progression-free survival (PFS). Cetuximab plasma concentrations were analysed according to a population PK model. Individual exposure parameters were confronted with soluble epidermal growth factor receptor (sEGFR) concentrations, tumour response and PFS.

Results: PK data (28 patients, 203 observations) were best described by a two-compartment model with linear elimination. Performance status (PS) significantly correlated to both cetuximab clearance and central volume of distribution with both parameters increasing by 33.3% (95% CI 1-65.6) for each 1-point increase of PS compared to PS = 0. Univariate analysis showed that patients with higher trough cetuximab concentrations at Day 7 (Cmin,D7 ) had better tumour response (P = 0.03) and longer PFS (P = 0.035). However, multivariate analysis revealed that only PS and tumour size at baseline remained significantly associated with PFS. Levels of sEGFR increased during cetuximab treatment but were not associated with PFS in the multivariate analysis.

Conclusions: Our study prospectively indicates that PS is likely a confounding factor in the relationship between cetuximab PK and PFS, patients with a poor PS having lower cetuximab plasma exposure and lower PFS.

Trial registration: ClinicalTrials.gov NCT02119559.

Keywords: HNSCC; cetuximab; concentration; efficacy; pharmacokinetics.

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Conflict of interest statement

F.L.L., C.A.‐P., T.L., B.C.A., R.G., L.D., D.C., J.‐P.D., B.L., M.A., K.A., M.M., F.B., F.P., E.C. and F.T. have no competing interests to declare. J.G. has served on advisory boards for AstraZeneca, Bristol‐Myers Squibb, Innate Pharma, Merck KGaA and Nanobiotix, and has received grants for research from GSK, Bristol‐Myers Squibb, Chugai and Merck KGaA.

Figures

Figure 1
Figure 1
Soluble EGFR concentrations (ng/mL) in healthy volunteers and patients at Day 0, 7 and 21. ***: P < 0.001
Figure 2
Figure 2
Cmin,D7 vs tumour response (A), or vs WHO PS (B). *: P < 0.05; ×: this concentration is below LLOQ (4.8 µg/mL)
Figure 3
Figure 3
Progression‐free survival (PFS) as function of WHO PS (A), initial tumour size (B), sEGFR (C), and Cmin,D7 (D). P‐values correspond to log‐rank tests. No P‐value was provided in Figure 3A because the log‐rank test must be performed between two groups, however the PFS was higher in patients with PS = 0 vs PS ≥ 1 (P = 0.011, n = 27), or in patients with PS ≤ 1 vs PS = 2 (P < 10−4, n = 27)
See this image and copyright information in PMC

References

    1. Haines GK. Pathology of head and neck cancer: Epithelial and related tumors In: Radosevich JA, ed. Head and Neck Cancer: Current Perspectives, Advances and Challenges. New York: Springer; 2013:257‐287.
    1. Ferlay J, Steliarova‐Foucher E, Lortet‐Tieulent J, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374‐1403. - PubMed
    1. Vermorken JB, Mesia R, Rivera F, et al. Platinum‐based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359(11):1116‐1127. - PubMed
    1. Licitra L, Mesia R, Rivera F, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first‐line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol. 2011;22(5):1078‐1087. - PMC - PubMed
    1. da Costa AABA, D'Almeida Costa F, Ribeiro AR, et al. Low PTEN expression is associated with worse overall survival in head and neck squamous cell carcinoma patients treated with chemotherapy and cetuximab. Int J Clin Oncol. 2015;20(2):282‐289. - PubMed

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