Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study

Tabernero, Josep; Ciardiello, Fortunato; Rivera, Fernando; Rodríguez-Braun, Edith; Ramos, Francisco Javier; Martinelli, Erika; Vega-Villegas, M. E.; Roselló, Susana; Liebscher, Stefan; Kisker, Oliver; Macarulla, Teresa; Baselga, José; Cervantes, A.

doi:10.1093/annonc/mdp549

Cited by 81 publications

(89 citation statements)

References 18 publications

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“…Pharmacological parameters such as the area under the curve (AUC) or the percentage of cell growth inhibition at a clinically relevant drug concentration of 10 mg ml À 1 (ref. 22) closely paralleled the response rates observed in patients 20,21 ( Supplementary Fig. 3a).…”

Section: Resultssupporting

confidence: 79%

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

et al. 2015

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The development of molecularly targeted anticancer agents relies on large panels of tumourspecific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.

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Section: Resultssupporting

confidence: 79%

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

et al. 2015

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“…A dose dependency of cetuximab pharmacokinetics was previously reported (21)(22)(23)(24)(25). This phenomenon was also observed in the present study, with an accelerated decrease at low concentrations.…”

Section: Translational Relevancesupporting

confidence: 90%

“…Cetuximab pharmacokinetics was also previously analyzed by nonparametric approaches, either given as monotherapy in different types of solid tumors (23) or associated with irinotecan and 5-fluorouracil/folinic acid (FOLFIRI) in metastatic colorectal cancer (25). Tan and colleagues reported a significant association between cetuximab clearance and both BSA and weight (23).…”

Section: Discussionmentioning

confidence: 99%

Cetuximab Pharmacokinetics Influences Progression-Free Survival of Metastatic Colorectal Cancer Patients

Azzopardi

Lecomte²,

Ternant³

et al. 2011

Clinical Cancer Research

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Purpose: An ancillary phase II study was conducted to study interindividual variability in cetuximab pharmacokinetics and its influence on progression-free survival (PFS) in metastatic colorectal cancer patients cotreated with irinotecan and 5-fluorouracil.Experimental Design: Ninety-six patients received cetuximab as an infusion loading dose of 400 mg/m 2 followed by weekly infusions of 250 mg/m 2 . Doses of irinotecan and 5-fluorouracil were adjusted individually. Cetuximab concentrations were measured by ELISA. Compartmental pharmacokinetic parameters were estimated by a population approach, and PFS was analyzed using a Cox model. Results: Cetuximab pharmacokinetics was best described using a two-compartment model with both first-order and saturable (zero-order) elimination. Estimated pharmacokinetic parameters (% standard error) were as follows:, and zero-order elimination rate k 0 ¼ 8.71 mg/d (10%). Body surface area influenced V 1 , V 2 , and k 0 . Pretreatment serum albumin influenced CL. Risk of disease progression decreased with cetuximab global clearance (cumulative dose/cumulative area under the concentration versus time curve; P ¼ 0.00016). Median PFS of patients with a cetuximab residual concentration on day 14 below median value was 3.3 months as compared with 7.8 months for the other patients (P ¼ 0.004).Conclusions: Cetuximab pharmacokinetics in colorectal cancer patients can be described using a model combining linear and nonlinear elimination rates. PFS is influenced by global clearance of cetuximab, a parameter that can be estimated using cetuximab residual concentration on day 14.

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“…In our institutions, we routinely administer CetIri as a simplifi ed regimen dispensed in only 90 minutes every other week based on pharmacokinetic data [15] as well as reported clinical experiences [4].…”

Section: Discussionmentioning

confidence: 99%

Addition of sunitinib to cetuximab and irinotecan in patients with heavily pre-treated advanced colorectal cancer

et al. 2010

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Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study

Abstract: Cetuximab can be safely administered once every second week at doses between 400 and 700 mg/m(2), with 500 mg/m(2) being the most convenient and feasible dose for future studies.

Cited by 81 publications

References 18 publications

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets

Cetuximab Pharmacokinetics Influences Progression-Free Survival of Metastatic Colorectal Cancer Patients

Addition of sunitinib to cetuximab and irinotecan in patients with heavily pre-treated advanced colorectal cancer

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