CETUXIMAB DOSE ESCALATION

J Clin Oncol. 2012 Jul 2. [Epub ahead of print]

Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study.

Van Cutsem E, Tejpar S, Vanbeckevoort D, Peeters M, Humblet Y, Gelderblom H, Vermorken JB, Viret F, Glimelius B, Gallerani E, Hendlisz A, Cats A, Moehler M, Sagaert X,Vlassak S, Schlichting M, Ciardiello F.

Source

Eric Van Cutsem, Sabine Tejpar, Dirk Vanbeckevoort, and Xavier Sagaert, University Hospital Gasthuisberg, Leuven; Marc Peeters, University Hospital Ghent, Ghent; Yves Humblet, Centre du Cancer, St-Luc University Hospital, Université Catholique de Louvain; Alain Hendlisz, Institute Jules Bordet, Brussels; Jan B. Vermorken, Antwerp University Hospital, Edegem, Belgium; Hans Gelderblom, Leiden University Medical Center, Leiden; Annemieke Cats, Netherlands Cancer Institute, Amsterdam, the Netherlands; Frederic Viret, Institut Paoli-Calmettes and Université de la Méditerranée, Marseille, France; Bengt Glimelius, University of Uppsala, Uppsala, Sweden; Elisa Gallerani, Oncology Institute of Southern Switzerland, Hospital San Giovanni, Bellinzona, Switzerland; Markus Moehler, University of Mainz, Mainz; Soetkin Vlassak and Michael Schlichting, Merck, KGaA, Darmstadt, Germany; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.

Abstract

PURPOSESkin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. PATIENTS AND METHODSAfter 21 days of standard-dose cetuximab (400 mg/m(2) initial dose, then 250 mg/m(2) per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m(2) per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C).ResultsThe intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 mg/m(2) were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups. Dose escalation (n = 44) was associated with an increase in skin reactions ≥ grade 2 compared with standard (n = 45) dosing (59% v 38%, respectively). Dose escalation, compared with standard dosing, showed some evidence for improved response rate (30% v 16%, respectively) and disease control rate (70% v 58%, respectively) but no indication of benefit in relation to overall survival. In an exploratory analysis, dose escalation seemed to increase response rate compared with standard dosing in patients with KRAS wild-type but not KRAS mutant tumors. CONCLUSIONCetuximab serum concentrations increased predictably with dose. Higher dose levels were well tolerated. The possible indication for improved efficacy in the dose-escalation group warrants further investigation.