TY - JOUR
T1 - Intrapatient cetuximab dose escalation in metastatic colorectal cancer according to the grade of early skin reactions
T2 - The randomized EVEREST study
AU - Van Cutsem, Eric
AU - Tejpar, Sabine
AU - Vanbeckevoort, Dirk
AU - Peeters, Marc
AU - Humblet, Yves
AU - Gelderblom, Hans
AU - Vermorken, Jan B.
AU - Viret, Frederic
AU - Glimelius, Bengt
AU - Gallerani, Elisa
AU - Hendlisz, Alain
AU - Cats, Annemieke
AU - Moehler, Markus
AU - Sagaert, Xavier
AU - Vlassak, Soetkin
AU - Schlichting, Michael
AU - Ciardiello, Fortunato
PY - 2012
Y1 - 2012
N2 - Purpose: Skin 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 Methods: After 21 days of standard-dose cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m2 per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). Results: The 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/m2 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. Conclusion: Cetuximab 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.
AB - Purpose: Skin 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 Methods: After 21 days of standard-dose cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m2 per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). Results: The 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/m2 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. Conclusion: Cetuximab 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.
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U2 - 10.1200/JCO.2011.40.9243
DO - 10.1200/JCO.2011.40.9243
M3 - Article
C2 - 22753904
AN - SCOPUS:84865092896
VL - 30
SP - 2861
EP - 2868
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 23
ER -