Cetuximab Dose Escalation May Increase Responses among Patients with Mild or No Initial Skin Reactions

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Escalating the dose of cetuximab (Erbitux) among patients with metastatic colorectal cancer who developed no or mild skin reactions on standard-dose cetuximab plus irinotecan “seemed to lead to an increase in response rate” as well as in the disease-control rate, according to a phase I/II study reporting clinical and pharmacokinetic data. Patients receiving escalated doses did not, however, have clear benefits in progression-free or overall survival compared to patients maintained on the standard cetuximab regimen.

The Evaluation of Various Erbitux Regimens by Means of Skin and Tumor Biopsies (EVEREST) study included 89 patients with no or grade 1 skin reactions in the first 21 days of treatment with standard-dose cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus irinotecan. Patients were randomly assigned to either continue the standard dose (group A, 45 patients) or to be dose-escalated to 500 mg/m2 per week (group B, 44 patients). The weekly doses “were well tolerated, and grade 3 and 4 adverse events were generally comparable between treatment groups,” the investigators stated. Dose escalation was associated with an increase in grade 2 or greater skin reactions, occurring in 59% of patients in group B vs 38% in group A.

The overall response rate was higher in group B (30% vs 16%), as was disease control rate (70% vs 58%), “although neither difference reached statistical significance,” the authors reported. Moreover, “there was no significant difference between these treatment groups for [progression-free or overall survival]. There was a tendency for a greater reduction in tumor size after response to treatment in group B than in group A.”

Genetic Marker

As in other randomized studies of cetuximab combined with chemotherapy in patients with metastatic colorectal cancer, “clinical outcomes were significantly superior for evaluable patients with KRAS wild-type compared with mutant tumors. Indeed, all but one of the patients with partial responses in the current study had KRAS wild-type tumors (35 of 89 patients with wild-type tumors vs 1 of 57 patients with mutant tumors),” the investigators noted.

“The [overall response rate] in patients with KRAS wild-type tumors with no or mild skin reactions after 21 days receiving a dose increase of cetuximab (group B) was 43% compared with 30% in patients treated with the standard dose (group A). We do not consider this difference to be practice-changing in view of the sample size of the study,” the authors wrote.

In an ongoing larger prospective study (EVEREST 2) of first-line treatment for metastatic colorectal cancer, patients without rash receive progressively higher doses of cetuximab.

Van Cutsem E, et al: J Clin Oncol 30:2861-2868, 2012.




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