A phase II study of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as frontline therapy for metastatic colorectal cancer. A Fox Chase extramural research study

Abstract

Objectives: Dual inhibition of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) demonstrated initial promise in clinical trials. This phase II study tested the efficacy and safety of capecitabine, oxaliplatin, and cetuximab with or without bevacizumab as first-line treatment for metastatic colorectal cancer patients.

Methods: Patients were randomized to receive capecitabine 850 mg/m2 PO twice daily for 14 days, oxaliplatin 130 mg/ m2 IV day 1, and cetuximab 400 mg/m2 IV loading dose followed by 250 mg/m2 IV days 1, 8, and 15 with (arm A) or without (Arm B) bevacizumab 7.5 mg/kg IV day 1 every 21 days. Tumor samples were collected and retrospectively analyzed for KRAS mutation status. The primary endpoint was response rate, with time to progression (TTP) and overall survival (OS) as secondary objectives.

Results: Twenty-three patients (12 in arm A, 11 in arm B) were enrolled onto the study. Median follow-up was 25.9 months. Both treatments were well tolerated, with expected higher rates of grade 1/2 hypertension and bleeding in arm A. The overall response rate was 54% (36.4% in arm A and 72.7% in arm B). Median time to progression was 8.7 months in arm A and 14.4 months in arm B. The median survival was 18.0 months in arm A and 42.5 months in arm B. The study was prematurely terminated after other studies reported inferior outcomes with dual antibody therapy.

Conclusions: Although terminated early, the study supports the detrimental effect of combining VEGF and EGFR inhibition in metastatic colorectal cancer.

Conflict of interest statement

Conflict of Interest Dr. Barbara Burtness receives research funding from Genentech.

Dr. Steven Cohen receives research funding from Genentech and BMS.

All other authors state that they have no relevant conflicts of interest.

Figures

Fig. 1

Kaplan–Meyer curves of time to progression (a) and overall survival (b) by treatment arm. Patients randomized to arm A received treatment with capecitabine, oxaliplatin, cetuximab, and bevacizumab. Patients randomized to arm B were treated with the same regimen without bevacizumab

Fig. 2

Overall survival by KRAS mutation status. Kaplan–Meier curve of overall survival of KRAS mutant and KRAS wild-type patients. HR=1.567; 95% CI: 0.396–6.20