Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status
J Clin Oncol. 2011 Apr 18;[Epub Ahead of Print], E Van Cutsem, CH Köhne, I Láng, G Folprecht, MP Nowacki, S Cascinu, I Shchepotin, J Maurel, D Cunningham, S Tejpar, M Schlichting, Zubel A, I Celik, P Rougier, F Ciardiello
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In post-hoc analysis of the phase III CRYSTAL study, KRAS wild-type status was associated with improved outcomes in response to cetuximab plus FOLFIRI compared with FOLFIRI alone, while BRAF mutations were associated with poorer outcomes.
SUMMARY
OncologySTAT Editorial Team
Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). In phase III studies, cetuximab has been shown to improve outcomes when added to standard chemotherapy for treatment of metastatic colorectal cancer. The Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study showed reductions in risk of progression and tumor response in patients who received cetuximab in addition to a chemotherapy regimen of irinotecan, infusional fluorouracil, and leucovorin (FOLFIRI). In particular, the benefits of cetuximab appeared to be limited to patients whose tumors were wild-type at the KRAS gene. This study is an updated analysis of the CRYSTAL study that evaluates outcomes after a longer follow-up time and in a larger number of patients evaluated for KRAS status. In addition, the significance of the BRAF gene, which is a downstream effector of KRAS was evaluated.
This was a retrospective subgroup analysis of KRAS mutation status in patients enrolled in an open-label, randomized, multicenter, phase III study of cetuximab plus FOLFIRI or FOLFIRI alone as first-line treatment for metastatic colorectal cancer.
The intention to treat (ITT) population comprised 1198 patients who were randomly assigned to receive cetuximab plus FOLFIRI (n=599) or FOLFIRI alone (n=599). The original analysis of KRAS evaluated 540 patients; this study extended the analysis to a total of 1063 patients (89%), with a median follow-up time of 46.8 months for the cetuximab plus FOLFIRI group and 46.2 months for the FOLFIRI alone group. A total of 487 patients (81%) died in the cetuximab plus FOLFIRI group, compared with 502 (84%) in the FOLFIRI alone group. Addition of cetuximab improved overall survival time (19.9 months vs 18.6 months; hazard ratio [HR], 0.878; 95% confidence interval [CI], 0.774 to 0995; P =.0419). Tumor tissue in 397 of 1063 patients (37%) had mutations in KRAS codons 12 or 13. More patients had KRAS mutations in the cetuximab plus FOLFIRI group than in the FOLFIRI alone group (40% vs 34%).
Among patients whose tumors were wild-type for KRAS, cetuximab plus FOLFIRI resulted in significantly reduced risk of disease progression (median progression free survival [PFS], 9.9 vs 8.4 months; HR, 0.96, P= .0012), significantly improved overall survival (23.5 vs 20.0 months; HR, 0.796; P = .0093), and significantly increased odds of response (best overall response rate 57.3% vs 39.7%; odds ratio, 2.069; P <.001) compared with FOLFIRI alone. Among patients with wild-type KRAS, those in the cetuximab plus FOLFIRI group who developed early acne-like rash had significantly prolonged survival time compared with those who did not develop early acne-like rash (26.4 vs 19.1 months).
Among patients with mutations in KRAS, the addition of cetuximab did not improve PFS, overall survival, or best overall response. KRAS mutations were associated with worse overall survival in both treatment groups compared with wild-type. Treatment effect and KRAS mutation status were associated with significant interaction effects for PFS (P =.0028), overall survival (P =.0463), and best overall response (P =.0005).
A total of 60 of 999 (6%) tumor samples evaluated for both BRAF and KRAS had BRAF V600E mutations. All but 1 patient with BRAF were wild-type for KRAS. Patients who were wild-type for both genes who received cetuximab plus FOLFIRI had significantly reduced risk of disease progression (HR, 0.637; P =.0037) and significantly increased odds of response (odds ratio, 2.175; P <.001) compared with FOLFIRI alone, but overall survival no longer differed significantly between treatment groups. BRAF mutation status was not associated with a significant treatment interaction effect, but was associated with worse outcomes in both treatment groups. KRAS mutation status was not associated with differences in safety outcomes.
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