No Disease-Free Survival Benefit of Adding Cetuximab to FOLFOX4 in KRAS Exon 2 Wild-Type Resected Stage III Colon Cancer
In an interim analysis of the European phase III PETACC-8 trial reported in The Lancet Oncology, Taieb et al found no disease-free survival or overall survival benefit with the addition of cetuximab (Erbitux) to standard adjuvant FOLFOX4 (oxaliplatin, fluorouracil, leucovorin) therapy in patients with KRAS exon 2 wild-type resected stage III colon cancer. Differences in outcome in some subgroups suggest the need for additional study of cetuximab and FOLFOX adjuvant therapy in this setting.
Study Details
In this open-label trial, 2,559 patients with resected (R0) stage III disease from 340 sites in Europe were randomly assigned between December 2005 and November 2009 to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab given on day 1 at 400 mg/m² in the first week and then at 250 mg/m² weekly. A protocol amendment in June 2008, after 2,096 patients had been randomly assigned, restricted enrollment to patients with KRAS exon 2 wild-type tumors. The primary endpoint was disease-free survival in the intention to treat population of 1,602 patients with KRAS exon 2 wild-type tumors, including 791 in the cetuximab/FOLFOX4 group and 811 in the FOLFOX4 group. The KRAS exon 2 mutant tumor population consisted of 738 patients, including 364 in the cetuximab group and 374 in the control group.
The cetuximab and control KRAS exon 2 wild-type tumor groups were balanced for age (median, 60 years in both), sex (59% and 58% male), World Health Organization performance status (0 in 79% in both, 1 in 18% and 17%), pT classification (1-3 in 79% and 82%), pN classification (1 in 61% and 63%), bowel obstruction or perforation (19% and 18%), type of surgery (open in 68% and 69%), tumor location (left in 63% and 64%, right in 36% and 35%), histopathology grade (1–2 in 80% and 79%), BRAF mutation status (wild-type in 62% and 61%), and EGFR expression status (detectable in 49% and 50%).
Disease-Free Survival Outcomes
Median follow-up was 3.3 years. Three-year disease-free survival was 75.1% in the cetuximab group vs 78.0% in the control group (hazard ratio [HR] = 1.05, P = .66). There was also no difference in disease-free survival among patients with KRAS exon 2 wild-type and BRAF wild-type tumors (75.9% vs 79.1%, HR = 0.99, P = .92) or those with KRAS exon 2 mutant tumors (70.7% vs 71.0%, HR = 1.06, P = .65).
Additional predefined subgroup analysis in the KRAS exon 2 wild-type population showed that disease-free survival differed by treatment in favor of chemotherapy alone in women (P = .023 for heterogeneity) and in those with right-sided tumors (P = .032 for heterogeneity) and in favor of cetuximab/FOFLFOX4 in patients with pT4/N2 disease (P = .028 for heterogeneity). disease-free survival was similar in the two groups among patients with detectable (HR = 1.22, P = .17) and undetectable (HR = 0.89, P = .46) EGFR expression.
There were no differences in 3-year overall survival in the cetuximab vs control groups among patients with KRAS exon 2 wild-type (88.3% vs 90.5%, HR = 1.09, P = .56), KRAS exon 2 wild-type and BRAF wild-type (89.7% vs 91.2%, HR = 0.98, P = .92), or KRAS exon 2 mutant tumors (87.2% vs 88.1%, HR = 1.06, P = .76).
Toxicity
Grade 3 or 4 adverse events were more common in the cetuximab group (81% vs 66%), including diarrhea (15% vs 9%) and decreased appetite (15% vs > 1%) and adverse events of special interest including acne-like rash (27% vs 1%), mucositis (8% vs 1%), and infusion-related reactions (7% vs 4%). The safety profile among cetuximab patients was similar in the KRAS exon 2 wild-type and mutant populations.
In the KRAS exon 2 wild-type population, grade 5 adverse events possibly related to treatment occurred in seven cetuximab patients (sudden death, bronchopneumonia and sepsis, pneumonia, inadequate control of diabetes, ischemic stroke, pulmonary embolism, and pulmonary fibrosis) and in three control group patients (death, pulmonary embolism, and respiratory failure). In patients with KRAS exon 2 mutant tumors, three deaths in the cetuximab group and one in the control group were considered possibly related to treatment.
The investigators concluded, “The addition of cetuximab to FOLFOX4 did not improve [disease-free survival] compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted.”
Julien Taieb, MD, of Paris Descartes University, is the corresponding author for the Lancet Oncology article.
The study was funded by Fédération Francophone de Cancérologie Digestive, Merck KGaA, and Sanofi-Aventis. For full disclosures of the study authors, visit www.thelancet.com.
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