Another study has shown that colon or rectal cancer patients whose tumors have mutated KRAS don’t benefit from Erbitux® (cetuximab). However, in the study when only patients with normal or wild-type KRAS were considered, survival time almost doubled after treatment with Erbitux began.
The National Cancer Institute of Canada sponsored a randomized trial (NCIC CTC C0.17) to compare Erbitux to the best supportive care for patients whose colorectal cancer had gotten worse on existing standard treatments that included 5FU, Eloxatin® (oxaliplatin) and Camptosar® (irinotecan). Trial results were published in the New England Journal of Medicine last fall, showing a survival benefit for Erbitux treated patients. Based on that study, the FDA approved a labeling change for Erbitux to reflect improved survival.
The new analysis, reported at the World Congress on Gastrointestinal Cancer in Barcelona showed that KRAS status predicted benefit from Erbitux. Median survival for patients with wild-type or normal KRAS was 9.5 months when they received Erbitux compared to 4.8 months for best supportive care alone. Patients with mutated KRAS had no similar benefit. For them median survival was 4.5 months whether or not they received Erbitux.
Researchers were able to analyze 394 colorectal tumors (69 percent of all patients in the trial). They found KRAS mutations in 42 percent of those tumors.
Besides an improvement in overall survival for those with wild-type KRAS, those patients also lived longer before their cancer got worse (progression-free survival). Progression-free survival for wild-type KRAS patients who got Erbitux was 3.8 months compared to 1.9 months for those receiving only supportive care. Again there was no benefit for patients with mutant KRAS. Their progression-free survival was 1.8 months.
However, KRAS status did not change overall survival for patients receiving supportive care alone. There was no significant difference in median survival time between wild-type and mutant KRAS patients.
Christos Karapetis from the Australasian Gastrointestinal Trials Group and his team concluded,
In the setting of pre-treated advanced colorectal cancer, there is an almost doubling of median overall and progression free survival in patients with wild-type K-Ras tumours while no significant benefit is observed in patients with mutant K-Ras. K-Ras mutation status did not demonstrate a prognostic effect within a ‘no treatment’ group. In this population, K-Ras mutation status is a strong predictive biomarker and K-Ras mutation analysis may now be considered a new standard of care in the selection of patients for EGFR targeted therapy.
Because the abstract is not yet available online, we are providing a copy of it below:
8. O-037. KRAS Mutation status is a predictive biomarker for cetuximab benefit in the treatment of advanced colorectal cancer – Results from NCIC CTG CO.17: A phase III trial of cetuximab versus best supportive care.
Christos Karapetis1, Shirin Khambata-Ford2, Derek Jonker3, Chris O’Callaghan3, Dongsheng Tu3, Niall Tebbutt1, John Simes1,Christiane Langer2, Malcolm Moore3, John Zalcberg1
1Australasian Gastrointestinal Trials Group, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; 2Bristol-Myers-Squibb Company, Princeton NJ & Wallingford CT, USA; 3National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, ON, Canada.
Background: Cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), improves overall survival (OS) and progression free survival (PFS) and preserves quality of life in patients with advanced colorectal cancer (CRC) that has progressed after chemotherapy. The presence of wild type K-Ras (WT) may predict which patients will optimally benefit from cetuximab in this setting. In addition, the prognostic significance of K-Ras mutation status is unclear. Methods: CRC tumour samples were collected and analysed as part of a phase III clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone (NEJM 2007; 357(20): 2040-8). Activating mutations in exon 2 of the K-Ras gene were detected in tumourderived genomic DNA by direct gene sequencing without knowledge of clinical outcome. The predictive effect of K-Ras mutation status on OS and PFS was examined using a Cox model with tests for treatment-biomarker interaction. Results: K-Ras mutation status was ascertained in 394 (69%) of the total study population (198 cetuximab, 196 BSC). Mutant K-Ras was detected in 164 (42%) patients. Within the mutant K-Ras group the median PFS was the same (1.8 months) for both groups (HR, 0.99; 95% CI, 0.73 to 1.35; p=0.96), while median OS was 4.6 months with cetuximab and 4.5 months with BSC (HR, 0.98; 95% CI, 0.70 to 1.37; p=0.89). In the 230 (58%) WT patients, median PFS was 3.8 months for the cetuximab treated group and 1.9 months with BSC (HR, 0.40; 95% CI, 0.30 to 0.54; p < 0.0001). The survival of patients with WT K-Ras was longer when they were treated with cetuximab, with a median OS of 9.5 months with cetuximab vs. 4.8 months with BSC (HR, 0.55; 95% CI, 0.41 to 0.74; p<0.0001). The test for interaction between K-Ras mutation status and cetuximab treatment demonstrates that the effect of cetuximab on OS (p=0.01) and PFS (p=0.0001) is significantly greater in the K-Ras WT group than mutant group. The difference in the OS of patients with either WT or mutant K-Ras in the BSC arm was not significant (HR, 1.01; 95% CI, 0.74 to 1.37; p=0.97). Conclusions: In the setting of pre-treated advanced CRC, there is an almost doubling of median overall and progression free survival in patients with WT K-Ras tumours while no significant benefit is observed in patients with mutant K-Ras. K-Ras mutation status did not demonstrate a prognostic effect within a ‘no treatment’ group. In this population, K-Ras mutation status is a strong predictive biomarker and K-Ras mutation analysis may now be considered a new standard of care in the selection of patients for EGFR targeted therapy.