NEW YORK (Reuters Health) May 26 - New data shows "unequivocally" that adding cetuximab (Erbitux) to first-line chemo for metastatic colorectal cancer extends survival only when tumors have the wild-type KRAS gene, European researchers are reporting.
The updated survival analysis of patients in the open-label phase III CRYSTAL study confirmed that adding cetuximab to the FOLFIRI regimen (irinotecan, fluorouracil and leucovorin) does not extend overall survival when tumors have mutant KRAS, according to lead author Dr. Eric Van Cutsem of University Hospital Gasthuisberg, Leuven, Belgium, and colleagues.
Along with more information on the KRAS status of the study population, the new analysis -- published online April 18 in the Journal of Clinical Oncology -- increases the follow-up by more than 16 months and adds new data about the prognostic value of the BRAF tumor mutation.
The CRYSTAL study featured an intent-to-treat population of 1,198 patients with metastatic colorectal cancer. Half received FOLFIRI alone and half received FOLFIRI plus cetuximab, which is an epidermal growth factor receptor (EGFR) inhibitor.
On day 1 of a 14-day treatment cycle, patients received an infusion of irinotecan 180 mg/m2, followed by an infusion of leucovorin 200 mg/m2 L-form, or 400 mg/m2 racemic, followed by fluorouracil, first as a 400 mg/m2 IV bolus, then a 2,400-mg/m2 continuous infusion.
Patients in the cetuximab arm received an initial infusion of cetuximab 400 mg/m2 an hour before FOLFIRI on day one and then 250 mg/m2 weekly.
In the original 2009 report of the study, KRAS status had been ascertained for only 45% of the participants. In the updated analysis, the authors had access to tumor DNA from tissue previously used to assess EGFR expression. That brought the ascertainment rate to 89% of the cohort. Also, the median follow-up was extended to more than 46 months, from nearly 30 months in the original report.
In the population whose KRAS status was known, 63% of the tumors were wild-type.
The new analysis found, as did the original, that overall survival was significantly increased by cetuximab (in this analysis from 20.0 to 23.5 months), but only in patients with wild-type KRAS disease. The risk of disease progression and the odds of response in such patients were also improved significantly by the addition of cetuximab.
No evidence was found of any clinical benefit from cetuximab in patients whose tumors carried mutations in KRAS.
BRAF V600E mutations were found in 60 (6%) of 999 tumor samples evaluable for both BRAF and KRAS, overwhelmingly in KRAS wild-type tumors. In patients whose tumors were wild-type for both genes, cetuximab was associated with significant improvements in progression-free survival and the odds of response, but the overall survival benefit was not quite significant (P = 0.0547).
In both study arms (with and without cetuximab), patients with wild-type KRAS and BRAF V600E mutations had worse outcomes for all efficacy end points, versus wild-type BRAF tumors.
The study was supported by Merck KGaA, Darmstadt, Germany, which distributes Erbitux outside the United States and Canada.
The updated survival analysis of patients in the open-label phase III CRYSTAL study confirmed that adding cetuximab to the FOLFIRI regimen (irinotecan, fluorouracil and leucovorin) does not extend overall survival when tumors have mutant KRAS, according to lead author Dr. Eric Van Cutsem of University Hospital Gasthuisberg, Leuven, Belgium, and colleagues.
Along with more information on the KRAS status of the study population, the new analysis -- published online April 18 in the Journal of Clinical Oncology -- increases the follow-up by more than 16 months and adds new data about the prognostic value of the BRAF tumor mutation.
The CRYSTAL study featured an intent-to-treat population of 1,198 patients with metastatic colorectal cancer. Half received FOLFIRI alone and half received FOLFIRI plus cetuximab, which is an epidermal growth factor receptor (EGFR) inhibitor.
On day 1 of a 14-day treatment cycle, patients received an infusion of irinotecan 180 mg/m2, followed by an infusion of leucovorin 200 mg/m2 L-form, or 400 mg/m2 racemic, followed by fluorouracil, first as a 400 mg/m2 IV bolus, then a 2,400-mg/m2 continuous infusion.
Patients in the cetuximab arm received an initial infusion of cetuximab 400 mg/m2 an hour before FOLFIRI on day one and then 250 mg/m2 weekly.
In the original 2009 report of the study, KRAS status had been ascertained for only 45% of the participants. In the updated analysis, the authors had access to tumor DNA from tissue previously used to assess EGFR expression. That brought the ascertainment rate to 89% of the cohort. Also, the median follow-up was extended to more than 46 months, from nearly 30 months in the original report.
In the population whose KRAS status was known, 63% of the tumors were wild-type.
The new analysis found, as did the original, that overall survival was significantly increased by cetuximab (in this analysis from 20.0 to 23.5 months), but only in patients with wild-type KRAS disease. The risk of disease progression and the odds of response in such patients were also improved significantly by the addition of cetuximab.
No evidence was found of any clinical benefit from cetuximab in patients whose tumors carried mutations in KRAS.
BRAF V600E mutations were found in 60 (6%) of 999 tumor samples evaluable for both BRAF and KRAS, overwhelmingly in KRAS wild-type tumors. In patients whose tumors were wild-type for both genes, cetuximab was associated with significant improvements in progression-free survival and the odds of response, but the overall survival benefit was not quite significant (P = 0.0547).
In both study arms (with and without cetuximab), patients with wild-type KRAS and BRAF V600E mutations had worse outcomes for all efficacy end points, versus wild-type BRAF tumors.
The study was supported by Merck KGaA, Darmstadt, Germany, which distributes Erbitux outside the United States and Canada.
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I believe I read about this.
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