Eric Van Cutsem1, Heinz-Josef Lenz2, Claus-Henning Köhne2, Volker Heinemann2, Sabine Tejpar2, Ivan Melezínek2, Frank Beier2, Christopher Stroh2, Philippe Rougier2, J Han van Krieken2, Fortunato Ciardiello2. 1. Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy. eric.vancutsem@uzleuven.be. 2. Eric Van Cutsem and Sabine Tejpar, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven, Belgium; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Claus-Henning Köhne, Klinikum Oldenburg, Oldenburg; Volker Heinemann, University Hospital Grosshadern, Munich; Ivan Melezínek, Frank Beier, and Christopher Stroh, Merck KGaA, Darmstadt, Germany; Philippe Rougier, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France; J. Han van Krieken, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; and Fortunato Ciardiello, Second University of Naples, Naples, Italy.
Abstract
PURPOSE: The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing. PATIENTS AND METHODS: Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations. RESULTS:Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations. CONCLUSION: In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
RCT Entities:
PURPOSE: The phase III CRYSTAL study demonstrated that addition of cetuximab to fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival, progression-free survival, and objective response in the first-line treatment of patients with KRAS codon 12/13 (exon 2) wild-type metastatic colorectal cancer (mCRC). Outcome was reassessed in subgroups defined by extended RAS mutation testing. PATIENTS AND METHODS: Existing DNA samples from KRAS exon 2 wild-type tumors from CRYSTAL study patients were reanalyzed for other RAS mutations in four additional KRAS codons (exons 3 and 4) and six NRAS codons (exons 2, 3, and 4) using beads, emulsion, amplification, and magnetics technology. No tissue microdissection was performed. A ≥ 5% mutant allele cutoff was used to call mutations. RESULTS: Mutation status was evaluable in 430 (64.6%) of 666 patients with KRAS exon 2 wild-type tumors. Other RAS mutations were detected in 63 (14.7%) of 430 patients. In those with RAS wild-type tumors, a significant benefit across all efficacy end points was associated with the addition of cetuximab to FOLFIRI. In patients with other RAS tumor mutations, no difference in efficacy outcomes between treatment groups was seen. The safety profile in RAS subgroups was similar and in line with expectations. CONCLUSION: In the first-line treatment of mCRC, patients with RAS wild-type tumors derived a significant benefit from the addition of cetuximab to FOLFIRI; patients with RAS tumor mutations did not. Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
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