Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Treatment and RAS Mutations in Colorectal Cancer
Open accessAbstract
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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In ML18147, interaction test by KRAS status showed no statistically significant difference in bevacizumab efficacy between KRAS mutant and wild-type tumors (p=0.443 for PFS, p=0.126 for OS).
“The interaction test by KRAS status showed no statistically significant difference in bevacizumab efficacy between KRAS mutant and wild-type tumors, with p = 0.443 for PFS and p = 0.126 for OS [23].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [23]
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- Authors
- Van Cutsem, E., Lenz, H.-J., Köhne, C.-H., Heinemann, V., Tejpar, S., Melezínek, I., Beier, F., Stroh, C., Rougier, P., van Krieken, J. H., & Ciardiello, F.
- Affiliations
- 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,...
- Merck KGaA, Darmstadt (Germany) (DE)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2015-03-01
- Volume
- 33
- Issue
- 7
- Pages
- 692-700
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2112570485
- Cited by
- 789
- References
- 21
- Citations by year
- 2026: 20 · 2025: 31 · 2024: 54 · 2023: 71 · 2022: 59 · 2021: 89 · 2020: 81 · 2019: 78 · 2018: 79 · 2017: 88 · 2016: 83 · 2015: 55 · 2014: 1
- FWCI
- 44.41
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Lirias (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- Sanofi
- Merck KGaA
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- cetuximab, FOLFIRI, metastatic colorectal cancer, RAS mutations, KRAS exon 2 wild-type, NRAS mutation, anti-EGFR therapy, first-line therapy, CRYSTAL trial, predictive biomarkers
- MeSH terms
- Cetuximab, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Leucovorin, Female, Fluorouracil, Genetic Testing, Humans, Male, Membrane Proteins, Middle Aged, Mutation, Proto-Oncogene Proteins, Biomarkers, Tumor, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Disease-Free Survival, ras Proteins, GTP Phosphohydrolases, Kaplan-Meier Estimate, Molecular Targeted Therapy, Antibodies, Monoclonal, Humanized, ErbB Receptors
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