FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer.
BACKGROUND
The OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing.


METHODS
Samples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%).


RESULTS
Other RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4.


CONCLUSIONS
Patients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.
Department of Oncology, Haematology and Bone Marrow Transplantation with Section Pneumology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
C
C
Bokemeyer
Klinikum Oldenburg, Oldenburg, Germany.
C-H
CH
Köhne
Division of Medical Oncology, Department of Experimental and Clinical Medicine and Surgery "F. Magrassi and A. Lanzara", Second University of Naples, Naples, Italy.
F
F
Ciardiello
Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
H-J
HJ
Lenz
Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Munich, Germany.
V
V
Heinemann
Global Clinical Development Unit Oncology, Merck KGaA, Darmstadt, Germany.
U
U
Klinkhardt
Global Biostatistics, Merck KGaA, Darmstadt, Germany.
F
F
Beier
Biomarker Technologies & Operations, Merck KGaA, Darmstadt, Germany.
K
K
Duecker
Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
J H
JH
van Krieken
Molecular Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium. Electronic address: sabine.tejpar@uzleuven.be.
S
S
Tejpar
D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000068818:Cetuximab; D003062:Codon; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005091:Exons; D005472:Fluorouracil / Q000008:administration & dosage; D011905:Genes, ras; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage
D061067:Antibodies, Monoclonal, Humanized; D003062:Codon; D009944:Organoplatinum Compounds; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil
Cetuximab; FOLFOX4; KRAS; NRAS; OPUS; RAS