Effect of KRAS and NRAS mutations on treatment outcomes in patients with metastatic colorectal cancer (mCRC) treated first-line with cetuximab plus FOLFOX4: New results from the OPUS study.

Cancers of the Colon and Rectum
Session Type and Session Title: 
General Poster Session C: Cancers of the Colon and Rectum
Abstract Number: 
J Clin Oncol 32, 2014 (suppl 3; abstr LBA444)
Sabine Tejpar, Heinz-Josef Lenz, Claus-Henning Köhne, Volker Heinemann, Fortunato Ciardiello, Regina Esser, Frank Beier, Christopher Stroh, Klaus Duecker, Carsten Bokemeyer; Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium; Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Onkologie Klinikum Oldenburg, Oldenburg, Germany; Comprehensive Cancer Center, Klinikum Grosshadern, University of Munich, Munich, Germany; Division of Medical Oncology, Department of Experimental and Clinical Medicine and Surgery "F. Magrassi and A. Lanzara," Second University of Naples, Naples, Italy; Merck KGaA, Darmstadt, Germany; University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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Abstract Disclosures


Background: Patients with KRAS exon 2 codon 12/13 wild-type (wt) mCRC benefit significantly from the addition of cetuximab to first-line FOLFOX4 in relation to response and progression-free survival. Patients with KRAS exon 2 codon 12/13 mutations show no benefit with a trend to worse clinical outcomes. Methods: Tumors from OPUS study patients previously defined as KRAS codon 12/13 wt (n=179) were screened for specific mutations in KRAS exons 3 and 4 (8) and NRAS exons 2, 3, and 4 (18) using BEAMing technology. Treatment outcomes were assessed according to mutation status. Results: RAS tumor mutation status was evaluable for 118/179 (66%) patients. Mutations at the screened loci were detected in 36 (31%) patients. In the RAS wt population, there was benefit associated with the addition of cetuximab to FOLFOX4 (Table). In the overall RAS-mutant population, there was less favorable clinical outcome and no benefit from the addition of cetuximab to FOLFOX4. Conclusions: Patients with mCRC harboring any activating mutation of KRAS or NRAS are unlikely to benefit from the addition of cetuximab to FOLFOX4. Definitive conclusions for patients with new tumor mutations cannot be drawn due to low patient numbers. Restricting cetuximab administration to patients with tumors wt at all such loci might enable the further tailoring of therapy to maximize patient benefit.

RAS wt
(all tested loci)
New RAS mt
RAS mt
(any tested locus)
Parameter N=36 N=46 N=17 N=19 N=94 N=78
Response rate, % 61.1 30.4 47.1 36.8 36.2 48.7
Odds ratio 3.46 1.50 0.61
95% CI 1.37–8.71 0.38–5.95 0.33–1.12
p-value* 0.008 0.57 0.11
Median PFS, months 12.0 5.8 7.3 7.4 5.6 7.8
HR 0.43 1.02 1.59
95% CI 0.21–0.88 0.41–2.55 1.08–2.36
p value** 0.018 0.96 0.018
Median OS, months 20.7 17.8 14.8 17.8 13.4 17.8
HR 0.83 1.41 1.35
95% CI 0.49–1.41 0.62–3.21 0.95–1.92
p value** 0.50 0.41 0.089

RAS evaluable population (n=118). Subset of the KRAS evaluable biomarkers population (n=315). * Cochran-Mantel-Haenszel. ** Log rank. Abbreviations: cet, cetuximab; HR, hazard ratio; mt, mutant; OS, overall survival; PFS, progression-free survival.