Treatment outcome according to tumor RAS mutation status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab.

Gastrointestinal (Colorectal) Cancer
Session Type and Session Title: 
Oral Abstract Session, Gastrointestinal (Colorectal) Cancer
Abstract Number: 
J Clin Oncol 32:5s, 2014 (suppl; abstr 3505)
Carsten Bokemeyer, Claus-Henning Kohne, Fortunato Ciardiello, Heinz-Josef Lenz, Volker Heinemann, Ute Klinkhardt, Frank Beier, Klaus Duecker, Sabine Tejpar; Department of Oncology, Hematology and BMT with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Onkologie Klinikum Oldenburg, Oldenburg, Germany; Medical Oncology, Second University of Naples, Naples, Italy; Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Department of Medical Oncology, Klinikum Grosshadern, University of Munich, Munich, Germany; Merck KGaA, Darmstadt, Germany; University of Leuven, KUL, Leuven, Belgium

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures


Background: The addition of cetuximab to FOLFOX4 significantly improved progression-free survival and response in the first-line treatment of patients (pts) with KRAS codon 12/13 (hereinafter exon 2) wild-type (wt) mCRC. Pts with KRASexon 2 tumor mutations showed no such cetuximab benefit, with a trend for worse outcome. Methods: Available KRAS exon 2 wt tumors from OPUS study pts were screened for 26 mutations (new RAS) in 4 additional KRAS codons (exons 3 and 4) and 6 NRAS codons (exons 2, 3 and 4) using BEAMing technology (5% sensitivity cutoff selected for analysis). Outcome was assessed according to RAS mutation status (KRAS exon 2 + new RAS). Results: Mutation status was evaluable in 118/179 (66%) pts with KRAS exon 2 wt tumors. New RAS mutations were detected in 31/118 (26%) pts. In those with RAS wt tumors, response was significantly improved by the addition of cetuximab to FOLFOX4 (Table). The treatment effect for those with new RAS tumor mutations could not be definitively assessed due to low pt numbers. In pts with any tumor RAS mutation (KRAS exon 2 + new RAS), no benefit from the addition of cetuximab to FOLFOX4 was seen, with a clear trend for worse outcome. Conclusions: Pts with mCRC harboring any activating RAS mutation are unlikely to benefit from the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to pts with tumors wt at all such loci might help further tailoring of therapy to maximize pt benefit. Clinical trial information: NCT00125034.

Parameter RAS wt*
(all loci)
New RAS mt*
RAS mt
(any locus)
+ cet
+ cet
+ cet
Response rate, % 57.9 28.6 53.3 43.8 37.0 50.7
Odds ratio 3.33 1.50 0.58
95% CI 1.36–8.17 0.35–6.53 0.31–1.08
P value 0.008 0.60 0.087
Median progression-free survival, months 12.0 5.8 7.5 7.4 5.6 7.8
HR 0.53 0.77 1.54
95% CI 0.27–1.04 0.28–2.08 1.04–2.29
P value§ 0.062 0.60 0.031
Median overall survival, months 19.8 17.8 18.4 17.8 13.5 17.8
HR 0.94 1.09 1.29
95% CI 0.56–1.56 0.44–2.68 0.91–1.84
P value§ 0.80 0.86 0.157

Abbreviations: cet, cetuximab; HR, hazard ratio; mt, mutant; *RAS evaluable population, N=118; Subset of the OPUS KRAS evaluable population, N=315; Cochran-Mantel-Haenszel; §log-rank.