RAS Mutational Analyses in mCRC Trials Highlight Need to 'Think Beyond KRAS'

Sandra Hanner
Published: Monday, Jan 20, 2014

2014 GI Cancers SymposiumStudies presented at the 2014 Gastrointestinal (GI) Cancers Symposium emphasized the need for full RAS mutational analyses in the management of metastatic colorectal cancer (mCRC) prior to initiating treatment with anti-EGFR monoclonal antibodies.

Mutations in KRAS exon 2, codons 12 and 13, are associated with a lack of benefit from EGFR inhibitors, such as cetuximab (Erbitux). However, data from the OPUS and CECOG/CORE2 trials presented at the GI Symposium suggested that additional KRAS and NRAS mutations are also associated with inferior outcomes from EGFR-targeted agents. Essentially, the data point to the need to “think beyond KRAS,” and consider other less common RAS mutations in the management of mCRC.  

OPUS Analysis of All-RAS Population

Patients with any activating RAS mutation were unlikely to benefit from the addition of cetuximab to FOLFOX4, in a new analysis of the OPUS trial presented at the meeting by Sabine Tejpar, MD, PhD, of the University Hospital Gasthuisberg in Leuven, Belgium.1 KRAS exon 2 codon 12/13 wild-type (wt) mCRC patients benefited significantly from first-line cetuximab, in terms of response and progression-free survival.

The 179 OPUS patients previously defined as KRAS codon 12/13 wt were screened for additional KRAS and NRAS mutations. Overall, mutation status was evaluable for 118/179 (66%) of patients with KRAS exon 2 codon 12/13 wt tumors.

Of these, 82 (69%) remained RAS wt, and 36 (31%) had new mutations at the screened loci, and these patients were labeled the “new RAS population.” The overall incidence of RAS mutations beyond KRAS exon 2 was as follows: KRAS exon 3 (6.8%), KRAS exon 4 (9.3%), NRAS exon 2 (7.6%), NRAS exon 3 (5.1%), and NRAS exon 4 (3.4%).

The analysis validated the benefit of adding cetuximab to FOLFOX4 in the RAS-wt population. It further showed that outcomes were less favorable among the overall RAS-mutant population, who derived no benefit from the EGFR inhibitor (Table). Patients with mCRC harboring any activating mutation of KRAS or NRAS were unlikely to benefit from the addition of cetuximab.

“In the RAS-wt population, there was significant benefit associated with the addition of cetuximab to FOLFOX4 in relation to progression-free survival [PFS] and objective response rate [ORR], while the hazard ratio for overall survival [OS] also favored the FOLFOX4/cetuximab arm,” Tejpar said. “In the RAS-mutant population, there was less favorable clinical outcome and no benefit…from  the addition of cetuximab to FOLFOX4 in relation to PFS, OS, and ORR.”

Table. OPUS Trial: Efficacy in RAS wild-type versus RAS mutant

  RAS wild type RAS mutant
Outcome FOLFOX 4
(n = 46)
FOLFOX4 + cetuximab
(n = 36)
(n = 78)
FOLFOX4 + cetuximab
(n = 94)
PFS (median, mo) 5.8 12.0 7.8 5.6
HR (95% CI) 0.43 (0.21-0.88) 1.59 (1.08-2.36)
P value .018 .018
OS (median, mo) 17.8 20.7 17.8 13.4
HR (95% CI) 0.83 (0.49-1.41) 1.35 (0.95-1.92)
P value .497 .089
ORR (%) 30.4 61.1 48.7 36.2
OR (95% CI) 3.46 (1.38-8.71) 0.61 (0.33-1.12)
P value .008 .110

HR indicates hazard ratio; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

In the “new” RAS mutant population, the patient numbers were small and efficacy outcomes were inconsistent, she added. In general, a higher ORR was observed in patients receiving FOLFOX4/cetuximab, PFS was comparable, and OS was less favorable for the cetuximab group, compared with patients receiving FOLFOX4 alone.

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