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

Studies 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.

OPUS Analysis of All-RAS Population

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. 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)

FOLFOX4

(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.

“Definitive conclusions for patients with new RAS tumor mutations (RAS mutations beyond KRAS exon 2) cannot be drawn due to low patient numbers,” she indicated.

CECOG/CORE2 Study

In an interview with OncLive.com, Tajpar summarized the main findings. “If you look at the new RAS mutations, which was not done in the past because of their low frequency, you see that they contribute another 10% to 15% of mutations, and for these patients there is absolutely no sign of benefit with cetuximab. These new mutations are behaving just like the other ones,” she said. “There is now sufficient evidence from cetuximab and panitumumab [studies] that we should not be treating those patients [with EGFR inhibitors].”First-line FOLFOX4 plus cetuximab was shown to be effective in 152 KRAS-wt mCRC patients in the randomized phase II CECOG/CORE2 study. The investigators subsequently analyzed tumors for mutations in KRAS exons 3 and 4, and NRAS exons 2, 3, and 4, which have been associated with worse outcomes with EGFR inhibitors in other studies. The impact of these additional mutations on the reported findings in the CECOG/CORE2 study was explored, and the results were reported at the GI Cancers Symposium by Thomas Brodowicz, MD, of the Medical University of Vienna, Austria, and Central European Cooperative Oncology Group.²

The analysis was performed on tumor samples of 148 randomized KRAS exon 2 wt mCRC patients, looking further at the more rare mutations. Investigators compared ORR, PFS, and OS according to mutational status for KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4.

Of the 148 KRAS exon 2 wt patients, 124 had RAS- and BRAF-wt tumors, 10 had RAS mutations only and 14 had BRAF mutations only.

In the RAS/BRAF-wt versus the RAS-mutant/BRAF-wt group, the ORR was 61.3% (95% CI, 52.1-69.9) versus 40% (95%CI, 12.2-73.8), respectively, producing an odds ratio of 0.43 (95% CI, 0.11-1.57; P = .1966). Median PFS was 9.7 months (95% CI, 8.9-11.2) versus 7.2 months (95% CI, 6.7-10.8), producing a hazard ratio (HR) of 0.56 (95% CI, 0.27-1.16; P = .1135). Median OS was 28.5 months (95% CI, 24.0-31.3) versus 16.3 months (95% CI, 15.9-20.7), with an HR of 0.43 (95% CI, 0.20-0.89; P = .0199), respectively.

In the 14-patient BRAF-mutant/RAS-wt group, ORR was 50% (95% CI, 23.0-77.0), producing an odds ratio of 0.58 (95% CI 0.19-1.80; P = .3435) compared to RAS/BRAF-wt patients, and median OS was 11.7 months, producing an HR of 0.23 (95% CI, 0.12-0.41; P <.0001) in this comparison.

“The marked difference in OS between mutant and RAS/BRAF wild-type patients remained statistically significant in the Cox model, if adjusted for significant confounding factors,” Brodowicz noted.

In the 124 patients whose tumors were completely RAS/BRAF wt, median OS was 3.3 months longer than in the 152 patients with KRAS exon 2 wt mCRC (28.5 months versus 25.2 months), he added.

“RAS/BRAF-wt patients treated with cetuximab and FOLFOX4 experience a significant prolongation of OS as compared to mutant patients. This analysis supports the findings of other trials that RAS mutational analyses in mCRC disease is recommended prior to the initiation of an EGFR-targeted monoclonal antibody therapy,” Brodowicz said.

1. Tejpar S, Lenz H-J, Köhne C-H, et al. 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. J Clin Oncol. 2014;32(suppl 3; abstr LBA444).
2. Brodowicz T, Vrbanec D, Kaczirek K, et al. FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type (wt) metastatic colorectal cancer (mCRC). J Clin Oncol. 2014;32(suppl 3; abstr LBA391).

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