Studies Emphasize Need for Full <em>RAS</em> Mutational Analyses in the Management of mCRC

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

OPUS Analysis of All-RASPopulation

Mutations inKRASexon 2, codons 12 and 13, are associated with a lack of benefit from EGFR inhibitors. However, data from the OPUS and CECOG/CORE2 trials presented at the GI Symposium suggested that additionalKRASandNRASmutations are also associated with inferior outcomes from EGFR-targeted agents. Essentially, the data point to the need to &ldquo;think beyondKRAS,&rdquo; and consider other less commonRASmutations in the management of mCRC.Patients with any activatingRASmutation 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.¹KRASexon 2 codon 12/13 wild-type (wt) mCRC patients benefited significantly from first-line cetuximab, in terms of response and progression-free survival.

Roberto Bordonaro, MD, on the Treatment of Advanced Colorectal Cancer

Bordonaro is the chair of medical oncology at Garibaldi Hospital, in Catania, Italy.

The 179 OPUS patients previously defined asKRAScodon 12/13 wt were screened for additionalKRASandNRASmutations. Overall, mutation status was evaluable for 118/179 (66%) of patients withKRASexon 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 &ldquo;new RAS population.&rdquo; The overall incidence ofRASmutations beyondKRASexon 2 was as follows:KRASexon 3 (6.8%),KRASexon 4 (9.3%),NRASexon 2 (7.6%),NRASexon 3 (5.1%), andNRASexon 4 (3.4%).

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

&ldquo;In theRAS-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,&rdquo; Tejpar said. &ldquo;In theRAS-mutant population, there was less favorable clinical outcome and no benefit&hellip;from the addition of cetuximab to FOLFOX4 in relation to PFS, OS, and ORR.&rdquo;

Table. OPUS Trial: Efficacy inRASwild-type versusRASmutant

RASwild type

RASmutant

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)

Pvalue

.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)

Pvalue

.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)

Pvalue

.008

.110

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

In the &ldquo;new&rdquo;RASmutant 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.

&ldquo;Definitive conclusions for patients with newRAStumor mutations (RASmutations beyondKRASexon 2) cannot be drawn due to low patient numbers,&rdquo; she indicated.

CECOG/CORE2 Study

In an interview with OncLive.com, Tajpar summarized the main findings. &ldquo;If you look at the newRASmutations, 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,&rdquo; she said. &ldquo;There is now sufficient evidence from cetuximab and panitumumab [studies] that we should not be treating those patients [with EGFR inhibitors].&rdquo;First-line FOLFOX4 plus cetuximab was shown to be effective in 152KRAS-wt mCRC patients in the randomized phase II CECOG/CORE2 study. The investigators subsequently analyzed tumors for mutations inKRASexons 3 and 4, andNRASexons 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 randomizedKRASexon 2 wt mCRC patients, looking further at the more rare mutations. Investigators compared ORR, PFS, and OS according to mutational status forKRASexons 2, 3, and 4 andNRASexons 2, 3, and 4.

Of the 148KRASexon 2 wt patients, 124 hadRAS-andBRAF-wt tumors, 10 hadRASmutations only and 14 hadBRAFmutations only.

In theRAS/BRAF-wt versus theRAS-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-patientBRAF-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 toRAS/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.

&ldquo;The marked difference in OS between mutant andRAS/BRAFwild-type patients remained statistically significant in the Cox model, if adjusted for significant confounding factors,&rdquo; Brodowicz noted.

In the 124 patients whose tumors were completelyRAS/BRAFwt, median OS was 3.3 months longer than in the 152 patients withKRASexon 2 wt mCRC (28.5 months versus 25.2 months), he added.

&ldquo;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 thatRASmutational analyses in mCRC disease is recommended prior to the initiation of an EGFR-targeted monoclonal antibody therapy,&rdquo; Brodowicz said.

1. Tejpar S, Lenz H-J, K&ouml;hne C-H, et al. Effect ofKRASandNRASmutations 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 withKRASandNRASwild-type (wt) metastatic colorectal cancer (mCRC).J Clin Oncol. 2014;32(suppl 3; abstr LBA391).