Time to Think Beyond KRAS in Metastatic Colorectal Cancer

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Eric Van Cutsem, MD, PhD

Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven in Belgium, told attendees at the 2013 European Cancer Congress that in the management of metastatic colorectal cancer, it is time to expand KRAS testing to include more rare mutations.

Until recently, KRAS status was the only validated predictive biomarker in this disease, with KRAS-mutated tumors demonstrating resistance to inhibitors of the epidermal growth factor receptor (EGFR). But while KRAS wild-type patients are likely to respond to anti-EGFR agents, response is not universal, leading to the quest to find reasons for this lack of response.

“One of the next challenges has been to fine-tune, in this KRAS wild-type population, which patients will be responders and which will not,” Dr. Van Cutsem said.

European Consortium

The European Consortium evaluated the role of various genetic markers in a large cohort of chemorefractory metastatic colorectal cancer patients treated with cetuximab plus irinotecan. In 773 primary tumor samples, they aimed to identify KRAS, BRAF, NRAS and PIK3CA mutations and relate these to clinical endpoints.1

They found that approximately 40% of tumors harbored a KRAS mutation, 14% had a PIK3CA mutation, 5% had a BRAF mutation, and about 3% had an NRAS mutation. In KRAS wild-type patients, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild-types. PIK3CA exon 20 mutations also conferred worse outcomes. The authors concluded that if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutational status gives additional predictive information for lack of benefit to cetuximab (Erbitux).

When the study population was not enriched at all by mutational status, the response rate to cetuximab/irinotecan was 24%. With KRAS mutational analysis, response rates rose to 36% in the KRAS exon 2 wild-type selected population and to 41% in patients with no mutations at all in KRAS, BRAF, NRAS, and PIK3CA exon 20, Dr. Van Cutsem reported.

Hotspots of Mutations

“Traditional KRAS testing identifies mutations in codons 12 and 13 of exon 2. We have now learned that in KRAS wild-type patients, around 15% to 20% have other, more rare mutations that are also very important,” he said.

These include NRAS mutations in exons 2, 3, and 4, and BRAF mutations in exon 15. These mutations outside of KRAS exon 2 are now being tested in several studies, including PRIME and PEAK, for panitumumab (Vectibix), and FIRE-3 for cetuximab (see related article on page 26).

“Today, we should not talk about testing for ‘KRAS’ but about ‘RAS’ testing,” he said. “These mutations are relatively rare, but very relevant.”

RAS Analyses in Panitumumab Studies

Recent analyses from the major anti-EGFR trials are supporting the findings made by the European Consortium. An extensive RAS analysis from the PRIME study, which evaluated FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin) with and without panitumumab, was published this year in The New England Journal of Medicine.2 In the initial analysis, only a nonsignificant trend for a survival benefit was observed with the addition of the EGFR inhibitor in KRAS exon 2 wild-type patients.

In a prospective-retrospective analysis, with longer follow-up and mutational analysis for KRAS exons 3 and 4, NRAS exons 2, 3, and 4, and BRAF exon 15, outcomes became much more favorable with panitumumab, including a statistically significant survival benefit for “all-RAS” wild-type patients.

Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumu-
mab-FOLFOX4 vs 7.9 months with FOLFOX4 alone (hazard ratio [HR] = 0.72; P = .004). Overall survival was 26.0 vs 20.2 months, respectively (HR = 0.78; P = .04). In the original analysis, the hazard ratios were 0.80 for progression-free survival and 0.83 for overall survival.

A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations, and these were associated with inferior progression-free survival and overall survival with panitumumab-
FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor, according to Douillard and colleagues.

“Aligning this recent concept of extending KRAS exon 2 testing to RAS, and looking at patients with all-RAS wild-type tumors, we can see the hazard ratio for panitumumab becomes more favorable [for overall survival, HR improved from 0.83 to 0.78]. For progression-free survival, there is a larger benefit when we exclude the more rare mutations,” Dr. Van Cutsem noted.

Even more importantly, he added, panitumumab in patients with wild-type KRAS exon 2 and mutations in the other RAS genes was potentially harmful in PRIME. Hazard ratios in this arm were 1.29 (P = .31) for overall survival and 1.28 (P = .32) for progression-free survival.

“This is the reason why we recommend using these drugs only with RAS wild-type patients, and we are not just talking anymore about KRAS wild-type. These are important data showing and endorsing the concept that we should test for the other RAS mutations,” he emphasized.

In the PICCOLO study, which evaluated the effect of adding panitumumab to irinotecan, patients with any mutation fared worse than those with all-RAS wild-type tumors.3 Similar findings were made in a recent study by Dr. Van Cutsem and colleagues using next-generation sequencing on 299 samples from a KRAS wild-type subset receiving panitumumab.4 They found mutation rates of 45% for KRAS, 5% for NRAS, 7% for BRAF, 9% for PIK3CA, along with a number of other aberrations. Among KRAS wild-type patients, only 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab.

Among wild-type KRAS patients, a treatment effect for progression-free survival favoring panitumumab occurred in patients with wild-type NRAS (HR = 0.39) and wild-type BRAF (HR = 0.37) but not mutant NRAS (HR = 1.94). For BRAF, mutation status was not predictive, he said.

RAS Analyses in Cetuximab Trials

In a retrospective pooled analysis from the CRYSTAL and OPUS trials, KRAS wild-type patients who had BRAF mutations had a poor prognosis, regardless of receiving chemotherapy or chemotherapy plus cetuximab: 9.9 and 14.1 months, respectively.5

“These BRAF-mutated patients really have worse survival than BRAF wild-type patients in the various trials, regardless of treatment,” he said. “The conclusion is that BRAF is prognostic, but not predictive.”

A preplanned subset analysis of the FIRE-3 trial, which evaluated cetuximab vs bevacizumab (Avastin) given with FOLFIRI (5-FU, leucovorin, irinotecan), also accentuates the importance of thinking beyond KRAS. While progression-free survival (a secondary endpoint) was similar between the arms in the KRAS exon 2 wild-type population, in the all-RAS wild-type analysis, a difference emerged favoring bevacizumab. The overall survival analysis (another secondary endpoint), however, favored cetuximab, which makes these findings “open to discussion,” he added.

“We are awaiting other head-to-head trials with overall survival as the primary endpoint,” he said, “but meanwhile, the bottom line message for me, from PRIME and FIRE-3, is that we should expand the testing of KRAS.” ■

Disclosure: Dr. Van Cutsem has received research funding paid to his institution by Merck Serono.


1. De Roock W, Claes B, Bernasconi D, et al: Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol 11:753-762, 2010.

2. Douillard JY, Oliner KS, Siena S, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 369:1023-1034, 2013.

3. Seymour MT, Brown SR, Middleton G, et al: Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): A prospectively stratified randomised trial. Lancet Oncol 14:749-759, 2013.

4. Peeters M, Oliner KS, Parker A, et al: Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res 19:1902-1912, 2013.

5. Bokemeyer C, Van Cutsem E, Rougier P, et al: Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 48:1466-1475, 2012.