BY ROBERT H. CARLSON
BARCELONA, Spain -- The limited effectiveness of anti-EGFR agents such as cetuximab is a concern not only in patients with KRAS-mutant tumors, but also potentially for patients with any RAS mutation, including NRAS. Extended analysis of clinical trials in metastatic colorectal cancer have established that in the first-line setting, patients with metastatic colorectal cancer harboring any activating RAS mutation, not only KRAS, are unlikely to benefit from the addition of cetuximab to FOLFOX or to FOLFIRI.
As Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven and Head of the Digestive Oncology Unit at University Hospital Gasthuisberg in Belgium, explained in an interview here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer, classic KRAS exon-2 testing finds the mutation in approximately 40 percent of these patients, but extended RAS analysis finds another 10 to 15 percent.
“We should do not only KRAS testing anymore, but also RAS testing,” he said. “Today we know that we have to look at RAS and other so-called rarer RAS mutations, which are on KRAS exon 3, KRAS exon 4, and NRAS.
“The group identified by extended RAS testing, compared with KRAS testing, is 10 to 15 percent, but that's added to the 40 percent of patients with a KRAS mutation exon 2,” said Van Cutsem, Chair of the Congress. “That brings us to around 50 percent of patients with metastatic colorectal cancer.”
Patients with a RAS mutation should not be treated with an anti-EGFR antibody, he said. “In Europe we have changed the label already for that, but in the U.S., although the data are strong, the FDA has not yet changed the label. In Europe we are a bit more dynamic on that and have followed the scientific evolutions more rapidly.”
Introduce All-RAS Analysis in Clinics
There is no doubt that there is a benefit to selecting patients with metastatic colorectal cancer by RAS status, said Congress Vice-Chair Josep Tabernero, MD, PhD, Head of Medical Oncology and Director of Clinical Research at Vall d'Hebron University Hospital and Institute of Oncology in Barcelona.
In a separate interview at the meeting, Tabernero recommended that all-RAS analysis should be introduced in the clinic to make the best treatment decision at the time of diagnosis of stage IV colorectal cancer, to decide the most appropriate first-line therapy as well as the sequence of treatments. He said there may also be benefit in analyzing BRAF status.
The need for all-RAS analysis can be seen, he said, in the PICCOLO study (Seymour et al: Lancet Oncology 2013;14:749-759), which showed that in patients with fluorouracil-resistant advanced colorectal cancer, the addition of panitumumab to irinotecan did not improve overall survival in the subgroup of patients with wild-type KRAS tumors. But the patients who had the worst overall survival were those with mutations in BRAF, NRAS, and PIK3A.
Not all RAS mutations are the same, Tabernero noted. In a pooled analysis of patients from seven clinical trials who were treated with chemotherapy-cetuximab versus chemotherapy alone, patients with KRAS (codon 12) G12V-mutated tumors treated with the cetuximab-containing regimen had inferior progression-free and overall survival and response rates compared with use of chemotherapy alone, as would be expected (De Roock et al: JAMA 2010;304:1812-1822). But patients with KRAS (codon 13) G13D-mutated tumors treated with chemotherapy-cetuximab had longer overall and progression-free survival than those treated with chemotherapy alone.
RAS analysis is also complicated because several different technologies are being used. The CRYSTAL and OPUS studies both used BEAMing technology from Sysmex Inostics; FIRE-3 used PyroMark (Qiagen) TheraScreenPyro Kits; and PRIME and PEAK used dideoxy sequencing with the WAVE MicroChip Electrophoresis System.
Adding further to the puzzle, sensitivity for RAS mutation detection with these systems ranges from 0.01 percent to 10 percent, Tabernero said.
Tabernero outlined a “switch” strategy to select the best candidates for first-line anti-EGFR therapy: patients with metastatic colorectal cancer would first be tested for KRAS exon-2 wild-type tumors, and those falling into this category would then be tested for all-RAS wild-type tumors. “This constitutes the first important step for stratified, personalized medicine in this setting,” he said. “The advantage in overall survival would be huge.”
OPUS Update: Any RAS Mutation Cancels Cetuximab Benefit
Updates with RAS analysis were presented here on two clinical trials, OPUS and CRYSTAL, highlighting the significance of expanded RAS analysis.
Researchers reported that an extended analysis of data on RAS mutation from the randomized Phase II OPUS trial (Bokemeyer et al: Ann Oncol 2011;22:1535-1546) shows that metastatic colorectal cancer patients harboring not just KRAS but any activating RAS tumor mutation are unlikely to benefit from the addition of cetuximab.
The original OPUS report showed that the addition of cetuximab to FOLFOX4 significantly increased response and progression-free survival in the first-line treatment of patients with KRAS exon-2 wild-type metastatic colorectal cancer. But patients with KRAS exon-2 tumor mutations showed no such benefit from cetuximab, with worse outcomes in patients in the FOLFOX4-cetuximab arm compared with FOLFOX4 alone. Those authors also concluded that KRAS mutation status is an effective predictive biomarker.
“Restricting administration of FOLFOX4-cetuximab to patients with RAS wild-type tumors enables further tailoring of therapy to maximize patient benefit and prevent harm,” said Sabine Tejpar, MD, PhD, Associate Professor of Medicine at University Hospital Gasthuisberg, who presented the extended analysis data at the World GI Congress.
And a retrospective subgroup analysis of data from the randomized, Phase III CRYSTAL trial (Van Cutsem E et al. N Engl J Med 2009; 360:1408-1417) showed no benefit from cetuximab in patients with RAS mutations. Those researchers initially reported that the addition of cetuximab to FOLFIRI significantly increased progression-free survival, overall survival, and response in the first-line treatment of patients with KRAS exon 2 (codon12/13) wild-type metastatic colorectal cancer, while patients with KRAS exon-2 tumor mutations showed no cetuximab treatment benefit.
The new data were presented here by Fortunato Ciardiello, MD, PhD, Professor and Head of the Division of Medical Oncology at Second University of Naples in Italy, who said they were consistent with less than five percent mutant sequences being a clinically appropriate cutoff to use in determining eligibility for first-line FOLFIRI-cetuximab.
“Molecular testing of tumors for all activating mutations of KRAS and NRAS are essential in selecting the most appropriate first-line treatment for patients with metastatic colorectal cancer,” he said.