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ASCO Presenter Urges KRAS Testing for All Colorectal Cancer Patients Before Erbitux Treatment

CHICAGO (GenomeWeb News) — Results from a large, multinational prospective clinical trial have shown that patients with metastatic colorectal cancer whose tumor carries the wild-type version of the KRAS gene are much more likely than patients with the mutated form of the gene to benefit from the monoclonal antibody Erbitux.
“KRAS testing should be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient,” urged Eric Van Cutsem, professor at the University Hospital Gasthuisberg in Leuven, Belgium, and the lead author of the study.
The widely followed study, which was both presented during a plenary session over the weekend and detailed in a news conference here during the annual meeting of the American Society of Clinical Oncology, added heft to earlier research conducted by Van Cutsem suggesting that the targeted biologic can help shrink colorectal tumors when used as a first-line drug together with chemotherapy in metastatic colorectal cancer.
Those findings, published last year in the Journal of Clinical Oncology, showed that Erbitux together with chemotherapy “is a highly active first-line treatment” for newly diagnosed colorectal cancer.
While Van Cutsem’s initial study suggested that Erbitux “has the potential to become part of the standard treatment for patients with newly diagnosed metastatic colorectal cancer,” the new research “helps us to identify which patients are most likely to benefit from adding the drug to treatment,” the researcher said during the news conference.
Erbitux, also known as cetuximab, was approved in the US in 2004 to be used with chemotherapy to treat metastatic colorectal cancer. Separately, KRAS mutations, which are found in 30 to 45 percent of all colorectal tumors, have been shown to predict whether patients will benefit from EGFR-inhibiting drugs like Erbitux in the second-line setting or later, according to the US Food and Drug Administration.
To arrive at their new results, Van Cutsem’s team used tumor samples from 587 patients with metastatic colorectal cancer to determine each tumor’s KRAS status. KRAS mutations were found in 35.6 percent of the samples in this population, which reflect the national breakdown.
The researchers found that 59.3 percent of patients with the wild-type KRAS gene responded to treatment with Erbitux and chemotherapy — that is, their tumors shrank by more than half — compared to 43.2 percent of patients who responded to chemotherapy alone.
By comparison, patients whose tumor carried the mutated KRAS gene experienced the same clinical results whether their regimen included Erbitux or not.
Moreover, while adding Erbitux to chemotherapy for all patients resulted in a 15 percent decrease in risk for cancer progression, wild-type carriers showed a 32 percent decreased risk.
According to Joe Nevins, director of the Center for Applied Genomics & Technology at Duke University’s Institute for Genome Sciences and Policy, the results of Van Cutsem’s findings show that the KRAS gene is “not a perfect but nevertheless an effective way” to identify patients who can benefit from Erbitux. Nevins did not participate in the study.
The study results, which could trim the patient population likely to benefit from the drug, were presented one day after European regulators narrowed its indication to include only patients whose tumor carries the wild-type KRAS gene.
Van Cutsem’s findings give oncologists ”new tools to identify the most appropriate treatment for each patient while avoiding over-treatment with drugs that have potentially toxic side effects,” said Julie Gralow, associate professor of medicine at the University of Washington, who moderated the news conference. “We now know the two-thirds of patients who will respond to [Erbitux], and we don’t need to give the drug to the [remaining] third now.”
Van Cutsem said there are “a few” PCR-based KRAS-status assays on the market today that can be applied to archived tumor samples, and urged oncologists to “routinely conduct” KRAS testing “in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient.”
The study was sponsored by Merck KGaA of Germany, which sells Erbitux in markets outside the US.
Separately here, molecular diagnostics firm Genomic Health presented findings from a study looking at KRAS status and colorectal cancer outcome. The paper, entitled “Evaluation of tumor gene expression and K-Ras mutations in FFPE tumor tissue as predictors of response to cetuximab in metastatic colorectal cancer,” was conducted with ImClone, the maker of Erbitux, and Bristol-Meyers Squibb, its US distributor.
According to the researchers, the findings suggest that a “multi-parameter marker test comprising KRAS mutation status in combination with the expression levels of a small number of genes could be developed further to select patients for cetuximab therapy. Applicability of this test to cetuximab combination therapy should be explored.”
In that study, the researchers used formalin-fixed paraffin-embedded primary tumors from 226 patients with metastatic colorectal cancer who were treated with Erbitux as a monotherapy in three separate studies. The samples were retrospectively assayed for KRAS mutations and for the expression of candidate genes, according to the paper’s abstract.
Using quantitative RT-PCR, the researchers found that 36 percent of these patients had KRAS mutations. Patients whose tumors carried the wild-type version of the gene, however, “had a significantly higher disease control rate than those with KRAS mutations,” the team found.