KRAS Predicts Which Colorectal Cancer Patients Will Benefit from Cetuximab

June 2, 2008 (Chicago, Illinois) — KRAS testing should be routinely conducted in all colorectal cancer patients immediately after diagnosis, report researchers. Presenting here at the American Society of Clinical Oncology (ASCO) 44th Annual Meeting, investigators showed that KRAS mutations, which are found in 30% to 45% of all colorectal tumors, are excellent indicators of which patients will benefit from the addition of cetuximab (Erbitux, Bristol-Myers Squibb).

The new results are from the CRYSTAL trial, a phase 3 study assessing the effectiveness of adding cetuximab to FOLFIRI as first-line therapy. The CRYSTAL trial was first presented at ASCO last year. As reported by Medscape Oncology at that meeting, the study showed that combination therapy reduced the risk for metastatic colorectal cancer growth or spread by 15%.

Despite the positive finding, many were underwhelmed by the study. At the time, press-briefing moderator William Blackstock, MD, from the Wake Forest University School of Medicine, in Winston-Salem, North Carolina, called the findings "modest." He said the new cetuximab combination simply added to a number of existing regimens.

Dr. Blackstock explained that although the combination would provide an important new option for some patients, he did not anticipate that it would change clinical practice. "It’s not that impressive," he said.

Lead investigator and presenter Eric Van Cutsem, MD, from the University Hospital in Leuven, Belgium, told Medscape Oncology that this new finding is more exciting.

"Some people were disappointed by the magnitude of the benefit we showed last year," Dr. Van Cutsem told reporters attending a press briefing. But results taking KRAS mutations into account are much more clinically meaningful, he noted.

Patients With KRAS Mutations Did Not Benefit From Cetuximab

Cetuximab is a monoclonal antibody that targets the epidermal growth-factor receptor. Patients received cetuximab 400 mg/m² as an initial dose and then 250 mg/m² per week. FOLFIRI, comprised of irinotecan 180 mg/m², folinic acid 400 mg/m², 5-fluorouracil bolus 400 mg/m², and 5-fluorouracil infusion 2400 mg/m² over 46 hours, was administered every 2 weeks.

Researchers had access to tumor samples from 587 of the nearly 2000 patients in the original trial. KRAS mutations were detected in 35.6% of patients.

Investigators found that among patients with normal KRAS, 59.3% responded to treatment and 43.2% responded to chemotherapy alone. These patients had a 32% decreased risk of progression with the addition of cetuximab (hazard ratio, 0.85 for all patients vs 0.68 in KRAS wild-type population).

Helping journalists put the results into context, Julie Gralow, ASCO’s cancer communications committee chair and associate professor of medicine from the University of Washington, in Seattle, said this study will help clinicians identify who will benefit from therapy and who won’t.

She estimates that about one third of colorectal cancer patients are KRAS-mutation positive. Doctors can therefore withhold treatment from such patients and spare the expense and toxicities of therapy.

The new CRYSTAL results were presented at the meeting’s plenary session. Gail Eckhardt, MD, from the University of Colorado, in Denver, discussed the findings after the talk. "Hopefully, this is only the beginning of the new era of targeted therapies," she said.

Dr. Eckhardt agreed that colorectal cancer patients should be tested for KRAS mutations and therapy targeted accordingly. She said the tests are sensitive, reproducible, and feasible.

Assays are already available and clinicians won’t have to do another biopsy, Dr. Van Cutsem emphasized. "There is no need for a fresh tumor sample for testing."

The researchers report having financial ties to Merck.

American Society of Clinical Oncology 2008 Annual Meeting: Abstract 2. June 1, 2008. Abstract

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