Colorectal Cancer Drugs Require Careful Patient Selection
Patients with advanced colorectal cancer who have mutant forms of the gene KRAS in their tumors should not receive chemotherapy plus cetuximab (Erbitux), because they are unlikely to benefit from the treatment and should be spared the side effects and cost, researchers said at the recent American Society of Clinical Oncology (ASCO) annual meeting in Chicago.
Based on a growing body of evidence, including findings presented at the meeting, several experts predicted that it will become standard practice to test all colorectal tumors for mutations in the KRAS gene before starting patients with advanced disease on therapies involving cetuximab and a similar drug, panitumumab (Vectibix).
"I believe it is now warranted to test all patients being considered for these agents," said Dr. Gail Eckhardt of the University of Colorado Denver, who was not involved in the research and discussed the findings at ASCO. "Patients with KRAS mutations should not receive cetuximab or panitumumab in [certain] settings."
These drugs are designed to block the activity of the epidermal growth factor receptor (EGFR) protein, which is often overactive in colorectal cancer.
An estimated 30 to 40 percent of colorectal tumors carry KRAS mutations, and commercial tests are available. Screening could proceed based on the breast cancer model, where women undergo testing for genetic characteristics of their tumors prior to treatment with trastuzumab (Herceptin).
"KRAS is the first molecular marker for targeted therapy in combination with standard chemotherapy as a first-line treatment for metastatic colorectal cancer," said Dr. Eric Van Cutsem of Gasthuisberg University Hospital in Leuven, Belgium, at the meeting. "If we know in advance that a patient has a KRAS mutation, then we know we don't have to treat the patient [with these agents]."
He presented new results from the CRYSTAL trial, which last year showed that some patients with metastatic disease benefited from cetuximab plus chemotherapy with respect to progression-free survival. But not all patients benefited and given growing interest in the KRAS gene, the researchers went back and looked at tumor tissue from 587 of the nearly 1,200 patients in the trial.
The results were striking: Only patients with normal KRAS genes benefited. Perhaps most important, findings from other studies, including the OPUS and EVEREST trials, support the findings from the CRYSTAL trial. Retrospective analyses of KRAS gene status and treatment outcomes have now been performed on 1,200 patients with advanced colorectal cancer from separate randomized trials.
"We now have substantial evidence that mutations in KRAS are a negative predictive marker for the use of cetuximab with chemotherapy and for panitumumab as a single agent based on results from a variety of trials," said Dr. Margaret Mooney of NCI's Cancer Therapy Evaluation Program, who was not involved in the research.
Before the meeting, European regulators approved cetuximab plus chemotherapy as a first-line treatment for colorectal cancer in patients with normal KRAS. Panitumumab is approved in Europe for treating advanced colorectal cancer, but also only in patients with the normal KRAS gene.
Prospective studies are now needed to validate the marker. Trials such as CRYSTAL were not designed to answer questions about cetuximab and KRAS, and the researchers do not have tumor tissue from all patients. These patients could provide useful information in developing new therapies.
Dr. Eckhardt stressed the importance of communicating to patients with KRAS mutations that current chemotherapy regimens are effective. "Hopefully," she added, this is "only the beginning of the era of individualized therapy for patients with colon cancer."
—Edward R. Winstead