KRAS gene status predicts response to initial biologic treatment for colorectal cancer

June 1, 2008

Patients with metastatic colorectal cancer are more likely to respond to initial treatment that includes cetuximab if they have nonmutated, wild-type KRAS gene status, reported Eric Van Cutsem, MD, University Hospital Gasthuisberg, Leuven, Belgium. "For the first time in colorectal cancer, we are able to predict which patients are likely to be helped by the new biologics," he said. "KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy regimen in first-line metastatic colorectal cancer. KRAS testing should be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient."

Patients with metastatic colorectal cancer are more likely to respond to initial treatment that includes cetuximab if they have nonmutated, wild-type KRAS gene status, reported Eric Van Cutsem, MD, University Hospital Gasthuisberg, Leuven, Belgium. "For the first time in colorectal cancer, we are able to predict which patients are likely to be helped by the new biologics," he said. "KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy regimen in first-line metastatic colorectal cancer. KRAS testing should be routinely conducted in all colorectal cancer patients immediately after diagnosis to ensure the best treatment strategies for the individual patient."

Dr Van Cutsem presented the results of a subanalysis of the CRYSTAL trial, which demonstrated that initial therapy with FOLFIRI chemotherapy plus cetuximab resulted in longer progression-free survival (PFS) than FOLFIRI alone (p = .048). The subanalysis was conducted to determine if there was an association between KRAS status and the potential benefit of combination initial therapy. Previous studies have demonstrated that KRAS mutations, present in 30% to 45% of colorectal tumors, predict whether patients will respond to epidermal growth factor receptor (EGFR) inhibition when these agents are used as second-line or later treatment for colorectal cancer.

In this subanalysis, researchers analyzed archived tumor material from 540 patients in the CRYSTAL trial and observed that 65% of patients had normal KRAS gene status and 35% had KRAS mutations. Among patients with normal KRAS gene status, 59.3% responded to chemotherapy plus cetuximab, and 43.2% responded to chemotherapy alone. Response was defined as tumor shrinkage of at least 50%. There was no difference in response rates between treatment with chemotherapy and treatment with combination therapy among patients with KRAS mutations.

The PFS rate at 1-year follow up among patients with normal KRAS gene status was 43% for the combination initial treatment compared with 25% for the FOLFIRI treatment alone. The mean PFS time was 9.9 months for those treated with the combination versus 8.7 months for those treated with chemotherapy alone (p = .017), a 32% reduction in disease progression. There was no difference in PFS between the 2 types of initial treatment observed in patients with KRAS mutations.

Dr Van Cutsem said that as expected, more patients receiving chemotherapy plus cetuximab experienced adverse events; the most common were neutropenia, diarrhea, vomiting, fatigue, an acne-like rash, and infusion-related reactions. "There were no new signals of toxicity or increased toxicity in patients with the wild-type tumor," he said. "Cetuximab in combination with a standard first-line treatment for metastatic colorectal cancer patients is an important new option for these patients."