ASCO: Cetuximab Adds to First-Line Chemotherapy Benefit for Metastatic Colorectal Cancer

CHICAGO, June 5 -- Cetuximab (Erbitux) added to first-line chemotherapy for metastatic colorectal cancer lengthens progression-free survival by about a month, researchers found.

In a large international trial, median time to tumor progression was 8.9 months with cetuximab and 8.0 months without it (P=0.0479), said Eric Van Cutsem, M.D., Ph.D., of the University Hospital Gasthuisberg, in Leuven, Belgium, and colleagues.

Although the treatment granted patients a relatively short progression-free advantage, it offered a 15% lower chance of progression at one year, Dr. Van Cutsem said at the American Society of Clinical Oncology meeting here.

Dr. Van Cutsem said the trial met its primary objective demonstrating that cetuximab could further improve the activity of one of the standard chemotherapy regimens used in first-line therapy of metastatic colorectal cancer.

"Of course, we don't cure patients with this treatment," he said, but added, "All steps in oncology are incremental."

Although Cetuximab is FDA approved as second- or third-line treatment for metastatic colorectal cancer, the study suggests it should be a new option in the growing ranks of first-line therapy, Dr. Van Cutsem said.

However, further studies will be needed to see how this regimen stacks up against others, particularly chemotherapy plus bevacizumab (Avastin), and for different patient populations, he added.

The CRYSTAL (Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial included 1,198 patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer in the intent-to-treat population.

Half of the patients were randomly assigned to FOLFIRI chemotherapy, which consisted of 180 mg/m² irinotecan (Camptosar) and 5-fluorouracil as a 400 mg/m² bolus then 2,400 mg/m² infusion over 46 hours plus leucovorin (Wellcovorin) every two weeks.

The other half was randomized to the same regimen with the addition of cetuximab given intravenously at 400 mg/m² on day one then 250 mg/m² weekly.

For the primary endpoint, the researchers found that progression-free survival in the intent-to-treat population was significantly improved with combination treatment compared with FOLFIRI chemotherapy alone (hazard ratio 0.851, P=0.0479).

The one-year progression-free survival rate was 11% higher with combination treatment as well (34% versus 23%). The median progression-free survival was 8.9 months in the cetuximab-treated group compared with 8.0 months in the FOLFIRI alone group.

Among the secondary endpoints, the overall response rate favored the combination as well (46.9% versus 38.7%, P=0.0038).

It also benefited surgical outcomes. Among patients with initially unresectable disease, combination treatment tripled the percentage of patients free of residual tumor after resection (R0 resection rates 4.3% versus 1.5%, P=0.0034).

The percentage of patients with liver metastases who had no residual tumor was about doubled with cetuximab plus FOLFIRI compared with FOLFIRI alone (9.8% versus 4.5%).

"Patients with liver-limited disease experienced a greater treatment benefit than the overall population," Dr. Van Cutsem noted.

Efficacy did not appear to correlate with EGFR expression, although about 80% of patients expressed the receptor as measured by immunohistochemistry.

The combination was generally well-tolerated, he added. Diarrhea, though, was more common with the combination (15% versus 10% with Grade 3-4).

And, as expected, there was more skin toxicity in the combination group (18% Grade 3, no Grade 4).

"But an important finding is that skin reactions showed a strong correlation with efficacy," he said.

There were no cetuximab-related deaths. All-cause mortality was similar between groups in the 60 days after treatment started and the 30 days after treatment ended.

The researchers are now working to find subgroups of patients who gain greater benefit.

Other research groups in the United States are looking at FOLFIRI and FOLFOX chemotherapy regimens in combination with another biologic agent, bevacizumab (Avastin).

The CRYSTAL findings support studying the combination of bevacizumab and cetuximab as well, said A. William Blackstock, M.D., of Wake Forest University in Winston-Salem, N.C., who commented on the study during a press conference.

Some of the researchers reported employment or leadership positions with Merck KGaA, consultant or advisory roles with Merck and Pfizer, and receiving honoraria and research funding from Merck and Pfizer. Dr. Blackstock disclosed being a consultant or advisor to Eli Lilly Oncology, Sanofi-Aventis and Protherics; receiving honoraria from Eli Lilly Oncology and Sanofi-Aventis; and receiving research funding from Eli Lilly Oncology, Merck, Sanofi-Aventis, and AstraZeneca.