Roxanne Nelson

June 01, 2014

CHICAGO — Four common first-line treatment regimens are equally effective for patients with metastatic colorectal cancer who have no KRAS mutations, according to data presented during the plenary session here at the 2014 Annual Meeting of the American Society of Clinical Oncology® (ASCO).

Overall and progression-free survival were similar for bevacizumab (Avastin) plus chemotherapy and cetuximab (Erbitux) plus chemotherapy. In addition, both FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) and FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) chemotherapy regimens are acceptable in combination with either of the 2 targeted therapies.

Dr. Alan Venook

"These 2 distinctly different biologic therapies in combination with chemotherapy did not impart a different outcome for the patients receiving either one," said lead author Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California in San Francisco, during a press briefing highlighting the results of the study.

Overall survival was 29.0 months with bevacizumab plus chemotherapy and 29.9 months with cetuximab plus chemotherapy (hazard ratio [HR], 0.92; P =.34). Progression free survival was 10.84 months in the bevacizumab group and 10.45 months in the cetuximab group (HR, 1.04; P = .55).

There is still a great deal of data pending. "There are information gaps that we will fill in as we go along, in the next 6 months to a year," Dr. Venook explained.

The missing data include response rates, duration of therapy, dose intensity, the specifics of surgery, and details on second-line and subsequent therapies.

Choice of Therapies

There really is no difference between these 2 therapies as a starting point.

"The conclusion is that there really is no difference between these 2 therapies as a starting point," Dr. Venook said, adding that 88% of patients did go on to other treatments. "At the end of the day, the survival was the same. For patients, what this tells us is that FOLFIRI or FOLFOX, with either bevacizumab or cetuximab, are perfectly reasonable first-line therapies."

Essentially, physicians now have 4 options, and patients can make a decision based on toxic effects and other issues. "The 2 drugs have very different toxicity profiles," he pointed out. "Cetuximab is renowned for its acne rash and bevacizumab is associated with clotting and bleeding."

The costs of bevacizumab and cetuximab are also comparable. "The difference is that cetuximab is given every week and bevacizumab is given every other week," Dr. Venook said. "So the infusion center costs are higher with cetuximab, and that will increase the total cost."

The other meaningful outcome from this study is that the overall survival exceeded 29 months in both groups, establishing a "new benchmark" in the treatment of colorectal cancer.

"This was accomplished across a broad clinical-trials network in the United States and Canada in a variety of practice settings, not just the academic setting," Dr. Venook reported.

Expanded molecular and clinical analyses might help identify subsets of patients who will benefit more or less from specific regimens, he noted.

Study Details

In this study, bevacizumab and cetuximab, in combination with FOLFOX or FOLFIRI, were used as first-line treatments for metastatic adenocarcinoma of the colon or rectum, but the optimal antibody combination was not known. When the study was started in 2005, both agents were new, and it was unclear which was the optimal treatment choice, he explained.

To address that question, Dr. Venook and colleagues randomized 1137 patients with KRAS wild-type (codons 12 and 13) untreated metastatic colorectal cancer to chemotherapy plus bevacizumab (5 mg/kg once every 2 weeks) or cetuximab (a loading dose of 400 mg/m² followed by 250 mg/m² once a week).

The chemotherapy regimen was left to the discretion of the physician; 26.6% received FOLFIRI and 73.4% received FOLFOX. The median follow-up was 24 months.

The overall survival analysis was planned at 849 events; there were 559 in the bevacizumab group and 578 in the cetuximab group. At a median follow-up of 40 months, 94 patients were disease-free after surgery. The toxicity profiles of the regimens were as expected.

Subgroup Analysis Pending

"This is a practice-confirming study," said Michael Pishvaian, MD, PhD, director of the Phase I Clinical Trial Program and assistant professor of medicine at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

"But importantly, this trial and an earlier study have consistently raised the bar for overall survival for metastatic colorectal cancer — from 24 months to 30 months — which is remarkable," he said. Many clinicians who treat gastrointestinal cancers will be watching for more subtle results from the subgroup analyses, he noted.

"The combination of FOLFOX and bevacizumab never has been proven, in a head-to-head study, to be better than FOLFOX alone in the front-line setting, although many of us choose the combination because other studies support its superiority," he explained. "This study doesn't compare FOLFOX and bevacizumab with FOLFOX alone, but we'll be looking at the subgroup analysis to get an indication of whether the results still support it."

He noted that the subgroup analysis for cetuximab and FOLFOX will be "watched closely," because previous studies have suggested that this combination is less effective than FOLFOX alone in the first-line setting. "If the conclusion is that cetuximab and FOLFOX is equal to bevacizumab and FOLFOX, that gives us new information and confidence in the cetuximab-based treatment," Dr. Pishvaian said.

The study was funded in part by the National Cancer Institute, ImClone, Roche, Genentech, BMS, and Eli Lilly. Dr. Venook reports financial relationships with Bristol-Myers Squibb, Roche, and Genentech. Some of his coauthors report financial relationships with Roche, Genentech, Bayer, Onyx, Sanofi, and Lilly.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA3. Presented June 1, 2014.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.