Roxanne Nelson

June 01, 2013

CHICAGO — Which targeted agent should be added to chemotherapy for first-line treatment of metastatic colorectal cancer? A new trial from Germany (FIRE-3) suggests that for patients with nonmutated forms of the KRAS gene, cetuximab (Erbitux, ImClone Systems Incorporated) appears to be more effective than bevacizumab (Avastin, Genentec, Inc.) when added to FOLFIRI chemotherapy (folinic acid, fluorouracil, irinotecan).

Although progression-free survival was nearly identical in the 2 study arms (10.0 vs 10.3 months), overall survival was longer among patients receiving cetuximab (28.7 months) as compared with the bevacizumab arm (25.0 months).

"The key finding is that there was a significantly longer survival with cetuximab than with bevacizumab," said lead author Volker Heinemann, MD, PhD, a professor of medical oncology at the University of Munich, Germany.

"First-line therapy with FOLFIRI plus cetuximab resulted in a clinically meaningful difference in median overall survival of 3.7 months," explained Dr. Heinemann. The hazard ratio was 0.77 (P = .017), and this translated to a "23% lower risk of death during the observation period."

Dr. Heinemann presented his findings at the 2013 Annual Meeting of the American Society of Clinical Oncology.

Cetuximab and bevacizumab are both approved for and commonly used in combination with chemotherapy as first-line therapy, but until this study, it has been unclear which strategy is more optimal for patients with wild-type KRAS. To date, note the authors, a head-to-head comparison of anti-EGFR (such as cetuximab) and anti-VEGF (such as bevacizumab) directed first-line therapy has not been reported using the FOLFIRI regimen.

FOLFIRI is standard chemotherapy regimen for patients with metastatic colorectal cancer in Germany, where this study was conducted. Conversely, in the United States, patients more commonly receive FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin). Previous studies have shown that both chemotherapy regimens are very effective in combination with cetuximab and bevacizumab, and a head-to-head comparison study of bevacizumab plus FOLFOX vs cetuximab plus FOLFOX is ongoing.

Subgroup Shows Better Response

In the current study, Dr. Heinemann and colleagues randomly assigned 592 patients with wild-type KRASmetastatic colorectal cancer to either FOLFIRI (Tournigand regimen) every 2 weeks plus cetuximab (400 mg/m² day 1, followed by 250 mg/m² weekly [arm A]) or bevacizumab (5 mg/kg every 2 weeks [arm B]).

Dr. Volker Heinemann

The median duration of treatment was 4.7 months in arm A, and 5.3 months in arm B. In the intent-to-treat analysis, the overall response rate was comparable in arm A vs B (62% vs 57%; odds ratio, 1.249), but a significant superiority was found for assessable patients in arm A.

Among patients who were assessable for efficacy, explained Dr. Heinemann, the overall response rate was 72.2% vs 63.1% (P = .017) in favor of cetuximab.

The median progression-free survival of the intent-to-treat population was nearly identical, but overall survival was significantly better among patients receiving cetuximab. In both groups, the 60-day mortality was low (1.01% vs 2.71%).

Unanswered Questions

This is a high-quality group who has been responsible for many good studies, commented Richard M. Goldberg, MD, physician-in-chief at the Ohio State University Comprehensive Cancer Center, Columbus. "But the second analysis of overall response, only in evaluable patients, is a bit problematic, because we don't know how exactly they defined this group."

Dr. Richard Goldberg

"Some would argue that it's the intent-to-treat analysis that matters," he told Medscape Medical News. Dr. Goldberg was not involved in the study.

"Having said that, I do believe that there was a difference in survival, but it is our responsibility to try to understand what caused that difference," Dr. Goldberg said. "I'm not certain that I believe it was the initial regimen that caused that difference."

There are a number of therapeutic agents now available to treat this population, plus surgery and radiation, he continued. "So it is likely that all of those things contributed to survival."

The patients were only in treatment for a median of 5 months, but the survival curves did not separate until about 24 months, he pointed out. "I think they need to go back and see what subsequent treatments the patients received and try to determine how that affected the ultimate outcome."

Other factors need to be considered, such as the toxicity profiles of both targeted agents.

"We still need to figure out how to optimally deploy all of the tools we have available now to treat these patients," Dr. Goldberg said. "And it's likely that these tools need to be deployed differently in different patients, as we are just beginning to understand heterogeneity of colon cancer and the different genomic abnormalities."

This research was supported by Merck & Co., Inc.. Dr. Heinemann and several coauthors reports relationships with Merck and Roche; coauthor Lynn Mara Schuchter, MD, reports research funding from Genentech, Inc., GlaxoSmithKline, Merck, and Roche.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstract LBA3506. Presented June 1, 2013.

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