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February 4, 2009 — More is not better when it comes to targeted therapies for metastatic colorectal cancer.
This was the finding from 2 new studies in which an anti-epidermal growth-factor receptor (EGFR) was added to a chemotherapy–bevacizumab combination, which is the standard first-line treatment for metastatic colorectal cancer.
Bevacizumab acts on vascular endothelial growth factor (VEGF) and thus, like an EGFR, is a monoclonal antibody or targeted therapy.
Both new studies showed that the addition of an EGFR (either cetuximab or panitumumab) to the standard first-line treatment reduced progression-free survival — and produced other negative results.
In effect, targeted therapies do not seem to act like chemotherapies, which provide greater benefit when given in combination with one another, notes Robert J. Mayer, MD, from the Dana-Farber Cancer Institute, in Boston, Massachusetts, in an editorial that accompanied the Dutch study published in the February 5 issue of the New England Journal of Medicine.
"Combing multiple forms of targeted therapies may not be analogous to combining different types of cytotoxic chemotherapy," notes Dr. Mayer.
"Since combining cytotoxic drugs that act through different mechanisms improved outcomes in patients with metastatic colorectal cancer, it seemed logical that further progress would result from combining bevacizumab with either cetuximab or panitumumab and administering these monoclonal antibodies together with chemotherapy," explains Dr. Mayer.
The negative results of this Dutch study and another new study, the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial, which was published online December 29 in the Journal of Clinical Oncology, were unexpected because preclinical and early clinical studies had shown promise.
The concept of using double-antibody therapy in metastatic colorectal cancer is falling out of favor.
Nevertheless, targeted therapies have value in this setting, writes Charles D. Blanke, MD, from the University of British Columbia, in Vancouver, in an editorial accompanying the PACCE trial. "Antibodies to either VEGF or the EGFR, utilized as the sole targeted agent, clearly have a place in the therapy of advanced metastatic colorectal cancer."
However, Dr. Blanke also concludes that "the concept of using double-antibody therapy in metastatic colorectal cancer is falling out of favor."
Addition of Cetuximab Also Reduces Median Overall Survival
Both of the new studies were phase 3 multicenter randomized trials conducted in patients with previously untreated metastatic colorectal cancer.
The Dutch study, led by Jolien Tol, MD, from the Radboud University Nijmegen Medical Center, was conducted in the Netherlands. It involved 732 patients treated with capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in cycles administered every 3 weeks.
After a median follow-up of 23 months, the addition of cetuximab to the combination of capecitabine, oxaliplatin, and bevacizumab significantly decreased median progression-free survival time, from 10.7 months to 9.4 months (P = .01). Furthermore, the addition of cetuximab was also associated with reduced median overall survival (19.4 months), compared with capecitabine, oxaliplatin, and bevacizumab treatment (20.3 months).
The investigators assessed tumor tissue for KRAS gene status in 71% of patients; mutations were found in 40% of the specimens. Anti-EGFR treatments, such as cetuximab, have been shown to be effective only in colorectal cancer patients with wild-type KRAS tumors.
However, in this study, the addition of cetuximab did not improve progression-free survival in patients whose tumors contained wild-type KRAS, and was harmful for those with tumors bearing a mutant KRAS gene. Nonetheless, it can be said that KRAS genotype affected the response to cetuximab, the researchers comment.
The rate of adverse events was similar in the 2 treatment groups, except that there were significantly more cetuximab-related cutaneous adverse effects (P < .001).
The Dutch study authors speculate that the negative results might be due to a "negative interaction between cetuximab and bevacizumab."
However, as Dr. Mayer notes in his editorial, there is "no obvious explanation" for the results, which were unexpected.
The PACCE Study
The PACCE study, led by J. Randolph Hecht, MD, from the David Geffen School of Medicine at the University of California at Los Angeles, was conducted in the United States and published online December 29 in the Journal of Clinical Oncology. It involved 823 patients treated with the FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen who also received either bevacizumab alone (the control group) or bevacizumab plus panitumumab (the panitumumab group).
In addition, a cohort of 230 patients treated with the FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen received either bevacizumab alone (the control group) or bevacizumab plus panitumumab (the panitumumab group).
Panitumumab was discontinued after a planned interim analysis of 812 patients in the FOLFOX cohort showed worse efficacy in the panitumumab group than in the control group.
In the final analysis of the FOLFOX cohort, median progression-free survival was worse in the panitumumab group (10.0 months vs 11.4 months) than in the control group (hazard ratio, 1.27; 95% confidence interval, 1.06 to 1.52). Median survival was also worse, at 19.4 months in the panitumumab group and 24.5 months in the control group.
In addition, grade 3/4 adverse events in the FOLFOX cohort were more frequent in the panitumumab group than in the control group, including skin toxicity (36% vs 1%), diarrhea (24% vs 13%), infections (19% vs 10%), and pulmonary embolism (6% vs 4%).
Increased toxicity without evidence of improved efficacy was also observed in the panitumumab group of the FOLFIRI cohort, write the study authors.
KRAS analyses showed adverse outcomes for the panitumumab group in both wild-type and mutant groups, they add.
Only Patients With Wild-Type KRAS
One other major clinical trial in metastatic colorectal cancer patients is ongoing, and consists of a treatment group with both antibody classes or targeted therapy types, writes Dr. Blanke.
C80405 is the North American Intergroup trial that combines FOLFOX- or FOLFIRI-based chemotherapy (investigator's choice) with bevacizumab, cetuximab, or both antibodies in untreated advanced metastatic colorectal cancer.
At least some experts feel the jury is still out on the double-antibody question in that population.
In 2008, the investigators decided to continue the study with its existing groups, but to modify it to include only patients with wild-type KRAS. "This indicated that at least some experts feel the jury is still out on the double-antibody question in that population," writes Dr. Blanke. However, he also notes that the PACCE trial has already demonstrated "less than ideal outcomes" in patients with wild-type KRAS given double-antibody therapy.
The Dutch study was supported by the Dutch Colorectal Cancer Group, which received grants for data management and analysis from the Commissie Klinisch Toegepast Onderzoek of the Dutch Cancer Foundation and unrestricted scientific grants from Roche, Merck Serono, Sanofi-Aventis, and DxS. Dr. Tol reports receiving grant support from the Netherlands Organization for Health Research and Development. The financial relationships of his coauthors can be found in the paper. The PACCE study was supported by Amgen, Inc.
N Engl J Med. 2009;360:563-572, 623-625.
J Clin Onc. Published online before print December 29, 2008.
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