Mixing Erbitux, Avastin Bad for Advanced Colon Cancer

Two breakthrough biotechnology drugs aren’t better than one when combined with chemotherapy against advanced colorectal cancer, according to a second major study.
In a trial of 732 participants, Dutch researchers found that adding Eli Lilly & Co.’s Erbitux to Genentech Inc.’s Avastin, along with a regimen of powerful chemotherapy drugs, worsened cancer and caused patients more severe discomfort than Avastin plus chemotherapy alone. The research appears in the Feb. 5 New England Journal of Medicine.

The combination studies tested a theory that pairing biological therapies -- medicines made from living organisms -- with a chemotherapy cocktail could boost benefits. They found that patients in the Erbitux group experienced faster tumor progression than those in the Avastin group. Those taking Erbitux also had more severe skin reactions and lower quality of life, plus a trend to lower overall survival that didn’t reach statistical significance, researchers said.

“More is not always better,” said Harvard Medical School professor Robert J. Mayer, vice chair of academic affairs at the Dana Farber Cancer Institute in Boston, in an editorial accompanying the journal report.

The study, called CAIRO2, is the second trial in two years to find that colorectal cancer patients fared worse when a second antibody-based drug was added to Avastin and chemotherapy. In March 2007, the PACCE study adding Amgen Inc.’s Vectibix to Avastin and chemotherapy was halted because of a higher death rate and toxicity.

The CAIRO2 study was first presented at the American Society for Clinical Oncology meeting in June 2008. This week’s journal article is its first publication in a peer-reviewed journal.

Targeted Therapies

Avastin, Erbitux and Vectibix are among a new generation of cancer medicines called targeted therapies, because they attack malignant cells by interfering with specific biological pathways involved in cancer. Erbitux and Vectibix are laboratory-designed antibodies that disable a protein known as epidermal growth factor receptor, or EGFR, involved in tumor cell division. Avastin, also an antibody, works by blocking vascular endothelial growth factor, or VEGF, a substance that stimulates growth of blood vessels that feed tumor growth.

“We think there may have been a negative interaction between the two antibodies,” said study author Cornelis J.A. Punt, chairman of the department of medical oncology at Radboud University Nijmegen Medical Center in Nijmegen, the Netherlands, in an e-mail.

Wrong Combination

The CAIRO2 study added Erbitux to a regimen of Avastin plus chemotherapy drugs capecitabine and oxaliplatin.

“Our results argue against the combined use of anti-VEGF and anti-EGFR monoclonal antibodies with chemotherapy in cases of metastatic colorectal cancer,” wrote lead authors Punt and Jolien Tol of Radboud University Nijmegen Medical Center.

Erbitux, which generated $182 million in North America in the fourth quarter of 2008, is marketed in the U.S. by Indianapolis-based Lilly and New York-based Bristol Myers-Squibb Co., and sold overseas by Germany’s Merck KGaA, who hasn’t reported its fourth-quarter sales yet. Genentech, of South San Franciso, California, sells Avastin, which had $2.69 billion in U.S. sales last year, with Swiss drugmaker Roche Holding AG. The Dutch Colorectal Cancer Group, which supported the study, received funds from Roche, Merck KGaA, Sanofi-Aventis AG and DxS Ltd.

The study, started in 2005, also confirms more recent findings that colorectal cancer patients with a mutated version of a gene called KRAS don’t benefit from Erbitux.

Patients with a mutated KRAS gene who got Erbitux “had significantly decreased progression-free survival” compared with patients with a normal KRAS gene who got Erbitux or patients with a mutated KRAS gene who got only Avastin and chemotherapy, the authors wrote.

Unexpected Interactions

While the outlook for patients with colorectal cancer “has brightened considerably” with new drug regimens, biological therapies may belie the more-is-better approach, Mayer wrote in the editorial. Biologic drugs may trigger unexpected interactions in cellular signaling that aren’t yet understood and could interfere with benefits of the treatment.

Cocktails of drugs with different mechanisms and side effects often provide synergistic benefits, Mayer said in an interview.

“There are intracellular interactions that may not be noticed until a double whammy is provided,” he added. “When you turn your key to start the car, it doesn’t start because of the key but because seven or eight things happened under the hood,” he said. “With Avastin and Erbitux, they act under the hood. This is a bit more complex than we have seen before.”

Mayer has received funds from drugmakers Celgene Corp., Momenta Pharmaceuticals Inc. and the genetic testing company Myriad Genetics Inc..

Doctors in 2008 diagnosed 148,810 people with colorectal cancer in the United States and 49,960 died of the disease, according to estimates by the American Cancer Society.