Hitting too many targets or not enough?

It wasn’t really too long ago that the efficacy and safety of STI571, or Gleevec (imatinib, Novartis), for the treatment of chronic myelogenous leukemia was published in the The New England Journal of Medicine (2001;344:1031) and appeared to herald a new era of targeted cancer therapy. Since then, this early optimism for “magic pills” for a wide range of malignancies has been tempered. Monoclonal antibodies and other targeted drugs have certainly led to significant benefits in patient survival for several solid and hematologic tumors, though usually not in dramatic fashion over previous standards of care. And it is not clear that simply adding additional targeted agents to chemotherapy cocktails is beneficial.

The evolving story of treatment for advanced colorectal cancer is a case in point; the anti-VEGF antibody bevacizumab (Avastin, Genentech) or the anti-epidermal growth factor receptor antibody cetuximab (Erbitux, Imclone), when added to 5-FU with oxaliplatin (Eloxitan, Sanofi-aventis) or irinotecan, appears to significantly benefit certain subpopulations of patients with this disease. But an article in this week’s The New England Journal of Medicine by Tol et al shows that when using cetuximab and bevacizumab together, more may not always be better. In fact, the combination of capecitabine (Xeloda, Roche), oxaliplatin, bevazicumab and cetuximab actually resulted in a lower median PFS (9.4 months) than the same combination without cetuximab in this study of 732 patients in the Netherlands with previously untreated metastatic colorectal cancer.

Dr. Robert Mayer noted in his editorial that the results “underscore the fundamental importance of subjecting hypotheses to carefully conducted clinical trials.” In this case, he notes that these results appear consistent with another study that demonstrated a negative effect of adding an anti-EGFR antibody to a chemotherapy-bevacizumab combination, the “Panitumumab Advanced Colorectal Cancer Evaluation” (PACCE) trial.

So what now for dual antibody therapy in metastatic colorectal cancer? An editorial in this week’s Journal of Clinical Oncology by Dr. Charles Blanke notes that the final chapter of this story may not yet have been written. In fact, intergroup study C80405, which compares FOLFOX or FOLFIRI-based chemotherapy with the addition of bevacizumab, cetuximab or both continues to enroll patients to the dual antibody arm. Whether this is appropriate or not, in light of the recently published results showing the negative effect of dual antibody therapy in advanced colorectal cancer, I will leave to more seasoned trialists to decide.