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Combining Targeted Drugs Is Worse in Colorectal Cancer

A randomized clinical trial testing chemotherapy combined with bevacizumab (Avastin) and cetuximab (Erbitux), and comparing this with chemotherapy and bevacizumab alone, found that the addition of cetuximab actually shortened patients’ recurrence-free and median survival.

This runs counter to some studies using animal models of cancer, which suggest that combining a drug that targets vascular endothelial growth factor (VEGF) with a drug that targets epidermal growth factor receptor (EGFR) may be more effective than either drug alone. The trial results appeared in the February 5, 2009, New England Journal of Medicine (see the journal abstract).

Investigators from the Netherlands enrolled 755 patients with metastatic, inoperable colon or rectal cancer into the trial, continuing treatment until disease progression, death, or unacceptable side effects. Overall, “the addition of cetuximab significantly decreased the median progression-free survival” from 10.7 months to 9.4 months, they reported. Median overall survival was 20.3 months for patients receiving chemotherapy and bevacizumab and 19.4 months for patients receiving chemotherapy, bevacizumab, and cetuximab. Patients who received cetuximab reported less improvement in overall quality of life and health during treatment.

The researchers analyzed these results in the context of whether patients had tumors with the normal or mutated form of a gene called KRAS. Numerous studies have shown that only patients with normal KRAS genes benefit from drugs that target EGFR, including cetuximab. Patients with mutant KRAS who were given cetuximab had a significantly shorter progression-free survival than patients in the chemotherapy and bevacizumab arm; for patients with normal KRAS, cetuximab had no effect on progression-free survival.

The cause of these unexpected negative results are not clear, explained the authors, though a negative interaction between cetuximab and bevacizumab is one possibility.

  • Posted: February 24, 2009