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Colorectal cancer (CRC) is the third most common cancer in the USA, and more than 500,000 people die from CRC each year worldwide. Panitumumab, a fully human monoclonal antibody that targets EGFR, is an approved therapy for metastatic CRC. Mutated KRAS is a negative predictor of response to panitumumab, but wild-type KRAS is a positive predictor of response. Two phase III randomized trials were conducted to test the efficacy of panitumumab with fluorouracil, leucovorin and oxaliplatin (FOLFOX4) or fluorouracil, leucovorin and irinotecan (FOLFIRI) in the first-line and second-line settings, respectively.

Both trials showed that the addition of panitumumab to chemotherapy significantly improved progression-free survival (PFS) but only in patients with wild-type KRAS. In the PRIME trial, 1,183 patients were randomly assigned to panitumumab and FOLFOX4 or FOLFOX4 alone. In patients with wild-type KRAS (60%), the median PFS was 1.6 months longer than those receiving the combination. However, patients with mutated KRAS had a significantly worse PFS when treated with panitumumab. A nonsignificant trend for an overall survival advantage was also observed for wild-type KRAS patients receiving panitumumab.

In the second trial, 1,186 patients with metastatic CRC who had received one prior chemotherapy regimen were randomly assigned to panitumumab and FOLFIRI or FOLFIRI alone. 55% of patients had wild-type KRAS and in these patients a 2-month improvement in PFS for the combination arm was noted (5.9 months versus 3.9 months). In patients with mutant KRAS, there was no significant difference in PFS between the two arms. The objective response rate was also significantly improved in patients with wild-type KRAS who received panitumumab. In both trials, the adverse effects were comparable across arms and the incidence of skin toxicity and other adverse effects were as expected for this drug class.

“This trial confirms the importance of KRAS as a predictive biomarker of efficacy...in mutant KRAS patients, the addition of panitumumab resulted in a significant detrimental effect on PFS,” comments Jean-Yves Douillard, lead investigator of the PRIME trial. “Panitumumab and FOLFIRI provides a convenient administration schedule with a manageable toxicity profile, representing an important new treatment option in patients with wild-type KRAS tumors”, conclude the FOLFIRI trial researchers.