Originally published as JCO Early Release 10.1200/JCO.2007.14.7116 on March 3 2008

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Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Rafael G. Amado, Michael Wolf, Marc Peeters, Eric Van Cutsem, Salvatore Siena, Daniel J. Freeman, Todd Juan, Robert Sikorski, Sid Suggs, Robert Radinsky, Scott D. Patterson, David D. Chang

From Amgen Inc, Thousand Oaks, CA; Ghent University Hospital, Ghent, Belgium; University Hospital Gasthuisberg, Leuven, Belgium; and the Ospedale Niguarda Ca’ Granda, Milan, Italy

Corresponding author: Rafael G. Amado, MD, Amgen, Inc, One Amgen Center Dr, MS 38-2-B, Thousand Oaks, CA 91320-1799; e-mail: ramado{at}amgen.com

Purpose: Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.

Patients and Methods: KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status.

Results: KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population.

Conclusion: Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

published online ahead of print at www.jco.orgon March 3, 2008.

Funded by Amgen Inc, Thousand Oaks, CA.

Presented in part in oral format at the 14th European Cancer Conference, Barcelona, Spain, September 23-27, 2007; and the American Society of Clinical Oncology Gastrointestinal Cancer Symosium, Orlando, FL, January 25-27, 2008.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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