Wild-Type <i>KRAS</i> Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer.

Abstract

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. <i>KRAS</i> 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 <i>KRAS</i> status. <i>KRAS</i> status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). <i>KRAS</i> mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) <i>KRAS</i> group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (<i>P</i> < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT <i>KRAS</i> 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 <i>KRAS</i> 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 <i>KRAS</i> group. No significant differences in toxicity were observed between the WT <i>KRAS</i> group and the overall population. Panitumumab monotherapy efficacy in mCRC is confined to patients with WT <i>KRAS</i> tumors. <i>KRAS</i> status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.