PD-0025 Evaluation of Codon 12 and 13 KRAS Mutations as Biomarkers of Response to Panitumumab in Patients with Metastatic Colorectal Cancer

Abstract

ABSTRACT Introduction Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), has demonstrated significant improvement in progression-free survival (PFS) in patients with wild-type (WT) KRAS metastatic colorectal cancer (mCRC) in three phase 3 trials: the first-line study 20050203 (panitumumab + FOLFOX4), the second-line study 20050181 (panitumumab + FOLFIRI), and the panitumumab monotherapy study 20020408. Mutations in codons 12 and 13 of KRAS are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis assessed the prognostic and predictive impact of individual codon 12 and 13 KRAS mutations on PFS, overall survival (OS), and response rate across three-lines of therapy. Methods Patients were randomized 1:1 to receive FOLFOX4, FOLFIRI, or best supportive care with or without panitumumab 6.0 mg/kg every two weeks. The primary endpoint in studies 20050203 and 20020408 was PFS; OS was a secondary endpoint. In study 20050181, the co-primary endpoints were PFS and OS. Mutant (MT) KRAS codon 12 and 13 status was ascertained with the Therascreen® K-RAS Mutation Kit (Qiagen) that identifies the seven most common KRAS mutations in codons 12 and 13 (KRAS G12A, G12C, G12D, G12R, G12S, G12V, G13D). Results KRAS ascertainment rates were 93% (study 20050203), 91% (study 20050181), and 92% (study 20050408). A total of 1052 patients with MT KRAS codon 12 and 13 alleles were included in the analysis: 440 patients from 20050203, 486 patients from 20050181, and 126 patients from 20020408. The frequency of MT KRAS alleles was conserved between studies and baseline demographic and clinical features were generally balanced. There were no consistent results that any single MT KRAS allele, compared with the other MT KRAS alleles or the entire MT KRAS group, differentially affected PFS or OS in patients treated in the control or panitumumab-containing arms. Only two individual MT KRAS alleles were significantly associated with outcomes by interaction testing: in the panitumumab + FOLFOX4 arm of study 20050203 G12V was favorably and G13D was unfavorably associated with OS. Response rates between MT KRAS allele groups were similar in the first-line 20050203 and second-line 20050181 studies. In the panitumumab monotherapy setting (20020408), no patients with MT KRAS codon 12 or 13 mCRC tumors responded. Finally, pooled analysis of all 3 trials suggested that only the G12A KRAS allele was significantly associated with a negative treatment effect on OS. Conclusion The results from this retrospective analysis of three phase 3 trials indicate that patients with MT KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Therefore, only patients with WT KRAS tumors should receive panitumumab therapy.