Mutant KRAS Codon 12 and 13 Alleles in Patients With Metastatic Colorectal Cancer: Assessment As Prognostic and Predictive Biomarkers of Response to Panitumumab

作者：Marc Peeters, Jean‐Yves Douillard, Eric Van Cutsem, Salvatore Siena, Kathy Zhang, Richard Thomas Williams, Jeffrey S. Wiezorek · 发表于：Journal of Clinical Oncology · 年份：2012 · DOI：10.1200/jco.2012.45.1492 · 被引用次数：235 · 研究领域：Colorectal Cancer Treatments and Studies、HER2/EGFR in Cancer Research、Protein Kinase Regulation and GTPase Signaling

PURPOSE: Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles. PATIENTS AND METHODS: Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis. RESULTS: No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V p...