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

Marc Peeters, Jean‐Yves Douillard, Eric Van Cutsem, Salvatore Siena, Kathy Zhang, Richard T. Williams, Jeffrey S. Wiezorek

Journal of Clinical Oncology · 2012 · 233 citations · 26 references

DOI Full text

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TL;DR

KRAS codons 12 and 13 mutations predict lack of response to anti‑EGFR antibody therapies. The study retrospectively assessed the prognostic and predictive impact of individual KRAS codon 12 and 13 mutant alleles in metastatic colorectal cancer. The analysis included 441, 486, and 126 patients from three phase III trials, with randomization to FOLFOX4, FOLFIRI, or best supportive care plus or minus panitumumab 6.0 mg/kg biweekly. No mutant KRAS codon 12 or 13 allele consistently predicted progression‑free survival or overall survival, and only G12A showed a negative predictive effect on overall survival; overall, mutant KRAS tumors are unlikely to benefit from panitumumab, which should be reserved for wild‑type KRAS patients.

Abstract

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 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.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 positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS.In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.