KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience Carsten Bokemeyer* I Bondarenko, J Hartmann, F De Braud, C Volovat, C Stroh, J Nippgen, I Celik, P Koralewski *Universitätsklinikum Eppendorf Hamburg, Germany
KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience. Carsten Bokemeyer* I Bondarenko, J Hartmann, F De Braud, C Volovat, C Stroh, J Nippgen, I Celik, P Koralewski. - PowerPoint PPT Presentation
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KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience
Carsten Bokemeyer*
I Bondarenko, J Hartmann, F De Braud, C Volovat, C Stroh,J Nippgen, I Celik, P Koralewski
*Universitätsklinikum EppendorfHamburg, Germany
ASCO disclosure information
• Yes, I have honoraria to disclose
Merck KGaA
• Yes, I have research funding to disclose
Merck KGaA
Epidermal growth factor receptor (EGFR) and KRAS
Cetuximab
• When KRAS geneis mutated, KRAS protein (p21 ras) is active regardless of EGFR activation
• KRAS gene mutations are an early event and are found in 40–45% of CRC patients
• KRAS mutations are generally associated with a poor prognosis
Retrospective studies supporting the correlation between KRAS mutations and lack of response to
EGFR inhibitors in chemorefractory mCRCReference Treatment No. of patients
(% mutant)Objective response
n (%)
Wild-type Mutant
A Lièvre et al, J Clin Oncol 2008
Cetuximab ± CT 114 (32) 34 (44) 0 (0)
S Benvenuti et al, Cancer Res 2007
Panitumumab or cetuximab or Cetuximab + CT
48 (33) 10 (31) 1 (6)
W DeRoock et al,Ann Oncol 2008
Cetuximab or Cetuximab + irinotecan
113 (41) 27 (41) 0 (0)
D Finocchiaro et al, ASCO Proceedings 2007
Cetuximab ± CT 81 (40) 13 (26) 2 (6)
F Di Fiore et al, Br J Cancer 2007
Cetuximab + CT 59 (27) 12 (28) 0 (0)
S Khambata-Ford et al, J Clin Oncol 2007
Cetuximab 80 (38) 5 (10) 0 (0)
RG Amado et al, J Clin Oncol 2008
Panitumumab 208 (40) 21 (17) 0 (0)
OPUS KRAS analysis: Objectives
Objective
A retrospective analysis investigated the impact on response rate and progression-free survival of the KRAS mutation status of tumors in the first-line treatment of metastatic CRC treated with FOLFOX ± cetuximab
OPUS: Study design
Primary endpoint
• Overall confirmed response rate (as assessed by independent review)
Secondary endpoints
• PFS time
• OS time
• Rate of curative surgery for metastases
• Safety
Cetuximab + FOLFOX4
400 mg/m2 initial IV infusion (day 1)
then 250 mg/m2 weekly+ oxaliplatin 85 mg/m2 + 5-FU/FA
every 2 weeks
FOLFOX4
Oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks
EGFR-detectablemCRC
Stratification by:
ECOG PS 0/1, 2
R
OPUS: Efficacy results
Outcome FOLFOX(n=169)
Cetuximab + FOLFOX(n=168)
p-value
RR, (%)ITT population
35.7 45.6 0.063a
RR, (%)ECOG PS 0/1
36.8 49.0 0.032a
Median PFS time, (months)
7.2 7.2
Hazard ratio for PFS 0.93 0.62
Bokemeyer C et al, ECCO 2007
aCochran-Mantel-Haenszel (CMH) test
Relating KRAS status to efficacy Methodology
• Efficacy analyses repeated to evaluate the influence of KRAS status on outcomes in OPUS patients
• Genomic DNA isolated from archived tumor material
• Paraffin-embedded, formalin-fixed tissue
• KRAS mutation status of codons 12/13 determined using quantitative PCR-based assay