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Carsten Bokemeyer*

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.

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Carsten Bokemeyer*

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  1. 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

  2. ASCO disclosure information • Yes, I have honoraria to disclose Merck KGaA • Yes, I have research funding to disclose Merck KGaA

  3. Epidermal growth factor receptor (EGFR) and KRAS • 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 Cetuximab

  4. Retrospective studies supporting the correlation between KRAS mutations and lack of response to EGFR inhibitors in chemorefractory mCRC

  5. 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

  6. OPUS: Study design 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 Primary endpoint • Overall confirmed response rate (as assessed by independent review) Secondary endpoints • PFS time • OS time • Rate of curative surgery for metastases • Safety EGFR-detectable mCRC R FOLFOX4 Oxaliplatin 85 mg/m2 + 5-FU/FA every 2 weeks Stratification by: ECOG PS 0/1, 2

  7. OPUS: Efficacy results aCochran-Mantel-Haenszel (CMH) test Bokemeyer C et al, ECCO 2007

  8. 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

  9. KRAS evaluable population 337 subjects (ITT) 233 subjects: KRAS evaluable population 134 (58%) KRAS wild-type 99 (42%) KRAS mutant Group A: 61 (46%) Group B 73 (54%) Group A52 (53%) Group B 47 (47%) Cetuximab + FOLFOX FOLFOX

  10. Patient demographics at baseline

  11. Cetuximab + FOLFOX 1.0 1.0 FOLFOX 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 6 4 12 0 8 10 2 6 12 0 4 8 10 2 ITT and KRAS evaluable population: Comparability ITT population (n=337) HR=0.93; p=0.6170mPFS Cetuximab + FOLFOX: 7.2 months mPFS FOLFOX: 7.2 months KRAS population (n=233) HR=0.93; p=0.6609mPFS Cetuximab + FOLFOX: 7.3 months mPFS FOLFOX: 7.2 months Progression-free survival estimate Months Months

  12. Relating KRAS status to efficacy Primary endpoint: Response – KRAS wild-type p=0.011 Odds ratio=2.544 (95% CI: 1.238–5.227) 70 60 61 50 40 Response rate (%) 30 37 20 10 0 FOLFOX Cetuximab +FOLFOX

  13. Relating KRAS status to efficacy Primary endpoint: Response – KRAS mutant p=0.106 Odds ratio=0.507(95% CI: 0.223–1.150) 70 60 50 40 49 Response rate (%) 30 33 20 10 0 FOLFOX Cetuximab +FOLFOX

  14. Cetuximab + FOLFOX FOLFOX Relating KRAS status to efficacySecondary endpoint: PFS – KRAS wild-type 1.0 KRAS wild-type: HR=0.57; p=0.016 mPFS Cetuximab + FOLFOX: 7.7 monthsmPFS FOLFOX: 7.2 months 0.9 0.8 0.7 0.6 0.5 Progression-free survival estimate 0.4 0.3 0.2 0.1 0.0 12 4 6 8 10 0 2 Months

  15. Cetuximab + FOLFOX FOLFOX Relating KRAS status to efficacySecondary endpoint: PFS – KRAS mutant 1.0 KRAS mutant HR=1.83; p=0.0192 mPFS Cetuximab + FOLFOX: 5.5 monthsmPFS FOLFOX: 8.6 months 0.9 0.8 0.7 0.6 0.5 Progression-free survival estimate 0.4 0.3 0.2 0.1 0.0 12 4 6 8 10 0 2 Months

  16. 1.0 0.9 Cetuximab +FOLFOX wild-type FOLFOX mutant 0.8 0.7 0.6 0.5 Cetuximab +FOLFOX mutant FOLFOX wild-type 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 Relating KRAS status to efficacyProgression-free survival Cetuximab + FOLFOX HR=0.448; p=0.0009 mPFS Cet + FOLFOX wild-type (n=61): 5.5 monthsmPFS Cet + FOLFOX mutant (n=52): 7.7 months FOLFOX HR=1.404; p=0.1655 mPFS FOLFOX wild-type (n=73): 7.2 monthsmPFS FOLFOX mutant (n=47): 8.6 months 1.0 0.9 0.8 0.7 0.6 Progression-free survival estimate 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 Months Months

  17. Relating KRAS status to efficacy Treatment exposure

  18. Relating KRAS status to efficacyMost common grade 3/4 AEs aTherewas no grade 4 acne-like rash

  19. OPUS trial: Conclusions • In patients with KRAS wild-type tumors, addition of cetuximab to FOLFOX resulted in a significant and relevant improvement in: • Response rate (61% vs. 37%; p=0.011) • Progression-free survival (HR=0.57; p=0.016) • In patients with KRAS mutant tumors, the addition of cetuximab to FOLFOX had no apparent benefit • The safety profiles of cetuximab and chemotherapy were generally comparable and consistent with their known safety profiles

  20. Acknowledgements • The authors would like to thank: • The patients • The investigators, co-investigators, and study teams at the 87 centers in 13 countries involved in this study • The study team at Merck KGaA, Darmstadt, Germany

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