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Authors: E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P.

KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience.

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Authors: E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P.

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  1. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience Authors:E. Van Cutsem, I. Lang, G. D'haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P. Rougier

  2. CRYSTAL Trial 10 Endpoint= PFS RANDOMI ZE FOLFIRI + Cetuximab N=608 N=1217 EGFR expression via IHC FOLFIRI N=609 * Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly 1:1 Van Custem E Proc ASCO 2007

  3. ResultsEfficacy p=0.0038 HR = 0.85 (0.73-0.99); p=0.048

  4. ResultsPatient Characteristics ITT Centrally assessed for KRAS mutation by QT-PCR exon 12/13 n =540 n = 1198

  5. ResultsEfficacy HR = 0.68; p 0.017 HR = 1.07; p 0.75 p 0.025 p 0.46

  6. KRAS status and efficacy in the first-line treatment of patients with mCRC treated with FOLFOX with or without cetuximab: The OPUS experience Authors: C Bokemeyer, I Bondarenko, J Hartmann, F De Braud, C Volovat, C Stroh,J Nippgen, I Celik, P Koralewski

  7. OPUS: Phase II RANDOMI ZE FOLFOX + Cetuximab N=170 N=338 EGFR+ Metasatic CRC FOLFOX N=168 * Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly 1:1

  8. ResultsEfficacy

  9. ResultsPatient Characteristics ITT Centrally assessed for KRAS mutation by QT-PCR exon 12/13 n =233 n = 337

  10. ResultsEfficacy HR = 0.57; p 0.016 HR = 1.83; p 0.019 p 0.011 p 0.11

  11. ResultsToxicity • No difference in skin rash or other toxicity by KRAS status in CRYSTAL or OPUS

  12. STUDY COMMENTARY • Together with Panitumumab monotherapy in 3rd line setting (Van Custem JCO 2007) these two trials demonstrate that monoclonal antibody blockade against EGFR only benefit patients with wild-type KRAS • Similar findings with EGFR TKIs in NSCLC and pancreatic adenoCA • No overall survival data reported for either CRYSTAL or OPUS

  13. Bottom Line for Canadian Medical Oncologists • Addition of Cetuximab to first line FOLFOX or FOLFIRI only benefits patients with wild type KRAS • Biologically plausible  mAb to receptor will not shut off signaling if a downstream kinase (KRAS) is constitutively active • Addition of Cetuximab to first line FOLFOX in KRAS mutant patients appears to be detrimental • ? Biology of this phenomenon • Optimal sequence of biological therapy in KRAS wild-type patients remains to be determined • Should obtain KRAS mutational status on all patients where Cetuximab is considered • NCIC CO.17 is the only trial to demonstrate OS benefit with EGFR mAb • Retrospective survival analysis by KRAS status is eagerly awaited

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