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

CRYSTAL Trial RANDOMI ZE FOLFIRI + Cetuximab FOLFIRI N=608 N=609 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

Results Efficacy Grade 3/4 toxicity FOLFIRI N = 650 (%) FOLFIRI + Cetuximab N = 648 (%) Response Rate 39 47 Median PFS 8.0 8.9 1 yr PFS 23 34 Median OS NR p=0.0038 HR = 0.85 (0.73-0.99); p=0.048

Results Patient Characteristics ITT Centrally assessed for KRAS mutation by QT-PCR exon 12/13 n = 1198 n =540 Wild-type KRAS (n=348) Mutant KRAS (n=192) Male, % 57.8 Age < 65, % 65.8 59.9 Prior adjuvant Rx, % 21.6 12.5 Treatment, n (%) FOLFIRI FOLFIRI + Cetuximab 176 (51) 172 (49) 87 (45) 105 (55)

Results Efficacy Wild-type KRAS Mutant KRAS FOLFIRI FOLFIRI + Cetux Median PFS, mos 8.7 9.9 8.1 7.6 1yr PFS rate, % 25 43 NR ORR CR PR 43.2 59.3 1.2 58.1 40.2 36.2 SD 43.8 30.8 46.0 46.7 HR = 0.68; p 0.017 HR = 1.07; p 0.75 p 0.025 p 0.46

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

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

Results Efficacy FOLFOX+ Cetuximab FOLFOX Response Rate 45.6% 35.7% Median PFS, months 7.2

Results Patient Characteristics ITT Centrally assessed for KRAS mutation by QT-PCR exon 12/13 n = 337 n =233 Wild-type KRAS (n=134) Mutant KRAS (n=99) Male, % 55.2 49.5 Age < 65, % 63.4 62.6 Prior adjuvant Rx, % 18.7 17.2 Treatment, n (%) FOLFOX FOLFOX + Cetuximab 73 (54) 61 (46) 47 (47) 52 (53)

Results Efficacy Wild-type KRAS Mutant KRAS FOLFOX FOLFOX + Cetux Median PFS, mos 7.2 7.7 8.6 5.5 1yr PFS rate, % NR ORR CR PR 37.0 1.4 35.6 60.7 3.3 57.4 48.9 4.3 44.7 32.7 SD 16.4 4.9 36.2 51.9 HR = 0.57; p 0.016 HR = 1.83; p 0.019 p 0.011 p 0.11

Results Toxicity No difference in skin rash or other toxicity by KRAS status in CRYSTAL or OPUS

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

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