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

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 gene is 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 mCRC ReferenceTreatmentNo. of patients (% mutant) Objective response n (%) Wild-typeMutant A Lièvre et al, J Clin Oncol 2008 Cetuximab ± CT114 (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 ± CT81 (40)13 (26)2 (6) F Di Fiore et al, Br J Cancer 2007 Cetuximab + CT59 (27)12 (28)0 (0) S Khambata-Ford et al, J Clin Oncol 2007 Cetuximab80 (38)5 (10)0 (0) RG Amado et al, J Clin Oncol 2008 Panitumumab208 (40)21 (17)0 (0)

First-line cetuximab + FOLFIRI: Correlation of KRAS status with efficacy First-line treatment: cetuximab then FOLFIRI + cetuximab (n=52) MonotherapyOverall assessment OutcomeWild-typeMutantWild-typeMutant RR (CR+PR), % p=0.015p=0.144 Median PFS, months–– HR=2.12 p= Tabernero J et al, ASCO GI 2008

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/m 2 initial IV infusion (day 1) then 250 mg/m 2 weekly + oxaliplatin 85 mg/m FU/FA every 2 weeks FOLFOX4 Oxaliplatin 85 mg/m FU/FA every 2 weeks EGFR-detectable mCRC Stratification by: ECOG PS 0/1, 2 R

OPUS: Efficacy results OutcomeFOLFOX (n=169) Cetuximab + FOLFOX (n=168) p-value RR, (%) ITT population a RR, (%) ECOG PS 0/ a Median PFS time, (months) 7.2 Hazard ratio for PFS Bokemeyer C et al, ECCO 2007 a Cochran-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

KRAS evaluable population 337 subjects (ITT) 233 subjects: KRAS evaluable population 134 (58%) KRAS wild-type99 (42%) KRAS mutant Group A: 61 (46%) Group B 73 (54%) Group A 52 (53%) Group B 47 (47%) FOLFOXCetuximab + FOLFOX

Patient demographics at baseline KRAS evaluable population KRAS wild-type (n=134) % KRAS mutant (n=99) % Age < Gender, male ECOG PS 0/ Prior adjuvant therapy Involved disease sites  Liver-limited disease

ITT and KRAS evaluable population: Comparability FOLFOX Cetuximab + FOLFOX Months KRAS population (n=233) HR=0.93; p= mPFS Cetuximab + FOLFOX: 7.3 months mPFS FOLFOX: 7.2 months Months ITT population (n=337) HR=0.93; p= mPFS Cetuximab + FOLFOX: 7.2 months mPFS FOLFOX: 7.2 months Progression-free survival estimate

Relating KRAS status to efficacy Primary endpoint: Response – KRAS wild-type FOLFOX (n=73) % Cetuximab + FOLFOX (n=61) % CR PR SD PD NE RR % CI26.0– –72.9 p=0.011 Odds ratio=2.544 (95% CI: 1.238–5.227) Response rate (%) Cetuximab + FOLFOX FOLFOX 37 61

Relating KRAS status to efficacy Primary endpoint: Response – KRAS mutant FOLFOX Cetuximab + FOLFOX FOLFOX (n=47) % Cetuximab + FOLFOX (n=52) % CR4.30 PR SD PD NE RR % CI34.1– –47.1 Response rate (%) p=0.106 Odds ratio=0.507 (95% CI: 0.223–1.150)

Relating KRAS status to efficacy Secondary endpoint: PFS – KRAS wild-type Months KRAS wild-type: HR=0.57; p=0.016 mPFS Cetuximab + FOLFOX: 7.7 months mPFS FOLFOX: 7.2 months FOLFOX Cetuximab + FOLFOX Progression-free survival estimate

Relating KRAS status to efficacy Secondary endpoint: PFS – KRAS mutant KRAS mutant HR=1.83; p= mPFS Cetuximab + FOLFOX: 5.5 months mPFS FOLFOX: 8.6 months FOLFOX Cetuximab + FOLFOX Months Progression-free survival estimate

Relating KRAS status to efficacy Progression-free survival Progression-free survival estimate Months Cetuximab + FOLFOX wild-type Cetuximab + FOLFOX mutant Months FOLFOX wild-type FOLFOX mutant Cetuximab + FOLFOX HR=0.448; p= mPFS Cet + FOLFOX wild-type (n=61): 5.5 months mPFS Cet + FOLFOX mutant (n=52): 7.7 months FOLFOX HR=1.404; p= mPFS FOLFOX wild-type (n=73): 7.2 months mPFS FOLFOX mutant (n=47): 8.6 months

Relating KRAS status to efficacy Treatment exposure 5-FUOxaliplatinCetuximab FOLFOX alone Cetuximab + FOLFOX FOLFOX alone Cetuximab + FOLFOX KRAS wild-type (n=73/61) Median duration of treatment, weeks Relative dose intensity ≥80%, % KRAS mutant (n=47/52) Median duration of treatment, weeks Relative dose intensity ≥80%, %

KRAS wild-typeKRAS mutant FOLFOX n=73 (%) Cetuximab + FOLFOX n=61 (%) FOLFOX n=47 (%) Cetuximab + FOLFOX n=52 (%) Any Neutropenia – Febrile neutropenia Diarrhea Peripheral sensory neuropathy Acne-like rash a Infusion-related reactions Relating KRAS status to efficacy Most common grade 3/4 AEs a There was no grade 4 acne-like rash

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

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