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Eric Van Cutsem*

KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. Eric Van Cutsem*

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Eric Van Cutsem*

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  1. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer treated with FOLFIRI with or without cetuximab:The CRYSTAL experience Eric Van Cutsem* I Lang, G D’Haens, V Moieseyenko, J Zaluski, G Folprecht, S Tejpar, O Kisker, C Stroh, P Rougier *University Hospital Gasthuisberg, Leuven, Belgium

  2. Disclosure slide • Research funding / advisory board: • Amgen • Merck KGaA • Novartis • Pfizer • Roche • Sanofi-Aventis

  3. Epidermal growth factor receptor (EGFR) and KRAS Khambata-Ford S, et al. J Clin Onc 2007;25:3230–7

  4. Anti-EGFR antibodies in mCRC

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

  6. First-line cetuximab + FOLFIRI: Correlation of KRAS status with efficacy First-line treatment: cetuximab (6 weeks monotherapy), followed by cetuximab + FOLFIRI (n=52) Tabernero J et al, ASCO GI 2008

  7. CRYSTAL trial in first-line mCRC Cetuximab + FOLFIRI Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly + irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus+ 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks EGFR-expressing metastatic CRC R FOLFIRI Irinotecan (180 mg/m2) + 5-FU (400 mg/m2 bolus+ 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks • Stratification factors • Regions • ECOG PS • Populations • Randomized patients n=1217 • Safety population n=1202 • ITT population n=1198 Van Cutsem E et al, ASCO 2007

  8. 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 20 0 2 4 6 8 10 12 14 16 18 Months Cetuximab + FOLFIRI (n=599) FOLFIRI (n-599) CRYSTAL trial – Primary endpoint PFSITT population independent review Van Cutsem E et al, ASCO 2007

  9. CRYSTAL trial - Secondary endpoint: Response rate (independent assessment - ITT) 60 p=0.0038a 50 47 40 39 30 Response rate (%) 20 10 0 FOLFIRI Cetuximab + FOLFIRI aCochran-Mantel-Haenszel (CMH) test Van Cutsem E et al, ASCO 2007

  10. KRAS analysis: Objective Objective A retrospective analysis investigated the impact on progression-free survival and response rate of the KRAS mutation status of tumors in the first-line treatment of metastatic CRC treated with FOLFIRI ± cetuximab

  11. Relating KRAS status to efficacy • Efficacy analyses repeated on KRAS evaluable population • 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

  12. KRAS evaluable population 1198 subjects (ITT) 587 subjects analyzed for KRAS mutation status 540 (45%) subjects: KRAS evaluable population 348 (64.4%) KRAS wild-type 192 (35.6%) KRAS mutant Group A: 172 (49.4%) Group B: 176 (50.6%) Group A: 105 (54.7%) Group B: 87 (45.3%) 171 subjects with events (49.1%) 101 subjects with events (52.6%) Cetuximab + FOLFIRI FOLFIRI

  13. Patient demographics at baseline according to KRAS status

  14. ITT population (n=1198) HR=0.85mPFS Cetuximab + FOLFIRI: 8.9 monthsmPFS FOLFIRI: 8.0 months KRAS population (n=540) HR=0.82mPFS Cetuximab + FOLFIRI: 9.2 monthsmPFS FOLFIRI: 8.7 months 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 Progression-free survival estimate 0.5 Progression-free survival estimate 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 0 10 20 6 8 12 14 16 18 8 12 18 2 4 2 4 0 6 10 14 16 20 Months Months Cetuximab + FOLFIRI FOLFIRI ITT and KRAS evaluable population: Comparability

  15. KRAS wild-type (n=348) HR=0.68; p=0.017mPFS Cetuximab + FOLFIRI: 9.9 months mPFS FOLFIRI: 8.7 months 1.0 0.9 0.8 0.7 0.6 1-year PFS rate 25% vs 43% Progression-free survival estimate 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 Months Cetuximab + FOLFIRI FOLFIRI Relating KRAS status to efficacyPrimary endpoint: PFS – KRAS wild-type

  16. KRAS mutant (n=192) HR=1.07; p=0.47mPFS Cetuximab + FOLFIRI: 7.6 months mPFS FOLFIRI: 8.1 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 14 16 Months Cetuximab + FOLFIRI FOLFIRI Relating KRAS status to efficacyPrimary endpoint: PFS – KRAS mutant

  17. 1.0 1.0 0.9 0.9 Cetuximab +FOLFIRI wild-type 0.8 0.8 0.7 0.7 0.6 0.6 FOLFIRI wild-type Progression-free survival estimate 0.5 0.5 Cetuximab +FOLFIRI mutant FOLFIRI mutant 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 0 2 4 6 8 10 16 12 14 0 2 4 6 8 10 16 12 14 Months Months Relating KRAS status to efficacy: PFS Cetuximab + FOLFIRI HR=0.63; p=0.007 mPFS wild-type (n=172): 9.9 monthsmPFS mutant (n=105): 7.6 months FOLFIRI HR=0.97; p=0.87 mPFS wild-type (n=176): 8.7 monthsmPFS mutant (n=87): 8.1 months

  18. Relating KRAS status to efficacySecondary endpoint: Response – KRAS wild-type p=0.0025a FOLFIRI Cetuximab + FOLFIRI aCochran-Mantel-Haenszel (CMH) test

  19. Relating KRAS status to efficacySecondary endpoint: Response – KRAS mutant p=0.46a FOLFIRI Cetuximab + FOLFIRI aCochran-Mantel-Haenszel (CMH) test

  20. Relating KRAS status to outcome: Treatment exposure

  21. Relating KRAS status to outcome:Most common grade 3/4 adverse events aThere was no grade 4 acne-like rash

  22. Summary of efficacy data aCochran-Mantel-Haenszel (CMH) test

  23. Cetuximab + CT in KRAS wild-type: Data consistency 1.0 CRYSTAL - KRAS wild-type: HR=0.68 0.9 32% risk reductionfor progression 0.8 0.7 0.6 PFS estimate 0.5 0.4 0.3 CRYSTAL (n=540) OPUS1(n=233) 0.2 p=0.017 0.1 0.0 70 61 0 2 4 6 8 10 12 14 16 18 59 Months 60 1.0 OPUS - KRAS wild-type: HR=0.57 43 50 0.9 37 43% risk reductionfor progression 0.8 40 0.7 Response rate (%) 0.6 30 0.5 PFS estimate 0.4 20 0.3 0.2 10 p=0.016 0.1 0 0.0 0 2 4 6 8 10 12 FOLFIRI Cetuximab + FOLFIRI FOLFOX Cetuximab + FOLF0X Months 1Bokemeyer C et al, ASCO 2008

  24. CRYSTAL trial: Conclusions (1) • Adding cetuximab to FOLFIRI in mCRC leads to a significant increase in PFS (HR=0.85; p=0.048) • The benefit of cetuximab + FOLFIRI is greater in patients with KRAS wild-type tumors: • PFS (HR=0.68; p=0.017) • Response rate 59% vs. 43% (p=0.0025) • Patients with KRAS mutant tumors do not benefit from the combination of cetuximab and FOLFIRI • The grade 3/4 adverse event profile was similar in the KRAS wild-type and mutant populations

  25. CRYSTAL trial: Conclusions (2) • KRAS is the first molecular marker for the selection of a targeted therapy in combination with a standard chemotherapy regimen in first-line mCRC • Patients with KRAS wild-type tumors have a strong benefit from the combination of cetuximab and FOLFIRI • Cetuximab in combination with a standard first-line treatment for mCRC patients is an important new option in patients with KRAS wild-type tumors

  26. CRYSTAL trial: Acknowledgements • The authors would like to thank: • The patients • The investigators, co-investigators, and study teams at the 201 centers in 32 countries involved inthis study • The study team at Merck KGaA, Darmstadt, Germany

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