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Eric Van Cutsem*, M Nowacki, I Lang, S Cascinu, I Shchepotin, J Maurel,

The CRYSTAL trial: Efficacy and safety of irinotecan and 5-FU/FA with and without cetuximab in the first-line treatment of metastatic colorectal cancer. Eric Van Cutsem*, M Nowacki, I Lang, S Cascinu, I Shchepotin, J Maurel, P Rougier, D Cunningham, J Nippgen, C-H K ö hne.

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Eric Van Cutsem*, M Nowacki, I Lang, S Cascinu, I Shchepotin, J Maurel,

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  1. The CRYSTAL trial: Efficacy and safety of irinotecan and 5-FU/FA with and without cetuximab in the first-line treatment of metastatic colorectal cancer Eric Van Cutsem*, M Nowacki, I Lang, S Cascinu, I Shchepotin,J Maurel, P Rougier, D Cunningham, J Nippgen, C-H Köhne *University Hospital Gasthuisberg, Leuven, Belgium

  2. Cetuximab: mechanism of action • Epidermal growth factor receptor (EGFR) is expressed by most CRCs • Cetuximab is an IgG1 monoclonal antibody that: • Specifically targets EGFR with high affinity • Inhibits endogenous ligand binding thereby blocking dimerization, TK phosphorylation, and receptor-dependent downstream signaling • Induces antibody-dependent cell-mediated cytotoxicity (ADCC)

  3. Phase I/II trials: cetuximab plus irinotecan in first line mCRC 1Rosenberg et al. ASCO 2002:Abstr 536; 2 Rougier et al, ASCO 2004:Abstr 3513; 3Folprecht et al. Ann Oncol 2006;17:450-456

  4. CRYSTAL trial:Study design 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 Stratification factors: • Regions • ECOG PS Populations • Randomized patients n=1217 • Safety population n=1202 • ITT population: n=1198 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

  5. CRYSTAL trial:Study endpoints • Primary endpoint: • Progression-free survival time (as assessed by blinded independent review) • Secondary endpoints: • Overall response rate (independently reviewed) • Disease control rate (CR+PR+SD) • Overall survival time • Quality of life (EORTC QLQ C30) • Safety

  6. CRYSTAL trial:Statistical considerations • Assumption for sample size calculation: • 633 events (documented PDs) required to detect a hazard ratio of 0.8 with 80% power • Protocol required a sample size of 1080 patients • A central stratified permuted block randomization procedure was used with regions (Western Europe, Eastern Europe, Rest of World) and ECOG PS (0/1, 2) as randomization strata • Two interim assessments of safety data were conducted by an independent DSMB • Assessments were performed every 8 weeks

  7. CRYSTAL trial:Main inclusion criteria • Histologically confirmed unresectable mCRC • EGFR expression in primary tumor or metastasis as detected by IHC • ≥ 1 bi-dimensionally measurable lesion • No previous chemotherapy for metastatic disease; adjuvant therapy was allowed if stopped at least 6 months before randomization (no irinotecan) • ECOG PS ≤ 2 at study entry • Adequate organ and bone marrow function • Signed informed consent

  8. CRYSTAL trial:Patient baseline characteristics (1)

  9. CRYSTAL trial:Patient baseline characteristics (2)

  10. CRYSTAL trial:Safety: Grade 3/4 AE aThere were no grade 4 skin reactions Magnesium levels were measured in only 20% of the patients (0.2% vs. 1.8%)

  11. CRYSTAL trial:Reasons for treatment discontinuation *SD=symptomatic deterioration

  12. CRYSTAL trial:Deaths on study *No deaths were cetuximab-related

  13. 0.9 Cetuximab + FOLFIRI, n=599 0.8 FOLFIRI, n=599 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 Subjects at risk FOLFIRI alone 599 492 402 293 178 83 35 16 7 4 1 Cetuximab + FOLFIRI 599 499 392 298 196 103 58 29 12 5 1 CRYSTAL trial: Primary endpoint PFS met ITT population independent review 1.0 HR = 0.851; 95% CI = [0.726-0.998] Stratified log-rank p-value = 0.0479 8.9 mo PFS estimate 1-year PFS rate 23% vs 34% 8.0 mo Progression-free survival time (months)

  14. CRYSTAL trial:Independent assessment of response p-value* = 0.0038 *Cochran-Mantel-Haenszel (CMH) test ** DCR: disease control rate

  15. FOLFIRI alone Cetuximab + FOLFIRI 10 9.8 9 8 7 6 5 Percentage (%) 4 4.5 3 2 1 0 No residual tumor in patients with liver metastases n=134 / n=122 CRYSTAL trial:Surgery with curative intent ITT population(pre-planned) Liver metastases only population(exploratory) p=0.0034* odds ratio 3.0 [95% CI: 1.4 - 6.5] n=599 / group n=599 / group *CMH test

  16. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 CRYSTAL trial: Primary endpoint PFS subgroup:liver metastases only Cetuximab + FOLFIRI, n=122 FOLFIRI, n=134 HR = 0.637; 95% CI = [0.432-0.941] Stratified log-rank p-value = 0.023 11.4 mo PFS estimate 9.2 mo Progression-free survival time (months) Subjects at risk FOLFIRI alone 134 115 93 68 36 18 6 3 7 4 1 Cetuximab + FOLFIRI 122 100 84 74 51 26 15 6 2 1 1

  17. CRYSTAL trial:PFS time subgroup analyses HR [95% CI] All ITT subjects (n=1198) 0.851 [0.726 - 0.998] Subgroup (number of patients) < 65 years (n=751) Age 0.775 [0.634 - 0.948] ≥ 65 years (n=446) 0.989 [0.759 - 1.288] ECOG Performance Status 0,1 (n=1156) 0.839 [0.713 - 0.998] 2 (n=42) 1.187 [0.551 - 2.556] Involved disease sites ≤ 2 (n=1016) 0.862 [0.724 - 1.026] > 2 (n=166) 0.794 [0.520 - 1.211] Livermetastasesonly Yes (n=256) 0.637 [0.432 - 0.941] No (n=942) 0.913 [0.765 - 1.088] Prior adjuvant therapy Yes (n=243) 0.816 [0.574 - 1.161] 0.858 [0.716 - 1.027] No (n=955) Leucocytes > 10000/mm3 (n=214) 0.765 [0.531 - 1.101] ≤ 10000/mm3 (n=943) 0.874 [0.728 - 1.050] AlkalinePhosphatase ≥ 300 U/L (n=151) 0.819 [0.537 - 1.249] < 300 U/L (n=986) 0.836 [0.698 - 0.999] > UNL (n=540) 0.790 [0.625 - 0.999] LDH 0.956 [0.745 - 1.226] ≤ UNL (n=516) 0.5 1 2 5 0.2 10 0.1 Favors FOLFIRI Favors Cetuximab+FOLFIRI

  18. 1.00 Skin reaction grade 3*, n=112 Skin reaction grade 2, n=243 0.75 Skin reaction grade 0 or 1, n=244 PFS estimate 0.50 11.3 mo 9.4 mo 5.4 mo 0.25 0.00 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Progression-free survival time (months) *There were no grade 4 skin reactions CRYSTAL trial:Subgroup analysis of PFS time by on-study skin reactions: cetuximab + FOLFIRI

  19. CRYSTAL trial:Treatment exposure

  20. CRYSTAL trial: Conclusions (1) • The CRYSTAL trial met its primary objective of demonstrating that the addition of cetuximab to FOLFIRI in the first-line treatment of EGFR-detectable mCRC significantly increased PFS • There was a 15% risk reduction for progression in patients treated with cetuximab plus FOLFIRI compared to FOLFIRI

  21. CRYSTAL trial: Conclusions (2) • The addition of cetuximab to FOLFIRI was associated with: • Higher response rates (p=0.0038) • Threefold higher R0 resection rates for initially unresectable disease (p=0.0034) • Patients with liver metastases as the only disease site achieved a longer PFS than the whole population • Skin reactions showed a strong correlation with efficacy

  22. CRYSTAL trial:Conclusions (3) • Treatment was generally well-tolerated • Neutropenia and febrile neutropenia were similar in both groups • Grade 3/4 diarrhea was more frequent with the combination • Skin toxicity was in the expected range • All cause mortality 60-days-after-treatment-start and 30-days-after-treatment-stop was similar in both groups • No cetuximab-related deaths

  23. CRYSTAL trial:Conclusions (4) • Survival follow-up, QoL and molecular marker evaluation is ongoing

  24. 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 in this study • The study team at Merck KGaA

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