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The New EPOC Study

Does the New EPOC trial eliminate anti-EGFR antibodies as part of pre-op therapy for curable liver only metastatic CRC?. No. The New EPOC Study. Randomi ze. Oxaliplatin or Irinotecan w ith FP + cetuximab. Surgery. Oxaliplatin or Irinotecan w ith FP + cetuximab. 6 cycles

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The New EPOC Study

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  1. Does the New EPOC trial eliminate anti-EGFR antibodies as part of pre-op therapy for curable liver only metastatic CRC? No

  2. The New EPOC Study Randomi ze Oxaliplatin or Irinotecan with FP + cetuximab Surgery Oxaliplatin or Irinotecan with FP + cetuximab 6 cycles (3months) Surgery N=268 patients Oxaliplatin or Irinotecan with FP Oxaliplatin or Irinotecan with FP • 2/3 FOLFOX, 20% CAPOX, 10% FOLFIRI • Primary EP: PFS (HR 0.68) • 268 pts with 212 events required • Trial closed after interim analysis after 123 events showed detrimental effect

  3. New EPOC Study PFS OS Primrose et al., ASCO 2013

  4. New EPOC Study • Detriment mainly in patients with traditionally good prognostic factors! Primrose et al., ASCO 2013

  5. Why this does not eliminate EGFR antibodies as part of pre-op therapy: • EGFR antibodies improve response rates • Better response  better survival • New EPOC did not include all-RAS analysis • Possibly oxaliplatin+ cetuximab effect • Is the detriment strictly postop?

  6. Response rates with EGFR antibodies in KRAS WT

  7. Therapy: 8 cycles (~ 4 months) Evaluation of resectability Technically resectable Technically non-resectable 4 additional therapy cycles Resection Therapy continuation for 6 cycles (~ 3 months) Patientswith non-resectable colorectallivermetastases(technically non-resectable / ≥ 5 livermetastases)without extrahepatic metastases CELIM Study Biopsy:EGFR screening Randomization FOLFOX6 + cetuximabFOLFIRI + cetuximab Primary endpoint: Response Folprechtet al., Lancet Oncology 2009

  8. CELIM Phase II Study - Results RFA = radiofrequency ablation. Folprechtet al., Lancet Oncology 2009

  9. Waterfall plot of resectability at baseline Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red. Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-” Folprechtet al., Lancet Oncology 2009

  10. Waterfall plot of resectability after chemotherapy Resectability according to imaging increased by 28% (32% → 60%), p<0.01 Votes for “resectable” are in green, for “borderline resectable, surgical exploration recommended” in light green, “chemotherapy preferred” in yellow and for “unresectable” in red. Actual R0 resected cases are marked with “|”, R+ resected cases and patients with radiofrequency ablation “-” Folprechtet al., Lancet Oncology 2009

  11. Survival and R0 resection Overall survival Progression freesurvival 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% — R0 resected — Not R0 resected — R0 resected — Not R0 resected HR 2.07 (1.35-3.16) p=0.001 HR 2.34 (1.37-4.01) p=0.002 Median PFS: 15.4 95%CI: 11.4-19.5 Median PFS: 8.9 95%CI: 6.7-11.0 Median OS: 46.7 95%CI: 30.7-62.7 Median OS: 27.3 95%CI: 21.2-33.3 0 12 24 36 48 60 0 12 24 36 48 60 100 89 78 64 49% 100 91 54 37 16% 100 91 82 59 46% 100 89 62 47 22% R0 resected, N=36 not R0 resected, N=70 R0 resected (k-ras wtsubset, N=22) not R0 resected (k-ras wtsubset, N=45)

  12. Importance of all RAS testing

  13. Importance of all RAS testing: Analysis of PRIME study 17% Oliner et al., ASCO 2013

  14. OS HR 0.83(KRAS wt cod 12/13) Detriment! HR 0.78 (all RAS wt) Oliner et al., ASCO 2013

  15. Is oxaliplatin + EGFR antibodies the wrong combination?

  16. EGFR antibody mCRC trials - KRAS WT patient subsets

  17. Is there detriment restricted to postoperative EGFR antibody administration?

  18. Analysis of N0147 • mFOLFOX6 (12 cycles) • Oxaliplatin 85 mg/m2 • LV 400 mg/m2 & • 5-FU 2,400 mg/m2 over 46 hrs • every 2 weeks R A N D O M I Z E Stage 3 Colon Cancer (N = 2300) • mFOLFOX6 + Cetuximab • (12 cycles) • mFOLFOX6 • Cetuximab days 1,8 • - 400 mg/m2 loading dose • - 250 mg/m2 weekly • n = 1864; med age 58 (19 – 86) • 14% ≥ 70 years • (n = 258) Alberts. JAMA 2012.

  19. Disease Free Survival (N=1847) Alberts. JAMA 2012.

  20. Is there detriment restricted to postoperative EGFR antibody administration? • Detriments in New EPOC and N0147 remain unexplained • PETACC-8 trial did not show detriment, even though no benefit to adjuvant

  21. Conclusions:Why New EPOC result do not eliminate EGFR antibodies as part of pre-op therapy: • EGFR antibodies improve response rates • Better response  improved R0 resections  better survival • Reasons for detriment are unexplained • New EPOC did not include all-RAS analysis • Possibly oxaliplatin + cetuximabeffect • Possibly a postoperative effect

  22. Thank you for your attention!

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