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Defining the Role of EGFR Monoclonal Antibody Therapy in Metastatic Colorectal Cancer

Defining the Role of EGFR Monoclonal Antibody Therapy in Metastatic Colorectal Cancer. Author: Dr. Phil Bedard Date Posted: December 12, 2007. Objectives. Review the rationale for targeting EGFR in metastatic colorectal cancer therapy

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Defining the Role of EGFR Monoclonal Antibody Therapy in Metastatic Colorectal Cancer

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  1. Defining the Role of EGFR Monoclonal Antibody Therapy in Metastatic Colorectal Cancer Author: Dr. Phil Bedard Date Posted: December 12, 2007

  2. Objectives • Review the rationale for targeting EGFR in metastatic colorectal cancer therapy • Outline the differences between the monoclonal antibodies against EGFR • Understand the common toxicities associated with EGFR monoclonal antibodies • Summarize the evidence supporting the use of EGFR monoclonal antibody therapy in the first-, second-, and third-line treatment of metastatic CRC • Discuss possible methods of selection of patients most likely to benefit from EGFR monoclonal antibody blockade with metastatic CRC

  3. Epidermal Growth Factor Receptor (EGFR) • Member of the epidermal growth factor receptor tyrosine kinase family • Ligand binding to extracellular domain leads to activation of intracellular signaling cascade, including Akt and MAPK • Results in proliferation, angiogenesis, increased cell motility, and resistance to chemotherapy

  4. EGFR in Colorectal Cancer • Expressed in 60-80% CRC • Risk factor for poor prognosis • Monoclonal antibodies (mAb) demonstrate activity as single agents and in combination with chemotherapy in CRC • To date, there is no proof that small molecular tyrosine kinase inhibitors (TKIs) are of benefit • CRC lacks EGFR mutations that have been asssociated with response to TKIs in other disease sites Townsley CA Br J Cancer 2006 Rothernberg ML JCO 2005

  5. Monoclonal AntibodiesAgainst EGFR • For treatment of metastatic colorectal cancer: • Cetuximab approved by Health Canada and FDA • Panitumumab approved by FDA

  6. Comparison: Cetuximab vs Panitumumab

  7. First-line Therapy:Cetuximab + Chemotherapy

  8. CRYSTAL Trial 10 Endpoint= PFS RANDOMI ZE FOLFIRI + Cetuximab N=648 N=1198 EGFR expression via IHC FOLFIRI N=650 * Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly 1:1 Van Custem E Proc ASCO 2007

  9. Toxicity

  10. Efficacy p=0.0038 HR = 0.85 (0.73-0.99); p=0.048

  11. PFS by Skin Reaction:FOLFIRI + Cetuximab * No Grade 4 Reaction Reported

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

  13. Toxicity

  14. Efficacy * No Survival Data Reported

  15. Response Rate by Skin Rash

  16. SWOG 80203 10 Endpoint= OS FOLFOX + Cetuximab RE GISTER RANDOMI ZE FOLFOX Inv choice FOLFOX alone FOLFIRI + Cetuximab FOLFIRI Inv choice FOLFIRI alone N=258 Metastatic Colorectal CA No EGFR expression required 1:1 Venook A Proc ASCO 2006

  17. SWOG 80203 • Planned sample size N=2200 • Trial stopped early January 2005 because of poor accrual • Publication of Hurwitz data with IFL + Bevacizumab (NEJM 2004) • Data reported with median F/U 16 months

  18. Efficacy

  19. Toxicity

  20. Efficacy: Cetuximabversus Chemotherapy Alone

  21. Medical Research Council: COIN Trial (Ongoing) 10 Endpoint= OS RANDOMI ZE FOLFOX/CapeOX until progression/intolerance N=2421 (Target) No EGFR testing FOLFOX/CapeOX + Cetuximab until progression/intolerance FOLFOX/CapeOXx12 weeks “Stop & Go” Strategy 1:1:1

  22. First-line Therapy:Panitumumab + Chemotherapy

  23. PRIME Trial: Ongoing 10 Endpoint= PFS RANDOMI ZE Panitumumab + FOLFOX N=900 (Target Accrual) Metastatic Colorectal CA No EGFR testing FOLFOX alone Expected Completion: March 2010 1:1

  24. First-line Therapy:Ceutximab + Chemotherapy + anti-VEGF

  25. CALGB/SWOG 80405: Ongoing 10 Endpoint= OS RANDOMI ZE FOLFOX or FOLFIRI + Bevacizumab + Cetuximab N=2300 (Target) Metastatic Colorectal CA No EGFR testing FOLFOX or FOLFIRI + Cetuximab FOLFOX or FOLFIRI + Bevacizumab 1:1:1

  26. Dutch Colorectal Cancer Group CAIRO-2: Ongoing N=750 (Target Accrual) Metastatic Colorectal CA No EGFR testing 10 Endpoint= PFS & Toxicity RANDOMI ZE CapeOX + Bevacizumab + Ceutximab CapeOX + Bevacizumab Expected Completion: December 2007 1:1

  27. Preliminary Toxicity Data

  28. First-line Therapy:Panitumumab + Chemotherapy + anti-VEGF

  29. Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) Panitumumab + Oxali-CT + Bevacizumab RE GISTER RANDOMI ZE Oxali-based CT (ie FOLFOX) Inv choice Oxali-CT + Bevacizumab Panitumumab + Iri-CT + Bevacizumab Iri-based CT (ie FOLFIRI) Inv choice Iri-CT + Bevacizumab 1:1 Hecht JR GI World Congress 2007

  30. PACCE • Trial stopped early after interim analysis suggested excess toxicity and inferior efficacy in treatment arm

  31. Toxicity

  32. Efficacy HR = 1.29 (1.05-1.58) HR = 1.44 (1.10-1.88)

  33. Summary: First Line • CRYSTAL trial suggests that Cetuximab can be safely combined with FOLFIRI in first line setting, with very modest lengthening of PFS of uncertain clinical importance • PACCE trial demonstrates significant added toxicity with combination of chemotherapy, anti-VEGF therapy and Panitimumab • Similar toxicity not reported with CAIRO-2 trial using chemotherapy, anti-VEGF therapy and Cetuximab • Data presently do not support routine use of EGFR mAb therapy in combination with chemotherapy +/- anti-VEGF therapy in first-line setting

  34. Second-line Therapy:Cetuximab + Chemotherapy

  35. Erbitux Plus Irinotecan in Colorectal Cancer (EPIC) RANDOMI ZE 10 Endpoint= PFS Cetuximab + Irinotecan N=648 Prior Oxaliplatin Chemotherapy EGFR+ (IHC) Irinotecan alone N=650 Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly Irinotecan 350mg/m2 q3weekly 1:1 Sobrero AF AACR 2007

  36. Toxicity

  37. Efficacy HR = 0.69 (0.62-0.78) HR = 0.98 (0.85-1.11)

  38. Post-Study Therapy

  39. Survival by Skin Reaction: Cetuximab + Irinotecan

  40. MRC: EXPLORE RANDOMI ZE 10 Endpoint= OS Cetuximab + FOLFOX N=52 Prior Irinotecan Chemotherapy EGFR+ (IHC) Metastatic CRC N=102 FOLFOX N=50 Cetuximab 400mg/m2 week 1; then 250mg/m2 weekly 1:1 Polikoff Proc ASCO 2005

  41. EXPLORE • Planned sample size N=1100 • Trial stopped early December 2004 because of poor accrual • Widespread adoption of FOLFOX in first-line setting

  42. Efficacy p=0.48

  43. Second-line Therapy:Panitumumab + Chemotherapy

  44. Panitumumab, Irinotecan & Cyclosporin in COLOrectal Cancer Therapy (PICCOLO): Ongoing 10 Endpoint= PFS RANDOMI ZE Irinotecan + Panitumumab N=1269 (Target) Prior 5-FU +/- Oxali +/- Bev No EGFR testing Irinotecan + Cyclosporin Irinotecan alone 1:1:1

  45. Second-line Therapy:Cetuximab + Chemotherapy + anti-VEGF

  46. SWOG S0600/ECOG/NCCTG/NCIC: Ongoing 10 Endpoint= OS RANDOMI ZE Irinotecan/FOLFIRI + Cetuximab + Bevacizumab N=1250 (Target) Prior Oxali-based CT Prior Bev allowed No EGFR testing No Prior anti-EGFR therapy Irinotecan/FOLFIRI + Cetuximab Irinotecan/FOLFIRI + Bevacizumab 1:1:1

  47. Summary - Second Line • EPIC trial shows that addition of Cetuximab to FOLFIRI produces statistically significant improvement in response rate and PFS • PFS improvement of questionable clinical significance with no overall survival benefit and added toxicity • lack of OS benefit due to cross over to cetuximab setting on progression in standard arm • S0600 will address whether addition of Cetuximab + anti-VEGF therapy to Irinotecan-based treatment can improve OS after progression on oxaliplatin-based chemotherapy • At present, data do not support routine use of anti-EGFR mAb therapy in 2nd line setting

  48. Third-line Therapy:Cetuximab Monotherapy

  49. NCIC CO.17 REGISTER RANDOMI ZE 10 Endpoint= OS Cetuximab* + BSC EGFR testing by IHC Best Supportive Care alone * Cetuximab 400 mg/m2 IV week 1 then 250 mg/m2 IV weekly 1:1 N=572 Prior 5FU, Iri, and Oxali-CT EGFR expression required • Stratification: • Centre • ECOG PS (0 or 1 vs. 2) Jonker DJ NEJM 2007

  50. Patient Characteristics

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