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BALKAN MCO 2011 - P. Stefanovski - Treatment of advanced disease

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BALKAN MCO 2011 - P. Stefanovski - Treatment of advanced disease

  1. 1. Colorectal Cancer Treatment of advanced disease Petar Stefanovski M.D., Ph.D. Clinical Hospital - Bitola
  2. 2. Medical treatment of mCRC in 2011 <ul><li>The efficacy of therapy </li></ul><ul><li>Availability of four active chemotherapy agents and three biologics </li></ul><ul><li>The efficacy of several lines of therapy </li></ul><ul><li>Real chance to cure some patients with combined use of chemotherapy and surgery </li></ul>
  3. 3. Frequency of mCRC <ul><li>25% of patients have metastatic disease at the time of diagnosis </li></ul><ul><li>Another 25% will develop metastasis in the first 2 years of diagnosis </li></ul>Proc ASCO 2004;22:3502 ~ 40%
  4. 4. Decision making process in mCRC <ul><li>Patient’s preferences </li></ul><ul><li>Age </li></ul><ul><li>PS </li></ul><ul><li>Resectability (potentially resectable/never resectable) </li></ul><ul><li>Symptoms (symptomatic/asymptomatic) </li></ul><ul><li>Tumor burden (bulky/non-bulky disease) </li></ul><ul><li>Clinical course of disease (rapid progression/indolent) </li></ul>
  5. 5. The aim of treatment in mCRC <ul><li>Symptom relief – better quality of live </li></ul><ul><li>To prolong the time of disease progression ( TTP) </li></ul><ul><li>To prolong survival </li></ul><ul><li>Individual patient decision </li></ul><ul><ul><li>To obtain response of disease </li></ul></ul><ul><ul><li>To achieve disease control </li></ul></ul><ul><ul><li>With the least toxic regimen available </li></ul></ul>
  6. 6. Treatment priority in mCRC <ul><li>Tumor shrinkage (40%) </li></ul><ul><li>potentially resectable, symptomatic, bulky, rapid progression </li></ul><ul><li>vs. </li></ul><ul><li>Delaying progression (60%) </li></ul><ul><li>never resectable, asymptomatic, non-bulky disease, indolent </li></ul>
  7. 7. Treatment ? <ul><li>AGGRESSIVE </li></ul><ul><li>VS </li></ul><ul><li>NON AGGRESSIVE </li></ul>
  8. 8. Medical treatment of mCRC <ul><li>CHEMOTHERAPY </li></ul><ul><li>5-Fluorouracil </li></ul><ul><li>Leucovorin </li></ul><ul><li>Capecitabin е </li></ul><ul><li>Irinotecan </li></ul><ul><li>Oxaliplatin </li></ul><ul><li>BIOLOGICAL THERAPY </li></ul><ul><li>Bevacizumab </li></ul><ul><li>Cetuximab </li></ul><ul><li>Panitumumab </li></ul>
  9. 9. 0 1 2 3 4 5 6 7 1960 1965 1970 1975 1980 1985 1990 1995 2000 2006 Year Cetuximab Bevacizumab Oxaliplatin Capecitabine Irinotecan/CPT-11 Leucovorin 5-fluorouracil Treatment options in mCRC Panitumumab 8
  10. 10. Irinotecan Oxaliplatin 5-FU Capecitabine
  11. 11. 5-FU <ul><li>In clinics more than 40 years </li></ul><ul><li>Pyrimidine analog </li></ul><ul><li>Inhibition of tymidylate synthase ( TS) </li></ul><ul><li>Typically administered with Leucovorin which stabilize connection with TS </li></ul>
  12. 12. <ul><li>19 randomized trials </li></ul><ul><li>3300 patients </li></ul><ul><li>5-FU – 11% RR </li></ul><ul><li>5-FU/LV – 20% RR </li></ul><ul><li>5-FU – OS 6 months </li></ul><ul><li>5-FU /LV – OS 12 months </li></ul>
  13. 13. <ul><li>5-FU/LV vs. 5-FU </li></ul><ul><li>> G3-4 diarrhea </li></ul><ul><li>> stomatitis </li></ul><ul><li>> haematotoxicity </li></ul>
  14. 14. 5-FU/LV bolus i.v. vs. 5-FU/LV c.i.v. <ul><li>Meta-analysis </li></ul><ul><li>6 randomized trials </li></ul><ul><li>RR 14% vs. 22% (p=0.0002) </li></ul><ul><li>MOS 11.3 months vs. 12.1 months (p=0.04) </li></ul><ul><li>> Myelosupresion vs. HFSy </li></ul>JCO 1998;16:301-308
  15. 15. <ul><li>topoisomerase 1 inhibitor </li></ul>Irinotecan (CPT-11)
  16. 16. Irinotecan – second line chemotherapy in mCRC Cunningam D. et al. Lancet 1998;352:1413-1418 Rougier P. et al. Lancet 1998;352:1407-1412 N RR (%) MPFS (months) OS (months) Irinotecan 189 NA NA 9.2 BSC 90 NA NA 6.5 Irinotecan 133 NA 4.2 10.8 5-FU 134 NA 2.9 8.5
  17. 17. Irinotecan – first line chemotherapy in mCRC Saltz LB et al. NEJM 2000;343:905-914 Douillard et al. Lancet 2000;355:1041-1047 N RR (%) MPFS (months) OS (months) IFL 231 39 p<0.001 7.0 p<0.004 14.8 p<0.04 5-FU/LV bolus 226 21 4.3 12.6 Irinotecan 226 18 4.2 12.0 FOLFIRI 198 34.8 p<0.005 6.7 p<0.001 17.4 p=0.031 5-FU/LV 187 21.9 4.4 14.1
  18. 18. TTP OS Lancet 2000;355:1041-1047. p<0.001 p=0.031
  19. 19. <ul><li>Combination of Irinotecan + 5FU/LV replace 5FU/LV as a standard first line treatment in mCRC </li></ul><ul><li>Diarrhea G3 is more frequent in Irinotecan combination </li></ul><ul><li>IFL is generally more toxic than FOLFIRI </li></ul>
  20. 20. <ul><li>Inhibition of DNA synthesis </li></ul>Oxaliplatin
  21. 21. Oxaliplatin – second line chemotherapy in mCRC Rothenberg ML et al. JCO 2003;21:2059-2069 N RR (%) MPFS (months) OS (months) FOLFOX 152 9.9 4.6 NA 5-FU/LV 151 0 2.7 NA Oxaliplatin 156 1.3 1.6 NA
  22. 22. Haller D.G. et al. JCO 2008;26:4544-4550. PFS OS p<0.0001 p=0.0072 Oxaliplatin – second line chemotherapy in mCRC N RR (%) MPFS (months) OS (months) IROX 317 22 5.3 13.4 Irinotecan 310 7 2.8 11.1
  23. 23. Oxaliplatin – first line chemotherapy in mCRC De Gramont et al. JCO 2000;18:2938-2947 Coldberg et al. (N9741 Study) JCO 2004;22:23-30 N RR (%) MPFS (months) OS (months) FOLFOX 210 50.7 9.0 16.2 (ns) 5-FU/LV 210 22.3 6.2 14.7 FOLFOX 267 45 8.7 19.5 IFL 264 31 6.9 15.0 IROX 264 35 6.5 17.4
  24. 25. Efficacy data from N9741 study - update Goldberg RM et al. JCO 2004;22:23-30. Sanoff HK et al. JCO 2008;26:5721-5727. Endpoint IFL FOLFOX IROX FOLFOX vs. IFL ORR, % 31 45 35 p = 0.002 OS, months 15 19.5 17.4 p = 0.0001 5-year survival (updated 2008) 14.6 20.2 17.3 p < 0.001 TTP, months 6.9 8.7 6.5 p = 0.0014 TTP, months (updated 2008) 6.1 8.9 6.7 p < 0.001
  25. 27. FOLFIRI FOLFOX6 (GERCOR Study) Tournigand C et al. JCO 2004;22:229-237
  26. 28. GERCOR Study Progression –free survival Time to second progression Overall survival Tournigand C et al. JCO 2004;22:229-237
  27. 29. Tournigand C et al. JCO 2004;22:229-237 FOLFIRI FOLFOX6 (GERCOR Study) N RR (%) MPFS (months) OS (months) FOLFIRI 1 st line 109 56 8.5 21.5 FOLFOX6 1 st line 111 54 8.0 20.6 FOLFIRI 2 nd line 69 4 2.5 NA FOLFOX6 2 nd line 81 15 p=0.05 4.2 p=0.003 NA
  28. 30. <ul><li>FOLFIRI </li></ul><ul><ul><li>G 3-4 mucositis </li></ul></ul><ul><ul><li>Nausea/vomiting </li></ul></ul><ul><ul><li>Alopecia G2 </li></ul></ul><ul><li>FOLFOX6 </li></ul><ul><ul><li>G 3-4 neutropenia </li></ul></ul><ul><ul><li>neurotoxicity </li></ul></ul>GERCOR Study Toxicity Tournigand C et al. JCO 2004;22:229-237
  29. 31. Progression –free survival Overall survival Colucci G. et al. JCO 2005;23:4866-4875.
  30. 32. Observed Toxicities for Both Treatment Arms Colucci G. et al. JCO 2005;23:4866-4875.
  31. 33. Capecitabine
  32. 34. Enzymatic activation of Capecitabine Intestine Liver Capecitabine 5 ' -DFCR 5 ' -DFUR CyD 5 ' -DFCR 5 ' -DFUR 5-FU Tumour Capecitabine Thymidine phosphorylase (TP) CyD CE 5 ' -DFCR = 5 ' -deoxy-5-fluorocytidine; 5 ' -DFUR = 5 ' -deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase
  33. 35. Capecitabine – first line chemotherapy in mCRC Hoff PM et al. JCO 2001;19:2282-2292 Van Cutsem E et al. JCO 2001;19:4097-4106 N RR (%) MPFS (months) OS (months) 5-FU/LV bolus 303 11.6 4.7 13.3 CPCT 302 25.8 p=0.005 4.3 12.5 5-FU/LV bolus 301 15 4.7 12.1 CPCT 301 18.9 5.2 13.2
  34. 36. Capecitabine – first line chemotherapy in mCRC TOXICITY Hoff PM et al. JCO 2001;19:2282-2292 Van Cutsem E et al. JCO 2001;19:4097-4106 N STOMATITIS Hand-Foot Syndrome 5-FU/LV 303 16% 1% CPCT 302 3% 18% 5-FU/LV 301 13.3% 0.3% CPCT 301 1.3% 16.2%
  35. 37. <ul><li>More toxicity than usual </li></ul><ul><li>19-48% diarrhea and dehydration </li></ul><ul><li>Particularly problematic in older patients </li></ul><ul><li>In some studies mortality in the first 60 days up to 6.6% </li></ul>Capecitabine + Irinotecan in mCRC Bajetta et al. Cancer 2004;15:279-287 Borner et al. Ann Oncol 2005;16:282-288 Fuchs et al. JCO 2007;25:4779-4786 Kohne et al. Ann Oncol 2007doi1093/annonc/mdm544:10
  36. 38. Capecitabine + Oxaliplatin in mCRC FOCA trial (Phase II)- Martoni et al. EJC 2006;42:3161-3168 US TREE-1 trial - Hochster et al. JCO 2006;24:18S N RR (%) MPFS (months) OS (months) XELOX 62 43 7 NA pviFOX 56 48 9 NA XELOX 48 27 5.9 17.2 bFOL 50 20 6.9 17.9 mFOLFOX 49 41 8.7 17.6
  37. 39. Capecitabine + Oxaliplatin in mCRC German trial - Porschen et al. JCO 2007;25:4217-4223 Spanish trial – Diaz-Rubio et al. JCO 2007;25:4224-4230 N RR (%) MPFS (months) OS (months) CAPOX 241 48 7.1 16.8 FUFOX 233 54 8.0 18.8 XELOX 171 37 8.9 18.1 FUOX 171 46 9.5 20.8
  38. 40. Capecitabine + Oxaliplatin in mCRC French trial (Phase III)- Ducreux et al. JCO 2007;25:18S COFFEE trial – Comella et al. ASCO GI Cancer Syposium 2008 N RR (%) MPFS (months) OS (months) XELOX 156 39 8.8 19.9 FOLFOX6 150 46 9.3 20.5 OXXEL 158 34 6.2 16.0 OXAFAFU 164 33 6.3 17.1
  39. 41. Progression –free survival Overall survival Rothenberg M.L. et al. Ann Oncol 2008;19:1720-1726.
  40. 43. XELOX-1/NO16966, a randomized Phase III trial of first-line XELOX compared with FOLFOX4 for patients with metastatic colorectal cancer: updated survival and tolerability results Cassidy et al. ASCO GI 2009: Abstract 382
  41. 44. NO16966 study: updated survival results (additional 26 months follow-up) XELOX + placebo (n=350) FOLFOX4 + placebo (n=351) XELOX + bevacizumab (n=350) FOLFOX4 + bevacizumab (n=349) XELOX (n=317) FOLFOX4 (n=317) Initial two-arm open-label study (n=634) Protocol amended to 2x2 placebo-controlled design after bevacizumab Phase III data became available (n=1400) Recruitment Feb 2004–Feb 2005 Cassidy et al. ASCO GI 2009
  42. 45. NO16966: XELOX primary objective met Non-inferior PFS HR=1.01 (97.5% CI: 0.91–1.12) Upper limit <1.23 (non-inferiority margin) 0.0 0.2 0.4 0.6 0.8 1.0 Months Estimated probability 8.0 8.5 42 36 30 24 18 12 6 0 ITT population XELOX/XELOX + placebo/ XELOX + bevacizumab (n=1017) 48% FOLFOX/FOLFOX + placebo/ FOLFOX + bevacizumab (n=1017) 47% RR Cassidy et al. J Clin Oncol 2008 Cassidy et al. ASCO GI 2009
  43. 46. Updated NO16966: overall survival in treatment subgroup comparisons* *ITT population Cassidy et al. ASCO GI 2009 No. of events Median time to event (months) HR [97.5% CI] FOLFOX4/FOLFOX4 + placebo/ FOLFOX4 + bevacizumab 847 19.5 0.95 [0.85–1.06] XELOX/XELOX + placebo/ XELOX + bevacizumab 820 19.8 FOLFOX 4 + bevacizumab 274 21.0 0.95 [0.78–1.15] XELOX + bevacizumab 274 21.6 FOLFOX4/FOLFOX4 + placebo 573 18.9 0.95 [0.83–1.09] XELOX/XELOX + placebo 546 19.0 FOLFOX4 284 17.7 0.87 [0.72–1.05] XELOX 266 18.8
  44. 47. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Overall study population FOLFOX4/FOLFOX4 + placebo/FOLFOX4 + bevacizumab (n=1017) XELOX/XELOX + placebo/XELOX + bevacizumab (n=1017) HR=0.95 [97.5% CI: 0.85  1.06] (ITT) HR=0.96 [97.5% CI: 0.86  1.08] (EPP)
  45. 48. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Initial two-arm study FOLFOX4 (n=317) XELOX (n=317) HR=0.87 [97.5% CI: 0.72–1.05] (ITT) HR=0.89 [97.5% CI: 0.73–1.08] (EPP )
  46. 49. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Combination with bevacizumab FOLFOX4 + bevacizumab (n=351) XELOX + bevacizumab (n=350) HR=0.95 [97.5% CI:0.78–1.15] (ITT) HR=0.95 [97.5% CI: 0.78–1.16] (EPP)
  47. 50. Updated NO16966: equivalent overall survival* Cassidy et al. ASCO GI 2009 *ITT population Estimated probability Months 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 60 Patients not receiving bevacizumab FOLFOX4/FOLFOX4 + placebo (n=668) XELOX/XELOX + placebo (n=667) HR=0.95 [97.5% CI: 0.83–1.09] (ITT) HR=0.97 [97.5% CI: 0.84–1.11] (EPP)
  48. 51. Updated NO16966: most common grade 3/4 treatment-related AEs* 0 20 40 60 Patients (%) Diarrhoea Neurosensory Venous thromboembolic Hand-foot syndrome Cardiac disorders Neutropenia Febrile neutropenia XELOX/XELOX + placebo (n=655) FOLFOX4/FOLFOX4 + placebo (n=649) *Safety population Cassidy et al. ASCO GI 2009
  49. 53. Hendric – Tobias et al. JCO 2008;26:5910-5917
  50. 54. Overall Response Rates Hendric – Tobias et al. JCO 2008;26:5910-5917
  51. 55. Progression Free Survival Hendric – Tobias et al. JCO 2008;26:5910-5917
  52. 56. Overall Survival Hendric – Tobias et al. JCO 2008;26:5910-5917
  53. 57. Hendric – Tobias et al. JCO 2008;26:5910-5917
  54. 58. Hendric – Tobias et al. JCO 2008;26:5910-5917
  55. 59. Triplet Chemotherapy Combination vs. Doublet Chemotherapy Combination
  56. 60. BJC 2006;94:798-805.
  57. 61. JCO 2007;25:1670-1676.
  58. 62. Planned Drug Sequences FOCUS CAIRO LIFE Seymour MT et al. Lancet 2007;370:143-152. Koopman M et al. Lancet 2007;370:135-142. Cunningham D et al. Ann Oncol 2009;20:244-250.
  59. 64. <ul><li>Doublets better than single agent 5-FU </li></ul><ul><li>FOLFIRI = FOLFOX </li></ul><ul><li>Capecitabine is equal with 5-FU in doublets </li></ul><ul><li>FOLFOXIRI is an option (perfectly fit, young, potentially resectable liver metastasis) </li></ul><ul><li>XELIRI ( High rate of G3-4 diarrhea and mortality) </li></ul>First line chemotherapy in mCRC
  60. 65. Treatment of mCRC <ul><li>AGGRESSIVE </li></ul><ul><li>Tumour shrinkage (40%) </li></ul><ul><li>potentially resectable, symptomatic, bulky, rapid progression </li></ul><ul><li>FOLFOX or XELOX or FOLFIRI </li></ul><ul><li>FOLFOXIRI (in selected patients) </li></ul>
  61. 66. Treatment of mCRC <ul><li>NON AGGRESSIVE </li></ul><ul><li>Delaying progression (60%) </li></ul><ul><li>never resectable, asymptomatic, non-bulky disease, indolent </li></ul><ul><li>5-FU/CPCT </li></ul><ul><li>OXALIPLATIN combination </li></ul><ul><li>IRINOTECAN combination </li></ul>
  62. 67. Bevacizumab Humanized monoclonal antibody Binds to vascular endothelial growth factor A (VEGF-A)
  63. 68. Chemotherapy + Bevacizumab in mCRC Kabinavar et al. JCO 2005;23:3697-3705. (Phase II First line) Hurwitz et al. NEJM 2004;350:2335-2342. (Phase III First line) N RR (%) MPFS (months) OS (months) 5-FU/LV + Placebo 105 15.2 5.5 12.9 5-FU/LV + Bevacizumab 104 26.0 9.2 16.6 IFL + Placebo 411 34.8 6.2 15.6 IFL + Bevacizumab 402 44.8 10.6 20.3
  64. 69. Chemotherapy + Bevacizumab in mCRC Hochster et al. JCO 2008;26:3523-3529. (Phase II First line) TREE-1 and TREE-2 Saltz et al. JCO 2008;26:2013-2019. (Phase III First line) N016966 N RR (%) MPFS (months) OS (months) FOLFOX6, bFOL, or CAPOX 150 - - 18.2 FOLFOX6, bFOL, or CAPOX + Bevacizumab 223 - - 23.7 FOLFOX4 or XELOX + Placebo 701 49 8.0 19.9 FOLFOX4 or XELOX + Bevacizumab 699 47 9.4 21.3
  65. 70. Chemotherapy + Bevacizumab in mCRC Giantonio BJ et al. JCO 2007;25:1539-1544. E3200 (second line) N RR (%) MPFS (months) OS (months) FOLFOX + Bevacizumab (Arm A) 291 22.7 7.3 12.9 FOLFOX (Arm B) 286 8.6 4.7 10.8 Bevacizumab (Arm C) 243 3.3 2.7 10.2
  66. 71. Chemotherapy + Bevacizumab in mCRC Tebbutt NC et al. JCO 2010;28:3191-3198. N RR (%) MPFS (months) OS (months) Capecitabine (C) 156 30.3 5.7 18.9 Capecitabine + Bevacizumab (CB) 157 38.1 8.5 18.9 CB + mitomycin (CBM) 158 45.9 8.4 16.4
  67. 72. Incidence (%) of grade 3-4 toxicities in studies of bevacizumab Hypertension Bleeding GI perforation Venous TEE Arterial TEE Proteinuria Hurwitz NEJM 2004 11.0 3.1 1.5 19.4 - <1 Kabbinavar JCO 2005 16 5 2 13 - 1 Hochster JCO 2008 16.4 - - 3.8 - - Saltz JCO 2008 4 2 <1 8 2 <1 Giantonio JCO 2007 7 <1 1 - - - Tebbutt JCO 2010 3.8 1.3 1.9 8.9 3.2 3.2
  68. 73. <ul><li>IFL + Bevacizumab (consistent results regarding RR, PFS, OS) in first line </li></ul><ul><li>FOLFOX/XELOX + Bevacizumab (only PFS improvement) (XELOX+Bevacizumab = FOLFOX) in first line </li></ul><ul><li>Capecitabine + Bevacizumab > Capecitabine (PFS) in first line </li></ul><ul><li>FOLFOX + Bevacizumab > FOLFOX (consistent results regarding RR, PFS, OS) in second line </li></ul>
  69. 74. Cetuximab cetuximab Chimeric (mouse/human) monoclonal antibody A n epidermal growth factor receptor (EGFR) inhibitor
  70. 75. Chemotherapy + Cetuximab in mCRC Cunningham et al. NEJM 2004;351:337-345. (BOND PhaseII Second line) Jonker et al. NEJM 2007;357:2040-2048. (NCIC CO-17 Phase III More lines) N RR (%) MPFS (months) OS (months) Cetuximab 111 10.8 1.5 6.9 Irinotecan + Cetuximab 218 22.9 4.1 8.6 BSC 285 0 NR 4.6 BSC + Cetuximab 287 8.0 NR 6.1
  71. 76. Chemotherapy + Cetuximab in mCRC Bokemeyer et al. JCO 2009;27:663-671. ( OPUS Phase II First line) Sobrero et al. JCO 2008;26:2311-2319. (EPIC Phase III Second line) N RR (%) MPFS (months) OS (months) Irinotecan 650 4.2 2.6 10.0 Irinotecan + Cetuximab 648 16.4 4.0 10.7 FOLFOX 168 36 7.2 - FOLFOX + Cetuximab 169 46 7.2 -
  72. 77. Chemotherapy + Cetuximab in mCRC Van Cutsem et al. NEJM 2009;360:1408-1417. (CRYSTAL Phase III First line) N RR (%) MPFS (months) OS (months) FOLFIRI 599 38.7 8.0 18.6 FOLFIRI + Cetuximab 599 46.9 8.9 19.9
  73. 78. Panitumumab Fully human monoclonal antibody B ind to the extracellular domain of the EGFR preventing its activation
  74. 79. Panitumumab in mCRC Van Cutsem et al. JCO 2007;25:1658-1664. ( Phase III More lines) N RR (%) MPFS OS (months) BSC 232 0 7.3 wk BSC + Panitumumab 231 10 8.0 wk NS
  75. 80. Incidence (%) of toxicities in studies of cetuximab and panitumumab * Cetuximab; ** Panitumumab Rash Diarrhea Low Mg Infusion reaction All Grades G3 G3-G4 All Grades G3 G3-G4 Cunningham* NEJM 2004 78.0 9.4 21.2 - - 3.5 Jonker * NEJM 2007 88.5 11.8 - 47.9 5.2 4.5 Sobrero* JCO 2008 76.3 8.2 28.4 33.8 3.3 - Bokemeyer* JCO 2009 90 11 8 - - 5 Van Cutsem* NEJM 2009 - 16.2 15.7 - - 2.5 Van Cutsem** JCO 2007 62 3.1 <1.0 - - -
  76. 81. Cancer Res 2006;66:3992-3995.
  77. 82. Chemotherapy + Cetuximab in mCRC by KRAS genotype Van Cutsem et al. NEJM 2009;360:1408-1417. (CRYSTAL Phase III First line) P=0.02 KRAS N RR (%) MPFS (months) OS (months) FOLFIRI WT 176 43.2 8.7 21.0 MT 87 40.2 8.1 17.7 FOLFIRI + WT 172 59.3 9.9 24.9 Cetuximab MT 105 36.2 7.6 17.5
  78. 83. Chemotherapy + Cetuximab in mCRC by KRAS genotype Bokemeyer et al. JCO 2009;27:663-671. ( OPUS Phase II First line) KRAS N RR (%) MPFS (months) OS (months) FOLFOX WT 73 37 7.2 - MT 47 49 8.6 - FOLFOX + WT 61 61 7.7 - Cetuximab MT 52 33 5.5 -
  79. 84. Cetuximab with chemotherapy as first-line treatment for mCRC: Analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status Bokemeyer et al. JCO 2010;28:(Suppl.) 3506 N RR (%) MPFS (months) OS (months) KRAS WT CT 447 38.5 7.6 19.5 Cetuximab + CT 398 57.3 p<0.0001 9.6 p<0.0001 23.5 p=0.0062 KRAS WT/ CT 381 40.9 7.7 21.1 BRAF WT Cetuximab + CT 349 60.7 p<0.001 10.9 p<0.0001 24.8 p=0.0479 KRAS WT/ CT 38 13.2 3.7 9.9 BRAF MT Cetuximab + CT 32 21.9 p=0.4606 7.1 p=0.2301 14.1 P=0.0764
  80. 85. Panitumumab in mCRC by KRAS genotype Amado et al. JCO 2008;26:1626-1634. ( Phase III More lines) Progression –free survival – KRAS Mutant Progression –free survival – KRAS WT KRAS N RR (%) MPFS (weeks) OS (months) BSC WT 119 0 7.3 7.6 MT 100 0 7.3 4.4 BSC + WT 124 17 12.3 8.1 Panitumumab MT 84 0 7.4 4.9
  81. 86. Chemotherapy + Panitumumab in mCRC by KRAS genotype Peeters et al. JCO 2010;28:4706-4713. (181 Study Phase III Second line) P=0.004 KRAS N RR (%) MPFS (weeks) OS (months) FOLFIRI WT 294 10 3.9 12.5 MT 248 14 4.9 11.1 FOLFIRI + WT 303 35 5.9 14.5 Panitumumab MT 238 13 5.0 11.8
  82. 87. Chemotherapy + Panitumumab in mCRC by KRAS genotype Douillard et al. JCO 2010;28:4697-4705. ( PRIME Phase III First line) WT MT KRAS N RR (%) MPFS (weeks) OS (months) FOLFOX WT 331 48 8.0 19.7 MT 219 40 8.8 19.3 FOLFOX + WT 325 55 9.6 23.9 Panitumumab MT 221 40 7.3 15.5
  83. 88. <ul><li>The EGF receptor antibodies are active only in KRAS WT CRC </li></ul><ul><li>FOLFIRI/FOLFOX + Cetuximab > FOLFIRI/FOLFOX (consistent results regarding RR,PFS,OS) in first line KRAS WT mCRC </li></ul><ul><li>FOLFOX + Panitumumab > FOLFOX (PFS) in first line KRAS WT mCRC </li></ul><ul><li>FOLFIRI + Panitumumab > FOLFIRI (PFS) in second line KRAS WT mCRC </li></ul>
  84. 89. Combination of Anti-VEGF and Anti-EGFR Treatment
  85. 90. Saltz et al. JCO 2007;25:4557-4561. N RR (%) MPFS (months) OS (months) Cetuximab + Bevacizumab 40 23 4.9 11.4 Cetuximab + Bevacizumab +Irinotecan 43 37 7.3 14.5
  86. 91. Saltz et al. JCO 2007;25:4557-4561.
  87. 92. Chemotherapy + Bevacizumab +Cetuximab mCRC Tol J. et al. NEJM 2009;360:563-572. CAIRO 2 N RR (%) MPFS (months) OS (months) CAPOX + Bevacizumab 368 50.0 10.7 20.3 CAPOX + Bevacizumab + Cetuximab 368 52.7 9.4 19.4
  88. 93. Hecht et al. JCO 2009;27:672-680. PACCE
  89. 94. Incidence (%) of grade 3-4 toxicities in studies of bevacizumab combined with cetuximab or panitumumab and chemotherapy in mCRC Rash Diarrhea GI perforation Hypertension Any Toxicity Saltz BOND-2 JCO 2007 21.0 28.0 2.3 - - Tol CAIRO 2 NEJM 2009 25.4 26.0 1.6 9.3 81.7 Hecht PACCE JCO 2009 35.6 23.8 0 5.3 90.0
  90. 95. <ul><li>Simultaneous use of the two </li></ul><ul><li>antibodies out of clinical trials </li></ul><ul><li>should be avoided! </li></ul>
  91. 96. Treatment of mCRC <ul><li>AGGRESSIVE </li></ul><ul><li>Tumor shrinkage (40%) </li></ul><ul><li>potentially resectable, symptomatic, bulky, rapid progression </li></ul><ul><li>FOLFOX or XELOX or FOLFIRI </li></ul><ul><li>FOLFOX/FOLFIRI + Cetuximab KRAS WT (PS 2?) </li></ul>
  92. 97. Treatment of mCRC <ul><li>NON AGGRESSIVE </li></ul><ul><li>Delaying progression (60%) </li></ul><ul><li>never resectable, asymptomatic, non-bulky disease, indolent </li></ul><ul><li>5-FU/CPCT + Bevacizumab </li></ul><ul><li>OXALIPLATIN combination (+Bevacizumab) </li></ul><ul><li>IRINOTECAN combination </li></ul><ul><li>FILFIRI/FOLFOX + Cetuximab (KRAS WT) </li></ul>
  93. 98. Dis Colon Rectum 2011;54:214-219

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