1. “Continuum of care” en cáncer de colon metastásico no curable Mauricio Lema Medina MD Clínica de Oncología Astorga – Clínica SOMA – Medicáncer Medellín, Colombia

2. Quimioterapia A qué llegamos?

3. Page  3 Fluoropirimidines en mCRC  No cambio en la supervivencia mediana con diferentes esquemas –Supervivencia mediana: ~ 12 meses RegimenRespuesta, % 5-FU en bolo7-15 5-FU en infusión20-30 5-FU/LV  Mayo, Roswell Park  de Gramont (LV5-FU2)  AIO (cada semana, 24-hour infusion) 12-35 28-33 25-44 Capecitabina20-25 Grothey A, et al. J Clin Oncol. 2005;23:9441-9442. www.clinicaloptions.com

4. Page  4 IFL (n=264) R FOLFOX (n=267) IROX (n=264) diseño n=795 Primary endpoint: PFS IFL vs FOLFOX vs IROX (N9741) Bolo (IFL) vs infusión (FOLFOX) Goldberg et al, JCO 2004

5. Page  5 N9741: Sanoff HK. J Clin Oncol 26:5721-5727.

6. Page  6 IFLFOLFOXIROX n264267264 RR (%)314535 PFS (m)6.98.76.5 OS (m)1519.517.4 p0.0001 N9741 Resultados Goldberg et al, JCO 2004

7. Page  7 FOLFIRI (n=144) R mIFL (n=141) XELIRI (n=145) Feb 2003 – April 2004 Initial design n=430 Primary endpoint: PFS Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design * Celecoxib data not shown Fuchs et al, JCO 2008 Courtesy of: Paulo Hoff

8. BICC-C Study: FOLFIRI vs mIFL vs CapeIRI Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786. 0102030 25 50 75 100 0 40 Months Progression Free (%) FOLFIRI vs mIFL: P =.004 FOLFIRI vs Capelri: P =.015 mIFL vs Capelri: P =.46 FOLFIRI mIFL Capelri FOLFIRI vs mIFL: P =.09 FOLFIRI vs Capelri: P =.27 mIFL vs Capelri: P =.93 0102030 25 50 75 100 0 40 Months Alive (%) FOLFIRI mIFL Capelri 50 Progression-Free SurvivalOverall Survival Fuchs CS, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first- line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779- 4786. Reprinted with permission from the American Society of Clinical Oncology.

9. Access to Chemotherapy Improves Survival Grothey A, et al. J Clin Oncol. 2005;23:9441-9442. 22 20 18 16 14 12 Median OS (Mos) 020406080 Patients With 3 Drugs (%) LV5FU2 Bolus 5-FU/LV Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin First-line therapy

10. Page  10 Efficacy: Sequence FOLFIRI/FOLFOX No statistically significant differences in first- or second-line therapy RR or TTP and OS Tournigand C, et al. J Clin Oncol. 2004;22:229-237. Results Arm AArm B FOLFIRI  FOLFOXFOLFOX  FOLFIRI Patients, n1098111169 Confirmed RR, %5615544 TTP, mos8.54.28.02.5 Survival, mos21.520.6

11. FOLFOXIRI vs FOLFIRI: Trial Design Patients with unresectable, previously untreated metastatic colorectal cancer (N = 244) Falcone A, et al. ASCO 2006. Abstract 3513. Primary endpoint: RR Stratification: study center, PS (0/1-2), adjuvant chemotherapy FOLFOXIRI Irinotecan 165 mg/m 2 Day 1 Oxaliplatin 85 mg/m 2 Day 1 LV 200 mg/m 2 over 2 hours Day 1 5-FU 3200 mg/m 2 48-hour infusion Days 2, 3 Every 2 wks (n = 122) FOLFIRI Irinotecan 180 mg/m 2 Day 1 LV 100 mg/m 2 over 2 hours Days 1, 2 5-FU 400 mg/m 2 bolus, then 600 mg/m 2 22-hour infusion Days 1, 2 Every 2 wks (n = 122)

12. FOLFOXIRI vs FOLFIRI: Efficacy and Tolerability FOLFOXIRI, % (n = 122) FOLFIRI, % (n = 122) P Value RR Complete76 <.0001* Partial5328 Stable disease2134-- Median PFS, mos9.86.9.0006 Median OS, mos22.816.7.032 Grade 3/4 toxicity Neutropenia5028.0008 Neurotoxicity † 200<.0001 Diarrhea2012.08 Falcone A, et al. ASCO 2006. Abstract 3513. * External review; 95% CI for overall response: 0.25-0.43 for FOLFIRI, 0.51-0.68 for FOLFOXIRI. † Includes grade 2 events.

13. Quimioterapia más Bevacizumab

14. Page  14 Adapted from Folkman. Cancer. Principles and practice of oncology 2005 VEGF es expresado durante toda la historia natural bFGF = basic fibroblast growth factor TGF  -1 = transforming growth factor  -1 PIGF = placenta growth factor PD-ECGF = platelet-derived endothelial cell growth factor PIGF PD-ECGF Pleiotrophin bFGF TGF  -1 bFGF TGF  -1 bFGF Evolución tumoral TGF  -1 PIGF PD-ECGF bFGF TGF  -1 VEGF www.clinicaloptions.com

15. Page  15 Bevacizumab (Avastin®): Mecanismo de Acción P P P P VEGF Bevacizumab

16. Page  16 VEGF Bevacizumab P P P P BLOQUEO de la activación del VEGFR Bevacizumab (Avastin®): Mecanismo de Acción

17. Page  17 Phase III Trial With Bevacizumab Therapy in First-Line MCRC Bolus IFL + BV (n = 403) 5-FU/LV + BV (n = 110): Closed due to lack of efficacy Bolus IFL + placebo (n = 412) Hurwitz. NEJM, 2004 RANDOMIZE UntreatedMCRC Courtesy of: Paulo Hoff

18. Page  18 Median PFS (months) IFL + placebo: 6.2 (95% CI: 5.6–7.7) IFL + bevacizumab: 10.6 (95% CI: 9.0–1.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001 Probability of being progression-free 1.0 0.8 0.6 0.4 0.2 0 0102030 PFS (months) 6.2 10.6 IFL + bevacizumab IFL + placebo Phase III Trial : PFS Hurwitz H et al. N Engl J Med 2004;350:2335–42 Courtesy of: Paulo Hoff

19. Page  19 Median survival (months) IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs IFL + bevacizumab: 20.3 (95% CI: 18.5–24.2) HR=0.66 (95% CI: 0.54–0.81) p<0.001 Probability of survival 1.0 0.8 0.6 0.4 0.2 0 010203040 Survival (months) IFL + bevacizumab IFL + placebo 15.6 20.3 Hurwitz H et al. N Engl J Med 2004;350:2335–42 Phase III Trial: Survival Courtesy of: Paulo Hoff

20. Page  20 FOLFIRI (n=144) R mIFL (n=141) XELIRI (n=145) Feb 2003 – April 2004 Initial design n=430 FOLFIRI+Bev. mIFL+Bev. (n=60) (n=57) May 2004 – Dec 2004 n=117 Primary endpoint: PFS Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design Protocol amended due to approval of bevacizumab Amended design R * Celecoxib data not shown Fuchs et al, JCO 2008 Courtesy of: Paulo Hoff

21. Page  21 Overall Survival Survival Time (months) Regimen Median OS (months)1 YearP Value FOLFIRI+ BEV2887%-- mIFL + BEV19.261%0.01 Proportion of Subjects Who Survived FOLFIRI + Bevacizumab mIFL + Bevacizumab 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 010204030 Fuchs et al. JCO 2008 Courtesy of: Paulo Hoff

22. Page  22 Phase III Trial of Bevacizumab + Panitumumab-CT With Bev-CT in CRC (PACCE) Hecht JR, et al. JCO 2008

23. Page  23 Impact of bevacizumab on OS in mCRC: a population-based study Renouf, et al. ASCO GI 2009 Patients with mCRC (n=1,417): 2003–2004 (pre-bevacizumab) versus 2006 (post-bevacizumab) Proportion of patients receiving Addition of bevacizumab to systemic chemotherapy significantly improved OS: 23.6 vs 18.6 months (p<0.001) Irinotecan or oxaliplatin and 5-FU: no change (p=0.68) Anti-EGFR therapy: no change (p=0.63) Bevacizumab therapy: increased 5.9% vs 30.6% (p<0.001)

24. Page  24 Estimated probability 1.0 0.8 0.6 0.4 0.2 0 06121824 Bevacizumab era (2006) 30.6% received bevacizumab Pre-bevacizumab (2003–2004) 5.9% received bevacizumab p<0.001 OS (months) Renouf, et al. ASCO GI 2009 30 Bevacizumab era (2006), n=448 Pre-bevacizumab (2003–2004), n=969 Bevacizumab + standard chemotherapy significantly improved OS: 23.6 vs 18.6 months (p<0.001) Impact of bevacizumab in mCRC: significantly improved OS

25. Page  25 Phase IV BRiTE Therapy in First-Line MCRC Bev + CT ENROLL UntreatedMCRC Grothey, et al. JCO 2008

26. Page  26 Phase IV BRiTE Therapy in First-Line MCRC Bev + CT ENROLL UntreatedMCRC Grothey, et al. JCO 2008 PFS FOLFIRI + Bev: 10.4 m (n=280) PFS FOLFOX + Bev: 10 m (n=1092)

27. Page  27 BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death) Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008 *Non-randomised, observational trial OS (months) 12.619.931.8 Post-progression bevacizumab HR=0.48 (95% CI: 0.41–0.57) 05101520253035 1.0 0.8 0.6 0.4 0.2 0 Estimated probability p<0.001 Post-progression therapy Bevacizumab post-PD (n=642) No bevacizumab post-PD (n=531) No treatment (n=253)

28. Quimioterapia más cetuximab

29. Page  29 Phase III MRC COIN XELOX/OxMdG + Cetuximab (n = 815) XELOX/OxMdG + Cetuximab (n = 815) Intermitent XELOX/OxMdG ESMO, 2009 RANDOMIZE UntreatedMCRC

30. Page  30 COIN: K-ras WT OS 1.00 0.75 0.50 0.25 0 Survival probability Time (months) 06121824303642 No. at risk Arm A Arm B 367 362 316 306 250 238 154 149 83 80 44 42 19 17 1313 ITT analysisMaughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA) Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX + cetuximab) Arm AArm BDiff. Median OS, months 17.917.0–0.92 2-year survival, % 36.134.4-1.66 HR point estimate = 1.038 95% CI 0.90–1.20 p=0.68

31. Page  31 1.00 0.75 0.50 0.25 0 Survival probability COIN: K-ras WT PFS ITT analysis No. at risk Arm A Arm B 0 367 361 245 249 92 103 41 42 18 22 11 9 6666 1010 Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA) Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX + cetuximab) Arm AArm BDiff. Median PFS, months 8.6 +0.07 HR point estimate = 0.959 95% CI 0.84–1.09 p=0.60 6121824303642

32. Page  32 COIN: No Significant Difference in OS, PFS Between Treatment Arms, Pt Subsets Survival Outcome, Mos Cetuximab + Chemotherapy ChemotherapyHR (95% CI)P Value Wild-type KRAS  Median OS17.017.91.038 (0.90-1.20).68  Median PFS8.6 0.959 (0.84-1.09).60 All wild-type patients  Median OS19.920.11.019 (0.86-1.20).86  Median PFS9.28.80.922 (0.80-1.07).36 Patients with mutated KRAS, NRAS, or BRAF  Median OS12.714.41.004 (0.87-1.15).96  Median PFS6.36.61.079 (0.95-1.23).33 Maughan TS, et al. ASCO 2010. Abstract 3502.

33. Page  33 ITT Survival: WT K-Ras (n=729) XELOX/OxMdGXELOX/OxMdG + Cetuximab HR (p value) OS (months) 17,917,01,038 (0,68) 2y OS (%) 36,134,4 PFS (months) 8,6 0,95 (0,60) ESMO, 2009

34. Page  34 Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA) COIN: K-RAS and Response All patientsK-ras WTK-ras MT FOLFOX/ XELOX (n=815) Cetuximab + FOLFOX/ XELOX (n=815) FOLFOX/ XELOX (n=367) Cetuximab + FOLFOX/ XELOX (n=362) FOLFOX/ XELOX (n=268) Cetuximab + FOLFOX/ XELOX (n=297) Best overall response (%) 515357644643 Odds ratio1.08 (p=0.428)OR=1.35 (p=0.049)OR=0.88 (p=0.449)

35. Page  35 NORDIC VII: Cetuximab in First Line mCRC Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W) Nordic FLOX + Cetuximab mCRC Endpoint: PFS Randomized patients: 571 R Tveit KM, ESMO 2010 Nordic FLOX stop & go + Cetuximab

36. Page  36 NORDIC VII: Cetuximab in First Line mCRC Nordic FLOX (FU 500 mg/m2 + LV 60 mg/m2, d1,2 Q2W) Nordic FLOX + Cetuximab mCRC Endpoint: PFS Randomized patients: 571 R Tveit KM, ESMO 2010 Nordic FLOX stop & go + Cetuximab OutcomeFLOXF+CetStop&Go-Cet PFS7.98.37.3 RR41%49%47% OS20.419.720.3

37. Page  37 TRIALS IN mCRC 1st Line treatment K-Ras status WT TRIALPHPFSOS CRYSTAL3 FOLFIRI FOLFIRI+ CETUXIMAB PFOLFIRI FOLFIRI + CETUXIMAB P 8.49.90.00172023.50.0094 OPUS2 FOLFOX FOLFOX + CETUXIMAB PFOLFOX FOLFOX + CETUXIMAB P 7.28.30.00618.522.80.3854 COIN3 XELOX/ FOLFOX XELOX/FOLFOX +CETUXIMAB P XELOX/ FOLFOX XELOX/FOLFOX + CETUXIMAB P 8.6 0.617.9170.68 NORDIC3 FLOX FLOX + CETUXIMAB PFLOX FLOX + CETUXIMAB P 7.98.30.320.419.70.30

38. Page  38 EPIC: Cetuximab + Irinotecan after Fluoropyrimidine + Oxaliplatin failure Cetuximab 400 mg/m 2 initial dose cycle 1, wk 1, 250 mg/m 2 weekly Irinotecan 350 mg/m2 (n=648) Irinotecan (n=650) mCRC with progression after 1 st line fluoropyirimidine and Oxaliplatin (n=1298) Primary endpoint: Overall survival R Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008

39. Page  39 Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC Cet + Iri (n=648) Iri (n=650) P value RR16.4%4.2%P<0.05 PFS4 months2.6 monthsP<0.005 OS10.7 m10 mP=0.71 Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008

40. Page  40 Cetuximab versus BSC BSC (285) Cetuximab + BSC (287) Jonker et al. NEJM 2007; 357: 2040 RANDOMIZERANDOMIZE Metastatic colorectal cancer with prior 5-FU, irinotecan and oxaliplatin (572 pts) Courtesy of: Paulo Hoff

41. Page  41 NCIC CTG C0.17: Overall Survival in K-ras Wild-Type Patients HR 0.55 95% CI (0.41,0.74) Log rank p-value: <0.0001 Study armMS (months)95% CI Cetuximab + BSC9.5 7.7 – 10.3 BSC alone4.8 4.2 – 5.5 Karapetis C et al, New Engl J Med 2008 0 0.2 0.4 0.6 0.8 1 024681012141618 Time from Randomization (Months) Proportion Alive Cetuximab BSC Cetuximab BSC 1171089581523420962 1139269362417125 3 3 Courtesy of: Paulo Hoff

42. Continuum of care

43. OPTIMOX2: Study Design Patients with metastatic colorectal cancer (N = 202) Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504. Until progression OPTIMOX1 (n = 100) OPTIMOX2 (n = 102) Started before tumor progression reached baseline measurements Chemotherapy- free interval* mFOLFOX7 6 cycles s5-FU/LV2 mFOLFOX7 6 cycles mFOLFOX7 6 cycles mFOLFOX7 6 cycles Primary endpoint: duration of disease control (DDC) *Median duration: 20 weeks

44. OPTIMOX2: DDC and PFS  No difference observed in duration of disease control between study arms  Longer median PFS with OPTIMOX1 regimen Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504. Results, mosOPTIMOX1OPTIMOX2P Value DDC12.911.7.41 Median PFS8.76.9.009

45. Alternating vs Continuous FOLFIRI Labianca R, et al. ASCO 2006. Abstract 3505. Evaluation for PD 2 mos from randomization, then every 4 mos thereafter Primary endpoint: OS Patients with advanced colorectal cancer without prior chemotherapy in the advanced setting (N = 331) No treatment 2 mos Continuous FOLFIRI Every 2 wks for 6 mos (n = 168) Alternating FOLFIRI Every 2 wks, 2 mos (n = 163) Alternating FOLFIRI Every 2 wks, 2 mos

46. Alternating vs Continuous FOLFIRI in Advanced Colorectal Cancer (cont’d) Labianca R, et al. ASCO 2006. Abstract 3505.  Alternating FOLFIRI not inferior to continuous FOLFIRI in terms of PFS and OS –Median follow-up: 30 months Results, mosA-FOLFIRIC-FOLFIRIHR (5% CI) Median PFS6.26.51.01 (0.78-1.27) Median OS16.917.61.03 (0.78-1.35)

47. XELOX + Bevacizumab (n = 239) Bevacizumab (n = 241) Patients with previously untreated mCRC (N = 480) Maintenance cycles administered q3w: Oxaliplatin 130 mg/m 2 IV on Day 1 Capecitabine 1000 mg/m 2 BID PO on Days 1-14 Bevacizumab 7.5 mg/kg IV on Day 1 Induction Therapy XELOX + Bevacizumab 6 cycles Disease progression, severe toxicity, or consent withdrawal Tabernero J, et al. ASCO 2010. Abstract 3501. MACRO: Maintenance Bev vs Continued Bev + XELOX in Patients With mCRC

48. MACRO: Duration of PFS Comparable Between Bev vs XELOX + Bev  No significant difference between treatment arms in any efficacy outcome  Noninferiority of bevacizumab vs XELOX + bevacizumab cannot be confirmed –The median PFS HR 95% CI (0.89-1.37) beyond the planned noninferiority limit of 1.32 OutcomeBevacizumab (n = 241) XELOX/ Bevacizumab (n = 239) HR (95% CI) OR (95% CI) Median PFS,* mos9.710.41.11 (0.89-1.37) -- Median OS,* mos21.723.41.04 (0.81-1.32) -- Confirmed objective response, % 4946--0.89 (0.62-1.27) *Median follow-up: 20.4-21.1 mos. Tabernero J, et al. ASCO 2010. Abstract 3501.

49. Page  49 BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death) Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008 *Non-randomised, observational trial OS (months) 12.619.931.8 Post-progression bevacizumab HR=0.48 (95% CI: 0.41–0.57) 05101520253035 1.0 0.8 0.6 0.4 0.2 0 Estimated probability p<0.001 Post-progression therapy Bevacizumab post-PD (n=642) No bevacizumab post-PD (n=531) No treatment (n=253)

50. Advanced/mCRC Patients Can Tolerate Intensive Therapy Primera líneaSegunda líneaTercera línea FOLFOX ± bevacizumab CapeOx ± bevacizumab FOLFIRI + bevacizumab FOLFIRI ± cetuximab* 5-FU/leucovorin + bevacizumab FOLFOXIRI (2B) FOLFIRI Irinotecan FOLFOX CapeOx Irinotecan + cetuximab* † FOLFOX CapeOx Irinotecan → Irinotecan + cetuximab* † Clinical trial BSC *KRAS no mutado. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V1.2010.

51. Page  51 FOLFOX + Bevacizumab 6 meses “Continuum of care” Bevacizumab Hasta progresión 1 o línea FOLFIRI + Bevacizumab 6 meses Fluoruracilo + Bevacizumab Hasta progresión 2 o línea Cetuximab +/- Irinotecán Mitomicina-FU Hasta progresión ≥3 o línea Hasta progresión Tabernero J, et al. ASCO 2010. Abstract 3501. Grothey A, et al. JCO Nov 20, 2008:5326-5334 Cunningham D, et al. N Engl J Med 2004;351:337-45.

52. Conclusiones  Debe recibir Irinotecán, Oxaliplatino y Fluoruracilo…  Bevacizumab + QT en primera línea metastásica  Cetuximab +/- Irinotecán en última línea  Disminución de intensidad (y toxicidad) es válida (sábados)  Suspender el tratamiento: disminuye la supervivencia (domingos)