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“Continuum of care” en cáncer de colon metastásico no curable

“Continuum of care” en cáncer de colon metastásico no curable . Mauricio Lema Medina MD Clínica de Oncología Astorga – Clínica SOMA – Medicáncer Medellín, Colombia. Quimioterapia. A qué llegamos?. Fluoropirimidines en mCRC. No cambio en la supervivencia mediana con diferentes esquemas

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“Continuum of care” en cáncer de colon metastásico no curable

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  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. Fluoropirimidines en mCRC • No cambio en la supervivencia mediana con diferentes esquemas • Supervivencia mediana: ~ 12 meses Grothey A, et al. J Clin Oncol. 2005;23:9441-9442. www.clinicaloptions.com

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

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

  6. N9741 Resultados Goldberg et al, JCO 2004

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

  8. BICC-C Study: FOLFIRI vs mIFL vs CapeIRI Progression-Free Survival Overall Survival FOLFIRI vs mIFL: P = .004 FOLFIRI vs mIFL: P = .09 100 100 FOLFIRI vs Capelri: P = .015 FOLFIRI vs Capelri: P = .27 mIFL vs Capelri: P = .46 mIFL vs Capelri: P = .93 75 75 FOLFIRI FOLFIRI mIFL mIFL 50 50 Progression Free (%) Alive (%) Capelri Capelri 25 25 0 0 0 10 20 30 40 0 10 20 30 40 50 Months Months 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. Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.

  9. Access to Chemotherapy Improves Survival 22 First-line therapy Infusional 5-FU/LV+ irinotecan 20 Infusional 5-FU/LV+ oxaliplatin 18 Median OS (Mos) Bolus 5-FU/LV+ irinotecan 16 Irinotecan+ oxaliplatin 14 Bolus 5-FU/LV LV5FU2 12 0 20 40 60 80 Patients With 3 Drugs (%) Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.

  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.

  11. FOLFOXIRI vs FOLFIRI: Trial Design FOLFOXIRIIrinotecan 165 mg/m2 Day 1Oxaliplatin 85 mg/m2 Day 1LV 200 mg/m2 over 2 hours Day 15-FU 3200 mg/m2 48-hour infusion Days 2, 3Every 2 wks (n = 122) Patients with unresectable, previously untreated metastatic colorectal cancer (N = 244) FOLFIRIIrinotecan 180 mg/m2 Day 1LV 100 mg/m2 over 2 hours Days 1, 25-FU 400 mg/m2 bolus, then 600 mg/m2 22-hour infusion Days 1, 2Every 2 wks (n = 122) Primary endpoint: RR Stratification: study center, PS (0/1-2), adjuvant chemotherapy Falcone A, et al. ASCO 2006. Abstract 3513.

  12. FOLFOXIRI vs FOLFIRI: Efficacy and Tolerability *External review; 95% CI for overall response: 0.25-0.43 for FOLFIRI, 0.51-0.68 for FOLFOXIRI.†Includes grade 2 events. Falcone A, et al. ASCO 2006. Abstract 3513.

  13. Quimioterapia más Bevacizumab

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

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

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

  17. Phase III Trial With Bevacizumab Therapy in First-Line MCRC R A N D O M I Z E Bolus IFL + placebo (n = 412) Untreated MCRC Bolus IFL + BV (n = 403) 5-FU/LV + BV (n = 110): Closed due to lack of efficacy Hurwitz. NEJM, 2004 Courtesy of: Paulo Hoff

  18. Phase III Trial : PFS 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 1.0 0.8 0.6 0.4 0.2 0 IFL + bevacizumab IFL + placebo Probability of being progression-free 6.2 10.6 0 10 20 30 PFS (months) Hurwitz H et al. N Engl J Med 2004;350:2335–42 Courtesy of: Paulo Hoff

  19. Phase III Trial: Survival 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 1.0 0.8 0.6 0.4 0.2 0 IFL + bevacizumab IFL + placebo Probability of survival 15.6 20.3 0 10 20 30 40 Survival (months) Hurwitz H et al. N Engl J Med 2004;350:2335–42 Courtesy of: Paulo Hoff

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

  21. Overall Survival 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Survived 0.5 0.4 0.3 FOLFIRI + Bevacizumab mIFL + Bevacizumab 0.2 0.1 0 0 10 20 30 40 Survival Time (months) Fuchs et al. JCO 2008 Courtesy of: Paulo Hoff

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

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

  24. Impact of bevacizumab in mCRC: significantly improved OS 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab era (2006)30.6% received bevacizumab Estimated probability Pre-bevacizumab (2003–2004)5.9% received bevacizumab p<0.001 Bevacizumab + standard chemotherapy significantly improved OS:23.6 vs 18.6 months (p<0.001) 0 6 12 18 24 30 OS (months) Bevacizumab era (2006), n=448Pre-bevacizumab (2003–2004), n=969 Renouf, et al. ASCO GI 2009

  25. Phase IV BRiTETherapy in First-Line MCRC E N R O L L Untreated MCRC Bev + CT Grothey, et al. JCO 2008

  26. Phase IV BRiTETherapy in First-Line MCRC PFS FOLFOX + Bev: 10 m (n=1092) E N R O L L Untreated MCRC Bev + CT PFS FOLFIRI + Bev: 10.4 m (n=280) Grothey, et al. JCO 2008

  27. BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death) Post-progression therapy 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab post-PD (n=642)No bevacizumab post-PD (n=531) No treatment (n=253) Estimated probability Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57) p<0.001 12.6 19.9 31.8 0 5 10 15 20 25 30 35 OS (months) Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008 *Non-randomised, observational trial

  28. Quimioterapia más cetuximab

  29. Phase III MRC COIN R A N D O M I Z E XELOX/OxMdG (n = 815) Untreated MCRC XELOX/OxMdG + Cetuximab (n = 815) XELOX/OxMdG + Cetuximab (n = 815) Intermitent ESMO, 2009

  30. COIN: K-ras WT OS Survival probability Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX + cetuximab) 1.00 0.75 0.50 0.25 0 HR point estimate = 1.03895% CI 0.90–1.20p=0.68 0 6 12 18 24 30 36 42 Time (months) No. at riskArm AArm B 367 362 316 306 250 238 154 149 83 80 44 42 19 17 1 3 ITT analysis Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

  31. COIN: K-ras WT PFS Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX + cetuximab) Survival probability 1.00 0.75 0.50 0.25 0 HR point estimate = 0.95995% CI 0.84–1.09p=0.60 6 12 18 24 30 36 42 0 No. at riskArm A Arm B 367 361 245 249 92 103 41 42 18 22 11 9 6 6 1 0 ITT analysis Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

  32. COIN: No Significant Difference in OS, PFS Between Treatment Arms, Pt Subsets Maughan TS, et al. ASCO 2010. Abstract 3502.

  33. ITT Survival: WT K-Ras (n=729) ESMO, 2009

  34. COIN: K-RAS and Response Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

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

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

  37. TRIALS IN mCRC 1st Line treatmentK-Ras status WT

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

  39. Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008

  40. Cetuximab versus BSC R A N D O M I Z E Cetuximab + BSC (287) Metastatic colorectal cancer with prior 5-FU, irinotecan and oxaliplatin (572 pts) BSC (285) Jonker et al. NEJM 2007; 357: 2040 Courtesy of: Paulo Hoff

  41. 1 0.8 0.6 Proportion Alive 0.4 0.2 Cetuximab BSC 0 0 2 4 6 8 10 12 14 16 18 Time from Randomization (Months) Cetuximab 117 108 95 81 52 34 20 9 6 2 113 92 69 36 24 17 12 5 3 BSC 3 NCIC CTG C0.17: Overall Survival in K-ras Wild-Type Patients HR 0.5595% CI (0.41,0.74) Log rank p-value: <0.0001 Courtesy of: Paulo Hoff Karapetis C et al, New Engl J Med 2008

  42. Continuum of care

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

  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.

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

  46. Alternating vs Continuous FOLFIRI in Advanced Colorectal Cancer (cont’d) • Alternating FOLFIRI not inferior to continuous FOLFIRI in terms of PFS and OS • Median follow-up: 30 months Labianca R, et al. ASCO 2006. Abstract 3505.

  47. MACRO: Maintenance Bev vs Continued Bev + XELOX in Patients With mCRC XELOX + Bevacizumab (n = 239) Induction Therapy XELOX + Bevacizumab 6 cycles Disease progression, severe toxicity, or consent withdrawal Patients with previously untreated mCRC (N = 480) Bevacizumab (n = 241) Maintenance cycles administered q3w: Oxaliplatin 130 mg/m2 IV on Day 1 Capecitabine 1000 mg/m2 BID PO on Days 1-14 Bevacizumab 7.5 mg/kg IV on Day 1 Tabernero J, et al. ASCO 2010. Abstract 3501.

  48. MACRO: Duration of PFS Comparable Between Bev vs XELOX + Bev *Median follow-up: 20.4-21.1 mos. Tabernero J, et al. ASCO 2010. Abstract 3501. • 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

  49. BRiTE:* continuation of bevacizumab post-first progression significantly increases OS (time from initiation of first-line treatment to death) Post-progression therapy 1.0 0.8 0.6 0.4 0.2 0 Bevacizumab post-PD (n=642)No bevacizumab post-PD (n=531) No treatment (n=253) Estimated probability Post-progression bevacizumabHR=0.48 (95% CI: 0.41–0.57) p<0.001 12.6 19.9 31.8 0 5 10 15 20 25 30 35 OS (months) Grothey, et al. ASCO 2007 (poster) Grothey, et al. JCO 2008 *Non-randomised, observational trial

  50. Advanced/mCRC Patients Can Tolerate Intensive Therapy *KRAS no mutado. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V1.2010.

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