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

Quimioterapia A qué llegamos? 2

Fluoropirimidines en mCRC No cambio en la supervivencia mediana con diferentes esquemas Supervivencia mediana: ~ 12 meses Regimen Respuesta, % 5-FU en bolo 7-15 5-FU en infusión 20-30 5-FU/LV Mayo, Roswell Park de Gramont (LV5-FU2) AIO (cada semana, 24-hour infusion) 12-35 28-33 25-44 Capecitabina 20-25 5-FU, fluorouracil; AIO, Arbeitsgemeinschaft Internische Onkologie; LV, leucovorin. Grothey A, et al. J Clin Oncol. 2005;23:9441-9442. www.clinicaloptions.com

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

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

N9741 Resultados IFL FOLFOX IROX n 264 267 RR (%) 31 45 35 PFS (m) 6.9 8.7 6.5 OS (m) 15 19.5 17.4 p 0.0001 Primum non nocere 2 yrs post bev Goldberg et al, JCO 2004

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

BICC-C Study: FOLFIRI vs mIFL vs CapeIRI Progression-Free Survival Overall Survival FOLFIRI vs mIFL: P = .004 FOLFIRI vs mIFL: P = .09 100 FOLFIRI vs Capelri: P = .015 100 FOLFIRI vs Capelri: P = .27 mIFL vs Capelri: P = .46 mIFL vs Capelri: P = .93 75 75 FOLFIRI FOLFIRI mIFL mIFL Progression Free (%) 50 Capelri Alive (%) 50 Capelri CapeIri, capecitabine, irinotecan; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; mIFL, modified irinotecan, bolus 5-fluorouracil, leucovorin. The BICC‑C trial was designed to determine the therapeutic efficacy of bolus 5-FU plus irinotecan in metastatic colorectal cancer. The first phase of the BICC‑C trial, before antibodies were included in the regimens, showed a statistically significant improvement in progression-free survival for FOLFIRI with infusional 5-FU superior to bolus administration. Modified IFL is attractive because of its decreased toxicity, but few data exist on its use in this setting and therefore I do not suggest using this regimen. The CapeIri regimen was investigated as well but was associated with greater toxicity. Overall survival did not reach statistical significance, although this phase of the trial was ended early when bevacizumab was added to the regimen. 25 25 10 20 30 40 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.

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 5-FU, 5-fluorouracil; LV, leucovorin; OS, overall survival. This slide demonstrates Grothey’s hypothesis, also known as the 3-drug hypothesis. This graph shows what percentage of patients in various studies received all 3 drugs, including oxaliplatin, which was later approved by the FDA. These data suggest that treatment with all 3 drugs during the course of therapy extends median overall survival time. This was independent of whether first-line treatment was administered as a doublet or singlet. A caveat is that this is a retrospective analysis of many different studies and not a randomized trial. Irinotecan + oxaliplatin 14 Bolus 5-FU/LV LV5FU2 12 20 40 60 80 Patients With 3 Drugs (%) Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.

Efficacy: Sequence FOLFIRI/FOLFOX Results Arm A Arm B FOLFIRI  FOLFOX FOLFOX  FOLFIRI Patients, n 109 81 111 69 Confirmed RR, % 56 15 54 4 TTP, mos 8.5 4.2 8.0 2.5 Survival, mos 21.5 20.6 No statistically significant differences in first- or second-line therapy RR or TTP and OS FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin; OS, overall survival; RR, response rate; TTP, time to progression.   Tournigand and colleagues conducted a study that mandated the crossover from either FOLFIRI or FOLFOX at the time of progression. Results showed no significant difference in overall survival regardless of treatment arm. Therefore, clinicians must decide whether to use FOLFIRI or FOLFOX. Tournigand C, et al. J Clin Oncol. 2004;22:229-237.

FOLFOXIRI vs FOLFIRI: Trial Design FOLFOXIRI Irinotecan 165 mg/m2 Day 1 Oxaliplatin 85 mg/m2 Day 1 LV 200 mg/m2 over 2 hours Day 1 5-FU 3200 mg/m2 48-hour infusion Days 2, 3 Every 2 wks (n = 122) Patients with unresectable, previously untreated metastatic colorectal cancer (N = 244) FOLFIRI Irinotecan 180 mg/m2 Day 1 LV 100 mg/m2 over 2 hours Days 1, 2 5-FU 400 mg/m2 bolus, then 600 mg/m2 22-hour infusion Days 1, 2 Every 2 wks (n = 122) Primary endpoint: RR Stratification: study center, PS (0/1-2), adjuvant chemotherapy Falcone A, et al. ASCO 2006. Abstract 3513.

FOLFOXIRI vs FOLFIRI: Efficacy and Tolerability FOLFOXIRI, % (n = 122) FOLFIRI, % (n = 122) P Value RR Complete 7 6 < .0001* Partial 53 28 Stable disease 21 34 -- Median PFS, mos 9.8 6.9 .0006 Median OS, mos 22.8 16.7 .032 Grade 3/4 toxicity Neutropenia 50 .0008 Neurotoxicity† 20 < .0001 Diarrhea 12 .08 *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.

Quimioterapia más Bevacizumab

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 factor TGFb-1 = transforming growth factor b-1 PIGF = placenta growth factor PD-ECGF = platelet-derived endothelial cell growth factor Adapted from Folkman. Cancer. Principles and practice of oncology 2005 www.clinicaloptions.com

Bevacizumab (Avastin®): Mecanismo de Acción VEGF KEY POINT: A number of environmental, hormonal, and genetic factors can lead to VEGF overexpression. P P P P

Bevacizumab (Avastin®): Mecanismo de Acción VEGF Bevacizumab KEY POINT: A number of environmental, hormonal, and genetic factors can lead to VEGF overexpression. P P P P BLOQUEO de la activación del VEGFR

Phase III Trial With Bevacizumab Therapy in First-Line MCRC D O M I Z E Bolus IFL + placebo (n = 412) Untreated MCRC Bolus IFL + BV (n = 403) A study of 800 patients investigated the efficacy and safety of bevacizumab (BV) in combination with bolus IFL as first-line therapy for metastatic colorectal cancer. Patients were randomized to receive one of 3 treatment strategies: IFL plus placebo with no BV allowed, even after disease progression (n=412), IFL plus BV with optional BV after disease progression (n=403), or 5-FU/LV plus BV with optional BV after disease progression (n=110). IFL treatment included bolus 5-FU (500 mg/m2), LV (20 mg/m2), and irinotecan (125 mg/m2) administered on weeks 4 and 6. 5-FU/LV treatment included bolus 5-FU (500 mg/m2) and LV (500 mg/m2) administered on week 6 and 8. BV (5 mg/kg) was administered every 2 weeks. The primary endpoint for the study was duration of survival. Secondary endpoints included response rate (PR + CR), PFS, QOL, and safety. 5-FU/LV + BV (n = 110): Closed due to lack of efficacy Hurwitz. NEJM, 2004 Courtesy of: Paulo Hoff Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

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 Probability of being progression-free IFL + bevacizumab IFL + placebo Progression-free survival was also significantly increased by 71% in the IFL/bevacizumab arm (10.6 [95% CI 9.0–11.0] vs 6.2 [95% CI 5.6–7.7] months, p<0.001). The stratified HR for disease progression or death during first‑line therapy in arm 2 relative to arm 1 was 0.54 (95% CI 0.45–0.66). It is interesting to note that the difference in overall and progression-free survival between the two treatment arms is relatively constant at 4.7 and 4.4 months. Together with the study design, in which the treatment arms differed only with the addition of bevacizumab to IFL and switching to alternative first-line therapies if toxicity occurred, this suggests that the increase in survival is due to the addition of bevacizumab. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. 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

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 IFL + bevacizumab IFL + placebo Probability of survival Survival, the primary endpoint, was significantly increased by 30% in the IFL/bevacizumab arm compared with the IFL/placebo arm (20.3 [95% CI 18.5–24.2] vs 15.6 [95% CI 14.3–17.0] months, respectively; p<0.001). The HR of death for arm 2 relative to arm 1 was estimated to be 0.66 (95% CI 0.54–0.81). This corresponds to an average reduction of 34% in the risk of death in the IFL/bevacizumab arm. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. 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

Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design Initial design Amended design FOLFIRI (n=144) FOLFIRI+Bev. (n=60) mIFL (n=141) mIFL+Bev. R R (n=57) n=430 n=117 XELIRI (n=145) 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

Proportion of Subjects Who Survived Survival Time (months) Overall Survival Regimen Median OS (months) 1 Year P Value FOLFIRI+ BEV 28 87% -- mIFL + BEV 19.2 61% 0.01 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 10 20 30 40 Survival Time (months) Fuchs et al. JCO 2008 Courtesy of: Paulo Hoff

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

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) Bevacizumab therapy: increased 5.9% vs 30.6% (p<0.001) Slide taken from Arnold presentation, GICEF 2009 Addition of bevacizumab to systemic chemotherapy significantly improved OS: 23.6 vs 18.6 months (p<0.001) Renouf, et al. ASCO GI 2009

Impact of bevacizumab in mCRC: significantly improved OS 1.0 0.8 0.6 0.4 0.2 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) 6 12 18 24 30 OS (months) Bevacizumab era (2006), n=448 Pre-bevacizumab (2003–2004), n=969 Renouf, et al. ASCO GI 2009

Phase IV BRiTE Therapy in First-Line MCRC O L Untreated MCRC Bev + CT Grothey, et al. JCO 2008 Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

Phase IV BRiTE Therapy in First-Line MCRC O L PFS FOLFOX + Bev: 10 m (n=1092) Untreated MCRC Bev + CT PFS FOLFIRI + Bev: 10.4 m (n=280) Grothey, et al. JCO 2008 Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

Estimated probability 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 Bevacizumab post-PD (n=642) No bevacizumab post-PD (n=531) No treatment (n=253) Estimated probability Post-progression bevacizumab HR=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 27 27

Quimioterapia más cetuximab

Phase III MRC COIN R A N D O M I Z E XELOX/OxMdG (n = 815) Untreated MCRC XELOX/OxMdG + Cetuximab (n = 815) A study of 800 patients investigated the efficacy and safety of bevacizumab (BV) in combination with bolus IFL as first-line therapy for metastatic colorectal cancer. Patients were randomized to receive one of 3 treatment strategies: IFL plus placebo with no BV allowed, even after disease progression (n=412), IFL plus BV with optional BV after disease progression (n=403), or 5-FU/LV plus BV with optional BV after disease progression (n=110). IFL treatment included bolus 5-FU (500 mg/m2), LV (20 mg/m2), and irinotecan (125 mg/m2) administered on weeks 4 and 6. 5-FU/LV treatment included bolus 5-FU (500 mg/m2) and LV (500 mg/m2) administered on week 6 and 8. BV (5 mg/kg) was administered every 2 weeks. The primary endpoint for the study was duration of survival. Secondary endpoints included response rate (PR + CR), PFS, QOL, and safety. XELOX/OxMdG + Cetuximab (n = 815) Intermitent ESMO, 2009 Hurwitz H, Fehrebacher L, Cartwright T, et al. Presented at the American Society of Clinical Oncology Annual Meeting. June 1, 2003, Chicago, Illinois.

HR point estimate = 1.038 95% CI 0.90–1.20 p=0.68 COIN: K-ras WT OS Survival probability Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX + cetuximab) 1.00 0.75 0.50 0.25 Arm A Arm B Diff. Median OS, months 17.9 17.0 –0.92 2-year survival, % 36.1 34.4 -1.66 HR point estimate = 1.038 95% CI 0.90–1.20 p=0.68 6 12 18 24 30 36 42 Time (months) No. at risk Arm A Arm 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)

HR point estimate = 0.959 95% CI 0.84–1.09 p=0.60 COIN: K-ras WT PFS Survival probability Arm A (XELOX/FOLFOX) Arm B (XELOX/FOLFOX + cetuximab) 1.00 0.75 0.50 0.25 Arm A Arm B Diff. Median PFS, months 8.6 +0.07 HR point estimate = 0.959 95% CI 0.84–1.09 p=0.60 6 12 18 24 30 36 42 No. at risk Arm A Arm B 367 361 245 249 92 103 41 42 18 22 11 9 6 1 ITT analysis Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

Cetuximab + Chemotherapy COIN: No Significant Difference in OS, PFS Between Treatment Arms, Pt Subsets Survival Outcome, Mos Cetuximab + Chemotherapy Chemotherapy HR (95% CI) P Value Wild-type KRAS Median OS 17.0 17.9 1.038 (0.90-1.20) .68 Median PFS 8.6 0.959 (0.84-1.09) .60 All wild-type patients 19.9 20.1 1.019 (0.86-1.20) .86 9.2 8.8 0.922 (0.80-1.07) .36 Patients with mutated KRAS, NRAS, or BRAF 12.7 14.4 1.004 (0.87-1.15) .96 6.3 6.6 1.079 (0.95-1.23) .33 Maughan TS, et al. ASCO 2010. Abstract 3502.

ITT Survival: WT K-Ras (n=729) XELOX/OxMdG XELOX/OxMdG + Cetuximab HR (p value) OS (months) 17,9 17,0 1,038 (0,68) 2y OS (%) 36,1 34,4 PFS 8,6 0,95 (0,60) ESMO, 2009

COIN: K-RAS and Response All patients K-ras WT K-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 (%) 51 53 57 64 46 43 Odds ratio 1.08 (p=0.428) OR=1.35 (p=0.049) OR=0.88 (p=0.449) Maughan, et al. ECCO-ESMO 2009 (abstract No. 6LBA)

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

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 Outcome FLOX F+Cet Stop&Go-Cet PFS 7.9 8.3 7.3 RR 41% 49% 47% OS 20.4 19.7 20.3 Endpoint: PFS Randomized patients: 571 Tveit KM, ESMO 2010

TRIALS IN mCRC 1st Line treatment K-Ras status WT PH PFS OS CRYSTAL 3 FOLFIRI FOLFIRI+ CETUXIMAB P FOLFIRI + CETUXIMAB 8.4 9.9 0.0017 20 23.5 0.0094 OPUS 2 FOLFOX FOLFOX + FOLFOX + CETUXIMAB 7.2 8.3 0.006 18.5 22.8 0.3854 COIN XELOX/ XELOX/FOLFOX+CETUXIMAB XELOX/FOLFOX + CETUXIMAB 8.6 0.6 17.9 17 0.68 NORDIC FLOX FLOX + CETUXIMAB 7.9 0.3 20.4 19.7 0.30

mCRC with progression after 1st line fluoropyirimidine and Oxaliplatin 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

Cetuximab + Irinotecan vs Irinotecan in 2nd line - EPIC Cet + Iri (n=648) Iri (n=650) P value RR 16.4% 4.2% P<0.05 PFS 4 months 2.6 months P<0.005 OS 10.7 m 10 m P=0.71 Sobrero AF. J Clin Oncol. 26: 2311-2319, 2008

Cetuximab versus BSC Cetuximab + BSC 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 Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23-30.

NCIC CTG C0.17: Overall Survival in K-ras Wild-Type Patients 0.2 0.4 0.6 0.8 1 2 4 6 8 10 12 14 16 18 Time from Randomization (Months) Proportion Alive Cetuximab BSC Study arm MS (months) 95% CI Cetuximab + BSC 9.5 7.7 – 10.3 BSC alone 4.8 4.2 – 5.5 HR 0.55 95% CI (0.41,0.74) Log rank p-value: <0.0001 Cetuximab BSC 117 108 95 81 52 34 20 9 6 2 113 92 69 36 24 17 12 5 3 Courtesy of: Paulo Hoff Karapetis C et al, New Engl J Med 2008

Continuum of care 42

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 Chemotherapy- free interval* mFOLFOX7 6 cycles mFOLFOX7: oxaliplatin, 100 mg/m2 Day 1; leucovorin, 400 mg/m2 Day 1; 5-fluorouracil 48-hour continuous infusion, 3000 mg/m2 Days 1-2; every 2 wks s5-FU/LV2: 5-fluorouracil 400 mg/m2 bolus Day 1, then 3000 mg/m2 48-hour continuous infusion Days 1-2; leucovorin, 400 mg/m2 Day 1; every 2 wks 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.

OPTIMOX2: DDC and PFS No difference observed in duration of disease control between study arms Longer median PFS with OPTIMOX1 regimen Results, mos OPTIMOX1 OPTIMOX2 P Value DDC 12.9 11.7 .41 Median PFS 8.7 6.9 .009 DDC, duration of disease control; PFS, progression-free survival Maindrault-Goebel F, et al. ASCO 2006. Abstract 3504.

Alternating vs Continuous FOLFIRI Continuous FOLFIRI Every 2 wks for 6 mos (n = 168) Patients with advanced colorectal cancer without prior chemotherapy in the advanced setting (N = 331) Alternating FOLFIRI Every 2 wks, 2 mos (n = 163) Alternating FOLFIRI Every 2 wks, 2 mos OS, overall survival; PD, progressive disease Alternating FOLFIRI; Irinotecan 180 mg/m2 Day 1, LV 100 mg/m2 over 2 hours Days 1, 2, 5-FU 400 mg/m2 bolus, then 600 mg/m2 22 hour infusion Days 1,2, every 2 wks, 2 mos on 2 mos off Continuous FOLFIRI; Irinotecan 180 mg/m2 Day 1, LV 100 mg/m2 over 2 hours Days 1, 2, 5-FU 400 mg/m2 bolus, then 600 mg/m2 22 hour infusion Days 1,2, every 2 wks for 6 mos No treatment 2 mos Evaluation for PD 2 mos from randomization, then every 4 mos thereafter Primary endpoint: OS Labianca R, et al. ASCO 2006. Abstract 3505.

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 Results, mos A-FOLFIRI C-FOLFIRI HR (5% CI) Median PFS 6.2 6.5 1.01 (0.78-1.27) Median OS 16.9 17.6 1.03 (0.78-1.35) A-FOLFIRI, alternating FOLFIRI; C-FOLFIRI, continuous FOLFIRI Labianca R, et al. ASCO 2006. Abstract 3505.

MACRO: Maintenance Bev vs Continued Bev + XELOX in Patients With mCRC XELOX + Bevacizumab (n = 239) Induction Therapy XELOX + Bevacizumab 6 cycles Patients with previously untreated mCRC (N = 480) Disease progression, severe toxicity, or consent withdrawal 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.

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 Outcome Bevacizumab (n = 241) XELOX/ Bevacizumab (n = 239) HR (95% CI) OR Median PFS,* mos 9.7 10.4 1.11 (0.89-1.37) -- Median OS,* mos 21.7 23.4 1.04 (0.81-1.32) Confirmed objective response, % 49 46 0.89 (0.62-1.27) *Median follow-up: 20.4-21.1 mos. Tabernero J, et al. ASCO 2010. Abstract 3501.

Estimated probability 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 Bevacizumab post-PD (n=642) No bevacizumab post-PD (n=531) No treatment (n=253) Estimated probability Post-progression bevacizumab HR=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 49 49

Advanced/mCRC Patients Can Tolerate Intensive Therapy Primera línea Segunda línea Tercera línea FOLFOX ± bevacizumab CapeOx ± bevacizumab FOLFIRI + bevacizumab FOLFIRI ± cetuximab* 5-FU/leucovorin + bevacizumab FOLFOXIRI (2B) FOLFIRI Irinotecan FOLFOX CapeOx Irinotecan + cetuximab*† Irinotecan → Irinotecan + cetuximab*† Clinical trial BSC BSC, best supportive care; CapeOx, capecitabine/oxaliplatin; FOLFIRI, 5-fluorouracil/leucovorin/irinotecan; FOLFOX, 5-fluorouracil/leucovorin/oxaliplatin; FOLFOXIRI, 5-fluorouracil/leucovorin/oxaliplatin/irinotecan; 5-FU, 5-fluorouracil.   The complexity of the 2010 National Comprehensive Cancer Network (NCCN) guidelines reflects the complexity of the decision you just made. Several options are available, including FOLFOX or FOLFIRI as the backbone with bevacizumab or cetuximab, CapeOX as a backbone, or 5-fluorouracil/leucovorin with bevacizumab. The NCCN would also allow for FOLFOX plus irinotecan (FOLFOXIRI), a multidrug combination therapy that has been tested in a few small studies. Second-line and third-line options include cetuximab with irinotecan or oxaliplatin-based therapies. The NCCN guidelines note that panitumumab should not be used in combination whereas cetuximab can be used in combination. Recent data also support the use of panitumumab in combination regimens. The asterisks  on this slide highlight an important development: Only patients with wild-type KRAS should be treated with anti-EGFR antibodies (cetuximab or panitumumab). *KRAS no mutado. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V1.2010.

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

Conclusiones FU / Iri / Ox en algún momento de la enfermedad 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)