Cáncer Colorrectal. P. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón de Madrid

Transcripción

1 Cáncer Colorrectal P. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón de Madrid

2 Metastatic Colorectal Cancer

3 «A continuum of care» 5FU, cape, TAS 102, oxaliplatino, irinotecan Treatment is a continuum of care, as many patients progress through multiple lines of therapy 30 months overall survival PFS 10 months 6 months 3 months few months Bevacizumab Panitumumab, cetu aflibercept, ramucirumab regorafenib Van Cutsem E. ESMO consensus guidelines for management of patients with mcrc. Annals of oncology 0:1-37, 2016.

4 Resultados de los ensayos fase III con inhibidores de EGFR Trial Fluoropyrimidine Irinotecan or oxaliplatin Significant improvement in EGFR inhibitor RR PFS OS CRYSTAL Inf + bolus 5-FU Irinotecan Cetuximab COIN Inf + bolus 5-FU Oxaliplatin Cetuximab + + Capecitabine Oxaliplatin Cetuximab NORDIC Bolus 5-FU Oxaliplatin Cetuximab PRIME Inf + bolus 5-FU Oxaliplatin Panitumumab Grothey & Lenz. J Clin Oncol 2012

5 Resultados de los ensayos fase III con Bevacizumab en primera línea de CCRm Regimen Tx line N Post-study therapy ORR (%) Median Median PFS OS (months) (months) Dobletes IFL 2L: ~50% IFL + bevacizumab 1 1L 813 2L: ~50% 35 45* * * XELOX/FOLFOX 2L: 53% XELOX/FOLFOX + bevacizumab 2 1L 1,401 2L: 46% * Monoterapia Capecitabine 68% Capecitabine + bevacizumab 3 1L % * Capecitabine 37% Capecitabine + bevacizumab 4 1L % 10 19* * *Statistically significant difference vs the control arm NR = not reported 1. Hurwitz, et al. NEJM 2004; 2. Saltz, et al. JCO 2008; 3. Tebbutt, et al. JCO Cunningham, et al. ASCO GI 2013; Falcone NE Med 2014

6 Selección de Tratamiento Biomarcadores Caracteristicas del paciente Edad PS Comorbilidades QT adyuvante Marcadores Clínicos Marcadores Moleculares Grado histológico CEA MSI KRAS NRAS BRAF Características Tumorales Volumen tumoral - Posible cirugía rescate - Síntomas y agresividad - Localización Factores socioeconómicos y preferencias del paciente Calidad de vida Perfil de toxicidad

7 Selección de Tratamiento Edad PS Comorbilidades Volumen tumoral - Posible cirugía rescate - Síntomas y agresividad Marcadores Clínicos Localización tumoral Factores socioeconómicos y preferencias del paciente Marcadores Moleculares Grado histológico CEA MSI KRAS NRAS BRAF

8 Marcadores moleculares

9 Mutaciones RAS KRAS exon 2 wild-type (2008) KRAS Exon 2 KRAS codon 13 mutant Extended RAS wild-type (2014) NRAS Exon 3 mutant NRAS Exon 2 mutant KRAS Exon 4 mutant NRAS Exon 4 mutant KRAS codon 12 mutant KRAS wild-type KRAS Exon 3 mutant KRAS codon 13 mutant RAS wild-type KRAS codon 12 mutant

10 OS estimate CRYSTAL study: OS KRAS exon 2 wt population 1 RAS wt population Cetuximab + FOLFIRI (n=316) FOLFIRI (n=350) 1.0 Cetuximab + FOLFIRI (n=178) FOLFIRI (n=189) HR 0.79 p= HR 0.69 p= Months Months Adapted from 1. Van Cutsem E, et al. J Clin Oncol 2011;29: and 2.Ciardiello F, et al. ASCO 2014 (Abstract No. 3506)

11 Proportion alive (%) Proportion alive (%) PRIME study: OS WT KRAS exon 2 1 WT RAS HR = 0.83 (95% CI, ) P = HR = 0.78 (95% CI, ) P = Months Months Panitumumab + FOLFOX4 (n = 325) Events n (%) Median (95% CI) months 165 (51) 23.9 ( ) FOLFOX4 (n = 331) 190 (57) 19.7 ( ) Panitumumab + FOLFOX4 (n = 259) Events n (%) Median (95% CI) months 128 (49) 26.0 ( ) FOLFOX4 (n = 253) 148 (58) 20.2 ( ) 1. Douillard JY, et al. J Clin Oncol 2010;28: ; 2. Douillard JY, et al. N Engl J Med 2013; 369: WT RAS, WT KRAS & NRAS exons 2/3/4 (includes 7 patients harbouring KRAS/NRAS codon 59 mutations)

12 BRAF Mutations in CRC BRAF es el primer efector de las señales de KRAS Mutaciones BRAF : Tumor Cell EGF Ocurre con más frecuencia en exon 15 (V600E) Aparece en 4%-14% de los pacientes con CCRm P P P P Ras Raf Mutuamente exclusiva con la mutación RAS MEK Pronóstico negativo con mediana OS de 10 meses Tumor cell proliferation and survival Erk Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol. 2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.

13 OS con inhibidores de EGFR en CCRm BRAF MT Meta-analysis of randomised clinical trials of cetuximab or panitumumab Study Log (hazard ratio) SE Weight (%) Hazard ratio (95% CI) Bokemeyer ( ) Douillard ( ) Karapetis ( ) Seymour ( ) Peeters ( ) Stintzing ( ) Total (95% CI) ( ) Heterogeneity: Tau 2 =0.11; Chi 2 =10.09 df=5 (p=0.07); I 2 =50% Test for overall effect: Z=0.48 (p=0.63) Favours EGFR inhibitors Favours control EGFR inhibitors are authorised only for RAS WT mcrc Pietrantonio, et al. Eur J Cancer 2015

14 Survival probability HERACLES A Un 5% de pacientes KRAS WT son HER/2 N: 54 previamente tratados HER2 + Response rate Response n (%) ORR 8 (34.7) CR 1 (4.3) PR 7 (30.4) SD 4 months 7 (30.4) SD <4 months 3 (13.0) PD 5 (21.7) Primary endpoint was met with 8/23 objective responses (as per protocol, 6/27 needed to declare the study positive) Disease control rate (DCR): 78% TTP HER2 3+ (95% CI: 1.8 NR) HER2 2+ (95% CI: 1.9 NR) p=ns Posible factor predictivo negativo a respuesta a anti/egfr (2) Time (months) 1. Sartore-Bianchi A et al. Lancet Oncol Siena, et al. ASCO Raghav KPS et al. ASCO 2016< 34>

15 MSI Predictor de respuesta la inmunoterapia (Categoría IIB) Pronóstico desfavorable Orienta en el Consejo Genético Determinación: Puede determinarse por dos métodos en tumor: Pérdida de expresión por IHQ de alguna de las proteínas reparadoras de DNA, hmlh1, hmsh2, hmsh6 y hpms2. Existencia de Inestabilidad de microsatélites por PCR. *NCCN guidelines validate testing for MSI-H 1. Sargent DJ et al. J Clin Oncol. 2010; 28(20): NCCN Guidelines V Venderbosch S et al. Clin Cancer Res. 2014; 20(20): Richman S. Int J Oncol. 2015; 47(4): Van Cutsem E et al. Ann Oncol. 2016; 27(8):

16 Genotipado del Colon Cancer: Molecular MSI vs MSS RAS WT vs MUT BRAF WT vs MUT Ensayos de Inmunoterapia

17 Características de los pacientes

18 Tratamiento de pacientes no subsidiarios de QT intensiva Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

19 Pembrolizumab: 10m g/k cada 2 semanas iv

20 Anti-PD1 pembrolizumab in mcrc: PFS and OS Le DT et al. NEJM 2015

21 Overall Survival (% of Patients) Progression-Free Survival (% of Patients) Check Mate-142: Nivolumab / Ipilimumab in Patients With MSI-H mcrc PFS Months No. at Risk Nivo Nivo + ipi OS Nivo 3 mg/kg 100 Nivo 3 mg/kg Nivo 3 mg/kg + ipi 1 mg/kg Months No. at Risk Nivo Nivo + ipi Nivo 3 mg/kg + ipi 1 mg/kg 0 0 PFS rate, % (95% CI) 6 mo 9 mo 12 mo OS rate, % (95% CI) 6 mo 9 mo 12 mo N3 (n=70) 45.9 (29.8, 60.7) 45.9 (29.8, 60.7) 45.9 (29.8, 60.7) N3 (n=70) 75.0 (58.5, 85.7) 65.6 (48.0, 78.6) 65.6 (48.0, 78.6) N3 + I1 (n=30) 66.6 (45.5, 81.1) NE NE mpfs, mo (95% CI) 5.3 (1.5, NE) NE (3.4, NE) N3 + I1 (n=30) 85.1 (65.0, 94.2) 85.1 (65.0, 94.2) NE mos, mo (95% CI) 17.1 (8.6, NE) NR (NE, NE) I1, 1 mg/kg ipilimumab; ipi, ipilimumab; mcrc, metastatic colorectal cancer; mos, median overall survival; mpfs, median progression-free survival; MSI-H, microsatellite instability-high; N3, 3 mg/kg nivolumab; NE, not evaluable; nivo, nivolumab; OS, overall survival; PFS, progression-free survival. Overman M et al. Poster presentation at ESMO P

22 Guías ESMO 2016 Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

23 OS (%) Landmark Papel de la resección La curación 100 HR mos 65.3 mo 60 55% 40 Pacientes CON Resección Hepática 20 mos 26.7 mo 19.5% Pacientes SIN Resección Hepática Time (months) OS 5 años 55% vs 19.5% Kopetz, S. et al. J Clin Oncol 2009; 27:

24 Anti-EGFR en Metástasis Hepáticas de CCR CELIM Folfox/Folfiri+ Cetuximab PLANET Abad et al. Presented at the 2014 European Society of Medical Oncology Meeting, September 26-30, 2014, Madrid, Spain; Abstract # 7823

25 Resection and response rates % (95% CI) Resection rate Bev + FOLFOXIRI (n=41) Bev + mfolfox6 (n=39) Difference p-value R0/R1/R2 a 61.0 ( ) 48.7 ( ) 12.3 ( ) R0/R ( ) 33.3 ( ) 17.9 ( ) R ( ) 23.1 ( ) 25.7 ( ) Overall response rate 80.5 ( ) 61.5 ( ) 18.9 ( ) Bridgewater, et al. ECC Abstract 2159 Intent to treat population. a Only two-stage hepatectomy

26

27 PEAK: PFS & OS WT KRASKRAS RAS WT WT RAS Schwartzberg LS. J Clin Oncol Jul 20;32(21):2240-7

28 FIRE-3: PFS and OS OR: 62% FOLFIRI+ Cetu vs 58% FOLFIRI+Beva ; p=0.18 Heinemann V et al. Lancet 2014

29 OR: 69 vs 54% p< 0.01 CALGB/SWOG 80405: Eficacia en RAS WT

30 Clinical Colorectal Cancer 2015

31 FIRE-3: Does depth of Response (DpR) correlates with OS?

32 Depth of response (DpR, %) Consistent efficacy and DpR in 4 1 st line studies 1 st Line 0 PEAK 1 PRIME 2 PLANET 3 (LLD) % % 65% P= % 54% p= % 71% p= NR 59% p= Pmab+mFOLFOX6 Pmab+FOLFOX4 Pmab+FOLFOX6 Pmab+FOLFIRI (RAS-WT) Beva+mFOLFOX6 FOLFOX4 Pmab+FOLFIRI Pmab+FOLFIRI (RAS-MT) 1. Rivera F et al. ECC Abstract 2014 and poster. 2. Douillard JY et al. Eur J Cancer Oxf Engl Jul;51(10): Abad A et al. ECC Abstract 2128 and poster. 4. Karthaus M et al. ECC 2015, Abstract 2130 and poster. Note: Data shown are not from comparative Bev: Bevacizumab, DpR: Depth of response, LLD: Liver-limited disease, NR: not reported, Pmab: Panitumumab studies and must be interpreted with caution.

33 II-A Guías ESMO 2016

34 Guías ESMO 2016

35 Guías ESMO 2016 TUMOR LOCATION Dcho vs izdo

36 66 studies pts Independent of the stage, race, adjuvant CT, year of study, number of participants and quality of included studies

37 OS estimate OS estimate CALGB 80405: OS in all RAS WT patients by tumor location 1.0 Left-sided tumors 1.0 Right-sided tumors BEV: 32.6 months (n=152) Cetuximab: 39.3 months (n=173) HR=0.77 (95% CI: ) Adjusted p= BEV: 29.2 months (n=78) Cetuximab: 13.6 months (n=71) HR=1.36 (95% CI: ) Adjusted p= N= N= mos 15.6 mos Time (months) Time (months) Lenz et al. ESMO Right or left metastatic colon cancer: will the side change your treatment?

38

39 Holch et al. Eur J Cancer 2017; 70: 87-98

40

41 RAS WT/BRAF MUTADO

42 Percent survival FOLFIRI + bev FOLFOXIRI + bev N Arm A Arm B HR [95% CI] Median OS Median OS ITT population [ ] R&B evaluable [ ] RAS mutated [ ] 100 BRAF mutated [ ] All wt patients [ ] RAS mutated FOLFOXIRI plus bev RAS mutated FOLFIRI plus bev BRAF mutated FOLFOXIRI plus bev BRAF mutated FOLFIRI plus bev All wt FOLFOXIRI plus bev All wt FOLFIRI plus bev Months

43 Guías ESMO 2016 Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016; Online Ann Oncol, July 2016

44 VISNÚ 1 (TTD-12-01) 3 CTC (n=350) 47% VISNÚ PROGRAM CTC Screening (n= 750 pts) 53% < 3 CTC (n=400) VISNÚ 2 (TTD-12-02) 60% KRAS WT N = 240 VISNÚ R KRAS mut (n=191) BRAF WT, PI3K WT (n=194) BRAF MUT o PI3K MUT (n=46) FOLFOX + + Bevacizumab Avastin (n (n = = 175) 193) Design Randomized Phase III FOLFOXIRI + Bevacizumab (n = 175) Primary endpoint: PFS (superiority 8 m vs 11,2 m, HR: 0.71) Secondary endpoint: RR, OS. R0 surgery, toxicity, CTC level basal, KRAS, BRAF, PI3K, Pten FOLFIRI + Cetuximab N=97 R FOLFIRI + Bevacizumab N=97 FOLFIRI + Cetuximab N=23 Design: Randomized Phase II Primary endpoint: -Group without mutation: minimum value 8.5 months optimum value 13 months and 1 year PFS rate IC less than (+/-10%) - Group with mutation: minimum value 2,5 months optimum value 6 months Secondary endpoint: TR, OS, R0 surgery, toxicity, CTC level basal, Pten R FOLFIRI + Bevacizumab N=23

45 Comparison of RR and PFS for BRAF mut CRC Regimen Response rate PFS Citation Single/Doublet BRAF/MEK Vemurafenib 5% 2.1 months Kopetz, ASCO 10 Dabrafenib 11% NR Falchook, Lancet 08 Encorafenib 16% NR Gomez-Roca, ESMO 14 Dabr +Tramet 12% 3.5 months Corcoran, ASCO 14 Doublet with EGFR Vem + Panit 13% 3.2 months Yeager et al CCR 14 Vem + Cetux 20% 3.2 months Tabernero et al ASCO 14 Encoraf + Cetux 23% 4.0 months Tabernero et al ESMO 14 Dabr + Panit 10% 3.4 months Atreya, ASCO 15 Triplet with EGFR Vem + Cetux + Irinotecan 35% 7.7 months Hong, Monday 1:15p, Abs 3511 Dabr + Tramet + Panit 26% 4.1 months Atreya, ASCO 15 Encoraf + Cetux + Alpelisib 32% 4.4 months Tabernero et al ESMO 14

46 Phase III Registration Trial of Encorafenib in BRAF V600E mutated CRC Safety Lead-in 1 objective: confirm Phase 3 dose Binimetinib (45 mg BID) + Encorafenib (300 mg QD) + Cetuximab (400/250 mg/m 2 Wkly) N=20 R * a n d o m i z e Phase 3 1 objective: Overall Survival Key 2 objective: ORR Other 2 objectives: PFS, DOR, TTR Arm A Binimetinib + Encorafenib + Cetuximab N=60 Arm B N=60 Encorafenib (300 mg QD) + Cetuximab (400/250 mg/m 2 Wkly) Interim analysis Continue Arm A or B N=173 N=60 N=173 Total N=233 Arm C Irinotecan 180 mg/m 2 q 2 wks + Cetuximab (400/250 mg/m 2 Wkly) Final analysis *Stratification factors: ECOG (0 vs. 1), prior irinotecan (yes vs. no), region (North America vs. rest of world)

47 Meta-analisis Beva maintenance PFS OS Clin Colorectal Cancer 2015

48 2ª line

49 ESMO Guidelines 2014 Annals of Oncology 25 (Supplement 3): iii1 iii9, 2014 doi: /annonc/mdu260 Published online 4 September 2014

50 Anti-angiogenic treatment in mccr

51 Antiangiogénicos en 2º línea asociados a FOLFIRI

52 2º line: Anti-EGFR combination

53 Anti-VEGF vs Anti-EGFR?

54 Survival Probability (%) Proportion Event-Free (%) PFS OS Panitumumab + FOLFIRI (n=91) Bevacizumab + FOLFIRI (n=91) Panitumumab + FOLFIRI (n=91) Bevacizumab + FOLFIRI (n=91) 70 HR=1.01 (95%CI: ) 70 HR=1.06 (95%CI: ) Months Months Hecht JR, et al. Clinical Colorectal Cancer 2015

55 CR-SEQUENCE: Planned study design Unresectable left-side mcrc WT RAS/ WT BRAF R Seq 1 Seq 2 FOLFOX + panitumumab FOLFOX + bevacizumab Progression Progression FOLFIRI + bevacizumab FOLFIRI + panitumumab Investigator choice: 1st line reintroduction Or Regorafenib Or Other N cycles until PD, toxicity or conversion surgery N cycles until PD or toxicity New RCT have to stratify by location If all the sequence matters we need prospective RCT based on molecular characteristics, in a dynamic scenario Primary endpoint: 2 nd progression/exitus free rate. (PFS1+PFS2): 30 vs 20 months. Total of 332 patients SEQUENCE 29/03/2017 PD, progressive disease.

56 3ª and 4ª line

57 ESMO 2016 RAS WT RAS MUT Annals of Oncology 0: 1 37, 2016 doi: /annonc/mdw235

58 3rd line - anti-egfr therapy ASPECCT trial: Panitumumab non inferior to Cetuximab Price T. Lancet Oncol 2014; 15:

59 MECANISMO DE ACCIÓN DE REGORAFENIB Endothelial Cell Tumor Cell Pericyte VEGFR1 PDGFR-β EGFR KIT VEGFR2 TIE-2 VEGFR3 PDGFR-β FGFR RAS Pl3K RAF BRAF AKT MEK mtor ERK Regorafenib ONCOGÉNESIS (KIT, RET, BRAF, RAF-1,PDGFR ) ANGIOGÉNESIS (VEGFR1-3, TIE2) TUMOR MICROENVIRONMENT (PDGFR-b, FGFR) 1. Grothey A, et al. Lancet. 2013; 381(9.863):303-12; 2. Wilhelm SM, et al. Int J Cancer 2011; 129:

60 Estudios con regorafenib

61 CORRECT CONCUR Regorafenib 1.9 m Placebo 1.7 m Regorafenib 3.2 m Placebo 1.7 m SLP SLP Regorafenib 6.4 m Placebo 5.0 m Regorafenib 8.8 m Placebo 6.3 m SG SG

62 Drug-related, treatment-emergent adverse events occurring in 10% of patients at any grade Adverse event, % All grades Regorafenib N=500 G-3 G-4 All grades Placebo N=253 Grade 3 Grade 4 Hand foot skin reaction Fatigue Hypertension Diarrhea Rash/desquamation Anorexia Mucositis, oral Thrombocytopenia Fever Nausea Bleeding Voice changes Weight loss

63

64 Trifluridina/tipiracilo (TAS-102) es un novedoso nucleósido antitumoral por vía oral Trifluridina (FTD) es un nucleósido basado en la timidina, que se incorpora al ADN de las células tumorales tras su fosforilación (es el componente activo) El hidrocloruro de tipiracilo (TPI) es un inhibidor de la timidina fosforilasa y evita la degradación de la FTD Se emplea para aumentar la concentración efectiva in vivo de FTD TAS desoxi-5-(trifluorometilo)uridina (trifluridina, FTD) [1] O monohidrocloruro de 5-cloro-6- [(2-iminopirrolidin-1-il)metil]pirimidina-2, 4(1H,3H)-diona (hidrocloruro de tipiracilo, TPI) [0,5] FTD es el componente activo HO O HN O N CF 3 + HCl. HN N H N O OH [Fracción molar] [1:0,5] La inhibición de la timidilato sintasa es el principal mecanismo de acción cuando FTD se administra por vía intravenosa. Cl O NH 64

65 Mayer RJ et al. NEJM 2015

66 RECOURSE: Overal Survival and PFS Control enfermedad 44% vs 16%, p<0.001 RR: 1,6% vs 0.4% OS m: TAS m Placebo 5.3 m TAS m Placebo 1.7 m

67 RECOURSE: Perfil de seguridad 1. Mayer RJ, et al. N Engl J Med. 2015; 372:1909

68 OS estimate RECOURSE: Onset of neutropenia predicts outcomes with TAS-102 in patients with mcrc OS estimate Objective: Post-hoc analysis of the RECOURSE study to explore the association between the onset of grade 3 neutropenia and OS/PFS, in mcrc patients treated with LONSURF or placebo Grade 3 neutropenia was associated with longer OS for TAS 102 vs placebo, irrespective of timing of onset OS for patients with onset of grade 3 neutropenia at cycle 1 TAS 102 Placebo OS for patients with no neutropenia onset TAS 102 Placebo Time (months) Time (months) Consistent treatment benefit was observed for OS and PFS regardless of cycle of onset of grade 3 neutropenia Outcome Median OS, months Median PFS, months LONSURF (n=75) HR, adjusted HR for LONSURF vs placebo. All placebo patients Earliest onset of grade 3 neutropenia Cycle 1 Cycle 2 (L) or 2 (P) Cycle 3 No grade 3 neutropenia Placebo (n=265) LONSURF (n=86) Placebo (n=215) LONSURF (n=39) Placebo (n=48) LONSURF (n=333) Placebo (n=265) HR 0.48 (95% CI: 0.32, 0.64) HR 0.56 (95% CI: 0.41, 0.78) HR 0.36 (95% CI: 0.17, 0.75) HR 0.97 (95% CI: 0.81, 1.16) HR 0.35 (95% CI: 0.25, 0.48) HR 0.34 (95% CI: 0.25, 0.46) HR 0.32 (95% CI: 0.18, 0.56) HR 0.69 (95% CI: 0.58, 0.82) Ohtsu A, et al. ASCO Abstract 3556 (poster presentation).

69 Secuencia de Regorafenib vs TAS 102 Regorafenib TAS 102 TAS 102 Regorafenib

70 Cetuximab rechallenge Mutations in RAS emerge during anti-egfr treatment and decline when treatment is suspendend RAS RAS wt wt RAS wt Basal RAS wt tumor Response to treatment Progression to treatment Off treatment Limited evidence for treatment with cetuximab

71 Rechallenge with anti-egfr therapy FIRE-4 (Phase III, n=550) RAS wt mcrc R 1st line 2nd line 3rd line Cetuximab + FOLFIRI Cetuximab + FOLFIRI Bevacizumab + FP maintenance Bevacizumab + FOLFOX/XELOX R Cetuximab + irinotecan/folfiri Regorafenib Liquid biopsy to track/identify resistance Primary endpoint: OS after randomization 2 Results expected: January 2022

72 Targeted therapy in clinical development for mcrc

73 Slide 32 Presented By Dirk Arnold at 2016 ASCO Annual Meeting

74 TARGET TRIAL

75 Median OS (months) Exposure to as many agents as possible prolongs OS First-line therapy p= Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU Patients with 3 drugs (%) FOLFOXIRI CAIRO 2007 OS (months) = (3 drugs % x 0.1), R 2 =0.85 Adapted from Grothey & Sargent. JCO 2005

76 Muchas Gracias!