Estrategia terapeutica del cáncer colorrectal: Selección individualizada del tratamiento

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1 Estrategia terapeutica del cáncer colorrectal: Selección individualizada del tratamiento P. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón de Madrid

2 Metastatic Colorectal Cancer BSC 5FU bolus 5FU i.c. IFL FOLFIRI FOLFOX IFL-Bev FOLFOX->FOLFIRI FOLFOX-Bev FOLFOX-Cetu FOLFIRI-Cetu FOLFOX-Pani CALGB FIRE Ras wt FOLFOX-Pani 2wt FOLFOXIRI-Bev 2wt 5 Mediana Sup 12,6 14,1 14,8 17,4 19,5 20,3 20,6 21,3 22,8 23,5 25, ,1 41,3 41, FOLFOXIRI-Bev 2wt FOLFOX-Pani 2wt FIRE Ras wt CALGB FOLFOX-Pani FOLFIRI-Cetu FOLFOX-Cetu FOLFOX-Bev FOLFOX->FOLFIRI IFL-Bev FOLFOX FOLFIRI IFL 5FU i.c. 5FU bolus BSC

3 ESMO GUIDELINES 2015

Para la toma de decisión de la1l de tratamiento en CCRm Medicina

Comorbilidades Perfil de toxicidad Flexibilidad Factores socio-

Presentación clínica: Localización del tumor Carga tumoral

de RAS Estatus mutacional de BRAF (1) Referencia: Van Cutsem, Arnold

4 Para la toma de decisión de la1l de tratamiento en CCRm Medicina Personalizada significa: Edad Performance status Función del órgano Comorbilidades Perfil de toxicidad Flexibilidad Factores socio- económicos Calidad de vida Preferecias y expectativas del paciente Presentación clínica: Localización del tumor Carga tumoral Características del tumor (1) Biología del tumor Estatus mutacional de RAS Estatus mutacional de BRAF (1) Referencia: Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer

5 Overall Survival (%) 21.5 months 20.6 months Tournigand C et al., J Clin Oncol 22: , 2004

6 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

7 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 IFL + bevacizumab 1 1L 813 2L: ~50% 2L: ~50% 35 45* * * XELOX/FOLFOX XELOX/FOLFOX + bevacizumab 2 1L 1,401 2L: 53% 2L: 46% * Monoterapia Capecitabine Capecitabine + bevacizumab 3 1L % 62% * Capecitabine Capecitabine + bevacizumab 4 1L % 37% 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

8 Estudio TRIBE 508 pacientes CCR EIV FOLFOXIRI + beva FOLFIRI + beva OR: 62.7 % vs 51.9%; p= ,1 vs 9,7 p 0, vs 25,8 p 0,054

9 Marcadores moleculares

Mutaciones RAS KRAS exon 2 wild-type (2008) KRAS

KRAS codon 12 mutant KRAS wild-type KRAS Exon 3

10 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

11 Study OS con inhibidores de EGFR en CCRm N RAS/KRAS exon 2 MT Meta-analysis of >5,000 patients from randomised clinical trials Any RAS MT OS Hazard ratio (95% CI) N KRAS exon 2 MT OS Hazard ratio (95% CI) ( ) ( ) ( ) ( ) CRYSTAL ( ) ( ) OPUS ( ) ( ) PICCOLO ( ) ( ) PRIME ( ) ( ) Summary 1.08 ( ) 1.05 ( ) p=0.14 p= Favours cetux/panit Favours no cetux/panit Favours cetux/panit Favours no cetux/panit EGFR inhibitors are authorised only for RAS WT mcrc Sorich, et al. Ann Oncol 2015

12 OS estimate OS estimate AVF2107g: OS con bevacizumab acorde a estado mutacional de KRAS KRAS MT (n=78) KRAS WT (n=152) 1.0 Bevacizumab + IFL (n=44) 1.0 Bevacizumab + IFL (n=85) Placebo + IFL (n=34) Placebo + IFL (n=67) 0.8 HR=0.69; p= HR=0.58; p= Time (months) Time (months) Hurwitz, et al. Oncologist 2009

13 OS estimate OS estimate BRAF MT se asocia con peor pronóstico BRAF MT patients have a significantly shorter median OS in 1L; only 39% of BRAF MT patients vs 60% BRAF WT received 2L treatment L treatment OS for BRAF MT vs BRAF WT L treatment OS for BRAF MT vs BRAF WT 0.75 BRAF WT BRAF MT HR=1.48 p< BRAF WT BRAF MT HR=1.17 p= Time (months) Time (months) Seligmann, et al. ASCO 2015

14 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

15 Percent survival TRIBE Predictive impact - OS 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

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

16 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

ESMO 2015: Consensus on treatment of advanced mcrc Fit Unfit (but may be suitable) Unfit FP +/- Bevacizumab Reduced dose doublet Anti-EGFR BSC Draft Cure Cytoreduction Disease control RAS WT RAS MT

17 ESMO 2015: Consensus on treatment of advanced mcrc Fit Unfit (but may be suitable) Unfit FP +/- Bevacizumab Reduced dose doublet Anti-EGFR BSC Draft Cure Cytoreduction Disease control RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT Surgery alone Surgery with perioperative/ postoperative CT Doublet + anti-egfr Combination + Bevacizumab Triplet + Bevacizumab CT + biological agent CT + Bevacizumab Unusual, see publication Re-evaluation/assessment of response every 2-3 months Cytoreduction (shrinkage) Disease control Progressive disease Continue; maintenance, or pause Progressive disease Continue Continue; maintenance, or pause 2L 2L Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015

18 ESMO 2015: Consensus on treatment of advanced mcrc Fit Unfit (but may be suitable) Unfit FP +/- Bevacizumab Reduced dose doublet Anti-EGFR BSC Draft Cure Cytoreduction Disease control RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT Surgery alone Surgery with perioperative/ postoperative CT Doublet + anti-egfr Combination + Bevacizumab Triplet + Bevacizumab CT + biological agent CT + Bevacizumab Unusual, see publication Re-evaluation/assessment of response every 2-3 months Cytoreduction (shrinkage) Disease control Progressive disease Continue; maintenance, or pause Progressive disease Continue Continue; maintenance, or pause 2L 2L Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015

19 Metástasis Hepáticas Irresecables o Potencialmente resecables

20 CELIM: Cetuximab + FOLFOX o FOLFIRI en metástasis hepáticas de CCR irresecables o mas de 5 metástasis

resection in each group; ORR: Objective response rate (not

21 PLANET study Response rate and resectability percentages calculated over the total number of patients with surgical resection in each group; ORR: Objective response rate (not confirmed*); *patients resected before response confirmation

Previously untreated, unresectable colorectal cancer with metastases confined to the liver N=80 Criteria for unresectability Stratification factors: Centre Randomization 1:1 ECOG performance status

22 Previously untreated, unresectable colorectal cancer with metastases confined to the liver N=80 Criteria for unresectability Stratification factors: Centre Randomization 1:1 ECOG performance status No. of metastatic lesions Patients had to meet at least one of the following criteria: no upfront R0/R1 resection of all hepatic lesions possible less than 30% estimated residual liver after resection disease in contact with major vessels of the remnant liver Bevacizumab + FOLFOXIRI Bevacizumab 5 mg/kg, oxaliplatin 85 mg/m 2, irinotecan 165 mg/m 2, folinic acid 200 mg/m 2 and 5-FU 3200 mg/m 2 46-hr infusion on day 1 q2w Bevacizumab + mfolfox6 Bevacizumab 5 mg/kg, oxaliplatin 85 mg/m 2, folinic acid 400 mg/m 2, bolus 5-FU 400 mg/m 2 then 5-FU 2400 mg/m 2 46-hr infusion on day 1 q2w FDG-PET was performed to exclude extrahepatic metastases Primary endpoint: overall resection rate (R0/R1/R2) Gruenberger, et al. Annals of Oncology 2014

23 Resection and response rates % (95% CI) Bev + FOLFOXIRI (n=41) Bev + mfolfox6 (n=39) Difference p-value Resection rate 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

24 Tratamiento de Metástasis Hepáticas: Revaluación de la respuesta cada 2 meses Citoreducción RAS y BRAF wt RAS mutado BRAF mutado Doblete + Anti-EGFR* Doblete o Triplete + Bevacizumab Triplete + Bevacizumab

25 ESMO 2015: Consensus on treatment of advanced mcrc Fit Unfit (but may be suitable) Unfit FP +/- Bevacizumab Reduced dose doublet Anti-EGFR BSC Draft Cure Cytoreduction Disease control RAS WT RAS MT BRAF MT RAS WT RAS MT BRAF MT Surgery alone Surgery with perioperative/ postoperative CT Doublet + anti-egfr Combination + Bevacizumab Triplet + Bevacizumab CT + biological agent CT + Bevacizumab Unusual, see publication Re-evaluation/assessment of response every 2-3 months Cytoreduction (shrinkage) Disease control Progressive disease Continue; maintenance, or pause Progressive disease Continue Continue; maintenance, or pause 2L 2L Van Cutsem, Arnold and Cervantes. Session XIX: Metastatic Colorectal Cancer. World Congress on Gastrointestinal Cancer, 2015

26 Phase 2 PEAK study mfolfox6 + panitumumab or bevacizumab in 1 st -line treatment of WT KRAS exon 2 mcrc mcrc WT KRAS exon 2 (n = 285) 1:1 R mfolfox6 (Q2W) + panitumumab 6 mg/kg (Q2W) mfolfox6 (Q2W) + bevacizumab 5 mg/kg (Q2W) Follow-up Survival: Q3M (± 28 days) Safety: 30 days after last study drug administration Tumour assessment Q8W (± 7 days); Treatment administered until disease progression, unacceptable toxicity, death, or withdrawal from study Study endpoints: PFS (1 ); OS, ORR, resection rate, safety, exploratory biomarker analysis No formal hypothesis testing was planned Schwartzberg LS, et al. J Clin Oncol 2014;32:2240 7; Protocol ID: ; ClinicalTrials.gov identifier: NCT mfolfox6, modified FOLFOX6.

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

28 FIRE-3 study design Heinemann V et al. Lancet 2014;.

29 Heinemann V et al. Lancet 2014 Fire-3: Tasa de Respuestas

30 Heinemann V et al. Lancet 2014 FIRE-3: PFS and OS

31 FIRE-3: Depth of Response (DpR) Correlates With OS

32 CALGB/SWOG 80405: <br /> FINAL DESIGN Presented By Alan Venook at 2014 ASCO Annual Meeting

% libre de eventos CALGB 80405: RAS-WT - Supervivencia Global Lenz, et al. ESMO 2014.

33 % libre de eventos CALGB 80405: RAS-WT - Supervivencia Global Lenz, et al. ESMO abstract 501O Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%) No. en riesgo Meses desde el ingreso al estudio

% libre de eventos CALGB 80405 RAS-WT: Resultados de SLP Lenz, et al. ESMO 2014.

34 % libre de eventos CALGB RAS-WT: Resultados de SLP Lenz, et al. ESMO abstract 501O Grupo N Mediana RR p (Eventos) (IC 95%) (IC 95%) No. en riesgo Meses desde el ingreso al estudio ORR: Chemo+cetux: 68,6% vs Chemo + Beva: 53,6% (p<0,01)

35 FIRE-3: diferencias en eficacia en tumores del lado derecho vs lado Right-sided (n=30) OS 0.34 ( ) PFS 0.43 ( ) izquierdo Effect of primary tumour location on outcomes Cetuximab + FOLFIRI (n=167) Left-sided (n=137) OR (p value) ORR, % (0.019) Cetuximab + FOLFIRI Right-sided (n=39) Multivariate Cox regression analysis (OS and PFS): location (left- vs right-sided tumour) Bevacizumab + FOLFIRI HR (95% CI) p value HR (95% CI) p value < ( ) ( ) Bevacizumab + FOLFIRI (n=166) Left-sided (n=127) OR (p value) (0.14) PFS, months (>0.001) (0.065) OS, months (<0.0001) (0.034) Heinemann, et al. ASCO 2014

36 Tratamiento de mantenimiento

37 CAIRO-3: Cape-Bev Maintenance vs Observation PFS1 PFS2 Patients with mcrc and SD or better after 6 cycles CAPOX-B, WHO PS 0-1 (N = 558) Primary endpoint: PFS2 Time from randomization to progression upon reintroduction of CAPOX-B PFS2 considered equal to PFS1 in patients who do not receive CAPOX-B again (for any reason) Median follow-up: 40 mos Observation (n = 279) Capecitabine + Bevacizumab (n = 279) Koopman M, et al. ASCO Abstract PD Reintroduce CAPOX-B OR Any treatment, including CAPOX-B PD PD TT2PD

38 CAIRO3: Maintenance Cape-Beva

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

40 Opciones terapéuticas en segunda línea

41 Median: BEV + CT 11.2 months, CT 9.8 months Median: BEV + CT 5.7 months, CT 4.1 months Lancet Oncol 2013 Jan;14(1):29-37.

42 Aflibercept Aflibercept 1. Adapted from Holash. Proc Natl Acad Sci. 2002;99: Adapted from Tew. Clin Cancer Res. 2010;16: Tabernero et al. Eur J Cancer. 2011;47(2): Abstract 6LBA 42

45 RAISE: Ramucirumab en CCR OR: 13.4% vs 12.5% p : 0.6

46 Antiangiogénicos en 2º línea asociados a FOLFIRI

47 2º line: Anti-EGFR combination

48 Cetuximab + 1L FOLFIRI (n=153) kras wt R Cetu + FOLFOX FOLFOX PD PD Primary endpoint: PFS from randomisation Secondary endpoints: OS from randomisation, best ORR, safety Ciardielo F et al. Annals of Oncology Advanced Acess 2016

49 CAPRI: PFS wt/mutated

50 Opciones terapéuticas en tercera y cuarta línea

Panitumumab 6 mg/kg IV (Q2W) Cetuximab 1:1 400 mg/m 2 loading dose, 250 mg/m 2 IV (QW) PD PD S u r v i v a l Study endpoints: OS (1

51 Panitumumab vs. cetuximab in 3 rd - line treatment of WT KRAS exon 2 mcrc (open-label, phase 3) Metastatic mcrc WT KRAS exon 2 (n = 999) R 1:1 Panitumumab 6 mg/kg IV (Q2W) Cetuximab 1:1 400 mg/m 2 loading dose, 250 mg/m 2 IV (QW) PD PD S u r v i v a l Study endpoints: OS (1 ); PFS, ORR, safety Crossover between arms during study treatment was not allowed Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation); Protocol ID: ; ClinicalTrials.gov identifier: NCT WT KRAS, WT KRAS in codons 12/13

52 Proportion alive (%) ASPECCT study: OS (primary analysis) Events n (%) Median (95% CI) months Panitumumab (n = 499) 383 (76.8) 10.4 ( ) Cetuximab (n = 500) 392 (78.4) 10.0 ( ) HR = 0.97 (95% CI, ) P = Z-score = Retention score = 1.06 (95% CI, ) Months Price T, et al. EJC 2013; 49 (suppl 3):LBA 18 (and oral presentation).

therapy, time from diagnosis of metastatic disease, geographical

53 Regorafenib: Estudio CORRECT Multicenter, randomized, double-blind, placebo-controlled, phase III Stratification: prior anti-vegf therapy, time from diagnosis of metastatic disease, geographical region Global trial: 16 countries, 114 centers Recruitment: May 2010 to March 2011

off (4-week cycle) n = 136 Stratification Metastases: single vs multiple Time from mcrc diagnosis: >18 vs <18 months Primary endpoint: overall survival (OS) One-sided alpha 0.2 and assumed 33.

54 CONCUR trial design Clinicaltrials.gov NCT Asian patients with mcrc who progressed after standard therapies 25 Centers: mainland China, Hong Kong, South Korea, Taiwan, Vietnam R 2:1 Regorafenib 160 mg daily 3 weeks on / 1 week off (4-week cycle) n = 136 Stratification Metastases: single vs multiple Time from mcrc diagnosis: >18 vs <18 months Primary endpoint: overall survival (OS) One-sided alpha 0.2 and assumed 33.3% OS improvement (HR=0.75 favoring regorafenib) with 154 events had 80% power Secondary endpoints: progression-free survival, response rate, disease control rate Placebo n = 68 All patients received best supportive care Treat until progression, unacceptable toxicity, or J. Li, et al. WCGI Abstract O Presented at WCGI 2014, Barcelona, withdrawal Spain. Kim TW et al Presented at ESMO 2014, September, Madrid Li J et al. Lancet 2015

55 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

56 Mayer RJ et al. NEJM 2015

57 TAS 102 EN CCR m REFRACTARIO, FASE III Mayer & Van Cutsem et al.

58 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

59 CR-SEQUENCE Planned study design Unresectable mcrc WT RAS R 1 1:1 FOLFOX + panitumumab FOLFOX + bevacizumab R 2 FOLFIRI + bevacizumab FOLFIRI + panitumumab Investigator choice: 1 st -line reintroduction or Regorafenib or other N cycles until PD, toxicity or conversion surgery FOLFIRI + bevacizumab N cycles until PD or toxicity

60 Futuro en CCR

61 CRC consensus molecular subtypes characteristics

62 Liquid Biopsy

63 Can Targeting EGFR Overcome Resistance to BRAF + MEK Inhibitors in BRAFm CRC? Presented By Chloe Atreya at 2015 ASCO Annual Meeting

64 Best Response With Confirmation <br />Percent Change from Baseline at Maximum Reduction in Tumor Measurement Presented By Chloe Atreya at 2015 ASCO Annual Meeting

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

66 Pembrolizumab en CCRm con MSI NR NR 2.2 m 5.0 m

67 HER2 como diana en CCRm: HERACLES trial: Lapatinib + Trastuzumab Survival probability N: 54 previamente tratados HER2 + Response rate TTP Response n (%) ORR 8 (34.7) CR 1 (4.3) PR 7 (30.4) HER2 3+ (95% CI: 1.8 NR) HER2 2+ (95% CI: 1.9 NR) p=ns SD 4 months 7 (30.4) 0.6 SD <4 months 3 (13.0) 0.4 PD 5 (21.7) 0.2 Primary endpoint was met with 8/23 objective responses (as per protocol, 6/27 needed to declare the study positive) Time (months) 15 Disease control rate (DCR): 78% Siena, et al. ASCO 2015

68 Muchas Gracias!

69 BSC 5FU bolus 5FU i.c. IFL FOLFIRI FOLFOX IFL-Bev FOLFOX->FOLFIRI FOLFOX-Bev FOLFOX-Cetu FOLFIRI-Cetu FOLFOX-Pani CALGB FIRE Ras wt FOLFOX-Pani 2wt FOLFOXIRI-Bev 2wt 5 Muchas Gracias! Mediana Sup 12,6 14,1 14,8 17,4 19,5 20,3 20,6 21,3 22,8 23,5 25, ,1 41,3 41, FOLFOXIRI-Bev 2wt FOLFOX-Pani 2wt FIRE Ras wt CALGB FOLFOX-Pani FOLFIRI-Cetu FOLFOX-Cetu FOLFOX-Bev FOLFOX->FOLFIRI IFL-Bev FOLFOX FOLFIRI IFL 5FU i.c. 5FU bolus BSC

First line treatment in metastatic colorectal cancer

First line treatment in metastatic colorectal cancer Claus-Henning Köhne University Clinic Onkology and Haematology North West German Cancer Center (NWTZ) A non authorised version of ESMO guidelines was