Manejo Actual del Cáncer de Colon y Recto. P. García Alfonso Sr. Oncología Médica HGU Gregorio Marañón de Madrid

Transcripción

1 Manejo Actual del Cáncer de Colon y Recto P. García Alfonso Sr. Oncología Médica HGU Gregorio Marañón de Madrid

2 Tasas de mortalidad USA en 2003 vs en 2012

3 Fundamento actual del tratamiento del CCR Nuevos Fármacos Cirugía de metástasis Cirugía de metástasis S U P E R V I V E N C I A 6 Soporte FU bolo FU IC Xeloda = 5 FU IC Combinacion IRINOTECAN Combinación OXALIPLATINO Bevacizumab Y Cetuximab Panitu mumab Tratamiento Individualizado K-ras

4 La era de la Quimioterapia

5 5-FU es la base de la quimioterapia en el tratamiento del CCR 5-FLUOROURACILO 1957 (1) : primera experiencia en el tto de CCR. Limitada eficacia 1989 (2) : biomodulación con leucovorín (Clínica Mayo) (3) : infusión continua prolongada de 5FU (Lokich) 1997 (4) : infusión continua intermitente (de Gramont) (1) Heidelberger. Nature 1957 (2) Poon. J Clin Oncol 1989 (3) Díaz-Rubio Eur J Cancer 1990 (4) De Gramont. J Clin Oncol 1997

6 FOLFIRI and FOLFOX6 sequencing trial in advanced CRC: Survival FOLFIRI/FOLFOX6 FOLFOX6/FOLFIRI Probability P = Median OS (Mos) Conclusion: no survival advantage to starting either FOLFIRI or FOLFOX6 Tournigand C, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2): Reprinted with permission from the American Society of Clinical Oncology. Tournigand C, et al. J Clin Oncol. 2004;22:

7 Access to Chemotherapy Improves Survival Median OS (Mos) Patients With 3 Drugs (%) Grothey A, et al. J Clin Oncol. 2005;23: First-line therapy Infusional 5-FU/LV + irinotecan Infusional 5-FU/LV + oxaliplatin Bolus 5-FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5-FU/LV LV5FU2

8 La era de los Biológicos

9 1. Hicklin & Ellis. JCO 2005; 2. Baka et al. Expert Opin Ther Targets Presta et al. Cancer Res 1997; 4. Jain et al. Nat Clin Pract Oncol Morabito et al. Oncologist 2006; 6. Kerbel. Science 2006; 7. Verheul & Pinedo. Nat Rev Cancer 2007 Various therapeutic strategies targeting VEGF have been explored Angio Approaches to VEGF inhibition include: 1 Anti-VEGF antibodies Anti-VEGFR antibodies Soluble VEGFR Small-molecule TKIs VEGFR Antibodies inhibiting VEGF Soluble VEGFRs (VEGF- TRAP) Precise inhibition of VEGF-mediated pathways avoids of target pathways affected by receptortargeting agents 2 7 Small molecules inhibiting VEGFRs (TKIs) Angiogenesis

10 Persistent activation of the EGFR pathway is a frequent event in mcrc From Ciardiello F & Tortora G. N Engl J Med 2008;358: Copyright (2008) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

11 Mutación de ras inactive GDP En el cáncer colorrectal ocurre en el 35-45% de los pacientes >95% de las mutaciones ocurren en el exon 2 de K-ras codón 12 (>90%) codón 13 codón 62 Impiden la hidrólisis del GTP (RAS permanentemente on ), y causan transformación celular active * GTP

12 Clasificación del CCRm KRAS wild-type versus KRAS mutant Therapeutic implications Anti-VEGF or anti-egfr antibodies versus No anti-egfr antibodies. Si anti-vegf

13 Bevacizumab targets VEGF Avastin binds all known isoforms of VEGF, preventing interaction with its receptors activation of downstream signalling pathways This ultimately leads to vascular regression, leaving the tumour dormant Avastin P P X X P P Growth Proliferation Migration Survival VEGF

14 First-Line Irinotecan/5-FU/LV + Bevacizumab IFL/bevacizumab (n = 402) IFL/placebo (n = 411) HR: 0.66; P < HR: 0.54; P <.001 OS (%) PFS (%) Months Months Copyright 2004 Massachusetts Medical Society. All rights reserved. Hurwitz H, et al. N Engl J Med. 2004;350:

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16 Adding bevacizumab to FOLFOX4 significantly improved OS and PFS in the 2nd-line setting... All patients had received prior chemotherapy for advanced CRC with irinotecan + a fluoropyrimidine Median survival (months) *p= vs FOLFOX4. p< vs FOLFOX4. 10,8 12.9* Overall survival FOLFOX4 (n=291) FOLFOX4 + bevacizumab (n=286) 4,7 7.3 Progression-free survival Adding bevacizumab also improved the overall response rate: 22.7% vs 8.6% (p<0.0001) Giantonio BJ et al. J Clin Oncol 2007;25:

17 Tripletes más Bevacizumab Estudio TRIBE: Fase III Avastin + FOLFOXIRI vs Avastin + FOLFIRI (# 336) Estudio TRIBE: 1L FOLFOXIRI + Avastin alcanza superior SLP que FOLFIRI + Avastin Previously untreated, unresectable mcrc (n=508) R Avastin 5 mg/kg q2w + FOLFIRI (up to 12 cycles) Avastin 5 mg/kg q2w + FOLFOXIRI (up to 12 cycles) Avastin + 5-FU Avastin + 5-FU PD PD PFS estimate Avastin + FOLFOXIRI (n=252) Avastin + FOLFIRI (n=256) Median PFS (months) Unstratified HR (95% CI, p value) Stratified HR (95% CI, p value) 0.73 ( , p=0.0012) 0.71 ( , p=0.0006) FOLFOXIRI + Avastin (n=252) FOLFIRI + Avastin (n=256) 0.2 Objetivo ppal: SLP Objetivos secundarios: response rate, duration of response, secondary R0 surgery rates of metastases, overall survival, biomarker evaluation Time (months) Loupakis, et al. Abstract 336 (presented Saturday January 26, ) FOLFIRI = irinotecan 180mg/m 2, LV 200mg/m 2, bolus 5-FU 400mg/m 2, infusional 5-FU 2,400mg/m 2 over 48 hours q2w; FOLFOXIRI = irinotecan 165mg/m 2, oxaliplatin 85mg/m 2, LV 200mg/m 2, bolus 5-FU 200mg/m 2, infusional 5-FU 3,200 mg/m 2 over 48 hours q2w FOLFOXIRI + Avastin alcanza superior SLP que FOLFIRI + Avastin Tambien alcanza incremento significativo en TR: 65% vs 53% (p=0.006) Median follow-up: 26.6 months Loupakis, et al. Abstract 336 (presented Saturday January 26, )

18 Capecitabina más Bevacizumab es eficaz en los ancianos Estudio fase III AVEX: 1L Xeloda + Avastin incrementa significativamente la SLP en pacientes 70 años Estudio fase III AVEX: OS and ORR también incrementos en los objetivos secundarios PFS estimate Xeloda + Avastin (n=140) Xeloda (n=140) Median PFS (months) HR (95% CI, p value) 0.53 ( , p<0.001) Time (months) Xeloda + Avastin (n=140) Xeloda (n=140) Xeloda + Avastin (n=140) Xeloda (n=140) HR (95% CI, p value) Response rate (%) NR (p=0.042) Median OS (months) ( , p=0.182) OS estimate Xeloda + Avastin (n=140) Xeloda (n=140) La SLP muestra beneficio similar en todos los subgrupos analizados, incluyendo los 75 años Time (months) Cunningham, et al. Abstract 337 (presented Saturday January 26, ) Cunningham, et al. Abstract 337 (presented Saturday January 26, )

19 Cual es la duración idonea del bevacizumab? VEGF VEGF bfgf TGFb-1 VEGF bfgf TGFb-1 PIGF VEGF bfgf TGFb-1 PIGF PD-ECGF VEGF bfgf TGFb-1 PIGF PD-ECGF Pleiotrophin Continuous VEGF inhibition with bevacizumab until PD is a rational approach Folkman. In: Cancer: Principles and Practice of Oncology 2005; Relf, et al. Cancer Res 1997 Hanrahan, et al. J Pathol 2003; Fontanini, et al. Clin Cancer Res 1997

20 Bevacizumab After First Progression: BRiTE Estimated Overall Survival, % Patients n = 253 n = 531 n = Months Postprogression therapy No treatment No bevacizumab Bevacizumab Grothey A, et al. ASCO Abstract 4036.

21 ML18147 study design (phase III) BEV + standard first-line CT (either oxaliplatin or irinotecan-based) (n=820) PD Randomise 1:1 CT switch: Oxaliplatin Irinotecan Irinotecan Oxaliplatin Standard second-line CT (oxaliplatin or irinotecanbased) until PD BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecanbased) until PD Primary endpoint Secondary endpoints included Stratification factors Overall survival (OS) from randomisation Progression-free survival (PFS) Best overall response rate Safety First-line CT (oxaliplatin-based, irinotecan-based) First-line PFS ( 9 months, >9 months) Time from last BEV dose ( 42 days, >42 days) ECOG PS at baseline (0/1, 2) Study conducted in 220 centres in Europe and Saudi Arabia

22 Lancet Oncol 2013 Jan;14(1): OS and PFS in the overall population OS PFS CT (n=410) BEV + CT (n=409) OS estimate HR: 0.81 (95% CI: ) p= (log-rank test) PFS estimate HR: 0.68 (95% CI: ) p< (log-rank test) Time (months) No. at risk CT BEV + CT Time (months)

23 Cetuximab (ERBITUX ) Mechanism of action Cetuximab (Erbitux ) IgG 1 monoclonal antibody Binds to EGFR with high specificity & affinity Blocks receptor dimerization, autophosphorylation and signal transduction Promotes receptor internalization May elicit ADCC response Promising pre-clinical activity

24 Cetuximab has shown activity alone and in combination with irinotecan in EGFR-expressing tumours (1) Patients had received at least one prior treatment regimen, including an irinotecan-based regimen Overall response rate (primary endpoint) was 22.9% vs 10.8% for combination therapy vs cetuximab monotherapy (p=0.007) Median (months) 12,0 10,0 8,0 6,0 4,0 2,0 8,6 6,9 Cetuximab + irinotecan (n=218) Cetuximab alone (n=111) 4,1 1,5 0,0 Overall survival* Time-to-progression *50% of patients in the monotherapy group received additional irinotecan after disease progression. Cunningham D et al. N Engl J Med 2004;351:

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27 COIN: Improved response but no survival benefit for cetuximab + mfolfox/xelox Arm A mfolfox/ XELOX (KRAS wt, n=367) Arm B mfolfox/ XELOX + cetuximab (KRAS wt, n=362) Odds ratio/ Hazard ratio p-value ORR, % OR= Median PFS, months HR= Median OS, months HR= Reprinted from The Lancet, 377, Maughan TS, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial., , 2011 with permission from Elsevier

28 NORDIC VII: phase III study of FLOX with or without cetuximab NORDIC VII Study J Clin Oncol 30: OS & PFS for (C) KRAS wild-type,

29 Panitumumab inhibe la unión de los ligandos al EGFR y la dimerización EGF, TGFα u otros ligandos que se unen al EGFR Panitumumab Inhibición de la unión de EGF al EGFR Anticuerpo monoclonal IgG2 del EGFR completamente humano* Gran afinidad, K D = 5 x M Inhibe la fosforilación de la tirosina del EGFR inducida por ligandos Esto puede derivar en: Proliferación celular Supervivencia celular Angiogénesis Diseminación metastásica * Que sea completamente humano no tiene correlación con su seguridad o eficacia

30 Panitumumab monotherapy in WT Kras CRC 100 Progression Free Survival (%) Median PFS: 7.3 weeks Median PFS: 12.3 weeks Panitumumab + BSC (n = 124) BSC (n = 119) HR: 0.45 (95% CI: ) P < Weeks Amado R, et al. J Clin Oncol 2008;26:

31 PRIME: Panitumumab + FOLFOX4 significantly improves RR and PFS vs FOLFOX4 (KRAS wt) Panitumumab + FOLFOX (n=325) FOLFOX (n=331) RR Response rate (%) p= FOLFOX Pani + FOLFOX PFS estimate PFS HR=0.80 p= Time (months) OS estimate OS HR=0.88 p= Time (months) Douillard JY, et al. J Clin Oncol 2010;28: Reprinted with permission. (2010) American Society of Clinical Oncology. All rights reserved; Douillard J-Y, et al. ASCO 2011 (Abstract No. 3510)

32 Panitumumab ± FOLFIRI is also an option in chemorefractory KRAS wild-type patients Like cetuximab, panitumumab is a monoclonal antibody that targets EGFR and inhibits the growth of tumour cells 1 Adding panitumumab to FOLFIRI improved PFS compared with FOLFIRI alone in KRAS wild-type patients 2 Response rate was improved to 35% vs 10% with the addition of panitumumab 2 Median survival (months) 16,0 14,0 12,0 10,0 8,0 6,0 4,0 2,0 0,0 Panitumumab + FOLFIRI (n=303) FOLFIRI alone (n=294) 5,9 p= ,9 Progression-free survival p= ,5 12,5 Overall survival 1. Vectibix Prescribing Information: Available at (Last accessed September 2012); 2. Peeters M et al. J Clin Oncol 2010;28:

33 CALGB-C80405: Head-to-head study of cetuximab and/or bevacizumab + CT in 1st line mcrc Open-label, randomized, multicenter Phase III Cetuximab + FOLFOX/FOLFIRI Patients with untreated KRAS wt mcrc N=2234 R Bevacizumab + FOLFOX/FOLFIRI Primary endpoints OS Secondary endpoints RR, PFS, time to treatment failure Duration of response Bevacizumab +cetuximab + FOLFOX/FOLFIRI* *Arm closed to accrual as of 09/10/2009 Available at clinicaltrials.gov/ct2/show/nct

34 Biological head-to-head study: PEAK Untreated (unresectable) KRAS wt mcrc n=285 R Panitumumab + mfolfox6 (experimental arm) Bevacizumab + mfolfox6 (comparator arm) Primary endpoint Progression-free survival (PFS) Secondary endpoints Overall survival (OS), objective response (OR), duration of response (DoR), time to progression (TTP), time to response (TTR) and resection rate Schwartzberg LS et al., ASCO GI 2013 (abstract 446)

35 PEAK: No significant difference in PFS or OS with panitumumab + CT vs BEV + CT PFS Proportion event-free (%) OS Bev + mfolfox6 Pani + mfolfox ( ) p= Months Proportion event-free (%) ( ) p= Months Pani + mfolfox6 (n=142) Bev + mfolfox6 (n=143) Median PFS #, mos (95% CI) 10.1 ( ) Median OS mos (95%CI) 25.4 ( ) ORR #, n (% [95%CI]) Pts receiving subsequent therapy after tx phase n (%) Anti-EGFR 17 (12) 44 (31) Anti-VEGF 43 (30) 32(22) Abbreviation: NR, not reached. #Assessments based on investigator review per modified RECIST 1.0. Pts with measureable lesion were included in the ORR analysis. Schwartzberg LS et al., ASCO GI 2013 (abstract 446)

36 (CAIRO 2)

37 PACCE trial Hecht JR JCO 2009

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39 Liver Metastases in Colorectal Cancer: Outcomes Liver Metastases Resectable 20% to 25% Nonresectable 75% to 80% Location Size Number Downsizing Survival Benefit 30% to 40% at 5 years 15% at 10 years Resectable 10% to 20%

40 All patients ERBITUX + FOLFOX6 ERBITUX + FOLFIRI KRAS wt KRAS mt n=106 n=53 n=53 n=67 n=27 CR/PR 62% 68% 57% 70% 41% 95% CI 52 72% 54 80% 42 70% 58 81% 22 61% R0 resections 34% 38% 30% 33% 30% 95% CI 25 44% 25 52% 18 44% 22 45% 14 50% Tumor response and R0 are higher in KRAS wild type Folprecht G, et al. Lancet Oncol 2010; 11: 38 47

41 Chemotherapy ± Cetuximab for Patients With KRAS Wild- Type Unresectable Colorectal Liver-Limited Metastases Le-Chi Ye et al. J Clin Oncol 2013;31

42 Estudios II de bevacizumab en pacientes con sólo metástasis hepáticas Altas tasas de respuesta de mas del 70% ORR (%) GONO 1 (n=30) Gruenberger 2 80% (n=56) 73% BOXER 3 (n=45) 78% 20 0 Bevacizumab + FOLFOXIRI Tasas de Resecabilidad del 20-40% Bevacizumab + XELOX Bevacizumab + XELOX 1. Masi, et al. Lancet Oncol 2010; 2. Gruenberger, et al. JCO 2008; 3. Wong, et al. Ann Oncol 2011

43 Bevacizumab más quimioterapia incrementa las tasas de respuestas patológicas Avastin mas quimioterapia incrementa significativamente las tasas de respuestas patológicas Respuesta patológica: bevacizumab mas quimioterapia Incremento significativo en la respuesta patológica mayor Patients with <25% residual viable tumour cells (%) % 5-FU + oxaliplatin (n=43) p= % Avastin + 5-FU + oxaliplatin (n=62) 22% absolute improvement in patients with <25% residual viable tumour cells (p=0.02) Ribero, et al. Cancer 2007; Klinger, et al. Ann Surg Oncol 2010 Major pathological response (%) % Chemotherapy (n=50) p< % Bevacizumab + chemotherapy (n=50) Klinger, et al. Ann Surg Oncol 2010

44 Estudio OLIVIA Fase II RANDOMIZADO Beva + FOLFOXIRI vs Beva + FOLFOX Previously untreated, unresectable mcrc (solo Metas R Avastin 5 mg/kg q2w + FOLFOX evaluación cada 4 ciclos) Cirugía de Metás + QT adyuvante Hepáticas) Avastin 5 mg/kg q2w + FOLFOXIRI evaluación cada 4 ciclos Cirugía de Metas + QT adyuvante Objetivo ppal: Tasa de Resecabilidad Objetivos secundarios: response rate, duration of response, secondary R0 surgery rates of metastases, overall survival, biomarker evaluation

45 Nuevos Fármacos

46 Aflibercept VEGFR-1 VEGFR-2 IgG Fc Aflibercept Soluble fusion protein Consists of portion of extracellular domains of human VEGF receptors 1 and 2 fused to human IgG1 Fc portion Binds all VEGF-A isoforms, VEGF-B and PlGF High affinity: binds VEGF-A and PlGF more tightly than native receptors Half-life in humans ~17 days Van Cutsem et al. Ann Oncol. 2011;22(suppl 5). Abstract O-0024

47 Van Cutsem 2012

48 Regorafenib (BAY ), an oral multikinase inhibitor targeting multiple tumor pathways : CORRECT 2:1 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 Evaluation with CT scan of abdomen and chest every 8 weeks

49 Overall survival (primary endpoint) Primary endpoint met prespecified stopping criteria at interim analysis (1-sided p< at approximately 74% of events required for final analysis)

50 2012 ESMO consensus guidelines Schmoll HJ et al. Ann Oncol 2012;23:

51 NCCN guidelines: date of access January 2013

52 2012 ESMO consensus guidelines therapy should be guided by patient characteristics Group 1 Patients with potentially resectable metastases Group 2 Patients with non-resectable metastases, high tumor burden, and tumor-related symptoms Group 3 Patients with less aggressive disease or who are unable to tolerate standard CT regimens Aggressive therapy Less aggressive therapy CT=chemotherapy Schmoll H-J, Sargent D. Lancet 2007;370: Expert discussion at ESMO/WCGIC June 2009, Barcelona

53 Biomarcadores y Conocimiento Biológico

54 Otros Biomarcadores en el tramiento anti-egfr en kras wt.

55 BRAF-mutant CRC: simply a different disease Percent survival Tran B et al. Cancer 2011;117:

56 KRAS: 40% PIK3-CA: 14.5% BRAF: 4.7% NRAS: 2.6%

57 Rodriguez J et al. European Journal of Cancer 2012

58 Bevacizumab efficacy not affected by biomarker status Placebo + IFL Bev + IFL Biomarker N n Median (months) n Median (months) HR (95% CI) HR All subjects ( ) KRAS mutation status Mutant Wild-type ( ) ( ) BRAF mutation status Mutant Wild-type ( ) ( ) KRAS and BRAF mutation status Mutant Wild-type ( ) ( ) p53 mutation status Mutant Wild-type NR ( ) ( ) p53 overexpression Positive Negative ( ) ( ) Survival benefit also independent of VEGF (plasma and tissue) and TSP-2 Bev = bevacizumab; TSP-2 = thrombospondin-2 Jubb, et al. JCO 2006; Ince, et al. JNCI 2005

59 Tumour VEGF-A and neuropilin expression: PFS NO16 966m CRC Category All VEGF-A HER2 EGFR Neuropilin VEGFR-1 Subgroup All First tertile Second tertile Third tertile First tertile Third tertile First tertile Second tertile Third tertile First tertile Second tertile Third tertile First tertile Second tertile Third tertile n HR (95% CI) ( ) Patients with higher levels of VEGF-A show increased benefit ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Patients with lower levels of neuropilin show increased benefit ( ) ( ) ( ) ( ) ( ) ( ) HR (95% CI) In this study, data suggest that high tumour VEGF-A and low neuropilin expression are associated with improved PFS Foernzler et al. ASCO GI 2010

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62 Caracterización Molecular del CCR: Atlas Genómico

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64 Oncotype DX Colon Cancer Assay Incorporating the Recurrence Score Result into Treatment The Recurrence Score result predicts recurrence risk in stage II and III colon cancer, revealing underlying biology to provide value beyond conventional measures. The Recurrence Score result enables better discrimination of absolute treatment benefit as a function of risk, with greatest clinical utility in T3 MMR-P stage II and stage IIIA/B patients. Incorporating the Recurrence Score result into the context of clinicopathologic variables may better inform adjuvant therapy decisions for patients with stage II and III colon cancer.

65 Screening Reducción de mortalidad por cáncer de colon El intestino elimina habitualmente 0,6-1,2 ml de sangre al día (Hb fecal < 2 mg por gramo de heces ). 0% -5% -10% -15% -20% -25% -30% -35% Minnesota (1) Nottingham (2) Funen (3) -30% -15% -18% Mandel, NEJM 1993 Hardcastle, Lancet 1996 Kronborg, Lancet 1996

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67 Muchas Gracias!