ENCAJE CLÍNICO DE AFLIBERCEPT EN EL CONTEXTO ACTUAL DEL CCRm

Presentación del tema: "ENCAJE CLÍNICO DE AFLIBERCEPT EN EL CONTEXTO ACTUAL DEL CCRm"— Transcripción de la presentación:

1 ENCAJE CLÍNICO DE AFLIBERCEPT EN EL CONTEXTO ACTUAL DEL CCRm
RUTH VERA ONCOLOGÍA MÉDICA CHN Madrid, 12 de Febrero de 2015

2 CÁNCER COLORRECTAL METASTÁSICO
Aflibercept 5-FU/LV Capecitabine Irinotecan Oxaliplatin Bevacizumab Cetuximab Regorafenib* Panitumumab *Not approved by the EMA or for use in the Czech Republic

3 Advances in the treatment of Stage IV CRC
2005 2010 2015 + 1980 1985 1990 1995 2000 BSC 5-FU Irinotecan Capecitabina Oxaliplatino Cetuximab Bevacizumab Panitumumab Survival benefit from 6 months to months Aflibercept Regorafenib Braun MS, et al. Ther Adv Med Oncol. 2011;3:43-52.

4 CONCEPTOS IMPORTANTES

5 CONDICIONADO POR LAS LÍNEAS ANTERIORES
ESTRATEGIA “Continnium of care” 1st line 70 % 2nd line CONDICIONADO POR LAS LÍNEAS ANTERIORES 3rd line

6 “GOALS” Prolongation of survival Cure
Improving tumour-related symptoms Stopping tumour progression And/or Quality of life

7 “Backbone of first Chemotherapy”
Fluoropiridin-based chemotherapy: Oxaliplatin Irinotecan FOLFIRI → FOLFOX FOLFOX → FOLFIRI R Similar activity Both partners for biological agents Different toxicity profile

8 “Exposure to All Drugs Is Important”
Exposure to all three active cytotoxic drugs improves survival1 No clear survival advantage to any one specific first-line regimen1 The availability of biologic therapies has improved survival further Ox + iri FU/Lv + iri IFL FU/Lv + Ox P=.0008 1. Grothey et al, J Clin Oncol 2004; 2. Falcone et al ASCO 2013; 3. Stintzing et al ASCO 2013, 4. Takahari et al ASCO 2013

9 “ only trials with a combination of citotoxics and bilogical agents … SURVIVAL > 24 months”

10

11 1st line 70 % 2nd line 3rd line

12 Irinotecán vs Irinotecán + CETUXIMAB
TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIEGFR CETUXIMAB en 2ª Linea EPIC (SOBRERO) Irinotecán vs Irinotecán + CETUXIMAB

13 20% K-ras 47% CET 13% BV previo ERBITUX + irinotecan (n=648)
Hazard ratio p-value ORR 16% 4% - <0.0001 PFS meses 4.0 2.6 0.69 ≤0.0001 OS, meses 10.7 10.0 0.975 0.71 20% K-ras 47% CET 13% BV previo

14 FOLFIRI vs FOLFIRI + PANITUMUMAB
TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIEGFR PANITUMUMAB en 2ª Linea PEETERS (181) FOLFIRI vs FOLFIRI + PANITUMUMAB

15 FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W*)
L o n g t e r m f o l l o w u p E n d o f t r e a t m e n t FOLFIRI (Q2W) + panitumumab 6 mg/kg (Q2W*) Metastatic CRC (n=1186) R 1:1 FOLFIRI (Q2W*) Stratification by: ECOG score: 0-1 vs. 2 Prior oxaliplatin exposure for mCRC Prior bevacizumab exposure for mCRC Study endpoints: PFS/OS (co-1°); ORR, safety, HRQoL Peeters M, et al. J Clin Oncol 2010; 28: 15

16 Panitumumab + FOLFIRI (n = 303) FOLFIRI (n = 294)
Median PFS, months 5.9 3.9 Hazard ratio (P-value) (P = 0.004) Median OS, months 14.5 12.5 0.85 (P = 0.12) ORR, n (%) (95% CI) (35) (30–41) (n = 297) (10) (7–14) (n = 285) Peeters M, et al. J Clin Oncol 2010; 28:

17 18% (107/597) of WT KRAS exon 2 tumours have RAS mutations
study RAS analysis EXON 2# EXON 3 EXON 4 EXON 1 12 13 61 117 146 EXON 2 44.9% 4.4% 7.7% 2.2% 5.6% 0% 59 NRAS KRAS Overall RAS ascertainment rate: 85% 18% (107/597) of WT KRAS exon 2 tumours have RAS mutations Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation). Prevalence is defined as mutations detected in a population of WT KRAS exon 2 patients whose tissues were deemed evaluable for RAS testing; #The KRAS exon 2 data is from the overall population; WT RAS, KRAS & NRAS exons 2/3/4

18 20050181 study RAS analysis PFS (primary analysis)
Events n (%) Median (95% CI) months Panitumumab + FOLFIRI (n = 204) 117 (57) 6.4 (5.5–7.4) FOLFIRI (n = 211) 138 (65) 4.4 (3.7–5.5) 100 90 80 HR = (95% CI, 0.536–0.903) Log-rank p-value = 0.006 70 60 Proportion event-free (%) 50 40 30 20 10 2 4 6 8 10 12 14 16 18 Months Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).

19 20050181 study RAS analysis OS (primary analysis)
Events n (%) Median (95% CI) months Panitumumab + FOLFIRI (n = 204) 127 (62) 16.2 (14.5–19.7) FOLFIRI (n = 211) 141 (67) 13.9 (11.9–16.1) 100 90 80 HR = (95% CI, –1.024) Log-rank p-value = 0.08 70 60 Proportion alive % 50 40 30 20 10 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Months Peeters M, et al. J Clin Oncol 2014; 32 (suppl 3):LBA387 (and oral presentation).

20 TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIANGIOGENICAS
BEVACIZUMAB en 2ª Linea ECOG 3200 Folfox4 vs Folfox4 + BEVACIZUMAB (10 mg) TML BEVACIZUMAB (5 mg) + Múltiples QT

21 Giantonio et al. J Clin Oncol 2007; 25(12):1539-44
Estudio ECOG E3200 (GIANTONIO) FOLFOX4 N= 291 pac. Pacientes con CCRm tratados previamente con Fluoropirimidinas e Irinotecán N= 820 pac. FOLFOX4 + BEVACIZUMAB N= 286 pac. BEVACIZUMAB N= 243 pac. No estaba permitido el uso previo de Oxaliplatino o Bevacizumab. Objetivo Primario: SG. Objetivo Secundario: SLP, TR y Seguridad. Giantonio et al. J Clin Oncol 2007; 25(12):

22 Giantonio et al. J Clin Oncol 2007; 25(12):1539-44
HR=0.61 HR=0.75 Giantonio et al. J Clin Oncol 2007; 25(12):

23

24 QT basada en Irinotecan 43% 42%
Régimen QT 2ª Linea BEV + QT (n=407) % QT QT basada en Irinotecan 43% 42% FOLFIRI (64) 16% (57) 14% LV5FU2 + CPT11 (Douillard regimen1) (27) 7% (30) 7% XELIRI (49) 12% Other regimens (41) 10% QT basada en Oxaliplatino 57% 58% FOLFOX4 (37) 9% (35) 9% mFOLFOX4 (38) 9% FOLFOX6 (53) 13% FUFOX (23) 6% XELOX (58) 14% (46) 11%

25 SG SLP J. Bennouna. Lancet Oncology 2013; 14: 29-37

26 FOLFIRI vs FOLFIRI+ AFLIBERCEPT
TRATAMIENTO DE SEGUNDA LÍNEA CON TERAPIAS ANTIANGIOGENICAS AFLIBERCEPT en 2ª Linea VELOUR FOLFIRI vs FOLFIRI+ AFLIBERCEPT

27 Estudio VELOUR FOLFIRI R 1:1 FOLFIRI + Aflibercept
N= 614 pac. Pacientes con CCRm tras fallo a un régimen previo basado en oxaliplatino. N= pac. R 1:1 FOLFIRI + Aflibercept N= 612 pac. Estratificación: ECOG: 0 vs. 1 vs. 2 Bevacizumab previo s/n Objetivo Primario: SG. Objetivo Secundario: SLP, TR, Seguridad y FC Van Cutsem et al, JCO 2012 Vol 30 (28):

28 OS

29 HAY CONSENSO EN EL MANEJO DEL CCRm ?

30 ESMO NCCN NICE

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35 ESMO guidelines: Treatment goals and strategies determined by patient and tumor characteristics
Group Clinical presentation Treatment goal Treatment intensity GROUP 0 Clearly R0-resectable liver and/or lung metastases Cure, decrease risk of relapse Nothing or moderate (FOLFOX) GROUP 1 Not R0-resectable liver and/or lung metastases only, may become resectable after induction CT Maximum tumor shrinkage Upfront most active combination GROUP 2 Multiple metastases/sites, with rapid progression and/or tumor-related symptoms Clinically relevant tumor shrinkage as soon as possible, control PD Upfront active combination: at least doublet GROUP 3 Multiple metastases/sites with no option for resection and/or initially asymptomatic with limited risk for rapid deterioration Prevent further progression, low toxicity Watchful waiting or sequential approach (triplet regimens only in selected patients) CT, chemotherapy PD, progressive disease Schmoll H-J, et al. Ann Oncol 2012;23:2479–2516 35

36 QT+ Biológico

37 Ningún estudio de secuencia …

38 Anti-EGFR Aflibercept AFLIBERCEPT Anti-VEGF FOLFOX FOLFIRI 5-FU/LV
Capecitabine Irinotecan 1ª Línea 2ª Línea Progresión FOLFOX FOLFIRI Oxaliplatin Bevacizumab Cetuximab RAS wt Regorafenib* Aflibercept Panitumumab Anti-EGFR AFLIBERCEPT Anti-VEGF 38

39 Conclusiones Importancia de la segunda línea en la estrategia de tratamiento (70% 2ª Línea) La elección de la 2ª línea va ligada directamente a la 1ª línea Aflibercept + FOLFIRI aumentan de forma significativa la Supervivencia Global, la Supervivencia libre de progresión y la Respuesta en pacientes con CCRm tratados previamente con un régimen basado en oxaliplatino (Nivel 1 de evidencia) Incluido en las Guías de NCCN, ESMO en base a su evidencia Hoy desconocemos la secuencia óptima de tratamiento