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

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

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 24-30 months Aflibercept Regorafenib Braun MS, et al. Ther Adv Med Oncol. 2011;3:43-52.

CONCEPTOS IMPORTANTES

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

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

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

“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

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

1st line 70 % 2nd line 3rd line

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

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

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

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; 28:4706-13. 15

Panitumumab + FOLFIRI (n = 303) FOLFIRI (n = 294) Median PFS, months 5.9 3.9 Hazard ratio (P-value) 0.73 (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; 28:4706-13.

18% (107/597) of WT KRAS exon 2 tumours have RAS mutations 20050181 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

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 = 0.695 (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).

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 = 0.803 (95% CI, 0.629–1.024) 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).

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

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):1539-44

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):1539-44

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%

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

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

Estudio VELOUR FOLFIRI R 1:1 FOLFIRI + Aflibercept N= 614 pac. Pacientes con CCRm tras fallo a un régimen previo basado en oxaliplatino. N= 1.226 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): 3499-3506.

OS

HAY CONSENSO EN EL MANEJO DEL CCRm ?

ESMO NCCN NICE

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

QT+ Biológico

Ningún estudio de secuencia …

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

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