Cáncer de páncreas Qué fármacos?, qué biomarcadores?, qué pacientes?

Cáncer de páncreas Qué fármacos?, qué biomarcadores?, qué pacientes? Fernando Rivera Herrero Sv Oncología Médica Hospital Universitario M. de Valdecilla

Guion Introducción Hasta el 2010 F III positivos: FOLFIRINOX / GEM-Abraxane Segundas líneas En el 2013-2014 otros dos fracasos más..: CO-101, Ganitumumab pero en el 2014 datos prometedores MM-398, Inmunoterapia, GS 1C4D4, Ruxolitinib, Veliparib Conclusiones

Cáncer de páncreas Qué fármacos?, qué biomarcadores?, qué pacientes? INTRODUCCIÓN Adenoca de Páncreas Sv 5a <5% 1 Sv 5 a Estadío Resecable (Est I-II) 15% Sv 5 a: 25% Loc. Avanzado (T4; St III) 40% Sv mediana : 12-15 m Metastásico (M1; St IV) 45% Sv mediana : 5-8 m 1.- De Angelis R et al. EUROCARE-5. Lancet Oncol 2014; 15: 23

Metastatic pancreatic cancer: Three groups of patients % of pts?? Optimum Suboptimum Fragile CRITERIA?? 20%? 40%? 40%? - PS (ECOG) 0-1 2 >2 - Weight loss <10% 10-25% >25% - Colest/Thromboemb no moderate important - Age <75y 75-85y >85y - Comorbidities no moderate important - Geriatric Sind no no yes

Advanced pancreatic cancer CT vs BSC Meta-analysis CT vs BSC (Sultana et al. J Clin Oncol. 2007 Jun 20;25(18):2607) 7 studies, 432 pts Improvement in OS with CT HR 0,64 95% C.I.: 0,42-0,98

C. páncreas metast. Tto hasta el 2010 Tres grupos de pacientes Óptimo Subóptimo Frágil Opciones 20% de pts? 40% de pts? 40% de pts? - Gem (30 min) + + - - GEMOX / GEMCAP + - - - Gem-Erlotinib + + -

Rta, SLP y Sv en Adenoca de Páncreas avanzado Tratamiento Rta SLP SV Sv 1a - Gem (30 min) 5-12% 3,5m 5,5m 18% - GEMOX / GEMCAP 25% 5 m 7m 25% - Gem-Erlotinib 8,6% 3,8m 6,3m 24%

342 PTS (2005-09, 48 centers) Rand PII: 88 pts RR 31,8 vs 11,3% P.III Criteria <76 y M1 PS ECOG 0-1 Bilirrubine < 1,5 x UNL Normal renal,hema.function No cardiocirc. disease... 1ºendpoint:OS F. II-III Prodige 4- ACCORD 11 FOLFIRINOX vs Gemcitabine FOLFIRINOX 6 m (stop and go) Gem (30 min) OS (median) 11,1 m HR 0,57 p<0,0001 6,8 m 1 year 48,4% 20,6% PFS 6,4 m HR 0,47 p<0,0001 3,3 m RR: 31,6% p<0,0001 9,4% Dis Control: 70,2% p<0,0001 50,9% Conroy T et al. N Engl J Med 2011;364:1817-25.

F. III Prodige 4- ACCORD 11 FOLFIRINOX vs Gemcitabina Obj 2º: SLP Mediana: 6,4 m vs 3,3 m HR 0,47 p<0,0001

F. III Prodige 4- ACCORD 11 Toxicity: G 3-4 G-CSF 42% 5% No colangitis and no more toxicity in patients with biliar stent

Guion Introducción Hasta el 2010 F III positivos: FOLFIRINOX / GEM-Abraxane Segundas líneas En el 2013-2014 otros dos fracasos más..: CO-101, Ganitumumab pero en el 2014 datos prometedores MM-398,Inmunoterapia, GS 1C4D4, Ruxolitinib, Veliparib Conclusiones

14 nab -Paclitaxel Complejo nab-paclitaxel Molécula individual nab-paclitaxel 4-14 nm de tamaño 3,4 Albúmina Paclitaxel 130 nm de tamaño 1,2 Una única molécula de albúmina puede unir hasta 6 o 7 moléculas de paclitaxel 5 nab es una marca comercial registrada de Celgene Corporation. 1. Desai et al. SABCS. 2004 [Abstract 1071]. 2. Kratz et al. J Control Release. 2008;132(3):171-183. 3. Peters,Jr. Serum albumin. Adv Protein Chem. 1985;37:161-245. 4. Desai. Drug Delivery Report. 2008;Winter 2007/2008(16):35-41. 5. Paal et al. Eur J Biochem. 2001;268:2187-2191.

Nab-Paclitaxel Explotando las propiedades transportadoras de la albúmina Albumina: transportador natural de moléculas hidrofóbicas (ácidos grasos, hormonas, vitaminas ) 1 3 Mecanismo antitumoral innovador Transcitosis Caveolar a través de la célula endotelial Captación metabólica de albúmina alta por tumor 3 Uníón SPARC-albumina en el estroma tumoral 1. Purcell et al. Biochim Biophys Acta. 2000;1478:61 68;. 2. Paal et al. Eur J Biochem. 2001;268:2187 2191 3. Desai N Drug Delivery Report. 2007/2008;16:37 41;

von Hoff, J Clin Oncol, Oct 2011 ; 1 Maitra et al., AACR-NCI-EORTC Molecular Targets, Boston 2009 ; Infante et al., 2007, J Clin Oncol 25(3): 319-25 nab-paclitaxel may deplete the fibrotic stroma in patient-derived pancreatic cancer xenografts IHC Staining of Tumor Collagen Type I substantial reduction in stromal components post-treatment with nab-paclitaxel but not gemcitabine alone. - stromal targeting?? - SPARC in stroma Further studies ongoing to evaluate role of stroma

861 PTS M1 KPS 70 Bilirrubine < UNL 1ºendpoint:OS F. III MPACT 1 nabpaclitaxel-gem vs Gemcitabine nabpaclitaxel-gem nabp; 125 mg/m2 iv Gem: 1000 mg/m2 iv semanalmente 3/4 sems Gem (30 min) Gem 1000 mg/m2 iv sem 7/8 sem seguido de 3/4 sems Sv 2 (mediana) 8.7 m HR 0,72 p<0,0001 6,6 m 1 año 35% 22% 2 años 10% 4% SLP 5.5 m HR 0,69 p<0,001 3,7 m Rta (rev central): 23% p<0,001 7% Dis Control: 48% p<0,001 33% SLP 1.- Von Hoff DD et al. N Engl J Med 2013; 2.- (OS updated results) Goldstein D et al. ASCO-GI 2014

OS - Prespecified Subgroups CA19-9, carbohydrate antigen 19-9; Gem, gemcitabine; KPS, Karnofsky performance status; nab-p, nab-paclitaxel; ULN, upper limit of normal. Von Hoff DD, Ervin T, Arena FP, et al. Randomized Phase III Study of Weekly nab-paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT) [abstract LBA148]. Oral presentation at: The Gastrointestinal Cancers Symposium 2013; January 24-26; San Francisco, CA. 1

Safety Preferred Term nab-p + Gem n = 421 Gem n = 402 Patients with at least 1 AE leading to death, % 4 4 Grade 3 hematologic AEs, a % Neutropenia Leukopenia Thrombocytopenia Anemia Patients who received growth factors, % 26 15 Febrile neutropenia, b % 3 1 Grade 3 nonhematologic AEs b in > 5% of patients, % Fatigue Peripheral neuropathy c Diarrhea Grade 3 neuropathy Time to onset in days, median Time to improvement by 1 grade in days, median Time to improvement to grade 1 in days, median Patients who resumed nab-p, % 38 31 13 13 17 17 6 140 21 29 44 27 16 9 12 7 < 1 1 113 29 -- -- a Based on lab values. b Based on investigator assessment of treatment-related events. C Grouped term. AE, adverse event, Gem, gemcitabine; nab-p, nab-paclitaxel. Von Hoff DD, Ervin T, Arena FP, et al. Randomized Phase III Study of Weekly nab-paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT) [abstract LBA148]. Oral presentation at: The Gastrointestinal Cancers Symposium 2013; January 24-26; San Francisco, CA. 14

NabPaclitaxel en Ca de Páncreas Reciente aprobación por FDA (2013) y EMA y AEM (2014) de nabpaclitaxel para adenoca de páncreas metástasico Abraxane en combinación con gemcitabina está indicado en el tratamiento de primera línea en pacientes adultos con adenocarcinoma de páncreas metastásico.

ABR/078/06-11/06-13 Date of prep: June 2011 SPARC (Secreted Protein Acidic and Rich in Cysteine, Osteonectina, BM-40) Glicoproteína con diversas funciones en el intersticio extracelular: mineralización ósea, interacción con colágeno, estímulo de MMP, angiogénesis SPARC es segregado por las células tumorales al intersticio 1 SPARC promueve las metástasis, la remodelación tisular y la angiogénesis 1 Niveles altos de SPARC a nivel intersticial son frecuentes en distintos tumores y se asocian a peor pronóstico 1 3 SPARC se une a la albúmina y por tanto también a nab-paclitaxel y este puede ser el mecanismo de la acción de nab- Paclitaxel sobre el intersticio tumoral 1 1. Aapro MS & Minckwitzb GV. Eur J Cancer Suppl. 2008;6:3 11. 2. Chin et al. Int J Cancer. 2005;913:789 797. 3. Watkins et al. Prostaglandins Leukot Essent Fatty Acids. 2005;72:267 272.

ABR/078/06-11/06-13 Date of prep: June 2011 SPARC Expression in Microarrays Performed on Tumors Taken Directly From Patients Tumor Type # with SPARC */# studied (%) Breast 6/9 67% Ovary 5/15 33% Pancreas 13/16 81% Melanoma 15/17 88% Adrenal 2/5 40% Colon 4/15 27% Total 76/113 67% *Increased expression at level of 0.001 versus normal tissue Data Courtesy, Dan Von Hoff Includes data not shown

ABR/078/06-11/06-13 Date of prep: June 2011 SPARC Protein (42kDa) is Overexpressed in Multiple Tumor Types - Marker of Poor Prognosis BREAST---Watkins et al. 2005 MELANOMA--Massi et al. 1999 GASTRIC---Wang et al. 2004 P = 0.047 NSCLC---Koukourakis et al. 2003 HEAD & NECK---Chin et al. 2005 BLADDER---Yamanaka et al. 2001 ESOPHAGEAL---Yamashita et al. 2003 PANCREATIC---Infante et al. 2007 MENINGIOMA---Bozkurt et al. 2009

CONFIDENTIAL STRICTLY FOR INTERNAL USE ONLY This document is intended for use by internal Celgene marketing personnel only and MUST NOT, under any circumstances, be distributed externally. This document is NOT for sales representative use. Should you wish to adapt any content for use in your market you MUST seek local review and approval prior to external dissemination. High SPARC Expression Correlated With Improved OS in Patients With Pancreatic Cancer Who Received nab -Paclitaxel Plus Gemcitabine in a Phase I/II Trial 24 OS in Advanced Pancreatic Cancer With nab-paclitaxel Plus Gemcitabine Therapy Probability of survival (%) 100 75 50 25 8.1 months High SPARC Expression (n = 19) Low SPARC Expression (n = 17) P =.0431 17.8 months Stromal SPARC correlated with OS (p=0.013) but SPARC in tumour cells did not (p=0.15) High SPARC Low SPARC 0 0 5 10 15 20 25 30 Months Investigation of the functional importance of SPARC with respect to nab-paclitaxel is ongoing. nab is a registered trademark of Celgene Corporation. OS, overall survival; SPARC, Secreted Protein Acidic and Rich in Cysteine. Von Hoff et al. J Clin Oncol. Oct 2011

MPACT: Biomarker analysis ongoing Stromal SPARC expression Invitrogen ON-1, IHC

SEGUNDAS LINEAS PS 0-1 Gemcitabina en 1ª línea (Gem; Gem-Abrax; Gem-Cap Gem-plat; Gem-Erlotinib) NO Gemcitabina en 1ª línea (Folfirinox) F. III CONKO 003 (Pelzer JCO 2008) PACREOX (Gill ASCO 2014) 5FU-AF-Oxa. vs 5FU-AF Gemcitabina en 1ª línea (Gem; Gem-Abrax; Gem-Cap Gem-plat; Gem-Erlotinib)

Advanced Pancreatic Cancer 2nd line Oxaliplatin (after Gem failure) P. III CONKO 003 Part 1 1 (Only 46 out of 165 planned pts were included) Ox-Fu-Fol vs BSC : OS 4 m vs 2,5 m p: 0,008 Part 2 2 : 168 pts Ox-Fu-Fol vs Fu-Fol 1º endpoint: OS Median OS mediana Ox-Fu-Fol 6,5 m Fu-Fol 3,2 m p: 0,014 P. III PANCREOX 3 108 pts FOLFOX vs FOLF mediana FOLFOX FOLF Median OS 6,1 m 9,9 m p: 0,02 1.- Oettle, ASCO-05 # 4031 2.- Pelzer. ASCO-08 # 4507 3.- Gill S, ASCO-2014 #4022

Cáncer de Páncreas metastásico M Benavides et al. Clin Transl Oncol DOI 10.1007/s12094-014-1177-7

Guion Introducción Hasta el 2010 F III positivos: FOLFIRINOX / GEM-Abraxane Segundas líneas En el 2013-2014 otros dos fracasos más..: CO-101, Ganitumumab pero en el 2014 datos prometedores MM-398,Inmunoterapia, GS 1C4D4, Ruxolitinib, Veliparib Conclusiones

Predictive Factors in Pancreatic Cancer hent1 Gem require hent1 to cross the plasma membrane Ventana hent1 assay (IHC): 66% low hent1 (primary=mts) hent1-low cells are resistant to gemcitabine 1 21 pts with Metastatic PC treated with Gem Low hent1 worse OS 2 Median OS 13 m Median OS 4 m 1.- Veltkamp et al. Oncologist. 2008;13:261 2.- Spratlin et al. Clin Cancer Res. 2004;10:6956 3.- Neptolemus JP et al, EPC Prague 2012

CO-101 Elaidic acid LEAP trial 367 pts Metastatic Panc Cancer hent1 (IHC) mandatory 64% low CO-101 Gem (30 min) 1º endpoint: OS Low hent1 pts All pts 2º endpoint: predictive value of hent1 No predictive value Poplin et al. J Clin Oncol 2013

GAMMA: Phase 3 Study of Ganitumab (AMG 479) in Combination with Gemcitabine in Metastatic Pancreatic Cancer GAMMA: Gemcitabine and Ganitumab in Metastatic Adenocarcinoma of the Pancreas N = 825, randomized 2:2:1 ratio * Key Inclusion Criteria Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas (AJCC Stage IV) ECOG PS of 0 or 1 Men or women 18 years of age Placebo Q2W + Gemcitabine Ganitumab 12 mg/kg Q2W + Gemcitabine Ganitumab 20 mg/kg Q2W + Gemcitabine Cycle repeated every 28 days (± 3 days) Primary Endpoint OS *Stratified by ECOG PS (0 or 1), and the presence of liver metastases (yes or no). On days 1 and 15 of each cycle Gemcitabine 1000 mg/m 2 days 1, 8, 15 of each cycle AE = adverse event, AJCC = American Joint Committee on Cancer, CR = complete response, DOR = duration of response, ECOG PS = Eastern Cooperative Oncology Group Performance Status, FACT-Hep-HS = FACT Hepatobiliary Questionnaire-Hepatobiliary subscale, ORR = objective response rate, OS = overall survival, PFS = progression-free survival, PK = pharmacokinetic, PR = partial response, Q2W = every 2 weeks, SD = stable disease, TTP = time to progression, Secondary Endpoints Available from http://www.clinicaltrials.gov. Accessed June 18, 2011. Data on file, Amgen. Study 20060540 Protocol. PFS 12-month survival rate Incidence of AE, laboratory abnormalities and immunogenicity OS within a biomarker-enriched sub-population ORR, TTP, DOR, Disease control (PR+CR+SD) Ganitumab dose exposure, dose intensity and PK parameters Change in hepatobiliary symptoms using FACT-Hep HS For reactive use only. 2011 Amgen Inc. All rights reserved.

MM-398 (nal-iri) (nanoliposomal irinotecan ) F. III NAPOLI-1 405 pts Metastatic Panc Cancer 2nd line after Gem MM-398/FU/Fol FU/Fol MM-398 1º endpoint: OS(median) 6.1 m HR 0.67;p 0.012 4.2 m p 0.94 4.9 m

CY/GVAX CRS-207 Rand P II: GVAX+CRS207 vs GVAX ASCO-GI 2013 Mesothelin specific T Cell Responses Mesothelin: broadly overexpressed in Pancreatic Cancer 1 1.- Hassan et al. Eur J Cancer 2008

Rand P II: GVAX+CRS207 vs GVAX ASCO-GI 2013 OS, 1º endpoint P.II Rand NCT 02004262 Adv Panc Canc 2nd line 1º endpoint OS GVAX+CRS207 QT CRS207

GS-1C4D4 (monoclonal anti-psca) Rand. F. II 1 196 pts Metastatic Panc Cancer GS-1C4D4-Gem Gem 1º endpoint: 6 m OS 60.9 % p 0.03 40.4 % median OS 7.6 m 5.5 m RR 21.6 % 13.1 % 1.- Wolpin BM et al. Ann Oncol 2013

Ruxolitinib (inhibidor de JAK-1 y JAK-2) F. II randomizado 127 pts Metastatic Panc Cancer 2nd line after Gem Cape-Ruxolitinib Cape- placebo 1º endpoint: OS(median) 4,5 m HR 0.79; p 0.25 4,3 m Hurwitz H et al. ASCO-2014, #4000

Veliparib (Inhibidor de PARP) Mut en BRCA 1,2 5-8% de C.Páncreas F IB : Cis-Gem-Veliparib 1 9 pts con mut BRCA 1,2: 5 RP y 4 EE F II rand Cis-Gem +/- Veliparib en pts con Mut en BRCA en marcha (NCT01585805) 1.- O Reilly EM, et al. ASCO 2014, #4023

Biologics in Panc Cancer / Biomarkers Hedgehog Inhibitors: IPI-926 Notch Pathway:Demcizumab Multi TKI: dasatinib, AZD0530 Antiangiogenics: VEGF-TRAP, PTK 787/ZK PI3K Inhibitors: BAY80-6946 HDAC Inhibitors: Depsipéptido, MGCD0103 Apoptosis targets: conatumumab, AEG 35156,CS-1008 HSP90 inhibitors: KOS-953, IPI-504 Hypoxia activated agents: TH 302 Inmunotherapy: GVAX/CRS207 Other.

Conclusiones

Conclusiones Mal pronóstico. Pts óptimos/subóptimos/frágiles Hasta el 2010: Gem; Gem-erlo; Gem-Cap; Gem-Ox Desde el 2010 dos importantes F III positivos FOLFIRINOX MPACT: Gem-Nabpaclitaxel Pendiente el análisis de SPARC en MPACT Papel de las segundas líneas en pacientes seleccionados. FOLF vs FOLFOX? (CONKO 003 y PANCREOX) Posible papel del MM-398 2013-14 0tros dos fracasos: CO-101, Ganitumumab En el 2014 resultados prometedores: Inmunoterapia, anti-psca, anti JAK y anti PARP Múltiples nuevas dianas en desarrollo necesidad de biomarcadores

Gracias Gracias