Quimioteràpia per l'adenocarcinoma de pàncrees. Com són de bons els resultats? Que esperem en un futur pròxim?

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1 Quimioteràpia per l'adenocarcinoma de pàncrees. Com són de bons els resultats? Que esperem en un futur pròxim? Carles Pericay (Oncologia. Hospital Parc Taulí)

2 Projecting Cancer Deaths to 2030 Lung Rahib et al, Cancer Res 2014

3 1ª línia al càncer de pàncrees

4 Treating advanced pancreatic cancer: the story so far Pre-1997: 5-fluorouracil monotherapy 1997: GEM monotherapy shown to improve survival, 1 becomes standard of care for advanced PC 2000s: Various GEM-based combinations fail to demonstrate clinically significant survival benefit 2007: Erlotinib/GEM shows significant survival benefit vs GEM, 2 approved in Europe 2011: FOLFIRINOX shows significantly improved survival and response rates vs GEM, 3 but is associated with greater toxicity 2013: MPACT Trial of nab-p + Gem as a backbone therapy of metastatic Pancreatic Cancer 1. Burris HA, et al. J Clin Oncol. 1997;15: ; 2. Moore MJ, et al. J Clin Oncol. 2007;25: ; 3. Conroy T, et al. N Engl J Med. 2011;364: GEM, gemcitabine; FOLFIRINOX, oxaliplatin, irinotecan, fluorouracil, leucovorin; PC, pancreatic cancer The FOLFIRINOX regimen has not been approved by the EMA for treatment of pancreatic cancer.

5 Chemotherapy for advanced disease Gemcitabine 5FU CBR 23.8% 4.8% Median TTF 9 weeks 4 weeks Median 5.6 months 4.4 months survival PR and SD for 44.4% 19% >8/52 1 year survival 18% 2% Burris et al JCO 1997

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8 Locally advanced/metastatic pancreatic cancer NCIC CTG PA.3 Overall Survival HR = 0.81* 95% CI (0.67, 0.97) P = Percentage Gemcitabine + Placebo Median = 5.91 months 1 Year Survival = 17% Gemcitabine + Erlotinib Median = 6.37 months 1 Year Survival = 24% Time (Months) * Adjusted for PS, pain and disease extent at randomization Moore JCO 2007

9 Study Design Planned N = 842 Stage IV No prior treatment for metastatic disease KPS 70 Measurable disease Total bilirubin ULN Primary Endpoint: OS Secondary Endpoints: PFS and ORR by Independent Review (RECIST) Safety and Tolerability by NCI CTCAE v3.0 nab-paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 2 IV qw 3/4 weeks 1:1, stratified by KPS, region, liver metastasis Gemcitabine 1000 mg/m 2 IV qw for 7/8 weeks then qw 3/4 weeks With 608 events, 90% power to detect OS HR = (2 sided α = 0.049) 1 interim analysis for futility Treat until progression CT scans every 8 weeks Von Hoff et al., ASCO GI 2013

10 Prodige 4 - ACCORD 11 trial design Metastatic pancreatic cancer 342pts ECOG PS 0-1 R A N D O M I Z E Folfirinox Gemcitabine for both arms: CT scans: obtained every 2 months 6 months of chemotherapy recommended Stratification : center performance status: 0 versus 1 location of the tumor: head versus other location of the primary

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15 2ª línia al càncer de pàncrees

16 BSC versus OFF: folinic acid 200 mg/m2 followed by 5-fluorouracil 2 g/m2 (24 h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m2 on days 8 and 22 every 43 days + BSC 165pt: 23 pt/23pt 1ªlínea: Gemcitabina SLP 4,57 m(bsc) vs 4,75m(OFF) 2ªlínea: OFF- 4,82m vs BSC- 2,30m (p=0,008)

17 Rama A: 5FULV2 + Cisplatino 50mg/m2 /2 semanas (102 pt) Rama B: Gemcitabina 1000mg/m2/semana/7 semanas /8 (100 pt) SLP: 3,4 m vs 3,5 m SG: 6,7 m vs 8,03 m

18 2ª linea (61%): Rama A: 68% Rama B: 55% 2ª linea por progresión: SLP1: 2,6m vs 3,6m SLP2: ITT. 5,03m vs 5,8m QT 2ª: 6,03 m vs 8,8 m

19 CONKO 003 FF OFF PFS from start 2 nd line Rx 9 weeks 13 weeks (log rank p =0.012) OS from start 2 nd line Rx 13 weeks 26 weeks (log rank p=0.014)

20 NAPOLI-1:Diseño del Estudio Cáncer de páncreas metastásico Recepción de gemitabina R Estratificados: - Albúmina - PS - Región Objetivo 1º:SG Objetivos 2º:SLP, tasa de respuestas, respuesta de Ca 19.9 y seguridad

21 NAPOLI-1:Resultados: SG

22 NAPOLI-1:Objetivos secundarios Variable SLP mediana,meses ( IC 95%) Tasa de respuestas,% (IC 95%) Reducción Ca 19.9, respuesta/evaluables MM FU/Lv (n:117) 3,1 (2,7-4,2) 16 (9,6-22,9) 36 (27/76) 5Fu/LV (n:119) 1,5 (1,4-1,8) 1 (0-2,5) 12 (8/69)

23 Efectos Secundarios

24 Biologia al càncer de pàncrees

25 Core signaling pathways in PC Iacobuzio-Donahue CA, Gut 2012

26 5- New agents/strategies on the horizon in pancreatic cancer: Philip A. Philip, MD, PhD, FRCP Garrido-Laguna and Hidalgo, Nature Reviews 2015

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31 Insulin-like Growth Factor Receptor (IGF1R) in PC The IGF1R axis has been shown to be a key signalling pathway in the growth and proliferation of malignant cells including PC Ganitumab is an anti-igf1r monoclonal antibody initially developed in patients with advanced pancreatic cancer. Two phase III studies in patients with locally advanced and metastatic disease were negative Kindler HL et al. Ann Oncol 2012

32 IGFR-1R inhibitors have more activity in patients with elevated free IGF-1 serum levels MM-141 is an IGF-1R and ErbB3 directed antibody. A phase II is planned in first line mpc with positive serum levels of free IGF-1 with MM-141+ Gem+ nab-paclitaxel vs Gem+nab-paclitaxel.

33 Stroma and PC Hidalgo and N Engl J Med 2010

34 Enzymatic targeting of the stroma Hyaluronic Acid (Hyaluronan): large linear glycosaminoglycan, composed of repeating N-acetyl glucosamine and glucuronic acid units Increase tumor interstitial pressure Compresses vasculature PEGPH20 (PEGylated Recombinant Human Hyaluronidase) Provenzano PP et al, Cancer Cell, 2012

35 Phase 1b Study: Increased PFS and OS in High HA Patients treated with PEGPH20 + Gemcitabine Hingorani, ASCO GI 2015

36 PFS in HA-High Patients Hingorani, ASCO 2015

37 OS in HA-High Patients Hingorani, ASCO 2015

38 ORR and DoR in HA-HIGH Patients (Blinded Central review Hingorani, ASCO 2015

39 Targeting the Notch pathway Notch Pathway Receptors: - Notch-1, -2, -3 & -4 Ligands: DLL-1, -3 & -4 JAG-1 & -2 Mediates intercellular signaling in stem-cell self-renewal, proliferation and differentiation Activation of Notch-2 & -3 has been implicated in several tumor types including PC Yabuuchi S et al. Cancer Lett 2013

40 Targeting the Notch pathway Demcizumab is humanized IgG2 antibody that binds to DLL4 (ligand that contributes to Cancer Stem Cells self-renewal and vascular development) Phase Ib completed, presented at ESMO Phase II in Gem +nab-paclitaxel +/- demcizumab Hidalgo et al, presented at ESMO 2014

41 Targeting the Notch pathway PR 41%, SD 45%, Clinical benefit rate 86% Hidalgo et al, presented at ESMO 2014

42 Targeting the Notch pathway Trial MOA Development Phase Status Line of Therapy Tarextumab (OMP-59R5) Abraxane + Gem Anti-Notch 2,3 Pathway Inhibitor Phase Ib/II Currently Recruiting 1st line advanced panc Demcizumab Abraxane + Gem Cancer Stem cell target DLL-4 mab Phase I/II Phase I completed Phase II in st line advanced panc

43 Tumor microenvironment: Subregional hypoxia Blood Vessels Hypoxic region Necrosis Hypoxia is a feature of solid tumors, including pancreatic cancer Hypoxic conditions are created by rapid cell proliferation and development of a disordered vascular network Tumor hypoxia is associated with a poor prognosis, aggressive phenotype, metastasis and relapse Pimonidazole staining (hypoxic regions) Blood vessels 150µm Minchinton A & Tannock I. Nat Rev Cancer 2006;6: Used with permission from the author 43 TH-302 Scientific Story Confidential Information 19 November 2012

44 Chemotherapy targets oxygenated tumor component Hypoxia leads to a more aggressive, invasive, metastatic phenotype, and is associated with treatment failure as conventional anticancer therapies struggle to penetrate hypoxic areas Vessels Doxorubicin Hypoxia Minchinton AI, Tannock IF. Nat Rev Cancer Aug;6(8): Used with permission from the author 44 TH-302 Scientific Story Confidential Information 19 November 2012

45 Evofosfamide (TH-302) in combination with gemcitabine in previously untreated patients with metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma: primary analysis of the randomized, double-blind phase III MAESTRO study

46 Randomized, double-blind phase III MAESTRO trial: design

47 Overall survival

48 Progression-free survival

49 ALGORITMO PACIENTE BUEN ECOG TUMOR CUERPO-COLA NO PROBLEMAS BILIARES-STENT PACIENTE BUEN-INTERMEDIO ECOG TUMOR CUERPO-COLA TUMOR CABEZA SIN PROBLEMAS BILIARES 1ª LINEA FOLFIRINOX NAB-PACLITAXEL + GEMCITABINA Gemcitabina + Erlotinib 2ª LINEA GEM Monoterapia GEM CAPE/CISPL Nab-Paclitaxel GEM Monoterapia GEM+CAPE FOLFOX/FOLFIRINOX MM-398+FUFA

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