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Quimioteràpia per l'adenocarcinoma de pàncrees. Com són de bons els resultats?
Que ̀ esperem en un futur pròxim?
Carles Pericay(Oncologia. Hospital Parc Taulí)
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 ratesvs GEM,3 but is associated with greater toxicity
• 2013: MPACT Trial of nab-P + Gem as a backbone therapy of metastaticPancreatic Cancer
1. Burris HA, et al. J Clin Oncol. 1997;15:2403‒2413; 2. Moore MJ, et al. J Clin Oncol. 2007;25:1960‒1966; 3. Conroy T, et al. N Engl J Med. 2011;364:1817‒1825.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.
Chemotherapy for advanced disease
Gemcitabine 5FU
CBR 23.8% 4.8%
Median TTF 9 weeks 4 weeks
Median survival
5.6 months 4.4 months
PR and SD for >8/52
44.4% 19%
1 year survival 18% 2%
Burris et al JCO 1997
* Adjusted for PS, pain and disease extent at randomization
HR = 0.81*95% CI (0.67, 0.97)P = 0.025
Gemcitabine + ErlotinibMedian = 6.37 months1 Year Survival = 24%
Gemcitabine + PlaceboMedian = 5.91 months1 Year Survival = 17%
Perc
enta
ge
0
20
40
60
80
100
Time (Months)0 6 12 18 24
Moore JCO 2007
Locally advanced/metastatic pancreatic cancerNCIC CTG PA.3 – Overall Survival
HR = 0.81*95% CI (0.67, 0.97)P=0.025
Gemcitabine + ErlotinibMedian = 6.37 months1 Year survival = 24%
Gemcitabine + PlaceboMedian = 5.91 months1 Year survival = 17%
Study Design
1:1, stratified by KPS, region, liver metastasis
Planned N = 842
• Stage IV• No prior treatment
for metastatic disease
• KPS ≥70 • Measurable disease• Total bilirubin ≤ULN
nab-Paclitaxel 125 mg/m2 IV qw 3/4 weeks
+Gemcitabine
1000 mg/m2 IV qw 3/4 weeks
Gemcitabine1000 mg/m2 IV qw for 7/8 weeks
then qw 3/4 weeks
Von Hoff et al., ASCO GI 2013
§ Primary Endpoint: – OS
§ Secondary Endpoints:– PFS and ORR by
Independent Review (RECIST)
§ Safety and Tolerability– by NCI CTCAE v3.0
• With 608 events, 90% power to detect OS HR = 0.769 (2–sided α = 0.049)
• 1 interim analysis for futility• Treat until progression• CT scans every 8 weeks
Prodige 4 - ACCORD 11 trial design
Stratification :
n centern performance status: 0 versus 1n location of the tumor: head versus other location of the primary
Metastaticpancreaticcancer
RANDOMIZE
Folfirinox
Gemcitabine6 months of
chemotherapyrecommended
CT scans: obtained
every 2 months
for both arms:
342ptsECOG PS 0-1
2002-2003165pt: 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)
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
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
2ª linea (61%): Rama A: 68%Rama B: 55%
2ª linea por progresión: SLP1: 2,6m vs 3,6mSLP2: ITT. 5,03m vs 5,8m
QT 2ª: 6,03 m vs 8,8 m
CONKO 003
FF OFF
PFS from start 2nd line Rx 9 weeks 13 weeks (log rank p =0.012)
OS from start 2nd line Rx 13 weeks 26 weeks (log rank p=0.014)
NAPOLI-1:Diseño del EstudioCáncer de páncreas metastásico
Recepción de gemitabina
Estratificados:- Albúmina- PS- Región
Objetivo 1º:SG
Objetivos 2º:SLP, tasa de respuestas, respuesta de Ca 19.9 y seguridad
R
NAPOLI-1:Objetivos secundarios
Variable MM-398+ 5FU/Lv(n:117)
5Fu/LV(n:119)
SLP mediana,meses( IC 95%)
3,1(2,7-4,2)
1,5(1,4-1,8)
Tasa de respuestas ,%(IC 95%)
16(9,6-22,9)
1(0-2,5)
Reducción Ca 19.9, respuesta/evaluables
36(27/76)
12(8/69)
Garrido-Laguna and Hidalgo, Nature Reviews 2015
5- New agents/strategies on the horizon in pancreatic cancer: Philip A. Philip, MD, PhD, FRCP
• The IGF1R axis has been shown to be a key signalling pathway in the growth andproliferation of malignant cells including PC
• Ganitumab is an anti-IGF1R monoclonal antibody initially developed in patientswith advanced pancreatic cancer.– Two phase III studies in patients with locally advanced and metastatic disease
were negative
Insulin-like Growth Factor Receptor (IGF1R) in PC
Kindler HL et al. Ann Oncol 2012
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 withMM-141+ Gem+ nab-paclitaxel vs Gem+nab-paclitaxel.
Enzymatic targeting of the stroma
Provenzano PP et al, Cancer Cell , 2012
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)
Hingorani, ASCO GI 2015
Phase 1b Study: Increased PFS and OS in High HA Patients treated with PEGPH20 + Gemcitabine
Yabuuchi S et al. Cancer Lett 2013
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
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 2014. •Phase II in 2015. Gem +nab-paclitaxel +/- demcizumab
Hidalgo et al, presented at ESMO 2014
Targeting the Notch pathway
Hidalgo et al, presented at ESMO 2014PR 41%, SD 45%, Clinical benefit rate 86%
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 completedPhase II in 2015
1st line advanced panc
Tumor microenvironment: Subregional hypoxia
• 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
Minchinton A & Tannock I. Nat Rev Cancer 2006;6:583-92.Used with permission from the author
150µm
Blood Vessels
Hypoxic region
Necrosis
Pimonidazole staining (hypoxic regions)Blood vessels
43 TH-302 Scientific Story Confidential Information 19 November 2012
Chemotherapy targets oxygenated tumor component
Vessels
Doxorubicin
Hypoxia
Minchinton AI, Tannock IF. Nat Rev Cancer. 2006 Aug;6(8):583-92.Used with permission from the author
• Hypoxia leads to a more aggressive, invasive, metastatic phenotype, and is associated with treatment failure as conventional anti-cancer therapies struggle to penetrate hypoxic areas
44 TH-302 Scientific Story Confidential Information 19 November 2012
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
ALGORITMO
PACIENTE BUEN ECOGTUMOR CUERPO-COLA
NO PROBLEMAS BILIARES-STENT
PACIENTE BUEN-INTERMEDIO ECOGTUMOR CUERPO-COLA
TUMOR CABEZA SIN PROBLEMAS BILIARES
FOLFIRINOXNAB-PACLITAXEL + GEMCITABINA1ª LINEA
2ª LINEA GEM MonoterapiaGEM CAPE/CISPL
Nab-Paclitaxel
GEM MonoterapiaGEM+CAPE
FOLFOX/FOLFIRINOXMM-398+FUFA
Gemcitabina+ Erlotinib