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Cáncer de Páncreas estadio IV Barcelona 19 de noviembre 2013 Dra. Antonieta Salud Salvia Servicio de Oncología Médica Hospital Universitari Arnau de Vilanova de LLeida
EPIDEMIOLOGIA • • • •
4ª causa de muerte por cáncer en países desarrollados En Europa en 2000 Æ 60.139 nuevos casos, con 64.801 muertos En USA en 2010 Æ 36.800 muertos Incidencia en aumento
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Etiología desconocida: obesidad, pancreatitis crónica, cirrosis hepática, alcohol, factores genéticos , tabaco, café
• • •
Baja tasa de curaciones Tasa global de supervivencia a los 5 años OS - Platinum-based combinations (HR of 0.85 (95% CI: 0.76 - 0.96, p = 0.010) - Fluoropyrimidine-based combinations (HR of 0.90 (95% CI: 0.81 - 0.99, p = 0.030) - Information of performance status (PS) was performed, 5 trials, 1682 patients. - Patients with good PS Æ OS > with combination chemotherapy (HR=0.76; 95% CI: 0.67-0.87; p< 0.0001) - Patients with poor PS Æ combination chemotherapy is ineffective (HR=1.08; 95% CI: 0.90-1.29, p=0.40)
Significant survival benefit with Gem+platinum analogs or Gem+fluoropyrimidines Based on a preliminary subgroup analysis (38% of all patients included in this metaanalysis), patients with a good PS appear to benefit from Gem-based cytotoxic combinations, whereas patients with a poor PS seem to have no survival benefit from combination chemotherapy.
Heinemann V et al. BMC Cancer 2008
OXALIPLATINO • After relapse in the adjuvant setting • GEMOX vs Gem: GERCOR and GISCAD trial: - RR 26.8% vs 17.3%, PFS 5.8 vs 3.7m (p=0.04) - OS: 9 vs 7 meses (p=0.14) • XELOX: mOS 23w, PFS 9.9w (2ª línea) • FOLFOX: - mTTP 12w, OS 22w, Disease control rate 49% - CONKO 003 Æ 2nd line FOLFOX vs BSC: OS 4,82m vs 2,3m Louvet et al. J Clin Oncol 2005 Xiong HQ, et al. Cancer 2008 Pelzer U, et al.Onkologie 2009 Pelzer U, et al. Eur J Cancer 2011.
FOLFIRINOX Oxaliplatin 85mg/m2 Irinotecan 180mg/m2 5FU bolus 400mg/m2 Ci 2400mg/m2 46h
– – – – –
Phase II/III 342 patients ECOG 0-1 FOLFIRINOX (N=171) vs GEM 1000mg/m2 (N=171) Median number cycles • FOLFIRINOX 10 (1-47) vs GEM 6 (1-26) – Disease progression before 12 cycles • FOLFIRINOX 54.6% vs GEM 79.9% Conroy T, et al. N Engl J Med 2011
FOLFIRINOX
Conroy T, et al. N Engl J Med 2011
FOLFIRINOX mOS: 11.1m vs 6.8m
mPFS: 6.4m vs 3.3m
Conroy T, et al. N Engl J Med 2011
FOLFIRINOX
Conroy T, et al. N Engl J Med 2011
nab- PACLITAXEL
nab-Paclitaxel + Gemcitabine In Patients With Metastatic Pancreatic Cancer Study Design Open label phase I/II study in chemotherapy-naive patients with metastatic adenocarcinoma of the pancreas Phase I gemcitabine 1000 mg/m2 followed by nab-paclitaxel 100, 125, or 150 mg/m2 IV on days 1, 8, and 15 every 28 days using standard 3+3 phase I dose-escalation design
Phase II accrual continued at the MTD to ≥ 42 patients to evaluate efficacy and safety of the combination
IV, intravenous; MTD, maximum tolerated dose.
Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554.
nab-Paclitaxel + Gemcitabine in Pancreatic Cancer • - Preclinical models – . nab-Paclitaxel (nab-P) active as single agent – . Synergistic activity in combination with gemcitabine – nab-Paclitaxel improved intratumoral concentration of gemcitabine
• - In a 67-patient phase I/II trial of nab-P + Gem – . MTD: nab-P 125 mg/m2 + Gem 1000 mg/m2 days 1, 8, and 15 every 28 days – . Promising activity at MTD • ORR: 48% • Median PFS: 7.9 months • Median OS: 12.2 months
Gem, gemcitabine; MTD, maximum tolerated dose; OS, overall survival. 1. Von Hoff DD, et al. J Clin Oncol. 2011;29:4548-4554. 2. Frese KK, et al. Cancer Discov. 2012;2:260-269.
Phase I/II nab- PACLITAXEL + GEM PET-TC
SPARC expression was evaluated by IHC by IHC
Von Hoff, et al. J Clin Oncol 2011
Personalized Treatment: SPARC as a Biomarker Marker
Effect • . High SPARC mRNA expression in the stroma was associated with a poorer prognosis than low SPARC, historically
SPARC
• . Inverse correlation between SPARC expression in distal stromal cells and survival • . Stromal SPARC expression may be an important marker of early activity of gemcitabine plus nabpaclitaxel combination regimens
PaC, advanecd pancreatic cancer; SPARC, secreted protein acidic and rich in cysteine.
1.Infante JR, et al. J Clin Oncol. 2007;25:319-325. 2.Miyoshi K, et al. Anticancer Res. 2010;30:867-871. 3.Mantoni TS, et al. Cancer Biol Ther. 2008;7:1806-1815. 4.Von Hoff D, et al. J Clin Oncol. 2011;29:4548-4554.
nab-Paclitaxel + Gemcitabine In Patients With Metastatic Pancreatic Cancer
Changes in Tumor Stroma in Xenograft Model
• . The stromal content of 2 gemcitabine resistant tumors in each of the treatment groups was analyzed by IHC for collagen type1 fibers • . nab-Paclitaxel treatment was associated with depletion of the desmoplastic stroma accompanied by dilated blood vessels in the tumor milieu
• . These results suggest that reduction in tumor stroma and the accompanied increase in vascularization facilitated the delivery of gemcitabine to these tumors
IHC, immunohistochemistry.
1. Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554.
nab-Paclitaxel Leads to a Higher Bioavailability of Unbound Paclitaxel vs Conventional Paclitaxel Nanoparticle Mean size 130 nm
Albumin-bound paclitaxel + free paclitaxel Hydrodynamic diameter ~ 7 nm
nab-Paclitaxel’s ~ 10-fold higher maximal plasma concentration and ~3-fold higher AUC of free paclitaxel may contribute to higher tumor accumulation
Upon infusion, paclitaxel exits Cremophor® micelles slowly compared with the dissolution of nab paclitaxel Gardner et al. Clin Cancer Res. 2008;14(13):4200-4205. Desai et al. Clin Cancer Res. 2006;12:1317-1324 Sparreboom A et al. Cancer Res. 1999;59[7]:1454-1457.
nab-Paclitaxel Concentrates in Tumors in Mice
Fluorescently-labeled nab-paclitaxel is injected
1 min after iv injection
Imaged tumor Mouse tumour model 15 min after iv injection
Nab-paclitaxel® containing 0.3% fluorescent marker Imaging under Hg-lamp with 500–550 nm bandpass excitation
Relative concentration (nab-Paclitaxel/Conventional paclitaxel)
nab-Paclitaxel Demonstrates Greater Tumor Selectivity
1.5
1.0
nab®-Paclitaxel
>
Conv paclitaxel
nab®-Paclitaxel
=
Conv paclitaxel
nab®-Paclitaxel
<
Conv paclitaxel
0.5
0 nab® is a registered trademark of Celgene Corporation. conv, conventional.
• Comparative tissue distribution (ratio) of radiolabeled drug in mice bearing human breast tumor xenografts 1 hour after dose 1. Hawkins et al. AACR. 2003. Poster 1189. 2. Scheff . Community Oncol. 2008;5(7 suppl 8):7-13.
nab-Paclitaxel + Gemcitabine In Patients With Metastatic Pancreatic Cancer Changes in CA19-9 • In the 125 mg/m2 nab-paclitaxel cohort, 92% of evaluable patients had ≥ 20% decrease in CA19-9 levels • In patients with ≥ 50% decrease in CA19-9 levels –
ORR: 62%
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Median PFS: 8.0 months
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Median OS: 13.6 months
• In patients with < 50% decrease in CA19-9 levels
a
–
ORR: 33%
–
Median PFS: 3.6 months
–
Median OS: 6.5 months
In patients receiving 125 mg/m2 nab-paclitaxel + gemcitabine. CA19-9, carbohydrate antigen 19-9; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.
1. Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554.
nab®-Paclitaxel + Gemcitabine In Patients With Metastatic Pancreatic Cancer (Phase I/II) Conclusions • - nab-Paclitaxel + gemcitabine was generally well tolerated in patients with advanced pancreatic cancer – MTD established as nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 • - nab-Paclitaxel + gemcitabine demonstrated substantial activity in pancreatic cancer • - Preliminary analysis suggested that SPARC positivity correlated with increased median OS • - Decrease in serum CA19-9 levels ≥ 50% was observed in a majority of patients and correlated with median PFS and OS
CA19-9, carbohydrate antigen 19-9; MTD, maximum tolerated dose; OS, overall survival; PFS, progression-free survival; SPARC, secreted protein acidic and rich in cysteine.
Von Hoff D, et al. J Clin Oncol. 2011;29(34):4548-4554
Randomized Phase III Study of Weekly nab-Paclitaxel Plus Gemcitabine vs Gemcitabine Alone in Patients With Metastatic Adenocarcinoma of the Pancreas (MPACT)
DD Von Hoff, T Ervin, FP Arena, EG Chiorean, J Infante, M Moore, T Seay, SA Tjulandin, W Ma, MN Saleh, M Harris, M Reni, RK Ramanathan, J Tabernero, M Hidalgo, E Van Cutsem, D Goldstein, X Wei, J Iglesias, MF Renschler
Von Hoff DD, et al. N Engl J Med. 2013
Phase III MPACT: Study Design Planned N = 842 • Stage IV • No prior treatment for metastatic disease • KPS ≥ 70 • Measurable disease • Total bilirubin ≤ ULN
431: nab-Paclitaxel 125 mg/m2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m2 IV qw 3/4 weeks
1:1, stratified by KPS, region, liver metastasis
430: Gemcitabine 1000 mg/m2 IV qw for 7/8 weeks then qw 3/4 weeks
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) • One interim analysis for futility • Treat until progression • CT scans every 8 weeks
Von Hoff DD, et al. N Engl J Med. 2013
2 4
Phase III MPACT: Overall Survival
Von Hoff DD, et al. N Engl J Med. 2013
PFS by Independent Review
Von Hoff DD, et al. N Engl J Med. 2013
Phase III MPACT: Response Rate
Variable
nab-P + Gem n = 431
Gem n = 430
Overall response rate
23
7
(19.1 - 27.2)
(5.0 - 10.1)
5% of patients,%) Fatigue Peripheral neuropathy Diarrhea
17 17 6
7