Cáncer de Páncreas estadio IV

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 60.139 nuevos casos, con 64.801 muertos En USA en 2010 36.800 muertos Incidencia en aumento Etiología desconocida: obesidad, pancreatitis crónica, cirrosis hepática, alcohol, factores genéticos, tabaco, café Baja tasa de curaciones Tasa global de supervivencia a los 5 años <5% Enfermedad metastática tiene un pronóstico muy pobre Mediana Supervivencia Global sin tratamiento es 3-6 meses No posibilidad de screening eficaz 1. 1.Hariharan D. HPB (Oxford). 2008;10(1):58-62. 2. 2.Cancer Facts & Figures 2010. Atlanta, Ga: American Cancer Society; 2010. 3. 3.Willett CG, et al. J Clin Oncol. 2005;23(20):4538-4544.

CLINICA Síntomas iniciales escasos diagnóstico en estadios avanzados Tumor de cabeza el más frecuente - Ictericia afecta al coledoco intrapancreático Tumor de cuerpo y cola diagnóstico más tardío - Dolor epigástrico profundo - Síndrome constitucional, pérdida de peso y anorexia Diabetes de nueva aparición 10 % de pacientes

ESTADIFICACIÓN Estadio IA (T1N0) Estadio IB (T2N0) Estadio IIA (T3N0) ENFERMEDAD RESECABLE Estadio IIB (T1,2,3N1) Estadio III (T4N0,1) Estadio IV (TNM1) L. AVANZADO IRRESECABLE quimioterapia

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer (113 randomized controlled trials, 9970 patients) Chemotherapy versus best supportive care (BSC) Fluorouracil (FU) vs FU combination chemotherapy Gemcitabine vs FU Gemcitabine vs gemcitabine combination chemotherapy - The primary end point was overall survival (OS) - Chemotherapy improved survival compared with BSC (HR=0.64;95% CI, 0.42-0.98) - FU-based combination no improved OS than FU alone (HR=0.94;95% CI, 0.82-1.08) - Insufficient survival difference in Gem vs FU (HR=0.75;95% CI, 0.42-1.31) - Improved survival after Gem combination vs Gem alone (HR=0.91;95% CI, 0.85-0.97) -There was a significant survival benefit for chemotherapy over BSC and gemcitabine combinations over gemcitabine alone. This supports the use of gemcitabine-based combination chemotherapy in the treatment of advanced pancreatic cancer Sultana A, et al. J Clin Oncol 2007

GEMCITABINA Meta-analysis of randomized trials: Benefit from gemcitabine-based combination chemotherapy (15 randomized controlled trials, 4465 patients) - Gem is a standard treatment. Gem-based combination chemotherapy can improve efficacy? - The primary end point overall survival (OS) - Gem + Chemotherapy (HR of 0.91 (95% CI: 0.85-0.97, p = 0.004) significant > 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 OS > with combination chemotherapy (HR=0.76; 95% CI: 0.67-0.87; p< 0.0001) - Patients with poor PS 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 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/m 2 Irinotecan 180mg/m 2 5FU bolus 400mg/m 2 Ci 2400mg/m 2 46h Phase II/III 342 patients ECOG 0-1 FOLFIRINOX (N=171) vs GEM 1000mg/m 2 (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/m 2 followed by nab-paclitaxel 100, 125, or 150 mg/m 2 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/m 2 + Gem 1000 mg/m 2 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 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. Upon infusion, paclitaxel exits Cremophor micelles slowly compared with the dissolution of nab paclitaxel

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-paclitaxe l containing 0.3% fluorescent marker Imaging under Hg-lamp with 500 550 nm bandpass excitation

nab-paclitaxel Demonstrates Greater Tumor Selectivity Relative concentration (nab-paclitaxel/conventional paclitaxel) 1.5 1.0 0.5 0 nab -Paclitaxel > nab -Paclitaxel nab -Paclitaxel = < Conv paclitaxel Conv paclitaxel Conv paclitaxel 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/m 2 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% Median PFS: 8.0 months Median OS: 13.6 months In patients with < 50% decrease in CA19-9 levels ORR: 33% Median PFS: 3.6 months Median OS: 6.5 months a In patients receiving 125 mg/m 2 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/m 2 + gemcitabine 1000 mg/m 2 - 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 Primary endpoint: OS Secondary endpoints: PFS and ORR by independent review (RECIST) Safety and tolerability by NCI CTCAE v3.0 431: nab-paclitaxel 125 mg/m 2 IV qw 3/4 weeks + Gemcitabine 1000 mg/m 1:1, stratified by KPS, 2 IV qw 3/4 weeks region, liver metastasis 430: 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 = 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 P Value Overall response rate Independent review % (95% CI) 23 (19.1-27.2) 7 (5.0-10.1) <0.001 Investigator assessment % (95% CI) 29 (25.0-33.8) 8 (5.3-10.6) 3.3 10 16 Disease control rate independent review % (95% CI) 48 (43.0-52.6) 33 (28.4-37.5) 7.2 10 6 Von Hoff DD, et al. N Engl J Med. 2013

Phase III MPACT: safety results 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,% Neutropenia Leukopenia Thrombocytopenia Anemia 38 31 13 13 27 16 9 12 Patients who received growth factors, % 26 15 Febrile neutropenia, % 3 1 Grade 3 nonhematologic Aes (> 5% of patients,%) Fatigue Peripheral neuropathy Diarrhea 17 17 6 7 < 1 1 Von Hoff DD, et al. N Engl J Med. 2013

Phase III MPACT: Conclusions Survival with nab-paclitaxel + gemcitabine is superior to gemcitabine: Median OS: 8.5 vs 6.7 months; HR 0.72; P = 0.000015 Long-term survival: 1 year: 59% increase (35% vs 22%) 2 years: doubled (9% vs 4%) Significant improvement in PFS, ORR, and all other efficacy endpoints Serious life-threatening toxicity not increased; AEs acceptable and manageable nab-paclitaxel + gemcitabine, a new standard for metastatic pancreatic cancer, is superior to gemcitabine alone and could become the backbone for new regimens Von Hoff DD, et al. N Engl J Med. 2013

Guidelines - NCCN

Treatment Options: Overview of NCCN Guidelines - Metastatic: Acceptable chemotherapy combinations for patients with good performance status FOLFIRINOX (Category 1) Gemcitabine + nab-paclitaxel (Category 1) Gemcitabine + erlotinib (Category 1) Gemcitabine + capecitabine (Category 2A) Gemcitabine + cisplatin (Category 2A) Fixed-dose rate gemcitabine + docetaxel + capecitabine (GTX regimen) (Category 2B) Fluropyrimidine + oxaliplatin (Category 2B) - Metastatic: Acceptable monotherapy options for patients with poor performance status Gemcitabine at 1000 mg/m 2 over 30 minutes, weekly for 3 weeks every 28 days (Category 1) Capecitabine or continuous infusion 5-FU (Category 2B) - The NCCN strongly encourages patients with pancreatic cancer to enroll in clinical trials 5-FU, 5-fluorouracil; FOLFIRINOX, 5-FU/LV + irinotecan + oxaliplatin; LV, leucovorin; NCCN, National Comprehensive Cancer Network. 1.NCCN Clinical Practice Guidelines in Oncology, Pancreatic Adenocarcinoma, v1.2013.

ESMO/WCGC recommendations for the first-line treatment of metastatic pancreatic cancer Recommendations: 1. FOLFIRINOX or the nab-paclitaxel + gemcitabine are reference treatments in patients ECOG PS 0-1, <75 years old, no/limited comorbidities, serum bilirubin <1.5 ULN) 10 35% of the population The anticipated benefits may be greater with FOLFIRINOX although toxicity is considered higher for FOLFIRINOX 2. Combination of gemcitabine with erlotinib, platinum derivatives or fluoropyrimidines represent options in ECOG PS 0-1 patients, who are not considered candidates for FOLFIRINOX or nab-paclitaxel 20 30% of the population 3. Gemcitabine monotherapy may be reserved for patients with poor performance status, the elderly and/or significant comorbidities 20 30% of the population Verslype et al. Ann Oncol 2013;24(Suppl 4):iv5-10

Nab-paclitaxel + Gem or FOLFIRINOX? Summary results of MPACT study and FOLFIRINOX Efficacy parameters Nab-paclitaxel + FOLFIRINOX gemcitabine Median overall survival 8.7 months 11.1 months Median progression free survival 5.5 months 6.4 months Response rate 23% 32.9% Toxicities of MPACT study and FOLFIRINOX Adverse events (grade 3) Nab-paclitaxel + FOLFIRINOX gemcitabine Fatigue 17% 24% Diarrhea 6% 13% Neutropenia 38% 46% Febrile neutropenia 3% 5% Peripheral neuropathy 17% 9% Thrombocytopenia 13% 9%

Farmacoeconomía

FOLFIRINOX Gemcitabina Gemcitabina Abraxane Oxaliplatino Leucovorin Irinotecan 5 FU (bolo) 5 FU (infusión contínua) PVL 50.20 50.20 240 165.2 6.8 245 3.67 3.67 PVL 7,5% RD 8/2010 (marcas) 222 mg/vial o mg/comp 1000 1000 100 100 100 500 100 100 Pauta de tratamiento (mg/m²) 1000 1000 125 85 400 180 400 2400 Superficie corporal (m²) 1.7 1.7 1.7 1.7 1.7 1.7 1.7 1.7 Dosis/dia (mg) 1700 1700 212.5 170 680 306 680 4080 Viales/dia 1.7 1.7 2 1.7 6.8 0.6 6.8 40.8 Dias tratamiento/ciclo 3 3 3 2 2 2 2 2 Numero de ciclos (PFS) 3.7 5.5 5.5 6.4 6.4 6.4 6.4 6.4 Coste tratamiento (reutilización vial) 947.27 1,408.11 7783.88 3594.75 592 1919.23 319 1916.62 Coste tratamiento (reutilización vial) 947 9191,99 8341,91

Abraxane Gemcitabina Tarceva (erlotinib) Gemcitabina PVL 240 50.2 2045.4 50.2 PVL 7,5% RD 8/2010 (marcas) 222 1892 Mg per vial o mg/comp 100 1000 150 1000 36 Pauta de tratamiento (mg/m2) 125 1000 100 1000 Superficie corporal (m2) 1.7 1.7 1.7 1.7 Dosis/día (mg) 212.5 1700 100 1700 Viales/día 2.1 1.7 1.7 Días tratamiento/ciclo 3 3 28 3 Número de ciclos 5.5 5.5 3.75 3.75 Coste por tratamiento (reutilización vial) 7,783.88 1,408.11 6,622.35 Coste por tratamiento (reutilización vial) 9191,99 7582,43 960.08

COSTE DE ADMINISTRACIÓN NAB-PACLITAXEL+GEMCITABINA vs FOLFIRINOX Coste de administración de nab-paclitaxel/gemcitabina vs FOLFIRINOX es un 44% inferior FUENTE DE DATOS TABLA: Tiempos de administración validados por un experto clínico Costes de administración publicados en la base de datos de costes sanitarios e-salud

COSTE DE LOS FACTORES NAB-PACLITAXEL+GEMCITABINA vs FOLFIRINOX El coste de los factores de crecimiento es un 75% inferior con nab-paclitaxel/gemcitabina vs folfirinox FUENTE DE DATOS TABLA: % de pacientes estimado a partir del ensayo Fase III (MPACT Von Hoff DD, et al. N Engl J Med. 2013) y estimación de experto clínico para Folfirinox Precios de los fármacos (PVL) publicados por el Ministerio de Sanidad

1ª Línea CON QUE GUIA NOS QUEDAMOS? Valorar ensayo clínico FOLFIRINOX en ECOG 0 o IK 90-100 Gemcitabina+Abraxane en ECOG 1 o IK > 70 Gemcitabina en ECOG 2 2ª Línea Valorar ensayo clínico FOLFIRINOX Gemcitabina+Abraxane si IK > 70 Gemcitabina+Abraxane FOLFIRINOX, FOLFOX ó Xelox o capecitabina ó 5FU IC en función del ECOG. 3ª Línea Valorar ensayo clínico, Ensayo Fase I Gemcitabina+Abraxane FOLFOX, Xelox,Capecitabina, 5FU IC FOLFIRI en función del ECOG. FOLFOXIRI Gemcitabina+Abraxane No línea

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