Avances recientes en el cáncer de páncreas avanzado. P. García Alfonso Jefe de Sección Oncología Médica HGU Gregorio Marañón de Madrid

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1 Avances recientes en el cáncer de páncreas avanzado P. García Alfonso Jefe de Sección Oncología Médica HGU Gregorio Marañón de Madrid

2 Pancreatic Cancer: Incidence & Mortality Siegel R, et al. CA Cancer J Clin. 2012;62:10-29.

3 3 Pancreatic Cancer Stage Distribution and Survival in the United States Less than 20% of patients have disease that is resectable at diagnosis 2 The median survival for unresectable disease (LAPC or MPC) is typically 3 to 18 months 3 a Based on restaging of patients in the National Cancer Institute s database who underwent pancreatectomy from 1992 to LAPC, locally advanced pancreatic cancer; MPC, metastatic pancreatic cancer. 1. SEER Stat Fact Sheets: Pancreas. Accessed November 7, Hidalgo M. N Engl J Med. 2010;362: O Reilly M. Gastrointest Cancer Res. 2009;3:S11-S15.

4 NIH-PA Author Manuscript NIH-PA Author Manuscript Refractario a tratamiento - Diagnóstico tardio - Neoplasia muy heterogénea. Pancreatic Cancer Genome Project: 63 alteraciones genéticas de media por tumor (Jones S et al. Science 2008) Jones et al. Page 11 - Mutaciones of the de 24 cancers. KRAS G12D en el 70% 90% - Subtipos moleculares Fig. 2. Number of genetic alterations detected through sequencing and copy number analyses in each

5 Key Milestones in the Treatment of Pancreatic Cancer FDA Approval for MPC 1 FOLFIRINOX 2011 MPC, metastatic pancreatic cancer, PDAC, pancreatic ductal adenocarcinoma. 1. Drugs@FDA.gov. Accessed June 20,

6 Cáncer de Páncreas: QT vs Tratamiento Sintomático Meta-análisis QT vs Tto sólo sintomático (7 estudios, 432 pts) Mejoría en Supervivencia con QT: HR 0,64 (IC 95%: 0,42-0,98) Sultana JCO 07

7 citabine Monotherapy

8 Phase III citabine Monotherapy in Advanced Pancreatic Cancer: Study Design Primary endpoint: improvement in specific disease-related signs and symptoms (clinical benefit), including pain and KPS Secondary endpoint: weight change Other endpoints: ORR, survival, time to progressive disease 5-FU, 5-fluorouracil; IV, intravenous; KPS, Karnofsky performance status; ORR, overall response rate; qw, weekly; qw ¾, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks. Burris III HA, et al. J Clin Oncol. 1997;15:

9 Phase III citabine Monotherapy in Advanced Pancreatic Cancer: Overall Survival Reprinted with permission. (1997) American Society of Clinical Oncology. All rights reserved. Burris III, HA et al: J Clin Oncol, Vol. 15(6), 1997: , gemcitabine, 5-FU, 5-fluorouracil; OS, overall survival. Burris III HA, et al. J Clin Oncol. 1997;15:

10 Phase III citabine Monotherapy in Advanced Pancreatic Cancer: Efficacy Outcomes Intent-to-Treat Clinical benefit, % Time to clinical benefit, median, weeks Duration of clinical benefit, mean, weeks OS, median, months OS rate, % 6 months 9 months 12 months PFS rate, % 6 months 9 months 12 months (n = 63) FU (n = 63) P Value Time to progression, median, months ORR, % PR SD n = n = NS 5-FU, 5-fluorouracil;, gemcitabine; NS, not significant; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, progressive disease; SD, stable disease. Burris III HA, et al. J Clin Oncol. 1997;15:

11 Doublets Therapy vs Alone Phase III Randomized Trials Study N Regimen 160 Berlin JD, et al Rocha Lima G, et al Louvet C, et al Oettle H, et al Abou-Alfa G, et al Heinemann V, et al Stathopoulos GP, et al Herrmann R, et al Cunningham D, et al Colucci G, et al FU + irinotecan + oxaliplatin + pemetrexed + exatecan + cisplatin + irinotecan + capecitabine + capecitabine + cisplatin Primary Endpoint OS OS OS OS OS OS OS OS OS OS Median OS, months HR (95% CI) P Value NR 0.09 NR ( ) 0.98 ( ) NR NR ( ) 0.86 ( ) 1.10 ( ) Berlin JD, et al. J Clin Oncol. 2002;20: Rocha Lima G, et al. J Clin Oncol. 2004;22: Louvet C, et al. J Clin Oncol. 2005;23: Oettle H, et al. Ann Oncol. 2005;16: Abou-Alfa G, et al. J Clin Oncol. 2006;24: Heinemann V, et al. J Clin Oncol. 2006;24: Stathopoulos GP, et al. Br J Cancer. 2006;95: Herrmann R, et al. J Clin Oncol. 2007;25: Moore MJ, et al. J Clin Oncol. 2007;25:

12 J Clin Oncol 2007 Jun 20;25(18):

13 BMC Cancer 2008 Mar 28;8:82

14 citabina se establece como tratamiento estándar en el manejo del cáncer de páncreas metastático durante los últimos 15 años Añadir otros citostáticos al tratamiento con citabina no ha demostrado un incremento significativo en supervivencia global. No están aconsejadas en primera línea en ESMO

15 citabine + Erlotinib

16 Phase III citabine + Erlotinib in Advanced Pancreatic Cancer: Study Design Primary endpoint: OS Secondary endpoints: PFS, ORR, response duration, toxicity, quality of life, correlation of baseline HER1/EGFR with outcomes Treat until disease progression or unmanageable toxicity ECOG, Eastern Cooperative Oncology Group; HER1/EGFR, epidermal growth factor receptor; IV, intravenous; LAPC, locally advanced pancreatic cancer; MPC, metastatic pancreatic cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PS, performance status; qw 3/4, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks. Moore MJ, et al. J Clin Oncol. 2007;25:

17 Phase III citabine + Erlotinib in Advanced Pancreatic Cancer: Overall Survival Reprinted with permission. (2007) American Society of Clinical Oncology. All rights reserved. Moore, MJ et al: J Clin Oncol, Vol. 25(15), 2007: HR, hazard ratio, OS, overall survival. Moore MJ, et al. J Clin Oncol. 2007;25:

18 Phase III citabine + Erlotinib in Advanced Pancreatic Cancer: Efficacy Outcomes Intent-to-Treat + Erlotinib (n = 285) (n = 284) OS, median, months HR (95% CI) 0.82 ( ) P Value year OS rate, % PFS, median months ( ) ORR, % PR + CR NA NS SD DCR, % NA 0.07 CR, complete response; DCR, disease control rate;, gemcitabine; HR, hazard ratio; NA, not available; NS, not significant; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease. Moore MJ, et al. J Clin Oncol. 2007;25:

19 Phase III citabine + Erlotinib in Advanced Pancreatic Cancer: Most Common Grade 3/4 AEs Event + Erlotinib (n = 282) (n = 280) Any toxicity, % Hematologic AEs, % Neutropenia Thrombocytopenia Nonhematologic AEs, % Infection (any) Fatigue Elevation of AST Diarrhea Rash No significant difference in quality of life was noted between the + erlotinib vs arms in most of the global quality-of-life or individual-domain measures The gem + erlotinib arm had a worse diarrhea change score vs the arm (P <0.001) Of the patients who received erlotinib, rash was more likely to occur in younger patients (< 65, P =0.01) or good PS (P = 0.03) Patients who developed rash were more likely to achieve disease control (P = 0.05) AE, adverse event; AST, aspartate aminotransferase;, gemcitabine; PS, performance status. Moore MJ, et al. J Clin Oncol. 2007;25:

20 Doublets Therapy vs Alone Phase III Randomized Trials (cont) Study N Regimen Primary Endpoint Median OS, months HR (95% CI) P Value Van Cutsem E, et al erlotinib + erlotinib + bev OS ( ) 0.21 Kindler H, et al bev OS ( ) 0.95 Philip P, et al cetuximab OS ( ) 0.23 Kindler H, et al axitinib OS ( ) 0.54 Gonçalves A, et al sorafenib PFS ( ) 0.26 Bev, bevacizumab; gem, gemcitabine; HR, hazard ratio; PFS, progression-free survival; OS, overall survival. 1. Cunningham D, et al. J Clin Oncol. 2009;27: Poplin E, et al. J Clin Oncol. 2009;27: Van Cutsem E, et al. J Clin Oncol. 2009;27: Colucci G, et al. J Clin Oncol. 2010;28: Kindler H, et al. J Clin Oncol. 2010;28: Philip P, et al. J Clin Oncol. 2010;28: Kindler H, et al. Lancet Oncol. 2011;12: Gonçalves A, et al. Ann Oncol. 2012;23: Von Hoff DD, et al. N Engl J Med Oct 16 [Epub ahead of print]. 7

21 Doublets Therapy vs Alone: Meta-Analysis Reprinted from Eur J Cancer, Vol 49, Issue 3, Cilberto D et al, Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials, , Copyright (2013), with permission from Elsevier. 5-FU, 5-fluorouracil; AXI, axitinib; BEV, bevacizumab; CAP, capecitabine; CDDP, cisplatin; CET, cetuximab; FUFA, fluorouracil and folinic acid;, gemcitabine; HR, hazard ratio; IRI, irinotecan; PEGF, cisplatin, epirubicin, fluorouracil, gemcitabine; PEM, pemetrexed; OX, oxaliplatin; TIPI, tipifarnib; UFT, ftorafur + uracil. 1. Ciliberto D, et al. Eur J Cancer. 2013;49:

22 FOLFIRINOX

23 Phase II/III FOLFIRINOX in Metastatic Pancreatic Cancer: Study Design Phase II Primary endpoint: tumor response Secondary end point: safety Phase III Primary endpoint: OS Secondary endpoints: PFS, tumor response, safety, quality of life 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; OS, overall survival; PFS, progression-free survival; PS, performance status; q2w, every 2 weeks, qw 3/4, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks. Conroy T, et al. N Engl J Med. 2011;364:

24 Phase II/III FOLFIRINOX in Metastatic Pancreatic Cancer: Overall Survival Subsequent therapy: 80 patients for FOLFIRINOX and 85 for Median survival was 4.4 months in both groups from the time of secondary therapy FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin;, gemcitabine; HR, hazard ratio; OS, overall survival; Pts, patients. Conroy T, et al. N Engl J Med. 2011;364:

25 Phase II/III FOLFIRINOX in Metastatic Pancreatic Cancer: Efficacy Outcomes Intent-to-Treat OS, median, months OS rate, % 6 months 12 months 18 months PFS, median, months PFS rate, % 6 months 12 months 18 months FOLFIRINOX (n = 171) (n = 171) HR (95% CI) 0.57 ( ) 0.47 ( ) P Value < < ORR, % NA < DCR, % NA < Response duration, median, months NA 0.57 DCR, disease control rate; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin;, gemcitabine; HR, hazard ratio; NA, not available; ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Conroy T, et al. N Engl J Med. 2011;364:

26 Phase II/III FOLFIRINOX in Metastatic Pancreatic Cancer: Most Common Grade 3/4 AEs Event Hematologic AEs, % Neutropenia Febrile neutropenia Thrombocytopenia Anemia FOLFIRINOX (n = 171) (n = 171) P Value < NS Nonhematologic AEs, % Fatigue Vomiting Diarrhea Sensory neuropathy Elevated level of alanine aminotransferase Thromboembolism NS NS < < < NS At 6 months, 31% patients in the FOLFIRINOX group had a definitive decrease in the Global Health Status and QoL scales vs 66% in the group (HR 0.47; 95% CI, ; P < 0.001) Patients in the FOLRIRINOX group had significant increase in the time until definitive deterioration in QoL for all functional and symptoms scales and appetite loss, dyspnea, and constipation AE, adverse event; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin;, gemcitabine; HR, hazard ratio; NS, not significant; QoL, quality of life. Conroy T, et al. N Engl J Med. 2011;364:

27 Modified FOLFIRINOX in Advanced Pancreatic Cancer: Retrospective Analysis First Author No. of Pts with Metastatic Disease Efficacy b Safety FOLFIRINOX Regimen/Delivery a5 OS PFS ORR Select Grade 3 AEs, g mos mos % (%) Gunturu 1 19 c Same starting dose used as reported by Conroy et al.5 All pts received pegfilgrastim; Lower median relative dose intensities vs Conroy et al 5 for irinotecan (64% vs 81%) and bolus 5-FU (66% vs 82%) Lowery 2 61 d Median starting dose was 80% as reported by Conroy et al 5 ; prophylactic growth factor was given in 84% of pts Mahaseth 3 28 Omitted bolus 5-FU, included mandatory G- CSF Vaccaro 4 36 e Starting dose undefined; 58% received prophylactic G-CSF; FOLFIRINOX dose was reduced to 75% in 23% of cycles Neutropenia (11.4), fatigue (5.7), diarrhea, (2.9),febrile neutropenia (2.9) 12.5 NR 40 Neuropathy (15), myelosuppression (7) NR f NR f 21 Fatigue (11), diarrhea (11), neuropathy (4), neutropenia (4) NA 8 g 25 g Neutropenia (16.6) a Modified based on Conroy study regimen; b OS and PFS given as median; outcomes for pts with metastatic disease only unless otherwise indicated; c Of the 35 pts were treated, 19 had metastatic disease and 17 pts were evaluable for efficacy; d Of the 80 pts enrolled, 61 had metastatic disease; e Identified as advanced, inoperable pancreatic cancer; 26 pts had metastatic disease. PFS and ORR apply to all 36 pts; f Median OS and PFS were NR after median 5.5 months follow-up; g In all treated pts. 5-FU, 5-fluorouracil; AE, adverse event; DCR, disease control rate; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; G-CSF, granulocyte colony-stimulating factor; mos, months; NA, not available; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; pts, patients. 1. Gunturu KS, et al. Med Oncol. 2013;30: Lowery MA, et al. J Poster presented at: ASCO [abstract 4057]. 3. Mahaseth H, et al. Abstract presented at: ASCO [abstract e14614]. 4. Vaccaro V, et al. Abstract presented at: ASCO [abstract e14661]. 5. Conroy T, et al. N Engl J Med. 2011;364:

28 GEMCITABINE PLUS nab-paclitaxel

29 Phase III citabine + nab-paclitaxel in Metastatic Pancreatic Cancer: Study Design Primary endpoint OS Secondary endpoints PFS and ORR by independent review (RECIST v1.0) Safety and tolerability By NCI CTCAE v3.0 With 608 events, 90% power to detect OS HR = (2-sided α = 0.049) Treat until progression or unacceptable toxicity Spiral CT or MRI scans every 8 weeks CA19-9 measurements at baseline and every 8 weeks CA19-9, carbohydrate antigen 19-9; CT, computed tomography; HR, hazard ratio; IV, intravenous; KPS, Karnofsky performance status; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; MRI, magnetic resonance imaging; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; qw 3/4, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks; RECIST, Response Evaluation Criteria In Solid Tumors; ULN, upper limit of normal. Von Hoff DD, et al. N Engl J Med Oct 16. [Epub ahead of print]. 32

30 Summary of Primary Results in the ITT Population From MPACT The primary report of MPACT showed superior efficacy for nab-p plus vs alone for OS (primary endpoint) and all secondary efficacy endpoints Parameter a nab-p + n = 431 n = 430 HR P Value Median OS, months < Median PFS, months < ORR, % Independent review Investigator review < < a Original database cutoff September 17, Von Hoff DD, et al. N Engl J Med. 2013;369:

31 Phase III citabine + nab-paclitaxel in Metastatic Pancreatic Cancer: Safety Preferred Term nab-p + (n = 421) (n = 402) Patients with at least 1 AE leading to death, % 4 4 Grade 3 hematologic AEs, a % Neutropenia Thrombocytopenia Anemia Patients who received growth factors, % Febrile neutropenia, b % 3 1 Grade 3 nonhematologic AEs b in > 5% pts, % Fatigue Peripheral neuropathy c Diarrhea Grade 3 neuropathy Time to onset, median, days Time to improvement by 1 grade, median, days Time to improvement to grade 1, median, days Pts who resumed nab-p, % NR NA a Based on laboratory values; b Based on investigator assessment of treatment-related events; c Grouped term. AE, adverse event;, gemcitabine; NA, not applicable; nab-p, nab-paclitaxel; NR, not reached; pts, patients. Von Hoff DD, et al. N Engl J Med. 2013;369(18):

32 Proportion of Survival Updated Overall Survival as of May 9, Events/n OS, months Median (95% CI) 75 th Percentile 0.8 nab-p + 380/ ( ) / ( ) HR % CI, P < Patients at Risk Time (months) nab-p + : : Goldstein D, et al. Oral presentation at: ASCO GI 2014 [abstract 178]. 3

33 Overall Survival Rates Survival Parameter Original Data Cutoff 9/17/12 nab-p + n = 431 Updated Cutoff 5/9/13 Original Data Cutoff 9/17/12 n = 430 Updated Cutoff 5/9/13 Median OS, months Survival rates 6 months 67% 66% 55% 55% 12 months 35% 35% 22% 22% 24 months 9% 10% 4% 5% 36 months 4% 0 40 months 3% 0 42 months 3% 0 Longer follow-up demonstrated a median OS difference of 2.1 months and identification of 3-year survivors in the nab-paclitaxel plus gemcitabine arm Goldstein D, et al. Oral presentation at: ASCO GI 2014 [abstract 178]. 3

34 OS Update for Prespecified Subgroups Group All patients Age < 65 years Age 65 years Female Male KPS KPS Primary tumor location: head Primary tumor location: other Liver metastases No liver metastases 1 metastatic site 2 metastatic sites 3 metastatic sites > 3 metastatic sites Normal CA 19-9 CA 19-9 ULN to < 59 ULN CA ULN Australia Eastern Europe Western Europe North America HR nab-p + Events/n Median OS, mo Events/n Median OS, mo HR P Value 380/ / < / / < / / / / / / / / < / / / / < / / / / < / / / / / / / / / / / / / / / / < / / / / / / / / < Favors nab-p + Favors Goldstein D, et al. Oral presentation at: ASCO GI 2014 [abstract 178]. 35

35 Proportion of Survival Influence of Baseline CA 19-9 on OS by Treatment a vs b: HR 0.983; 95% CI, ; P = c vs d: HR 0.773; 95% CI, ; P = Time (months) nab-p +, CA 19-9 < median a (a) nab-p +, CA 19-9 median a (b), CA 19-9 < median a (c), CA 19-9 median a (d) Patients at Risk (a): (b): (c): (d): a The median baseline CA19-9 level for all patients was units/ml (range ,207,654.2) Goldstein D, et al. Oral presentation at: ASCO GI 2014 [abstract 178]. 36

36 Conclusions Updated analysis confirmed the treatment effect in favor of nab- P + for overall survival (> 2-month difference at the median), including at the tail of the survival curve Longer follow-up allowed identification of long-term (> 3 years) survivors in the nab-p + arm Treatment with nab-p + appeared to reduce the effect of CA 19-9 as a prognostic factor Goldstein D, et al. Oral presentation at: ASCO GI 2014 [abstract 178]. 37

37 Algoritmo Terapéutico

38 20-60% RECIBEN SEGUNDAS LÍNEAS

39 Folfirinox (%) N:171. (%) N:171 Nab (%) N:421. (%) N:402 Neutrop. 45.7* NF 5.4* Trombop. 9.1* ALT * Diarrea 12.7* Neuropatía 9* Alopecia (G2) Muerte Tox

40 Pippa G. Corrie. PeerVoice.

41 Segundas Líneas PS 0-1 citabina en 1ª línea NO citabina en 1ª línea (Folfirinox) CONKO 003 (Pelzer JCO 2008) 5FU-AF-Oxa. vs 5FU-AF. / nab paclitaxel citabina. / Capecitabina. / Erlotinib

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45 Conclusiones Hay que conseguir un diagnóstico más temprano de la enfermedad La quimioterapia es el tratamiento estándar Las combinaciones de citabina con Nabpaclitaxel y el Folfirinox han mejorado las tasas de supervivencia. La citabina sigue siendo el estándar para pacientes con bajo ps Necesitamos una extensa investigación para mejorar el pronóstico de esta enfermedad

46 Muchas Gracias!