Opciones terapéuticas de 1ª línea de cáncer de páncreas metastásico. Fernando Rivera Herrero Hospital Universitario Marqués de Valdecilla, Santander

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1 Opciones terapéuticas de 1ª línea de cáncer de páncreas metastásico Fernando Rivera Herrero Hospital Universitario Marqués de Valdecilla, Santander

2 Finantial disclosure Consultor: CELGENE Research fundings: AMGEN., MERCK-SERONO, ROCHE, SANOFI, BAYER, LILLY, CELGENE Honoraria: AMGEN., MERCK-SERONO, ROCHE, SANOFI, BAYER, LILLY, CELGENE, TECNOFARMA

3 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

4 By the year 2020: Pancreatic cancer is expected to represent the second-leading cause of cancer-related mortality in US, trailing only lung cancer

5 mpc is not an easy enemy but we have to help our patients and avoid panic and pessimism

6 Hidalgo M et al. CTO 2016 % of pts?? 30%? 35%? 35%?

7 It is important to avoid delays in the treatment of mpc Suzuki R et al. ASCO-GI 2015 Short: <10 days Sv

8 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

9 Advanced pancreatic cancer CT vs BSC Meta-analysis CT vs BSC (Sultana et al. J Clin Oncol Jun 20;25(18):2607) 7 studies, 432 pts Improvement in OS with CT HR 0,64 95% C.I.: 0,42-0,98

10 RR, PFS and OS in mpc Treatment RR PFS OS 1y OS - Gem (30 min) 5-12% 3,5m 5,5m 18% - GEMOX / GEMCAP 25% 5 m 7m 25% - Gem-Erlotinib 8,6% 3,8m 6,3m 24%

11 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

12 342 PTS ( , 48 centers) Rand PII: 88 pts RR 31,8 vs 11,3% P.III Criteria <76 y (28% > 65 y) M1 PS ECOG 0-1 Bilirrubine < 1,5 x UNL Normal renal,hema.function No cardiocirc. disease... 1ºendpoint:OS P. II-III Prodige 4- ACCORD 11 FOLFIRINOX vs Gemcitabine FOLFIRINOX 6 m (stop and go) Gem (30 min) OS (median) 11,1 m HR 0,57 p<0,0001 6,8 m 1 year 48,4% 20,6% PFS 6,4 m HR 0,47 p<0,0001 3,3 m RR: 31,6% p<0,0001 9,4% Dis Control: 70,2% p<0, ,9% Conroy T et al. N Engl J Med 2011;364:

13 F. III Prodige 4- ACCORD 11 Toxicity: G 3-4 G-CSF 42% 5% No colangitis and no more toxicity in patients with biliar stent

14 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

15 861 PTS (151 sites, 11 contries) M1 KPS 70 Bilirrubine < UNL 1ºendpoint:OS P. III MPACT 1 nabpaclitaxel-gem vs Gemcitabine nabpaclitaxel-gem nabp; 125 mg/m2 iv Gem: 1000 mg/m2 iv weekly 3/4 w Gem (30 min) Gem 1000 mg/m2 iv weekly 7/8 w followed by 3/4 w OS 2 (mediana) 8.7 m HR 0,72 p<0,0001 6,6 m 1 y 35% 22% 2 y 10% 4% PFS 5.5 m HR 0,69 p<0,001 3,7 m RR (central rev): 23% p<0,001 7% Dis Control: 48% p<0,001 33% PFS 1.- Von Hoff DD et al. N Engl J Med 2013; 2.- (OS updated results) Goldstein D et al. ASCO-GI 2014

16 OS - Prespecified Subgroups >65: 42% KPS 70-80: 40% CA19-9, carbohydrate antigen 19-9; Gem, gemcitabine; KPS, Karnofsky performance status; nab-p, nab-paclitaxel; ULN, upper limit of normal. Von Hoff DD, Ervin T, Arena FP, et al. Randomized Phase III Study of Weekly nab-paclitaxel plus Gemcitabine vs Gemcitabine Alone in Patients with Metastatic Adenocarcinoma of the Pancreas (MPACT) [abstract LBA148]. Oral presentation at: The Gastrointestinal Cancers Symposium 2013; January 24-26; San Francisco, CA. 1

17 Safety 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, a % Neutropenia Leukopenia Thrombocytopenia Anemia Patients who received growth factors, % Febrile neutropenia, b % 3 1 Grade 3 nonhematologic AEs b in > 5% of patients, % Fatigue Peripheral neuropathy c Diarrhea Grade 3 neuropathy Time to onset in days, median Time to improvement to grade 1 in days, median Patients who resumed nab-p, % <

18 .- OS with longer follow-up Sept 2012 mayo 2013 (median follow-up 13,9 m).- Prognostic and predictive value of - CA NLR.- Tox and IK ( vs 70-80) OS 35% vs 22% 10% vs 5% 4% vs 0%

19 OS: Ca 19.9 and NLR Ca 19.9 median HR 0,61, p<0,001 GA GA G G Ca 19.9 < median (2470 U/ml) HR 0,83, p 0,11 NLR > 5 (median = 5.6 vs 4.3 m HR = 0.81, P =.079). GA G GA G NLR 5 (63% of pts) median = 10.9 vs 7.9 m, HR = 0.67, P <.001 Goldstein D et al, JNCI 2015

20 MPAC: Toxicity according to IK Goldstein D et al, JNCI 2015

21 Abraxane in mpc Abraxane was approved by FDA (2013) and EMA (2014) for first line treatment of metastatic pancreatic adenocarcinoma

22 Primary Endpoint OS mos 8.7 m NP-G vs. 6.6 m G Von Hoff DD, N Engl J Med. 2013;369: mos 11.1m FOLFIRINOX VS. 6.8 m G Conroy T. N Engl J Med 2011;364:

23 Características de las poblaciones MPACT Estudio PRODIGE/ACCORD FOLFIRINOX MPACT GZT+NBP Edad (mediana y rango) 61 años (25-76) 63 años (27-86) Pacientes ancianos >76 años No Si Pacientes PS0 37% 16% Pacientes PS2 1% 7% Mediana de localizaciones metastásicas Ca19.9 >59 LAN (medida indirecta carga tumoral) % Población con características clínicas más desfavorables en cáncer de páncreas: más jóvenes y más sanos %

24 Pacientes ECOG 0-1 MPACT Mediana de SG con Gem-Abx: 9,7 meses Tabernero et al. Beaujon Conference 2014 Tabernero J et al, The Oncologist 2015;20:1 8

25 FOLF-Ox-Naliri (P I/II NCT ) - Metastatic Pancreatic Adenoca - 1st line - ECOG-0-1 P. I FOLF-OX-Naliri (6-18 pts) 1º endpoint DLT /Toxicity Rand P II (150 pts): 1º endpoint PFS - FOLF-Naliri - FOLF-Ox-Naliri - Gem-Abx

26 F. I/II SEQUENCE (TTD 15-05): sequencial AG-mFOLFOX - Metastatic Pancreatic Adenoca - 1st line - ECOG-0-1 d Gem Gem Gem mfolfox Abx Abx Abx P I (6-24 pts) 1º endpoint DLT /Toxicity P II (156 pts) 1º endpoint 12 m OS

27 BRCA mutations and platinum sensitivity in PC 5-7 % of PC BRCA-2 mutations 1. Defects in BRCA-1-2, PALB-B2, FANC Increase sensibility to platinum Goggins, Cancer Res 1996, 2- Golan, Br. J Cancer 2014.

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30 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

31 MPACT: impact of PS Poor KPS (70-80) Good KPS (90-100) Chiorean et al, ESMO 2015

32 Nab-Paclitaxel + Gem in suboptimum pts: ECOG 2 F. I/II FRAGANCE - Metastatic Pancreatic Adenoca - 1st line - ECOG-2 Part 1: rand 24 pts 1º endpoint Part 1 Tox Arm B Abx 150 Arm C Arm D Arm E Abx 100 Abx 125 Abx 125 Gem 1000 Gem 1000 Gem 1000 Gem 1000 d 1,15 / 28 d d 1,8,15 / 28 d d 1,15 / 28 d d 1,8,15 / 28 d Part 2, rand 221 pts 1º endpoint Part 2 OS Hidalgo M et al, ESMO 2017

33 FRAGANCE Hidalgo M et al, ESMO 2017

34 FRAGANCE MPACT (GA): 8.7 m MPACT (GA): 5.5 m Hidalgo M et al, ESMO 2017

35 ABI-007-PANC-004: Phase I nab-paclitaxel + Gemcitabine in Patients With Advanced Pancreatic Cancer With Elevated Bilirubin Levels 1,2 35 Study start: 11/2014 Estimated study completion: 10/2018 Primary endpoints: MTD, PK Secondary endpoints: Objective tumor response, PFS, OS, safety a Patient enrollment in cohorts 2 and 3 may only begin after safety and PK review of the prior cohort. Region: Germany, US 1. ClinicalTrials.gov. NCT Accessed March 17, Celgene Corporation. Clinical Trials Brochure. Winter/Spring 2015.

36 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

37 Retrospectivo Study of CT in mpc Data base IntelliDose (USA), total pts with mpc and CT 1 ª línea Gem: pts > 80 a FOLFIRINOX pts < 60 a Gem-nabPacl pts a Abrams TA et al. ASCO #4131

38 FOLFIRINOX en práctica clínica habitual N 224 >75 años 7% PS2 4% Maroun J et al. ESMO 2015: 302P

39 Proportion of survival Proportion of survival 1 st -line nab-paclitaxel + gemcitabine in advanced PC: Real-life data from Italy (multicentre, retrospective analysis) Overall survival % Progression-free survival 12 % OS 0 (months) Survival function Censored Survival function Censored PFS (months) Patients received 1cycle of nab-p (100/125 mg/m 2 ) + gem (1000 mg/m 2 ) as 1 st -line treatment for PC N=208; median (range) age, 67 (37-86) years; ECOG PS 0, 45.2%; 1, 37%; and 2, 17.8% Median OS, 11.3 months (95% CI: months); median PFS, 6.7 months (95% CI: months) Treatment was safe and manageable; only 4 patients discontinued due to unacceptable toxicity Reduction in CA19-9 of 50% from baseline appeared to be a good prognostic indicator High NLR (>5) and LDH were related to poor PFS and a worse outcome This study confirms the efficacy and safety of nab-p + gem as 1 st -line treatment in a real-life, unselected patient population Giordano et al. ECC 2015, abstract 2334

40 Retrospective Study Gem/Abx in mpc 9 italian centres total 120 pts 43 pts (35%) 70 y RR 28,3% (p 0,60) 27,9 % RR+SD 55,8 % (p 0,55) 53,5 % PFS: 7 m (lrk p 0,37) 7 m OS: 11 m (lrk p 0,54) 10 m Giordano G et al. ASCO-GI 2015

41 Retrospective Study Gem/Abx in mpc 9 Italian centres total 120 pts 43 pts (35%) 70 a Giordano G et al. ASCO-GI 2015

42 Retrospective Study Gem/Abx and FOLFIRINOX in mpc U.S. community oncology Database (Jun 2013->Jun 2014) Gem-Abx 122 pts FOLFIRINOX 80 pts Age (mean) 67 y 61.4 y Braiteh, ASCO-GI Abst 433

43 FOLFIRINOX modificado Nab-P/G PS % 99 % MTS HEPATICAS MTS PERITONEALES 56% 49% 34% 31% STENT BILIAR 21% 17% > 75 AÑOS* 4,3% 12% FOLFIRINOX modificado FOLFIRINOX modificado N 70 Nab-P/G Tasa R* 27 % 39 % Control Enfermedad 79 % 92 % m SG 11,5 m 14 m mpfs 5,7 m 6,5 m Supv a 1 año* 44 % 67 % nabpaclitaxel/gemcitabina N 65 FOLFIRINOX modificado Nab-P/G Neutropenia 47 % 45 % Diarrea 1,4 % 2 % Neuropatía Periférica Neutropenia febril 4,2 % 4,6 % 8,5 % 2 % Uso G-CSF* 21 % 0 % Anorexia* 13 % 3% CARACTERÍSTICAS EFICACIA TOXICIDAD * significación estadística Watanabe K et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 438)

44 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

45 MM-398 (nal-iri) (nanoliposomal irinotecan ) F. III NAPOLI pts Metastatic Panc Cancer 2nd-3rd line after Gem MM-398/FU/Fol FU/Fol MM-398 1º endpoint: OS(median) 6.1 m HR 0.67;p m p m A. Wang-Guillam, Lancet 2016

46 Potential treatment sequencing approach for MPC in 2017? 1 st line 2 nd line 3 rd line Nab-paclitaxel + gemcitabine MM FU/LV Platinum-based tx (depending on prior exposure) OFF FOLFIRINOX FOLFIRINOX NOTE: Nab-paclitaxel is licensed for use in combination with gemcitabine as 1 st -line therapy for patients with MPC mfolfox6 or CAPOX Capecitabine / 5 FU FOLFIRI?? Gemcitabine Nab-paclitaxel + gemcitabine (if no neuropathy) MM FU/LV (depending on prior exposure) Platinum-based tx (depending on prior exposure) MM FU/LV (depending on prior exposure) Supported by RCT data Supported by retrospective data or small, single arm trials

47 Treatment options for 1 st line mpc Summary Introduction Treatment of mpc before 2011 FOLFIRINOX (Prodige-4) Gem-Abraxane (MPACT) ECOG-2 / Colestasis Observational studies Sequence of treatment Conclusions

48 Conclusions

49 Conclusions - Before 2011 (Gem; Gem-erlo; Gem-Cap; Gem-Ox): low activity - In 2011: P III FOLFIRINOX: Active but toxic - In 2013 P III Gem/Abx (MPACT): Active and less toxic - Two standard treatments in mpc -- Gem-Abx adequate for ECOG-2 - Observational studies: Gem/Abx increasingly used, active and well tolerated even in elderly pts -Sequence Gem-Abx 2nd line (FOLF-naliri) is attractive - - Combinations with new targeted drugs - and Biomarkers

50 Gracias Thank you