La terapia nel setting metastatico

Transcription

1 Modena Cancer Center La terapia nel setting metastatico Stefano Cascinu Modena Cancer Center Department of Oncology/Haematology Università degli Studi di Modena e Reggio Emilia Policlinico di Modena, Italy

2 Prof. Stefano Cascinu Conflict of interest disclosure: Consultant or Advisory Board: Celgene; Baxalta Research grant: Merck; Bayer; Celgene Honoraria: Celgene

3 Epidemiology (Italy): new cases/year Stage Incidence (%) 5 year survival (%) Resectable 20% 20% Borderline resectable 10% 0 5% Locally advanced/ 30% 0% unresectable Metastatic 40% 0%

4 Qualche progresso nella terapia? Sopravvivenza a 5 anni

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6 The role of Chemotherapy Glimelius B, 1996 Sultana A.: J Clin Oncol 2007

7 Which chemotherapy? GEM vs 5 FU GEM 5 FU P value Clinical Benefit 23.8% 4.8%.002 Responders Median duration 18 weeks 13 weeks of Clinical Benefit Onset of Clinical 7 weeks 3 weeks Benefit OS median 5.6 m 4.4 m.002 OS at 1 year 18% 2% TTP median 9 wks 4 wks.0002 ORR 5.4% 0% N.S Burris HA, 1997

8 GEM vs GEM doublets Author Regimen Patients OS Results Berlin GEM+/-5FU vs 6.7 negative Cunningham GEM+/-Cape vs 7.4 negative Hermann GEM+/-Cape vs 8.4 negative Heinemann GEM+/-CDDP vs 8.3 negative Colucci GEM+/-CDDP vs 6.7 negative Louvet GEM+/-Oxali vs 8.5 negative Rocha Lima GEM+/-CPT vs 6.6 negative Oettle GEM+/-PEM vs 6.3 negative Abou-alfa GEM+/-Exatecan vs 6.2 negative

9 Molecular pathology in pancreatic cancer: Target identification and agent development Tumor cells K ras tipifarnib Metalloprotease marimastat EGFR erlotinib/cetuximab HER 2 trastuzumab Microenviroment VEGF A bevacizumab VEGFR 1,2,3 axitinib VEGFR3; RAF/MEK sorafenib

10 GEM vs GEM+ERLOTINIB Mortality 2.1% vs 0% Interstitial lung disease 2.5% vs 0.4% G3-4 rash 6% vs 1% Worse diarrhea p < days! 0% 18 months

11 New trials: negative! Gem + Saridegib (HH) Gem + Vismodegib (HH) Gem + AMG-479 (IGF-1R) Gem + Sorafenib Gem + Masitinib (C-kit, PDGFR, FGFR3, mast cells) Gem + Rigosertib (polo-like kinase) Carbo-paclitaxel + reovirus (Ras)

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13 HR= 0.51 HR= 0.65

14 Triplet 2011

15 Doublet 2013 PFS by Independent Review Overall Survival val tion of free Surviv Proport gression-f Pro 1.0 PFS, months Events/N (%) Median (95% CI) Percentile 0.8 nab-p + Gem 277/431 (64) 5.5 ( ) Gem 265/430 (62) 3.7 ( ) HR = % CI ( ) P = Pts at Risk nab-p + Gem: 431 Gem: Months PFS Rate at nab-p + Gem Gem % Increase 6 months 44% 25% 76% 12 months 16% 9% 78% f Survival Pro oportion of Pts at Risk nab-p + Gem Gem Events/N (%) OS, months Median (95% CI) 75 th Percentile 333/431 (77) 8.5 ( ) /430 (83) 6.7 ( ) HR = % CI ( ) 0.2 P = Months nab-p + Gem: Gem:

16 Gem-nab or FOLFIRINOX? Trial ORR mos 1 y OS 18 mo OS FOLFIRINOX 32% % 19% Delta 23% % Gem 9% % 6% Deltas not due to under or over performing of control Gem 7% % 9% Delta 17% % Gem nab 24% (29%) % 16%

17 Gem-nab or FOLFIRINOX? Generalizability Gem nab FOLFIRINOX Number of patients Continents 3 1 Countries 11 1 Centers Trial population Gem nab FOLFIRINOX Age (range) 62 (27, 86) 61 (25, 76) PS % 77% 7% 38.6% 61.4% 0% Head 44% 39% Biliary stent 19% 16% Metastatic 100% 100% Liver mets 85% 88% CA ULN 46% 41%

18 Gem-nab or FOLFIRINOX? G3-4 Toxicity Gem nab Gem FOLFIRINOX Neutropenia 38% 24% 46% Febrile neutropenia 3% 1% 5% Fatigue 17% 12% 24% Vomiting nr 8% 15% Thromboembolism nr nr 7% Liver nr 20% 7% Diarrhea 6% 1% 13% Neuropathy 17% 0% 9%

19 Gem-nab or FOLFIRINOX? Treatment burden Gem nab FOLFIRINOX Accesses/month 3 4 Central catheter no yes Infusion duration 1 h 4 h Infusion pump no 46 h/2 w G CSF 26% 43%

20 Gem nab or FOLFIRINOX? Applicability CPT11 reduced/omitted; oxa ; no FU bolus G CSF (84% MSKCC) Hospitalization rate (41% MGH) Median starting dose: 80% (MSKCC, et al.) Full dose 1 st cycle: 17% (Yale) PRODIGE 24: mfolfirinox

21 Linee Guida AIOM Grado di raccomandazione SIGN D A A Raccomandazione clinica La GEM dovrebbe essere somministrata ai pazienti con malattia M+ e PS < 70 Pazienti con età 70 e miglior PS potrebbero essere trattati con combinazioni di 3 farmaci Pazienti con età 18 e PS > 60 possono essere trattati con GEM-nab-paclitaxel Forza della raccomandazione clinica Positiva debole Positiva debole Positiva forte

22 The second line therapy: a role in PDAC? Data from Gemcitabine era: 40 50% of patients receive a second line therapy To whom? Generally, patients responding to first line and with a good PS Which regimen? FOLFOX after GEM is effective (CONKO 003 trial: improvements in PFS (13 vs. 9 weeks; P=0.012) and OS (20 vs. 13 weeks; P=0.014) FOLFIRI has an activity thought modest (Zaniboni A, Cancer Chemother Pharmacol 2012)

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25 Outcome of Second-Line Treatment Following nab-paclitaxel Overview of + Survival Gemcitabine Times or with Gem Duration Alone for of M+ 1L Pancreatic Cancer Variable n, % OS median, mo Time from randomization to 1 st dose of 2L tx, median, mo Time from 1 st dose of 2L tx to death, median, months Any 2L Therapy nab-p + Gem Gem 5FU/cape containing nab-p + Gem Gem Other than 5/Fu/cape) nab-p + Gem Gem 5-FU or Cape Combo nab-p + Gem Gem 5-FU or Cape Mono nab-p + Gem Gem FOLFIRINOX nab-p + Gem Gem FOLFOX/OFF nab-p + Gem Gem 170 (39) 177 (41) 132 (39) 135 (41) 38 (22) 42 (24) 98 (74) 107 (79) 34 (26) 28 (21) 18 (14) 17 (13) 36 (27) 49 (36) Goldstein D and Chiorean EG et al, Abstract 333; 2016, Gastrointestinal Cancers Symposium; January 21-23, 2016; San Francisco, CA

26 Effetti ella 2L dopo una 1L con nab paclitaxel +Gem o Gem in mono Una 2L dopo una 1L con Nab Paclitaxel + Gemcitabina è associato ad un aumento statisticamente significativo dell OS La sopravvivenza è meigliore nei pazienti che ricevono Nab paclitaxel+ gemcitabina vs gemcitabina, I pazienti che traggono maggiore beneficio dalla terapia di 2L hanno una sopravvivenza libera da progressione più lunga durante il trattamento 1L e un migliore performance status alla fine della terapia 1L Goldstein D, et al. Poster at ASCO GI 2016 [abstract 333].

27 Trial world vs real world: patients treated within or out of clinical trials El Rayes BF, 2010

28 Trial world Younger patients Best PS Limited disease No biliary obstruction Real world Palliative simultaneous care Bile drainage Pain relief Nutritional support Bowel obstruction control Diabetes control

29 Gemcitabine in elderly Locher C, 2008 PFS 7 m OS 10 m

30 Gemcitabine: OS by Karnofsky N = 3023 pts Storniolo, 1999

31 Performance Status is Critical in Selecting Treatment for Advanced Pancreatic Cancer Meta analysis of randomized trials confirms that performance status is the critical factor in determining who is more likely to benefit from combination chemotherapy Performance Scores Benefit From Combination Therapy? ECOG PS 0 1/Karnofsky PS 90% to 100% Yes (HR: 0.76; P <.0001) ECOG PS 2/Karnofsky PS 60% to 80% No (HR: 1.08; P =.40) Heinemann V, et al. BMC Cancer. 2008;8:82.

32 Combination therapy According to age and/or PS

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34 Phase III Trial of nab P + Gem vs Gem f or Metastatic Pancreatic Cancer OS in Patients With a Decrease in CA19 9 Level 20% at Week 8 CI, confidence interval; Gem, gemcitabine; HR, hazard ratio; nab-p, nab-paclitaxel; OS, overall survival. Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer [abstract 4058]. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.

35 Phase III Trial of nab P + Gem vs Gem for Metastatic Pancreatic Cancer Efficacy Summary (Week 8 CA19 9 Decreases 20% and 90%) Variable nab-p + Gem Gem HR or RRR P Value Decrease in CA19-9 level 20% at 8 weeks n Radiologic ORR, % < Median PFS, mo Median OS, mo < year OS, % Decrease in CA19-9 level 90% at 8 weeks n Radiologic ORR, % Median PFS, mo Median OS, mo year OS, % CA19-9, carbohydrate antigen 19-9; Gem, gemcitabine; HR, hazard ratio; nab-p, nab-paclitaxel; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RRR, response rate ratio. Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer [abstract 4058]. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.

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37 Metformin and pancreatic cancer (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase 2 trial Reni M,. Clin Cancer Res PEXG PEXG+metformin p N PFS-6 52% 42% 0.61 mpfs * mos PR 34.5% 35.5% DCR 79.5% 64.5% 0.26 * adjusted p-value; HR 2.00 ( ) adjusted p-value; HR 1.56 ( )

38 Modena Cancer Center Early clinical Trials Unit Maur M; Fontana ; Cancer Genetics and Precision Medicine Unit Cortesi L; Toss A. Oncology Medicine and Emergency Unit Longo G; Fiorani; Ferrara; Malavasi; Carboni; Postiglioni Palliative Care Unit Dini D Medical Oncology Luppi G GI Unit Zironi S; Cloe; D Emidio K; Gelsomino F; Spallanzani A GU Unit Sabattini R; Filieri; Guida A H&N; Lung, Melanoma Unit Barbieri F; Bertolini F; Depenni R; Tomasello C. Breast Unit Piacentini F; Moscetti L; Omarini C;