LA CHEMIOTERAPIA DI I LINEA

Transcription

1 DECIDERE LA CHEMIOTERAPIA ADIUVANTE E DELLA MALATTIA METASTATICA LA CHEMIOTERAPIA DI I LINEA Michele Reni Department of Medical Oncology IRCCS Ospedale San Raffaele Milan, Italy

2 THE HISTORY OF PC TREATMENT Whipple refines the PD procedure Italian surgeons develop the pylorus-preserving PD 1 st combination chemotherapy showing superiority over GEM 1 st targeted agent approved for LA or metastatic PC Multidrug regimen shows significant OS benefit in metastatic disease Chemo added to RT improved survival vs RT alone in LAPC The 1st chemotherapeutic agent receives FDA approval in advanced metastatic disease 1st study to demonstrate OS benefit with ADJ CHEMO for resectable disease

3 Patients surviving (%) 1 ST -LINE OPTIONS IN MPC: GEMCITABINE? Gemcitabine 5-FU msv 1y OS 5-FU % GEM % P =.0025 N 126 Stage IV 93 (74%) KPS (69%) Log rank test p= KPS (31%) Time (months) Burris et al. JCO 1997;15:

4 1 ST -LINE OPTIONS IN MPC: Unresectable PDA Countless negative trials over last decades Drug G +X G P value bolus 5FU 6.7 mo 5.4 mo 0.11 c.i. 5FU 5.9 mo 6.2 mo pemetrexed 6.2 mo 6.3 mo 0.85 capecitabine 8.4 mo 7.3 mo irinotecan 6.3 mo 6.6 mo cisplatin 7.6 mo 6.0 mo 0.12 oxaliplatin 9.0 mo 7.1 mo GEMCITABINE?

5 1 ST -LINE OPTIONS IN MPC? GEM+erlotinib : 1 positive phase III trial level 1 evidence : CLINICALLY IRRELEVANT benefit (HR 0.82) GEM+platinum salt: 5 negative phase III trials level 1 evidence : LACK OF any relevant BENEFIT (HR>0.85) GEM+capecitabine : 2 negative phase III trials level 1 evidence : LACK OF any relevant BENEFIT (HR 0.86)

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7 Moore et al JCO 2007;25:1960-6; 1 ST -LINE OPTIONS IN MPC: GEMCITABINE + ERLOTINIB? 10 days! 0% 18 mo

8 1 ST -LINE OPTIONS IN MPC : FOLFIRINOX phase II-III trial Metastatic pancreatic cancer (n 342) R A N D O M I Z E FOLFIRINOX gemcitabine No prior chemo PS 0-1 <76 y T. Bilirubin < 1.5x ULN Conroy T, et al. NEJM 2011

9 1 ST -LINE OPTIONS IN MPC : FOLFIRINOX FFX: 11.1 mo Gem: 6.8 mo Conroy T, et al. NEJM 2011

10 1 ST -LINE OPTIONS IN MPC : NAB-PACLITAXEL-GEMCITABINE Planned N = 842 Stage IV No prior treatment for M+ disease KPS 70 Measurable disease Total bilirubin ULN No age limitation nab-p 125 mg/m 2 IV qw 3/4 + Gem 1000 mg/m 2 IV qw 3/4 1:1, stratified by KPS, region, liver metastasis Gem 1000 mg/m 2 IV qw 7/8 then qw 3/4 This study enrolled 861 pts at 151 sites in North America, Europe, and Australia Von Hoff DD, et al. N Engl J Med. 2013; 369:

11 1 ST -LINE OPTIONS IN MPC : NAB-PACLITAXEL-GEMCITABINE Von Hoff DD, et al. N Engl J Med. 2013; 369:

12 Nab-paclitaxel + gem vs FolfIrinOx ORR mos 1y OS 18-mo OS FOLFIRINOX 32% % 19% GEM 9% % 6% GEM 7% % 9% GEM-nab 24% % 16%

13 1 st -line treatment: what criteria to select one treatment or the other? ACCORD 11 and MPACT cannot be directly compared (regional vs global settings; differences in eligibility criteria, in 2 nd -line use and efficacy )

14 Nab-paclitaxel + gem vs FolfIrinOx Comparable populations?

15 BEWARE of APPLES FOLFIRINOX FFX: 11.1 mo Gem: 6.8 mo

16 Nab-paclitaxel + gem vs FolfIrinOx Comparable populations? #259 ASCO GI 2015 who is eligible? N=473 M+ treated with GEM in Canada mos 1) Eligible for FOLFIRINOX 24.7% 8.6 2) Eligible for nab-gem 45.2% 6.7

17 Nab-paclitaxel + gem vs FolfIrinOx Geographical setting GEM GEM-nab North America Australia Eastern Europe Western Europe

18 Nab-paclitaxel + gem vs FolfIrinOx is FOLFIRINOX better? Gem-nab FolfIrinOx mpfs 5.5 mo 6.4 mo 6-mo PFS 44% 53% 45.4% 1-y PFS 16% 12% Conroy T, et al. NEJM 2011; 364:

19 FOLFIRINOX is median OS correctly calculated? nabp+gem mos phase II 12.1 phase III 8.7 Conroy T, et al. NEJM 2011

20 Nab-paclitaxel + gem vs FolfIrinOx Comparable populations? 2 nd line FOLFIRINOX 47% Gem-nab 38%

21 is modified FolfIrinOx equally effective? Stein 1 Uesugi 2 Conroy (# 395) (#422) (NEJM) N ECOG 0 46% nr 37% M+ liver 54% nr 88% CA19.9 <59 ULN 49% nr 44% mos PR 35% nr 31.6% (stage III) 17% na na 1. Stein S. ASCO GI 2016 #395. IRI 135 includes locally advanced 2. Uesugi K. ASCO GI 2016 #422. FU ; IRI 150

22 Median OS is overestimated? Modified FOLFIRINOX is less effective? Maroun J ESMO P

23 COMBINATION CHEMOTHERAPY G3-4 ADVERSE EVENTS Gem-nab FolfIrinOx PEXG neutropenia 38% 46% 35% PLT 13% 9% 10% neutrop fever 3% 5% 1% Hb 13% 8% 13% vomiting nr 15% 4% fatigue 17% 24% 9% diarrhea 6% 13% 8% neuropathy 17% 9% 0%

24 1 ST -LINE OPTIONS IN MPC mos 1y 2y GEM-nab (10.7) 4 35% (39%) 4 9% FolfIrinOx % 11% PEXG % 17% 1) VanHoff DD, et al N Engl J Med. 2013;369(18): ) Conroy T, et al N Engl J Med 2011; 364: ) Reni M, et al Cancer Chemother & Pharmacol 2012: 69: ) Tabernero J, et al OncoTargets and Therapy 2017; 10:

25 PACT-19 - PHASE II Chemo-naive patients randomised, monocentric age yr Karnofsky PS 70 R Metastatic disease Gem+nabpaclitaxel PAXG Reni M, et al. BJC 2016; 115: p0=45%; p1=65%, α=0.05, power=80%; N=42 eligible patients If 25/42 PFS-6, the regimen will be considered active

26 RESULTS CR PR SD PD CA % CA % PAXG 1 (2%) 20 (48%) 14 (33%) 7 (17%) 12 (38%) 10 (31%) AG* 2 (5%) 10 (24%) 18 (44%) 8 (20%) 13 (42%) 6 (19%) VonHoff 29% 31% *3 patients not assessable

27 RESULTS (Apr 2014 May 2016) Baseline Characteristic A: PAXG B: AG Number Male/female 19/23 24/17 KPS (95%) 38 (93%) Age median range CA19.9 >ULN 32 (76%) 31 (76%) median range Biliary Stent 12 (29%) 7 (17%) NLR 5 6 (14%) 8 (19%) Liver metastasis 29 (69%) 32 (79%) Peritoneal metastasis 9 (21%) 6 (15%)

28 RESULTS PAXG AG VonHoff 2 PFS6 31 (74%) 49% 44% mpfs mos y OS 62% 44% 35% 2y OS 24% 12% 9%

29 OSR stage IV by REGIMEN N mos 1y 2y PEFG PEXG AG PAXG

30 LINEE GUIDA AIOM Qualità dell evidenza SIGN A A B Raccomandazione clinica Nei pazienti affetti da PDAC M+ KPS>70 età 70 anni, una chemioterapia di 1 linea con 3 o 4 farmaci può essere presa in considerazione come opzione di 1 intenzione in alternativa alla monoterapia con gemcitabina In pazienti con PS 70 ed età >18 anni una chemioterapia di I linea con gemcitabina-nab-paclitaxel dovrebbe essere preso in considerazione come opzione terapeutica di 1 intenzione in termini di incremento di PFS e OS La gemcitabina settimanale può essere presa in considerazione come opzione terapeutica di 1 intenzione in pazienti con malattia avanzata e KPS <70 Forza della raccomandazione clinica Positiva debole Positiva forte Positiva debole