LA CHEMIOTERAPIA DI I LINEA -...

Michele Reni

Department of Medical Oncology

IRCCS Ospedale San Raffaele

Milan, Italy

DECIDERE LA CHEMIOTERAPIA ADIUVANTE E

DELLA MALATTIA METASTATICA

LA CHEMIOTERAPIA DI I LINEA

THE HISTORY OF PC TREATMENT

Whipple refines the PD procedure

Italian surgeons develop the pylorus-preserving PD

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

1st targeted agent approved for LA or

metastatic PC

Multidrug regimen shows significant

OS benefit in metastatic disease

19

30

19

40

19

50

19

60

19

70

19

80

19

90

20

00

20

10

1st combination chemotherapy showing superiority over GEM

mSv 1y OS

5-FU 4.41 2%

GEM 5.65 18%

P = .0025

1.0 –

0.9 –

0.8 –

0.7 –

0.6 –

0.5 –

0.4 –

0.3 –

0.2 –

0.1 –

0.0 –

0 4 8 12 16 20

1ST-LINE OPTIONS IN MPC: GEMCITABINE ?

Burris et al. JCO 1997;15:2403-13

100

80

60

20

0

40

20 0 2 6 8 12 14 18 4 10 16

Time (months)

Patients

surv

ivin

g (

%)

Log rank test p=0.0025

Gemcitabine

5-FU

N 126

Stage IV 93 (74%)

KPS 50-70 87 (69%)

KPS 80-100 39 (31%)

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 0.683

pemetrexed 6.2 mo 6.3 mo 0.85

capecitabine 8.4 mo 7.3 mo 0.314

irinotecan 6.3 mo 6.6 mo 0.789

cisplatin 7.6 mo 6.0 mo 0.12

oxaliplatin 9.0 mo 7.1 mo 0.13

….

1ST-LINE OPTIONS IN MPC: GEMCITABINE ?

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)

1ST-LINE OPTIONS IN MPC ?

10 days ! 0% 18 mo

1ST-LINE OPTIONS IN MPC: GEMCITABINE + ERLOTINIB ?

Moore et al JCO 2007;25:1960-6;

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

1ST-LINE OPTIONS IN MPC : FOLFIRINOX

FFX: 11.1 mo Gem: 6.8 mo


1ST-LINE OPTIONS IN MPC : FOLFIRINOX

• This study enrolled 861 pts at 151 sites in North America, Europe, and Australia

1:1, stratified by KPS, region, liver metastasis

nab-P 125 mg/m2 IV qw 3/4

+

Gem 1000 mg/m2 IV qw 3/4

Gem 1000 mg/m2 IV qw 7/8

then qw 3/4

Planned N = 842 •Stage IV •No prior treatment for M+ disease •KPS ≥ 70 •Measurable disease •Total bilirubin ≤ ULN •No age limitation

Von Hoff DD, et al. N Engl J Med. 2013; 369: 1691-1703.

1ST-LINE OPTIONS IN MPC : NAB-PACLITAXEL-GEMCITABINE

Von Hoff DD, et al. N Engl J Med. 2013; 369: 1691-1703.

1ST-LINE OPTIONS IN MPC : NAB-PACLITAXEL-GEMCITABINE

ORR mOS 1y OS 18-mo OS

FOLFIRINOX 32% 11.1 48% 19%

GEM 9% 6.8 21% 6%

GEM 7% 6.7 22% 9%

GEM-nab 24% 8.5 35% 16%

Nab-paclitaxel + gem vs FolfIrinOx

ACCORD 11 and MPACT cannot be directly compared

(regional vs global settings; differences in eligibility

criteria, in 2nd-line use and efficacy …)

1st-line treatment: what criteria to select one treatment or the other?

Nab-paclitaxel + gem vs FolfIrinOx Comparable populations ?

FFX: 11.1 mo Gem: 6.8 mo

BEWARE of APPLES

FOLFIRINOX

#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


GEM GEM-nab

North America 6.6 8.8

Australia 6.7 9.4

Eastern Europe 5.9 7.7

Western Europe 6.9 10.7

Nab-paclitaxel + gem vs FolfIrinOx Geographical setting

Gem-nab FolfIrinOx

mPFS 5.5 mo 6.4 mo

6-mo PFS 44% 53%

1-y PFS 16% 12%

45.4%

Conroy T, et al. NEJM 2011; 364: 1817-1825

Nab-paclitaxel + gem vs FolfIrinOx is FOLFIRINOX better ?

nabP+gem mOS phase II 12.1 phase III 8.7

FOLFIRINOX is median OS correctly calculated ?


2nd line

FOLFIRINOX 47%

Gem-nab 38%


is modified FolfIrinOx equally effective ?

Stein1 Uesugi2 Conroy (# 395) (#422) (NEJM) N 37 19 171 ECOG 0 46% nr 37% M+ liver 54% nr 88% CA19.9 <59 ULN 49% nr 44%

mOS 10.2 10.32 11.1

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 0+2400; IRI 150

Maroun J ESMO 2015 302P

Median OS is overestimated ? Modified FOLFIRINOX is less effective ?

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%

COMBINATION CHEMOTHERAPY G3-4 ADVERSE EVENTS

mOS 1y 2y

GEM-nab1 8.7 (10.7)4 35% (39%)4 9%

FolfIrinOx2 11.1 48% 11%

PEXG3 10.6 41% 17%

1) VanHoff DD, et al N Engl J Med. 2013;369(18):1691-703 2) Conroy T, et al N Engl J Med 2011; 364: 1817-1825 3) Reni M, et al Cancer Chemother & Pharmacol 2012: 69: 115-123 4) Tabernero J, et al OncoTargets and Therapy 2017; 10: 591-596

1ST-LINE OPTIONS IN MPC

R

Gem+nab-paclitaxel

PAXG

p0=45%; p1=65%, α=0.05, power=80%;

N=42 eligible patients

If ≥ 25/42 PFS-6, the regimen will be considered active

Reni M, et al. BJC 2016; 115: 290-296

Chemo-naive patients

age 18-75 yr

Karnofsky PS ≥ 70

Metastatic disease

PACT-19 - PHASE II

randomised, monocentric

RESULTS

CR PR SD PD ↓CA19.9 ≥90%

↓CA19.9 50-89 %

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

RESULTS (Apr 2014 – May 2016)

Baseline Characteristic A: PAXG B: AG

Number 42 41

Male/female 19/23 24/17

KPS 80-100 40 (95%) 38 (93%)

Age median 66 64

range 44-75 29-75

CA19.9 >ULN 32 (76%) 31 (76%)

median 2230 1201

range 53-36645 46-739108

Biliary Stent 12 (29%) 7 (17%)

NLR ≥5 6 (14%) 8 (19%)

Liver metastasis 29 (69%) 32 (79%)

Peritoneal metastasis 9 (21%) 6 (15%)

RESULTS

AG VonHoff2

PFS6 49% 44%

mPFS 6.1 5.5

mOS 11.2 8.5

1y OS 44% 35%

2y OS 12% 9%

PAXG AG VonHoff2

PFS6 31 (74%) 49% 44%

mPFS 8.1 6.0 5.5

mOS 14.4 11.2 8.5

1y OS 62% 44% 35%

2y OS 24% 12% 9%

OSR stage IV – by REGIMEN

N mOS 1y 2y

PEFG 96 8.7 39 12

PEXG 134 10.2 41 17

AG 41 11.2 44 12

PAXG 42 14.4 62 24

LINEE GUIDA AIOM

Qualità dell’evidenza

SIGN

Raccomandazione clinica Forza della raccomandazione

clinica

A

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

Positiva debole

A

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

Positiva forte

B

La gemcitabina settimanale può essere presa in considerazione come opzione terapeutica di 1° intenzione in pazienti con malattia avanzata e KPS <70

Positiva debole

LA CHEMIOTERAPIA DI I LINEA -...

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