La chemioterapia di I linea

(1)

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

(2)

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

1^st targeted agent approved for LA or

metastatic PC

Multidrug regimen shows significant

OS benefit in metastatic disease

1930 1940 1950 1960 1970 1980 1990 2000 2010

1^st combination

chemotherapy showing superiority over GEM

(3)

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

1

^ST

-LINE OPTIONS IN MPC:

GEMCITABINE ?

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

100

80

60

20

0

40

20

0 2 4 6 8 10 12 14 16 18

Time (months)

Patients surviving (%)

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%)

(4)

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

….

1

^ST

-LINE OPTIONS IN MPC:

GEMCITABINE ?

(5)

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)

1

^ST

-LINE OPTIONS IN MPC ?

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10 days ! 0% 18 mo

1

^ST

-LINE OPTIONS IN MPC:

GEMCITABINE + ERLOTINIB ?

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

(8)

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

1

^ST

-LINE OPTIONS IN MPC :

FOLFIRINOX

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FFX: 11.1 mo Gem: 6.8 mo

1

^ST

-LINE OPTIONS IN MPC :

FOLFIRINOX

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• 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.

1

^ST

-LINE OPTIONS IN MPC :

NAB-PACLITAXEL-GEMCITABINE

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

1

^ST

-LINE OPTIONS IN MPC :

NAB-PACLITAXEL-GEMCITABINE

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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

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ACCORD 11 and MPACT cannot be directly compared (regional vs global settings; differences in eligibility criteria, in 2^nd-line use and efficacy …)

1

^st

-line treatment: what criteria to

select one treatment or the other?

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Nab-paclitaxel + gem vs FolfIrinOx

Comparable populations ?

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FFX: 11.1 mo Gem: 6.8 mo

BEWARE of APPLES

FOLFIRINOX

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#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

Nab-paclitaxel + gem vs FolfIrinOx

Comparable populations ?

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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

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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 ?

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nabP+gem mOS phase II 12.1 phase III 8.7

FOLFIRINOX

is median OS correctly calculated ?

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2^nd line FOLFIRINOX 47%

Gem-nab 38%

Nab-paclitaxel + gem vs FolfIrinOx

Comparable populations ?

(21)

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

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Maroun J ESMO 2015 302P

Median OS is overestimated ?

Modified FOLFIRINOX is less effective ?

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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

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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

1

^ST

-LINE OPTIONS IN MPC

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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

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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

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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%)

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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%

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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

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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