Opciones terapéuticas de 1ª línea de cáncer de páncreas ... · Opciones terapéuticas de 1ª...

Opciones terapéuticas de 1ª línea de

cáncer de páncreas metastásico

Fernando Rivera Herrero

Hospital Universitario Marqués de Valdecilla, Santander

– Consultor: CELGENE

– Research fundings: AMGEN., MERCK-SERONO, ROCHE, SANOFI,

BAYER, LILLY, CELGENE

– Honoraria: AMGEN., MERCK-SERONO, ROCHE, SANOFI, BAYER,

LILLY, CELGENE, TECNOFARMA

Finantial disclosure

Summary

Introduction

Treatment of mPC before 2011

FOLFIRINOX (Prodige-4)

Gem-Abraxane (MPACT)

ECOG-2 / Colestasis

Observational studies

Sequence of treatment

Conclusions

Treatment options for 1st line mPC

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

mPC is not an easy enemy …

… but we have to help our patients and avoid panic and pessimism

Hidalgo M et al. CTO 2016

% of pts ??

30% ? 35% ? 35% ?

It is important to avoid delays in the treatment of mPC

Suzuki R et al. ASCO-GI 2015

Sv

Short: <10 days

Summary

Introduction




ECOG-2 / Colestasis



Conclusions


Advanced pancreatic cancer CT vs BSC

Meta-analysis CT vs BSC

(Sultana et al. J Clin Oncol. 2007 Jun 20;25(18):2607)

7 studies, 432 pts

Improvement in OS with CT

HR 0,64 95% C.I.: 0,42-0,98

RR, PFS and OS in mPC

- 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%

Treatment RR PFS OS 1y OS

Summary

Introduction




ECOG-2 / Colestasis



Conclusions


342 PTS (2005-09, 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...

FOLFIRINOX

P. II-III Prodige 4- ACCORD 11 FOLFIRINOX vs Gemcitabine

Gem (30 min)

6 m (stop and go)

1ºendpoint:OS 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<0,0001 50,9%

Conroy T et al. N Engl J Med 2011;364:1817-25.

G-CSF 42% 5%

F. III Prodige 4- ACCORD 11 Toxicity: G 3-4

No colangitis and no more toxicity in patients with biliar stent

Summary

Introduction




ECOG-2 / Colestasis



Conclusions


861 PTS (151 sites, 11 contries) M1

KPS ≥ 70

Bilirrubine < UNL

nabPaclitaxel-Gem nabP; 125 mg/m2 iv Gem: 1000 mg/m2 iv weekly 3/4 w

P. III MPACT 1 nabPaclitaxel-Gem vs Gemcitabine

Gem (30 min)

Gem 1000 mg/m2 iv weekly 7/8 w followed by 3/4 w

1ºendpoint:OS

1.- Von Hoff DD et al. N Engl J Med 2013; 2.- (OS updated results) Goldstein D et al. ASCO-GI 2014

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

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.

OS - Prespecified Subgroups

1

6

>65: 42%

KPS 70-80: 40%

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

38

31

13

13

27

16

9

12

Patients who received growth factors, % 26 15

Febrile neutropenia,b % 3 1

Grade ≥ 3 nonhematologic AEsb in > 5% of patients, %

Fatigue

Peripheral neuropathyc

Diarrhea

17

17

6

7

< 1

1

Grade ≥ 3 neuropathy

Time to onset in days, median

Time to improvement to grade ≤ 1 in days, median

Patients who resumed nab-P, %

140

29

44

113

--

--

Safety

.- OS with longer follow-up Sept 2012 mayo 2013 (median follow-up 13,9 m)

.- Prognostic and predictive value of - CA 19.9 - NLR .- Tox and IK (90-100 vs 70-80)

35% vs 22%

10% vs 5% 4% vs 0%

OS

OS: Ca 19.9 and NLR

Goldstein D et al, JNCI 2015

Ca 19.9 ≥ median HR 0,61, p<0,001

GA

G

Ca 19.9 < median (2470 U/ml) HR 0,83, p 0,11

GA

G

NLR > 5 (median = 5.6 vs 4.3 m HR = 0.81, P = .079).

GA

G

NLR ≤ 5 (63% of pts) median = 10.9 vs 7.9 m, HR = 0.67, P < .001

GA

G

MPAC: Toxicity according to IK

Goldstein D et al, JNCI 2015

Abraxane in mPC

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

Primary Endpoint OS

Conroy T. N Engl J Med 2011;364:1817-

25

mOS 11.1m FOLFIRINOX VS. 6.8 m G

mOS 8.7 m NP-G vs. 6.6 m G

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

Características de las poblaciones

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

2 3

Ca19.9 >59 LAN

(medida indirecta carga tumoral)

++ 42%

+++ 52%

MPACT

• Población con características clínicas más desfavorables en cáncer de páncreas: más jóvenes y más “sanos”

Tabernero et al. Beaujon Conference 2014

Pacientes ECOG 0-1 MPACT

Mediana de SG con Gem-Abx: 9,7 meses

Tabernero J et al, The Oncologist 2015;20:1–8

- 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): - FOLF-Naliri - FOLF-Ox-Naliri - Gem-Abx

1º endpoint

PFS

FOLF-Ox-Naliri (P I/II NCT02551991)


- 1st line

- ECOG-0-1

d 1 8 15 21 28 35 42

Gem Gem Gem mFOLFOX

Abx Abx Abx

F. I/II SEQUENCE (TTD 15-05): sequencial AG-mFOLFOX

P I (6-24 pts)

1º endpoint

DLT /Toxicity

P II (156 pts)

1º endpoint

12 m OS

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 2.

1 -Goggins, Cancer Res 1996, 2- Golan, Br. J Cancer 2014.

Summary

Introduction




ECOG-2 / Colestasis



Conclusions


MPACT: impact of PS

Poor KPS (70-80)

Good KPS (90-100)

Chiorean et al, ESMO 2015

Nab-Paclitaxel + Gem in “suboptimum” pts: ECOG 2


- 1st line

- ECOG-2

Abx 150

Gem 1000

d 1,15 / 28 d

F. I/II FRAGANCE

Abx 125

Gem 1000

d 1,8,15 / 28 d

Abx 100

Gem 1000

d 1,8,15 / 28 d

Abx 125

Gem 1000

d 1,15 / 28 d

Part 1: rand 24 pts 1º endpoint Part 1

Tox

Part 2, rand 221 pts

1º endpoint Part 2

OS

Arm B

Hidalgo M et al, ESMO 2017

Arm C Arm D Arm E

FRAGANCE


FRAGANCE

MPACT (GA): 8.7 m MPACT (GA): 5.5 m


35

ABI-007-PANC-004: Phase I nab-Paclitaxel + Gemcitabine in Patients With

Advanced Pancreatic Cancer With Elevated Bilirubin Levels1,2

a Patient enrollment in cohorts 2 and 3 may only begin after safety and PK review of the prior cohort.

1. ClinicalTrials.gov. NCT02267707. https://clinicaltrials.gov/ct2/show/NCT02267707. Accessed March 17, 2015. 2. Celgene Corporation. Clinical

Trials Brochure. Winter/Spring 2015.

Study start: 11/2014 Estimated study completion: 10/2018

Primary endpoints: MTD, PK

Secondary endpoints: Objective tumor response,

PFS, OS, safety

Region: Germany, US

Summary

Introduction




ECOG-2 / Colestasis



Conclusions


Abrams TA et al. ASCO-2014. #4131

Retrospectivo Study of CT in mPC Data base IntelliDose (USA), 20052014

total 3.459 pts with mPC and CT

1 ª línea

Gem: pts > 80 a

FOLFIRINOX pts < 60 a

Gem-nabPacl pts 60-80 a

FOLFIRINOX en práctica clínica habitual

Maroun J et al. ESMO 2015: 302P

N 224 >75 años 7%

PS2 4%

1st-line nab-paclitaxel + gemcitabine in advanced PC: Real-life data from Italy (multicentre, retrospective analysis)

• Patients received 1cycle of nab-P (100/125 mg/m2) + gem (1000 mg/m2) as 1st-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: 9.337-11.236 months); median PFS, 6.7 months (95% CI: 6.197-7.203 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

Giordano et al. ECC 2015, abstract 2334

This study confirms the efficacy and safety of nab-P + gem as 1st-line treatment in a real-life, unselected patient population

Overall survival

0.0

Pro

po

rtio

n o

f su

rviv

al

OS (months) 36.0

18.0

42.0

48.0

0.2

0.4

0.6

1.0

0.8

Survival function Censored

0.0

6.0 12.0

24.0

30.0

0.0

Pro

po

rtio

n o

f su

rviv

al

PFS (months) 18.0

9.0 21.0

24.0

0.2

0.4

0.6

1.0

0.8

Survival function Censored

0.0

3.0 6.0 12.0

15.0

43%

12%

Progression-free survival

Giordano G et al. ASCO-GI 2015

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

Retrospective Study Gem/Abx in mPC 9 Italian centres

total 120 pts 43 pts (35%) ≥ 70 a

Braiteh, ASCO-GI. 2016. Abst 433

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

Watanabe K et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 438)

FOLFIRINOX modificado

N 70

nabPaclitaxel/Gemcitabina N 65


Nab-P/G

PS 0-1 100 % 99 %

MTS HEPATICAS

56% 49%

MTS PERITONEALES

34% 31%

STENT BILIAR 21% 17%

> 75 AÑOS* 4,3% 12%

FOLFIRINOXmodificado

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 %


Nab-P/G

Neutropenia 47 % 45 %

Diarrea 1,4 % 2 %

Neuropatía Periférica

4,2 % 4,6 %

Neutropenia febril

8,5 % 2 %

Uso G-CSF* 21 % 0 %

Anorexia* 13 % 3%

CARACTERÍSTICAS EFICACIA TOXICIDAD

* significación estadística

Summary

Introduction




ECOG-2 / Colestasis



Conclusions


MM-398 (nal-IRI) (nanoliposomal irinotecan )

417 pts Metastatic Panc Cancer

2nd-3rd line after Gem

MM-398/FU/Fol FU/Fol

1º endpoint: OS(median) 6.1 m HR 0.67;p 0.012 4.2 m p 0.94 4.9 m

F. III NAPOLI-1

MM-398

A. Wang-Guillam, Lancet 2016

Potential treatment sequencing approach for MPC in 2017?

FOLFIRINOX

Nab-paclitaxel + gemcitabine

(if no neuropathy)

Gemcitabine

FOLFIRINOX

Nab-paclitaxel + gemcitabine

MM-398 + 5-FU/LV

OFF

Capecitabine / 5 FU

MM-398 + 5-FU/LV (depending on

prior exposure)

1st line 2nd line 3rd line

NOTE: Nab-paclitaxel is licensed for use in combination with gemcitabine as

1st-line therapy for patients with MPC

mFOLFOX6 or CAPOX

Platinum-based tx (depending on

prior exposure)

Supported by RCT data

Supported by retrospective data or small,

single arm trials

¿¿FOLFIRI??

MM-398 + 5-FU/LV (depending on

prior exposure)

Platinum-based tx (depending on

prior exposure)

Summary

Introduction




ECOG-2 / Colestasis



Conclusions


Conclusions

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

-

Gracias Thank you

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