Post on 05-Jun-2020
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
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
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
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
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
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
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)
- Metastatic Pancreatic Adenoca
- 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
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
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
- Metastatic Pancreatic Adenoca
- 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
Hidalgo M et al, ESMO 2017
FRAGANCE
MPACT (GA): 8.7 m MPACT (GA): 5.5 m
Hidalgo M et al, ESMO 2017
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
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
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
FOLFIRINOX modificado
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 %
FOLFIRINOX modificado
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
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
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
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
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