cáncer de páncreas -...

Diez años de avances

en el tratamiento de los tumores digestivos:

Cáncer de Páncreas

Fernando Rivera Herrero

Sv de Oncología Médica

Hospital Universitario Marqués de Valdecilla. Santander

Finantial disclosure

– Consultor: CELGENE

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

BAYER, LILLY, CELGENE

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

LILLY, CELGENE, TECNOFARMA

Diez años de avances en el tto de los T. Digestivos: Cáncer de Páncreas

Summary

Introduction

Treatment of no metastatic PC Resectable and Borderline PC

Locally advanced PC

Treatment of metastatic PC Before 2010

FOLFIRINOX / Gem-Abx /Naliri-FuFol

New treatments

Conclusions

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

PC is not an easy enemy …

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

Adenoca de Páncreas Sv 5a 5% 1

INTRODUCCIÓN Cáncer de páncreas

Sv 5 a

1.- De Angelis R et al. EUROCARE-5. Lancet Oncol 2014; 15: 23–34

Epidemiology

5 y OS: 20%


Summary

Introduction


Locally advanced PC



New treatments

Conclusions

Non metastatic Pancreatid Cancer Resectability NCCN Guidelines 2017

Epidemiology

5 y OS: 20%

Resectable PC: Adjuvant CT improves DFS and OS

CT (5-FU) 5y OS: 25%

No CT 10%

ESPAC-1 1

1.- Neoptolemos et al. NEJM. 2004 2.- Oettle et al, JAMA 2007 3.- Nptolemos et al. JAMA 2010

OS HR 0.71 p 0.009

OS p 0.005

CT (Gem) 5y OS: 21 %

No CT 9 %

CONKO-3 2

CT (Gem) 5y OS: 21 %

CT (5-FU-Fol) 21 %

OS HR 0.94 p 0.39

ESPAC-3 3

Resectable PC: Adjuvant CT improves DFS and OS

CT (S1) 5y OS: 44 %

CT (Gem) 24 %

JASPAC-1 1

1.- Uesaka K, et al. Lancet 2017 3.- Nptolemos JP et al. Lancet 2017

OS HR 0.57 p < 0.001

ESPAC-4 2 CT (Gem-Cap) 5y OS: 32 %

CT (Gem) 18 %

OS HR 0.82 p 0.03

Postoperative Chemotherapy Ongoing Phase III trials

PRODIGE-24

490 PTS

R0-1 Resected Panc.Adenoca

Postop.mFOLFIRINOX

(6 months)

Postop. Gem

(6 months) Primary endpoint: DFS

F III APACT 800 PTS


Postop.Gem-nabPaclitaxel (6 months)

Postop. Gem


Italy, GIP-2

490 PTS


Postop.FOLFOXIRI (6 months)

Postop. Gem


Resectable PC: Doubts about the role of RT

CT/RT (5-FU) 5y OS: 12%

NoCT/RT 20 %

ESPAC-1 1

1.- Neoptolemos et al. NEJM. 2004 ; 2.- Smeenk et al, Ann Surg 2007 ; 3.- Safran et al, ASCO 2017

OS HR 1,28 p 0.05

CT/RT (5-FU) 5y OS: 25%

NoCT/RT 22 %

EORTC-40891 2

OS HR0,91 p 0.5

R0-1

Resected Panc.Adenoc. Observation Postop RT/Fu or Cape

RTOG (2nd Rand) 3 Postop. CT

(6 months)

Resectable PC: Doubts about the role of RT

RESECTABLE PC: Preoperative CT/RT or CT

Retrospective studies - SEER: 3008 pts Preoperative RT

Postoperative RT

No RT

Rand P.II : Interdisciplinary Cancer Group of Gastrointestinal Tumours (AIO, ARO, CAO)

Cis-Gem/RT Surg Gem

Surg Gem

P.III NEOPAC 1º endpoint PFS

GemOx Surg Gem

Surg Gem

310 resectable p

166 PTS

Periop.Gem-Abx

(x2 Cir x4)

Postop. Gem-Abx

(x 6)

Primary endpoint: DFS

F II Rand NEONAX

Ongoing Rand trials

Borderline PC

Epidemiology

5 y OS: 20%

Locally Advanced PC: FOLFIRINOX

Suker M, et al. Lancet Oncol. 2016;17(6):801-810.

FOLFIRINOX for Locally Advanced Pancreatic Cancer:A Systematic Review and Patient-Level Meta-Analysis

Background: 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis

Suker M, et al. Lancet Oncol. 2016;17(6):801-810.

FOLFIRINOX for Locally Advanced Pancreatic Cancer:A Systematic Review and Patient-Level Meta-Analysis

Background: 35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis

• Applicability of results from trials on stage IV to stage III may be tricky

• Stage-specific trials are mandatory and patients should be offered them

GAP (Gemcitabine Abraxane Pancreas) TrialPhase III PRODIGE 29-NEOPAN Trial in LAPC:

FOLFIRINOX vs Gemcitabine

National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT02539537 and

http://clinicaltrials.gov/ct2/show/NCT02043730. Accessed: 21 September 2017.

Suker M et al. Lancet Oncol 2016

Locally Advanced PC: Gem-Abx

Hammel P et al. ASCO-GI 2018 LAPACT: P II Gem-Abx in LAPC

• Applicability of results from trials on stage IV to

stage III may be tricky

• Stage-specific trials are mandatory and patients

should be offered them

GAP (Gemcitabine Abraxane Pancreas) Trial

Phase III PRODIGE 29-NEOPAN Trial in LAPC:

FOLFIRINOX vs Gemcitabine

National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT02539537 and

http://clinicaltrials.gov/ct2/show/NCT02043730. Accessed: 21 September 2017.

442 pts Locally Advanced PC

Gem-erlotinib x 4 Gem x 4

P III LAP 07 (GERCOR)

Cap-RT Gem / Gem-erlo x 2

1º endpoint OS

269 pts (61%)

Hammel P et al. JAMA 2016

Hammel P, et al. JAMA. 2016;315(17):1844-1853.

Effect of Chemoradiotherapy vs Chemotherapyon Survival in Patients With Locally Advanced

Pancreatic Cancer Controlled After Four Monthsof Gemcitabine With or Without Erlotinib

The LAPO7 Randomized Clinical Trial

Locally Advanced PC: Radiotherapy??

Strobel O, et al. Surgery. 2012;152(3 Suppl 1):S33-S42.

Overall Post-Operative Survival

Resection After Neoadjuvant Therapy for Locally Advanced, “Unresectable” Pancreatic Cancer

P<.004

P = .19

Locally Advanced PC: Salvage suergery


Summary

Introduction


Locally advanced PC



New treatments

Conclusions

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


Locally advanced PC


FOLFIRINOX / Gem-Abx / Naliri-FuFol

New treatments

Conclusions

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


Locally advanced PC



New treatments

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

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

3

4

>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

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

FRAGANCE: Gem-Abx in mPC with ECOG 2

MPACT (GA): 8.5 m MPACT (GA): 5.5 m

Hidalgo M et al, ESMO 2017

FRAGANCE

Hidalgo M et al, ESMO 2017

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

Date of preparation March 2016 INT-ABR160015

151611844624 14 3 1 11

OFF vs FF as 2nd-line therapy for APC*

(CONKO-003)

OFF†

FF

Stratification: Presence of metastases, duration of 1st-line gemcitabine therapy (3, 3–6, or >6 months),

KPS (70–80% or 90–100%)

Primary endpoint: OS

Secondary endpoints: TTP, tolerability

• PD following gemcitabine 1st-line therapy

• KPS ≥70

• Measureable

disease

100

80

60

20

0

40

Time (months)

86 0 3 12 15 24 27 38 33 6 9 18 21 30

0 76 34 6 5 1 1 0 1 14 7 5 3 1 1 84 20 3 3 2 2 1 2 9 7 2 2 2 FF

OFF No at risk

100

80

60

20

0

40

Time (months) No at risk

48 18 9 12 0 3 6 36 24 30 42 86 54

FF OFF 2 10 22 15 76 59 37 4 6 5 3 0 1

Overa

ll s

urv

ival (%

) P

rogre

ssio

n-f

ree s

urv

iva

l (%

)

OFF median 2.9 months (95% CI 2.4–3.2)

FF median 2.0 months (95% CI 1.6–2.3)

HR 0.68 (95% CI 0.50–0.94) p=0.019

OFF median 5.9 months (95% CI 4.1–7.4)

FF median 3.3 months (95% CI 2.7–4.0)

HR 0.66 (95% CI 0.48–0.91) p=0.010

R 1:1

Oettle et al. JCO 2014;32:2423-9

*>88% of patients had metastatic disease †OFF differs from FOLFOX (folinic acid, fluorouracil, and oxaliplatin)

with respect to the frequency of treatment administration: fluorouracil

is administered weekly for the first 4 weeks, and oxaliplatin is

administered on Days 8 and 22 of a 6-week cycle

2nd line in mPC

Naliri: NAPOLI-1

Oxali: CONKO-003

Oxali: PANCREOX

Sequence of treatment in mPCP

2017: A Classical Case of mPDAC

Nab-paclitaxel +

gemcitabine

2018


Summary

Introduction


Locally advanced PC



New treatments

Conclusions

Veliparib (Inhibidor de PARP)

F IB : Cis-Gem-Veliparib 1 9 pts con mut BRCA 1,2: 5 RP y 4 EE

1.- O´Reilly EM, et al. ASCO 2014, #4023

Olaparib in BRCA mutated PC

1.- Kaufman et al, J Clin Oncol 2014

F II Olaparib 1 en Mut gBRCA 1-2: 23 pts refractarios a Gem

Cubillo A et al. ESMO 2017

O´Reilly E et al. ASCO-GI 2017

mPC: Targeting the Notch pathway

279 pts HA hight 84 pts (30%)

420 PTS

Placebo-Gem-Abx PEGPH20-Gem-Abx Primary endpoints: PFS / OS

P III HALO 301

mPC; HA hight

Possibilities of combination with Immune checkpoint inhibitors

Philip AP. ASCO-GI 2017

Protegido del sistema inmune

IDO inh

Pharmacological inhibition of BTK (ibrutinib) in PDAC can reactivate adaptive immune responses.

Gunderson et al, Cancer discov 2016

Stromal –associated fibtroblast recruits

B regs (produces TP), may be inhibited by BTK

inhibitors, such ibrutinib


Summary

Introduction


Locally advanced PC



New treatments

Conclusions

Conclusions

Conclusions .- Resectable PC

Adj CT: Gem-Cap (waiting for FOLFIRINOX and Gem-Abx)

Borderline PC Preoperative CT (+/-RT)

.- Locally Advanced PC

CT: FOLFIRINOX or Gem-Abx

No stablish role for RT

Salvage Sx if feasible

.- Metastatic PC

In 2010: P III FOLFIRINOX: Active (but toxic)

P III MPACT: Gem-Abx is active and less toxic.

FRAGANCE: Gem-Abx in ECOG-2

New targeted drugs: some negative trials but a lot of ongoing trials

Gracias Thank you

cáncer de páncreas -...

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