NOVITA’ NELLA TERAPIA DEL CARCINOMA DEL
PANCREAS
FEDERICA MORANO
ONCOLOGIA MEDICA 1 FONDAZIONE IRCCS ISTITUTO NAZIONALE DEI TUMORI MILANO
NUMBERS
Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western societies.
However, it is projected to be the second within a decade1-2.
1. Rahib L. et al, Cancer Res, 2014 2. SEER database, last update July 2016 3. Kleef J et al, Nat Rev Dis Primers, 2016
Due to the aggressive nature of PC, its late presentation and the lack of effective screening, around 50% of patients are metastatic at the time of diagnosis.
5-yrs survival in mPC is around 1%3.
1994 1998 2002 2006 2010 2013 2015
TREATMENTS APPROVED IN PC
FOLFIRINOX
GEMCITABINE + NABPACLITAXEL
GEMCITABINE
S1
Japan
AGENDA
ADJUVANT TREATMENT IN RESECTABLE PATIENTS
NEOADJUVANT TREATMENT IN RESECTABLE, BORDERLINE RESECTABLE AND LOCALLY ADVANCED PATIENTS
METASTATIC DISEASE: WHAT TO DO AFTER THE FIRST LINE?
FUTURE SCENARIOS
ESPAC-4
3-monthly follow-up from randomization to
death Gemcitabine 1000 mg/mq
d 1,8,15 for 6 cycles
Gemcitabine 1000 mg/mq d 1,8,15 for 6 cycles + Capcitabine 1660 mg/m2/day
d 1-21 q28 for 6 cycles R
A N D O M I Z E (1:1) R0/R1 resected PDAC
Curative resection ≤12 weeks
(n=722)
Phase III, multicenter, international, open-label trial of gemcitabina + capecitabine (GEMCAP) vs gemcitabine alone in patients with resected pancreatic dutal adenocarcinoma (PDAC).
Primary endpoint: Overall survival
Secondary endopoints: relapse free survival, toxicity, 2 and 5 yrs survival, QoL
Neoptolemos J, ASCO 2016
ESPAC-4
Adjuvant treatment is the standard after resection of PC and this standard is getting better. The combination of chemotherapy futher improves the outcome in survival.
median OS (months) ESPAC-11
No chemo CT/RT (5FU/RT) 5FU/FA
8.0 10.8 21.0
CONKO-0012
Gemcitabine 22.1
ESPAC-33
5FU
Gemcitabine
23.0 23.6
1. Neoptolemos J et al, NEJM, 2004 2. Oettle H et al, JAMA 2007 3.Neoptolemos J et al, JAMA, 2010
ESPAC-4
The chemotherapy combination improved survival in poor grade tumors and in stage III.
440 (60%) patients were R1, define as ≤ 1mm from any surface.
The adjuvant combination may performe less well in patients with positive resection margin.
However, GEMCAP improved surivival in R1 patients when compared with gemcitabine.
Neoptolemos J, ASCO 2016
JASPAC 01
3-monthly follow-up from randomization to
death Gemcitabine 1000 mg/mq
d 1,8,15 for 6 cycles
S1 40 /50/60 mg bid according to BSA
d 1-28 q42 for up to four cycles R
A N D O M I Z E (1:1) R0/R1 resected PDAC
Curative resection ≤10 weeks
(n=385)
Randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan.
Primary endpoint: Overall survival
Secondary endpoint: Relapse-free surivival
Uesaka K et al, Lancet 2016 Median OS: 46.5 months
Median OS: 25.5 months
Median RFS: 22.9 months Median RFS: 11.3 months
ONGOING ADJUVANT TRIALS
PHASE R0/R1 N TREATMENT PRIMARY ENDPOINT NCT01964430
APACT
Accrual complete 03.16
III R0/R1 800 Gemcitabine + Nab-Paclitaxel vs Gemcitabine
DFS
NCT01526135
UNICANCER group
III R0/R1 490 mFOLFIRINOX vs
Gemcitabine
Relapse free survival
NCT02355119 III N/A 310 FOLFOXIRI
vs
Gemcitabine
DFS
NCT01013649 RTOG 0848
III R0/R1 952 Gemcitabine (± Erlotinib) ±
ChemoRT
OS
NCT01072981 IMPRESS
NEGATIVE (05.16)
III R0/R1 722 Gemcitabine (±
ChemoRT)
±
Algenpantucel-L
OS (27.3 mos Experimental vs
30.4 Control)
AGENDA
ADJUVANT TREATMENT IN RESECTABLE PATIENTS
NEOADJUVANT TREATMENT IN RESECTABLE AND BORDERLINE RESECTABLE PATIENTS
METASTATIC DISEASE:WHAT TO DO AFTER THE FIRST LINE?
FUTURE SCENARIOS
DEFINITIONS
1. SEER database, last update July 2016 2. Katz et al, Ann Surg Oncol, 2013
Potentially Resectable
Borderline Resectable
Locally advanced Portal Vein/
SMV
TVI < 180° TVI ≥180° and/or reconstructable
occlusion
Unable to reconstruct
Hepatic Artery
No TVI Reconstructable short-segment TVI of any degree
Unable to reconstruct
Superior Mesenteric Artery
No TVI TVI < 180° TVI ≥180°
Celiac Trunk No TVI TVI < 180° TVI ≥180°
STATE OF THE ART: 3 META-ANALYSES
Gillen et al 2010 Muru Assifi et al 2011 Andrulli et al 2012
• Retrospective and prospective studies
•Neoadjuvant therapy consisting of RT, RT-CT or CT
• 111 studies
• 4394 patients
• Time period 1980-2009
• Prospective Phase 2 studies only
•Gem- or 5FU based therapy
• 14 studies
• 536 patients
• Time period 1993-2010
• Prospective studies only
• Gem-based therapy ± RT
• Resectable or unresectable PC
• Chemo-naïve patients
• 20 studies
• 707 patients
• Time period 1998-2008
For initially resectable tumors, resection rates and survival are
comparable with NACT vs upfront surgery + adj CT
1/3 of unresectable coverted to resectable with NACT, with comparable survival to initially
resectable patients
Some activity in patients with borderline/unresectable disease – 1/3 of borderline
converted to resectable
Until more effective agents are available, only patients with locally advanced sidease are likely to benefit from NACT
Marginal support for NACT in resectable patients
Potential advantage for NACT only in a minority of
unresectable patients
NACT IN RESECTABLE PC
N Treatment Resected (%) OS (months)
OS resected (months)
Evans D et al, JCO 2008 86 Gem-RT 64 (74%) 22.7 34
Varadhachary G et al, JCO 2008 90 Cis/Gem + Gem-RT
52 (58%) 17.4 31
O’Reilly E et al, Ann Surg 2014 38 Gem/Ox + Adj Gem
27 (71%) 27.2 NR
(3yrs OS 60%)
Marsh et al, ASCO 2016
-21 resectable patients treated with mFOLFIRINOX per 8 cycles (4 pre and 4 post- surgery)
-17 patients were resected with 94% R0 resection -OS 33.4 months
Barbour et al, ASCO 2016
-42 resectable patients treated with Gemcitabine+Nab-Paclitaxel per 4 cycles (2 pre and 2 post-surgery)
-Only 60% got post-operative treatment
-30 patients were rected with 50% R0 resection
SWOG S1505
Phase II, multicenter trial of neoadjuvant therapy in resectable PC
Gemcitabine + nab-Paclitaxel x 3 cycles SURGERY
Gemcitabine + nab-Paclitaxel x 3 cycles
mFOLFIRINOX x 6 cycles SURGERY
mFOLFIRINOX x 6 cycles R
A N D O M I Z E (1:1) Resectable pancreatic
ductal adenocarcnoma (n=112)
Primary endpoint: Evaluate 2 years OS (‘PICK THE WINNER’)
NACT IN BORDERLINE-RESECTABLE PC
N Treatment Resected (%) OS (months)
OS resected (months) Christians et al, Oncologist
2014
18 FOLFIRINOX
±CTRT
67% 22 NR
Paniccia et al, Medicine 2014 18 FOLFIRINOX
±CTRT
94% 25 NR
Rose et al, Ann Surg Oncol 2014
64 Gem/Docetax el + CTRT
48% 23.6 22 (81%)
Katz et al, JAMA Surg 2016 23 FOLFIRINOX
±CTRT
68% 18 NR
Kim et a, ASCO GI 2016 26 FOLFIRINOX 77% PFS 22.5 NR
Idrees et al, ASCO GI 2016 58 FOLFIRINOX
±CTRT
84% 27.4 NR
AGENDA
ADJUVANT TREATMENT IN RESECTABLE PATIENTS
NEOADJUVANT TREATMENT IN RESECTABLE AND BORDERLINE RESECTABLE PATIENTS
METASTATIC DISEASE:WHAT TO DO AFTER THE FIRST LINE?
FUTURE SCENARIOS
METASTATIC DISEASE
Two active front-line regimens: FOLFIRINOX1 and Gemcitabine+nab-Paclitaxel2
No clear data to guide which is best
Gemcitabine and Nab-Paclitaxel :
- Appicable to broader patient population - Older, less robust PS
1. Conroy T et al, NEJM 2011 2. Van Hoff D et al, NEJM , 2013
FOLFIRINOX N=342
Gemcitabine + nab-Paclitaxel N=861
Eligibility, PS ECOG 0-1 KPS 70-100
Survival, median
% at 1 yr
11.1 months 48%
8.5 months 35%
Toxicity (G3/4) Fatigue 24%
Neutropenia 48%
Fatigue 17%
Neutropenia 38%
Poorer PS pts? N/A Benefit in KPS 70/80 pts
Biomarker data N/A SPARC: non predictive
METASTATIC DISEASE
MPACT: 2° LINE THERAPY (Post Hoc)1
N=170
Gem + nab-P
Any Therapy
Median OS 12.8 months
N=18
Gem + nab-P
FOLFIRINOX
Median OS 15.7 months
1. Goldstein DS et al, JCO 2016 2. Portal A et al, Br J Cancer, 2015
AGEO Prospective Cohort2
N=57
FOLFIRINOX
Gem + nab-P
PR 10 (18%)
SD 23 (41%)
Median PFS 5.1 months Median OS (2°) 8.8 months Median OS (1°) 18 months
METASTATIC DISEASE
Mixed data are available on the use of Oxaliplatin in second-line treatment
CONKO-0031 PANCREOX2
FF (5FU/LV) OFF (OXA/5FU) 5FU/LV mFOLFOX
Median OS 3.3 m 5.9 m 9.9 m 6.1 m
HR 0.068 HR 1.78
Median TTP 2.0 m 2.9 m
Median PFS 2.9 m 3.1 m
1. Oettle H et al, JCO 2014 2. Gill s et al, ASCO 2014
NAPOLI-1
MM-398 100 mg/m2 q3 wks (N=151)
MM-398 + Infusional 5FU/LV q2 wks (N=117)*
*after protocol amendmend R
A N D O M I Z E Metastatic PDAC
Prior Gemcitabine KPS 70/100%
(n=417)
Infusional 5FU/LV wkly x 4 q 6wks (N=149)
Primary endpoint: Overall survival
Secondary endopoints: PFS, RR, Ca 19.9, Safety, QoL
Wang-Gillam A et al, Lancet 2016
Phase III, randomzed, open label trial with nanoliposomal irinotecan. The nanoliposomal irinoteca (MM-398)comprises irinotecan free base encapsulated in liposomenanoparticles.
The liposome is designed to keep irinotecan in the circulation longer than free irinotecan.
METASTATIC DISEASE: MAINTENANCE?
Maintenance vs Observation (after 6 months)1:
- Sunitinib 37.5 mg daily or observasion (N=28) - Median PFS 3.2 months vs 2.0 months (p <0.01) - Median OS 10.6 months vs 9.2 months (p =0.11) - 6-months PFS: 22.2% vs 3.6%
- 2-years OS: 22.9% vs 7.1%
If patients have stable disease after FOLFIRINOX or platinum-based therapy, two ongoing trials:
1. Reni M et al, Eur J Cancer 2013
1. NCT0189686: phase II trial of chemo vs Ipilimumab + GVAX (Allogeneic GM-CSF-Transduced Pancreatic Tumor Cell Vaccine )
2. NCT02184195: phase III trial of Olaparib vs placebo (gBRCA mutation) – the POLO trial
METASTATIC DISEASE
Gemcitabine- Nab-Paclitaxel
MM-398+5FU/LV;
5FU/LV; Cape
FOLFOX/XELOX?
FOLFIRINOX
Gemcitabine- Based
1° LINE
2° LINE
3° LINE
AGENDA
ADJUVANT TREATMENT IN RESECTABLE PATIENTS
NEOADJUVANT TREATMENT IN RESECTABLE AND BORDERLINE RESECTABLE PATIENTS
METASTATIC DISEASE:WHAT TO DO AFTER THE FIRST LINE?
FUTURE SCENARIOS
COMPLEX MUTATIONAL LANDSCAPE
Bailey P et al, Nature 2016
92%
Well known activating mutation of KRAS are ubiquitous and inactivation of TP53, SMAD4 and CDKN2A occur in >50%. Genes involved in chromatin modification, DNA repair and other mechanisms important in the carcinogenensis are mutated in ca 10%.
Furthermore, the association on infrequently mutated genes leads to intertumor heterogeneity.
COMPLEX MUTATIONAL LANDSCAPE
Waddell N et al, Nature 2015
COMPLEX BIOLOGICAL LANDSCAPE
Bailey P et al, Nature 2016
Four classes of PC based on trancription factors and downstream targets were identified:
Squamous subtype
Pancreatic progenitor subtype
Abberantly differentiated endocrine exocrine (ADEX) subtype;
Immunogenic subtype
PD-1 BLOCKADE IN MMR DEFICIENT
30 patients with non-colorectal cancer deficient in Mismatch repair were treated with Pembrolizumab (10 mg/Kg every 2 weeks)
Dung L et al, ASCO 2016
However, PC is poorly enriched with CD8 and T cells. So, potentially, standard approaches with checkpoint inhibitors may not work.
THE ROLE OF MICROENVIRONMENT
The microenvironment of PC is unique and critically important. Chemokines and their receptors play a critical role in conditioning the metastatic niche.
They are used to recruit to tumor side and to
“corrup” neutrophils (TANs), monocytes/macrophages (TAMs) and fibroblast with different properties that evenutally lead to tumor growth and spreading.
THE MAESTRO TRIAL
Van Cutsem E et al, ASCO 2016
Evofosfamide 340 mg/m2+
Gemcitabine 1000 mg/mq d 1,8,15 q28
Placebo +
Gemcitabine 1000 mg/mq d 1,8,15 q28
R A N D O M I Z E (1:1) Unresectable, locally
advanced or metastatic pancreatic cancer
(n=693)
Primary endpoint: Overall survival
Secondary endopoints: PFS, RR, safety and tollerability, QoL, PK
Tumor microenvironment in PC is characterized by HYPOXIA. EVOFOSFAMIDE is an hypoxia-activated prodrug that releases the cytotoxic Bromo-isophoramide mustard (Br- IPM) in area of severe hypoxia.
Combining Evofosfamide with conventional CT may potentially induce cell death in hypoxic and normoxic tumor cells.
THE MAESTRO TRIAL
Van Cutsem E et al, ASCO 2016
Phase III, open-label, randomized trial of gemcitabine ± Evofosfamide in first line PC.
Overall Survival (HR 0.84, p 0.059) Progression Free Survival (HR 0.75, p 0.002)
Nywening TM et al, Lancet Oncol 2016
TARGET TAMs WITH CCR2 INHIBITION
FOLFIRINOX x 6 cycles (N=8)
FOLFIRINOX + PF-04136309 Standard 3+3 dose de-esclation
(N=39) Border-line, locally
advanced pancreatic cancer
(n=47)
Open-label, non-randomised, dose-finding phase 1 trial. The chemokine CCL2 is responsible for the recruitment of CCR2 +ve inflammatory monocytes from bone marrow to peripheral blood where they migrate to PC and become TAMs.
Primary endpoint:
safety and tollerability of PF-04136309 in combiation with FOLFIRINOX
Nywening TM et al, Lancet Oncol 2016
TARGET TAMs WITH CCR2 INHIBITION
PF-04136309 in combination with FOLFIRINOX did not result in additional toxicity.
CCR2 blockade led to reduction of infiltration of TAMs and showed evidence of tumor response.
