Novel Targets and Therapies in
Clinical Trials for Pancreatic Cancer
Maeve Lowery MD
Memorial Sloan Kettering Cancer Center
The Problem and Challenges…
• New diagnoses U.S. 2009: 42,470
• Mortality U.S. 2009: 35,240
• 10th most common cancer (3% new cancers)
• 4th leading cause of cancer mortality (6%)
• Overall 5-year survival ~3-4%
• Risk of developing PC: 1 in 9-11,000 (~0.01%)
www.cancer.org (ACS 2009).
http://srab.cancer.gov/devcan.
Ries LA. SEER, 2006
Overall Survival in Advanced
Pancreatic Ca by Performance Status
(Pooled Data CALGB 80303 )
Proportion Surviving
1.0
0.8
PS 0: 8.0 mos
PS 1: 4.8 mos
PS 2: 2.8 mos
0.6
p=0.0001
0.4
0.2
0.0
0
5
10
15
Months from Study Entry
Kindler, et al. ASCO, 2007 (Abst #4508)
20
25
Landmark Phase III Trial APC
Gemcitabine vs 5-FU
100
Median Survival
Gemcitabine
5.6 mos
5-FU
4.3 mos
% Patients Surviving
80
p=0.0009 (Log-Rank Test)
60
40
20
0
0
2
4
6
8
10
12
14
Survival Time (months)
Burris, et al. J Clin Oncol, 1997
16
18
20
PA.3 trial : Gemcitabine +/- Erlotinib
Overall Survival
Survival Function
1.00
Med. Survival (mos)
1-Year Survival
CR + PR
CR + PR + SD
0.75
G + Erlotinib G + Placebo
(N=261)
(N=260)
6.24
5.9
23%
17%
8.6%
8%
57%
49%
HR=0.82 (95% CI: 0.69-0.99), p=0.038
0.50
0.25
0
0
6
*Adjusted for PS and extent of disease at baseline
† From Cox regression model
‡ From 2-sided log-rank test
Moore, et al. J Clin Oncol, 2007
12
Months
18
24
FOLFIRINOX vs Gemcitabine
Prodige 4- ACCORD 11
Untreated
Metastatic Panc
Adenocarcinoma
ECOG 0-1
R
A
N
D
O
M
I
Z
E
Randomization 1: 1
Stratification
FOLFIRINOX
(N= 167)
Gemcitabine
(N= 169)
₋ PS: 0-1 vs 2; Primary tumor location, Center
Primary Endpoint: Overall Survival
Conroy, et al. NEJM, 2011
FOLFIRINOX vs Gemcitabine
Overall Survival
FOLFIRINOX
1 .0 0
P ro b a bility
Gemcitabine
0 .7 5
Median 11.1 mo
HR = 0.57
P < 0.0001
0 .5 0
0 .2 5
Median 6.8 mo
0 .0 0
0
3
6
9
12 15 18 21 24 27 30 33 36
Mo nth s
Number at risk
Gemcitabine
171 134 89
48 28 14 7
3
3
2
2
2
FOLFIRINOX
171 146 116
81 62 34 20 13 9
5
3
2
2
6
Conroy, T. NEJM, 2011
FOLFIRINOX vs Gemcitabine
Secondary Endpoints
FOLFIRINOX Gemcitabine
(N= 167)
(N= 169)
P-Value
Febrile neutropenia
5.4%
0.6%
0.009
Thrombocytopenia
9.1%
2.4%
0.008
9%
—
0.001
Vomiting
14.5%
4.7%
0.002
Diarrhea
12.7%
1.2%
0.0001
Filgrastim support
42.5%
5%
Overall response rate
31.6%
9.4%
0.0001
6.4 mths
3.3 mths
0.0001
HR= 0.47
Peripheral neuropathy
Median PFS
Conroy T, et al. NEJM, 2011
Nab-Paclitaxel vs Gemcitabine
MPACT Trial
Untreated Met
Panc Adenoca
ECOG 0-1
R
A
N
D
O
M
I
Z
E
Nab-Paclitaxel &
Gemcitabine
Gemcitabine
N= 861
N=842
patients,
primary
Primary
endpoint:
OSendpoint overall survival
Prospective
evaluation
of SPARCtumor
expression
as predictive
Stratification:
KPS, primary
location,
Center biomarker
Recruitment complete, results awaited
MPACT: Efficacy Outcomes
Gem
Gem & Nab-P
Stats
Median OS
6.7 mo
8.5 mo
HR=0.71
P=0.000015
1 year OS
Median PFS
1 year PFS
Time to
treat failure
RR
22%
3.7 mo
5.5%
5.1 mo
35%
5.5 mo
3.7%
3.6 mo
P=0.0002
7%
23%
Von Hoff et all, NEJM 2013
P=0.000024
HR=0.7
P<0.0001
HR=0.70
p< 0.0001
MPACT: Toxicity
Grade 3 / 4
neutropenia
Febrile
neutropenia
Fatigue
Neuropathy
Von Hoff et all, NEJM 2013
Gem
27%
Gem & Nab-P
38%
1%
3%
7%
<1%
17%
17%
Gemcitabine Combinations
Meta-Analysis (N= 4,465, 15 Trials)
HR
95% CI, P-value
Gem vs Gem + X
0.91
0.85- 0.97, p= 0.004
Gem vs Gem + Platin
0.85
0.76- 0.96, p= 0.01
Gem vs Gem + 5-FU
0.90
0.81- 0.99, p= 0.03
PS= 0, Combination
0.76
0.67- 0.87, p< 0.0001
Heinemann, et al. BMC, 2008
Selected Phase III Trials PC
Drug
Gem + Cisplatin
Gemcitabine
Gem + Cisplatin
Gemcitabine
Gem + Irinotecan
Gemcitabine
Gem + DX-8951f
Gemcitabine
Gem + Pemetrexed
Gemcitabine
Gem + Oxaliplatin
Gemcitabine
Gem + Capecitabine
Gemcitabine
N
53
54
96
99
180
180
175
174
283
282
157
156
267
266
RR
26%
9%
–
–
16%
4%
8%
7%
15%
7%
26%
16%
14%
7%
Med Surv
6.9 mos
4.6 mos
8.3 mos
6.0 mos
6.3 mos
6.4 mos
6.7 mos
6.2 mos
6.2 mos
6.3 mos
9.0 mos
7.1 mos
7.4 mos
6.0 mos
1-Yr Surv
–
–
–
–
~20%
~20%
23%
21%
21.4%
20%
34.7%
27.8%
26%
19%
Reference
Colucci 2002
Heinemann 2003
Rocha-Lima 2004
Abou-Alfa 2006
Richards 2004
Louvet 2005
p=0.13
Cunningh. 2005
p=0.014
Where do we go from here?
•
•
•
•
•
Targeted therapy for genetic subgroups
Immunotherapy
Stromal Depletion
Targeting stem cells
Specific inhibitors of key signaling
pathways
• Radioimmunotherapy
Pancreas Cancer & BRCA Mutations
• Rare in general population
– Increased prevalence in Ashkenazi population
– Founder mutations
• BRCA 1 185delAG, 5832insC
• BRCA 2 6174delT
• MSKCC data
– Resected pancreas ca 5.5% BRCA mutation (selected on
basis of Ashkenazi heritage)
– Ashkenazi breast-pancreas families 14.2% BRCA positive
Ferrone, C. J Clin Oncol, 2009. Stadler, ZK. Cancer, 2012
PALB2 (FANCN)
• Partner and localizer of BRCA2
• Binds to BRCA2 stabilizing it and anchoring to
structures in the nucleus allowing BRCA2 to
repair DNA
Jones, S. Science, 2009. Tischkowitz, MD. Gastroenterol, 2009. Stadler, ZK. Clin Gen, 2011. Slater, EP. Clin Gen, 2010
PC, BRCA & PARP Inhibition
• BRCA 1, 2 function integral to DS DNA repair
• PARP inhibition established value in ovary,
breast cancer with BRCA-related mutations
• Preclinical data in PC – Capan-1
– Very susceptible to KU-0058684
– Susceptible to alkylating agents
• Anecdotal clinical data in PC
Friedensen. Med Gen Med, 2005. Couch. Can Epid Biom Prev, 2007.
McCabe. Cancer Biol Therapeut, 2005. Goggins, M. Cancer Res, 1996
Loss of Functional BRCA-1 or 2 Affects
DNA Double-Strand Break Repair Pathway
Ashworth, et al. J Clin Oncol, 2008
Poly (ADP-Ribose) Polymerase (PARP)
DNA damage –
endogenous,
cytotoxics,
radiation, etc.
If PARP is inhibited, SSB repair prevented,
leading to increased double strand DNA
breaks
Sensitivity of BRCA Mut. + Wild-type PC
Cell Lines to AZD-2281 (Olaparib)
120
% survival
100
80
41.09 (BRCA 2 mutant)
B1.8 (BRCA 1 mutant)
60
41.05 (Wild-type)
40
43.16 (Wild-type)
20
0
0
0.1
0.5
1
4
8
Lowery, MA, Moynahan, ME (MSKCC)
Olaparib dose mM
Stage IV Panc with BRCA1187delAG Mutation:
Response to Gemcitabine/ AZD-2281
Randomized Phase II Cisplatin + Gem +/Veliparib in BRCA/ PALB2 mutated PC
• Eligibility
– Untreated LA or metastatic PC with BRCA 1-2, PALB2 m
– ECOG 0-1
Randomized phase II (N= 50)
Arm A: Cisplatin + gemcitabine + veliparib
Arm B: Cisplatin + gemcitabine
Gemcitabine + cisplatin d3+10, q 21
Veliparib dosing day 1-12, BID, PO
Dosing veliparib from ongoing phase I (NCT01282333)
PI: E.M. O'Reilly (CTEP, Lustgarten Foundation)
Chemotherapy +/- PARP Inhibitor
ABT-888 in BRCA 1 / 2 Mutated PC
Untreated Met
or LA Panc
Adenoca.
BRCA 1/ 2 or
PALB2
mutation
ECOG 0-1
R
A
N
D
O
M
I
Z
E
Gemcitabine +
Cisplatin
Gemcitabine +
Cisplatin + ABT-888
Phase I trial do determine MTD currently enrolling (no randomization)
Randomized phase II trial will evaluate addition of PARP inhibitor
Targeting Stroma to Improve Drug
Delivery
Feig C et al. Clin Cancer Res 2012;18:4266-4276
©2012 by American Association for Cancer Research
Hedgehog Pathway and PC
• Developmental pathway – neural, teeth, GI tract,
lungs, etc
• Expressed abnormally in 70-80% pancreas adenoca
• Activation of pathway important in carcinogenesis,
progression of panc ca
• Hh pathway: stroma/desmoplasia, stem cells
• SMO inhibitors
– Cyclopamine, GDC-0449, IPI-926, LDE225
Von Hoff, D. NEJM, 2009. Thayer, S. Nature, 2003. Feldmann, G. Gut, 2008. Jimeno, A. Mol Can Ther, 2009. Oliver, K. Science, 2009
Rand. Phase II: Gem + Vismodegib/P
Interim Analysis after 50% PFS Events
Gem/ Vismodegib
(N= 53)
Gem/ Placebo
(N= 56)
CR/ PR
-/-
3%/ 11%
Stable Disease
49%
31%
3.7 months (2.4- 4.6)
2.4 months (1.9- 3.2)
Med. PFS (95% CI)
Adjusted HR 0.92 (0.52- 1.63)
Med. OS (95% CI)
6.3 months (4.9- 7.8)
5.4 months (4.2- 8.0)
Adjusted HR 0.97 (0.47- 2.01)
One- Year survival
24%
Correlatives: [Shh], CT perfusion
Catennaci, D. Proceedings ASCO, 2012 Abst # 4022
24%
PEGPH20: Recombinant Hyaluronidase
• HA is a glycosaminoglycan abundant in the
extracellular matrix of PDA.
• Combination therapy with PEGPH20 and
gemcitabine inhibited tumor growth and
prolonged survival in a genetically engineered
mouse model of PAC
– Degrades hyaluronan
– Facilitates drug delivery
– Reduces interstitial fluid pressure
Jacobeth, M. Gut, 2012. Hingorani, S. Cancer Cell, 2012. NCT01453153
SWOG S1313 (NCT01959139)
Randomized phase Ib/II
Untreated Met
Panc Adenoca
ECOG 0-1
MPACT Trial
R
A
N
mFOLFIRINOX
D
O
M
I
mFOLFIRINOX &
Z
PEGPH20
E
N=138 patients
N=842endpoint:
patients, primary
endpoint overall Recruitment complete,
Primary
OS
results awaited
Correlatives:
plasma & tumor HA
HALO-109-202(NCT01839487)
Randomized phase II
MPACT Trial
Untreated Met
Panc Adenoca
KPS ≥ 70%
R
A
N
D
O
M
I
Z
E
Gem & Nab-Paclitaxel
Gem & Nab-Paclitaxel
& PEGPH20
N=132 patients
N=842 patients,
primary
Primary
endpoint:
PFS endpoint overall Recruitment complete,
results awaited
TH-302: A Hypoxia-Activated Prodrug
Weiss G J et al. Clin Cancer Res 2011;17:2997-3004
©2011 by American Association for Cancer Research
TH CR-404
Borad et al, ESMO 2012
MAESTRO Trial (NCT01746979)
Randomized phase III
MPACT Trial
Untreated Met
Panc Adenoca
ECOG 0/1
R
A
N
D
O
M
I
Z
E
Gem & Placebo
Gem & TH-302
N=660 patients
N=842 patients,
primary
Primary
endpoint:
OS endpoint overall Recruitment complete,
results awaited
Immune checkpoints as therapeutic targets
Kandalaft L E et al. JCO 2011;29:925-933
©2011 by American Society of Clinical Oncology
CTLA4 Blockade: Success in Melanoma
Ipilimumab + gp100 vs gp100; HR=0.68 (95% CI: 0.55, 0.85), P=0.0004
Ipilimumab vs gp100; HR=0.66 (95% CI:0.51, 0.87), P=0.0026
Ipilimumab
Ipilimumab + gp100
Ipilimumab
Ipilimumab + gp100
gp100
Immune cell infiltrates during pancreatic tumor
progression
Zheng et al, Gastroenterology, Volume 144, Issue 6, 2013, 1230 - 1240
Phase II: VY/GVAX +/- CRS-207
• Metastatic PDA patients ECOG 0-1,n=90
previously treated, randomized 2:1 to either
CY/GVAX followed CRS-207 or CY/GVAX
• Primary endpoint was overall survival
• Results: OS arm A 6 months, arm B 3.4 months
P=0.0057 HR 0.4477
• ? Increased benefit in 3rd line patients
• Both vaccines well tolerated
Le et al GI ASCO 2014
Eclipse Trial (NCT 02004262)
Randomized phase III
MPACT Trial
Previously
Treated Met Panc
Adenoca
ECOG 0/1
R
A
N
D
O
M
I
Z
E
GVAX &
Cyclophosphamide
& CRS-207
CRS-207
Chemotherapy*
N=240
N=842patients
patients, primary endpoint overall Recruitment complete,
Primary
endpoint: OS
results awaited
*Gem/Capecitabine/Erlotinib/Irinotecan
Immunotherapy Trials in Met PAC
• Algenpantucel-L: human PAC cell lines genetically
engineered to express αGal, ongoing phase III
studies in locally advanced/borderline resectable
and resected PAC (IMPRESS, PILLAR)
• Ipilimumab & Nivolumab combination phase I:
dose expansion cohort for met PAC (anti-CTLA4
&PD1 inhibition)
• MEDI4736 phase I with expansion cohort for met
PAC (PDL1 inhibition)
Radioimmunotherapy for Met PAC
• hPAM4, monoclonal
antibody targeting an
antigen found in > 85% of
panc ca
• Conjugate labeled with
yttrium-90
(90Y-hPAM4), a
therapeutic β-emitting
radionuclide
Ocean et al, Cancer May 2012
Phase III Trial of Gem +/- 90Y-hPAM4 in
Refractory Met PAC (NCT NCT01956812)
Metastatic PC,
at least 2 prior
chemotherapy
regimens
ECOG 0-1
N= 440 patients
*Low dose
gemcitabine
R
A
N
D
O
M
I
Z
E
Gemcitabine*
+ 90Y-hPAM4
Gemcitabine*
+ Placebo
Recent Negative Trials…
Phase
Drug
Outcome
Ref
III
GAMMA
Gem +/- AMG479 (IGF-IR)
No difference
Press release
08/12
III BAYPAN
Gem +/Sorafenib
Med PFS 5.7 vs
3.8
P=0.902
Gonclaves,Ann
Oncol 2012
II LEAP
Gem _/Masitinib
Med OS 7.7 vs 7.0 Deplanque GI
HR 0.9, p=0.74
symposium 2013
II
Gem +/- IPI-926
Med OS 6.0 vs 5.9 Press release
HR NS
01/12
II
Gem +/Vismodegib
Med OS 6.3 vs 5.3 Catenacci
HR 0.97
ASCO 2012
II/III
Gem +/Rigosertib
No difference
Press release
12/13
1st line Randomized Phase II Trials: Met PAC
NCT
Trial Design
N
Target
Sponsor
01839487
Gem/Nab-P +/- PEGPH20
132
Hyaluron
Halozyme
01621243
Gem + nab-P +/- M402
148
Anti-stromal
Momenta
01647828
Gem + nab-P +/- OMP59R5
140
Notch inhibitor
Stem cells
OncoMed
01844817
Gem +nab-P +/- OGX-427
132
HSP27
OncoGenix
01016483
Gem +/- MSC1936369B
174
MEK
Merck,EU
01728818
Gem +/- Afatinib
117
EGFR, Her2, 4
Boehringer, EU
01509911
Gem +/- TL-118
80
Angiogenesis
Titan Pharm
01505530
LY249555 + chemo(inv
choice)
120
Myostatin
Eli-Lilly
01280058
Carbo+Paclitaxel +/Reovirus
70
Ras
NCI
01585805
Gem, Cisplatin +/- Veliparib
70
PARP (BRCA+)
NCI, Lustgarten
01209111
Gem, Erlotinib +/Metformin
120
Multiple
U Amsterdam
01167738
PEXG +/- Metformin
82
Stem cells
San Raffaele
RECAP Trial
• Randomized phase II study, Capecitabine +/Ruxolitinib
• N= 138 patients with progressive PAC on 1 line
of prior chemotherapy (gem)
• Primary endpoint: OS
• ITT HR= 0.79, p=0.12 NS
BUT: Subgroup HR=0.47, p=0.005 & 6 month OS
42% vs 11% (Press release 08/13)
Ongoing 2nd/3rd Line Phase II-III Trials: Met PAC
NCT
Trial Design
N
Target/Drug
Sponsor
01494506
Randomized
Phase III
MM-398 +/5FU/LV
405
(fully
enrolled,
results
pending)
Liposomal
irinotecan
Merrimack
Pharm NAPOLI1
01954992
Randomized
Phase III
5FU/LV (bolus) vs
Glufuosfamide
480
Conjugate of
ifosfamide
Eleison Pharm
01658943
Randomized
133
Phase I
FOLFOX vs
Selumetinib +MK2206
MEK, AKT
SWOG1115
Conclusion
• Nab-paclitaxel & gem likely favored backbone
for development of combination therapies
• Multiple agents in development, esp phase II
• 2nd/3rd line therapy trials feasible and area for
drug development
• Future looks brighter…