improving the outcome of patients with metastatic
TRANSCRIPT
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Improving the Outcome of Patients with Metastatic
Pancreatic CancerPhilip Agop Philip, MD, PhD, FRCP
Professor of Oncology and PharmacologyKarmanos Cancer CenterWayne State University
Detroit, MI
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Median overall survival following standard frontline therapies in metastatic disease: 1997 -
1 year
6 months
Gemcitabine Gemcitabineerlotinib
Gemcitabinenabpaclitaxel
FOLFIRINOX
Burris et al, JCO, 1997;Moore et al, JCO, 2007; Conroy, et al. NEJM, 2011, Von Hoff, D. NEJM, 2013
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How to improve on current gains with induction chemotherapy?• Increasing cytotoxic power (and toxicity!) in the frontline and beyond
•Rational sequencing of tolerable therapies•Maintenance after shorter induction therapy•Ablative/surgical strategies to treat residual disease
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PRODIGE 35: PANOPTIMUX study allows interruption of FOLFRINOX after 8 cycles without loss in survival
Arm A Arm B Arm CMedian OS in mo 10.1 11.0 7.36 mo (%) 73.6 75.0 60.012 mo (%) 43.3 28.0 13.918 mo (%) 18.5 28.0 13.9
Dahan L, et al, ASCO 2018
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Drugs and targets that failed in clinical trials involving pancreatic adenocarcinoma: December 2015 – May 2018Drug Target/Mechanism Phase Number of patients
Evofosfamide Alkylator (Hypoxia) 3 694
Ruxolotinib JAK1/2 3 Early termination
Necuparanib Heparan mimetic 1/2 128
Masatinib TKI (Kit, Lyn, Fyn) 3 353
Vandetanib TKI (VEGFR2, RET, EGFR) 2 142
Algenpantucel-L Vaccine 3 722
CRS-207 + GVAX Vaccine 2b 240
Tarextumab Notch2/3 2 177
Demcizumab DLL4 2 204
90Y-Clivatuzumab Tetraxetan MUC1 3 334
Apatorsen HSP27 2 132
Simutuzumab LOX-2 2 240 (159)
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A shifting paradigm in developing new therapies for pancreatic adenocarcinoma
Targeting isolated gene product and/or pathway
• No driver genes• Complex biology • No good correlation
with clinical outcome
Modifying unique aspects of pancreas
cancer biology
• Better correlation with clinical outcome
• Opportunities for rational drug combinations
• Benefiting from evolving molecular classifiers
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Integrated genomic characterization of pancreatic cancer (TCGA)
Raphael et al, Cancer Cell, 32:185-203, 2017
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Exploiting DNA repair defects in pancreatic cancer
Waddell et al, Nature, 518:495, 2015
DNA repair defects
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PARP inhibitors and platinums in BRCAmutated tumors: emerging prospective data
Stage III-IVgBRCA+
ECOG PS 0-1
Gemcitabine CisplatinVeliparib
GemcitabineCisplatin
The pilot study The current RP2 studyO’Reilly et al, Cancer 2018 N = 50, Primary EP = RR
R
N = 17
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POLO: Phase 3 international PARPi maintenance study in gBRCA mutated patients
Metastatic pancreas caPrior platinum therapy
Germline BRCA mutECOG 0-1
Olaparib300 mg po BID
Placebo300 mg po BID
RANDOMIZE
Primary EP = PFSN = 145
NCT02184195
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Modulating the unique microenvironment of pancreatic adenocarcinoma
• Promotes/sustains cancer progression and drug resistance
• Very desmoplastic• Limits drug delivery
• An “Immune desert”
J Natl Cancer Inst. 2010;102(7):448-450;
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Select stromal targeting• Hedgehog inhibitors • Recombinant human hyaluronidase:
PEGylated-rHuPH20 (PEGPH20)• CD40 agonists• Vitamin D analogues• Focal adhesion kinase (FAK)
inhibitors
Olive, Science 2009; 324:1457-61Provenzano, Cancer Cell 2012; 21:418-29Beatty, Science 2011; 331:1612-6Sherman, Cell 2014;159:80-93Alvarez, Br J Cancer 2013, 109:926-33
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Hyaluronan (HA) targeting with pegylated recombinant human hyaluronidase (PEGPH20)
PFS in HA high group VTEs (%)
HALO-301 Phase Sites HA N Status
Gem/nab-paclitaxel +/- PEGPH20NCT02715804
III Global High only 420 Ongoing
• Study 202: PEGPH20 improved PFS with manageable thrombotic events
• Hyaluronan (HA) IHC as a companion diagnostic and predictive biomarker
Hingorani et al, JCO 2018
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A Phase IB/II Randomized Study of mFOLFIRINOX (mFFX) + PEGPH20 versus mFFX in Patients with Metastatic Pancreatic Adenocarcinoma
unselected for HA expression: SWOG- S1313
56 31 19 6 3 255 22 6 2 1 0
At Risk
0 5 10 15 20 25
Months After Registration
0%
20%
40%
60%
80%
100%
12
2: PEGPH20 + mFOLFIRINOX1: mFOLFIRINOX
4.34755PEGPH20 + mFO LFIRINO X6.24256mFO LFIRINO X
Median in MonthsFailedAt Risk
Progression-Free SurvivalData as of December 5, 2017
56 43 29 13 4 255 30 17 6 4 1
At Risk
0 5 10 15 20 25
Months After Registration
0%
20%
40%
60%
80%
100%
12
2: PEGPH20 + mFOLFIRINOX1: mFOLFIRINOX
7.73955PEGPH20 + mFO LFIRINO X14.43056mFO LFIRINO X
Median in MonthsDeathsAt Risk
Overall SurvivalData as of December 5, 2017
HR 0.61 95% CI: 0.40-0.93, P=0.02
HR 0.50 95% CI: 0.31-0.81, P<0.01
Ramanathan et al, ASCO GI, 2018
PEGPH20 + mFFX mFFXMedian # of cycles 4 8Response (%) 29 45
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Targeting metabolism in pancreatic cancer
The Warburg effect Interaction of metabolism with signaling pathways
Vander Heiden et al, Science, 2009, 324:1029-1033
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pyruvate
citrate
isocitrate
α-ketoglutaratesuccinyl-CoA
oxaloacetate
acetyl-CoA
succinate
fumarate
malate
glucose
glutamate
glutamine
PDH
CPI-613: selectively blocks PDH and KGDH triggering cell death that is highly selective to tumor Cells
KGDH
CPI-613
LipidsProteinsNucleic Acids
CPI-613 + lower dose FOLFIRINOXOxaliplatin 65 mg/m2Irinotecan 140 mg/m25FU 2,400 mg/m2
Alistar et al, Lancet Oncology, Vol 18, June 2017
Pilot clinical trial
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Phase III trial :CPI-613 plus mFOLFIRINOX to be launched Q3/2018
RANDOMIZE
CPI-613 500 mg/m2Oxaliplatin 65 mg/m2Irinotecan 140 mg/m2
5FU 2,400 mg/m2
“Full dose" FOLFIRIONX
Sponsored by Rafael
Previously untreated metastatic
pancreatic cancer
EECOG 0/1
N = 500Primary EP = RR/PFS
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L-asparaginase prolongs survival in a pilot trial in patients after failure of frontline therapy
18
Time (Weeks)
Chemotherapy plus eryaspase
N = 95
Chemotherapy aloneN =46
Events n (%)Censored n (%)
79 (83%)16 (17%)
40 (87%)6 (13%)
OS HR (95% CI)P-value
0.60 (0.40,0.88)0.009
Median OS (weeks) 26.1 19.0
OS rate at 24 weeksOS rate at 52 week
46%15%
37%3%
ASNS
ASNase
Asn
ProliferationGln + Asp Asn + Glu
Gln
ATP
NH3EIF2AK4
EIF2A
Protein Synthesis
Cancer Cell
ATF4
?
necrosis
apoptosis
RED ANSase Sensitivity
BLUE ASNase Resistance
NARS
QARS
DDIT3
CASP3
GSH
GLS
GLUL
ROSα-KG
TCA
lactate
pyruvate
Hammel et al, ESMO 2017
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Immunotherapy for pancreatic cancer
• Pancreas cancer is non-immunogenic because:• immunosuppressive cells and cytokines• low tumor mutational burden • paucity of T cells in tumor (number and function)
• Single agent therapeutic approaches focusing on overcoming T-cell immunologic endpoints with immune checkpoint inhibitors or vaccines are not encouraging
Royal Re et al. J Immonother 210;33:828-833Topalian SL. N Engl J Med. 2012;366:2443-2454
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PD-1 inhibitor (durvalumab) with or without CTLA4 inhibitor (tremelimumab): did not work!
O’Reilly et al, ASCO GI, 2018
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Russell Bonneville; Melanie A. Krooket al; JCO Precision Oncology 2017, 1, 1-15.
MSI-high pancreatic cancers (1-2%) may respond to PD-1 inhibitors
Dung T. Le, et al. Science, Volume 357(6349):409-413, July 28, 2017
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Targeting tumor infiltrating macrophages (TAMs) and myeloid derived suppressor cells
• Myeloid-derived suppressor cells promote disease progression, metastasis, and immune suppression
• Targeting macrophages can improve cytotoxic efficacy and increases antitumor T-cell response in animals
• Targeting macrophage signaling (e.g., CCR2) will block myeloid monocyte/macrophage recruitment to tumor microenvironment
Lesokhin et al, Cancer Res; 72(4); 876–86. 2011; Mitchem JB et al, Cancer Res; 73(3) February 1, 2013
Nywening TM et al, Lancet Oncology, 17:651–,662 2016
Pilot trial
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Select major ongoing immunotherapy combination studies in advanced pancreatic cancer
PD-1i/PD-L1i ChemoXRT
Vaccines
CD40agonist
Anti-CXCR4
Anti-CSF1R
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Stay tuned to these randomized trials!Study Target(s) Drug Biology Chemo
platformPhase
RESOLVE Bruton’s tyrosine kinase
Ibrutininb mast-cells, inflammation, activity of T cells
Gem/Nab-paclitaxel
II/III
SEQUOIA IL-10 receptor
pegilodecakin Enhance T cells
FOLFOX* III
CanStem111P STAT3 napabucassin Cancer stem cells
Gem/Nab-paclitaxel
III**
CARRIE IGF-1R/ Erb-3
MM-141 signaling Gem/Nab-paclitaxel
II
*Second line** N > 1,00 NCT02436668, NCT02923921, NCT02993731, NCT02399137
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Systemic therapy landscape for metastatic pancreatic cancer in 2018: outside of a clinical trial
Relapse/progression < 6 months of adjuvant therapy Metastatic de novo BRCA
mutated MSI-High
Chemo PD-1iPlatinum
based
PARPi
PS 3
mFFX
PS 0-2
GemNAP BSC
GemNAP
mFFXNAL/FU
OFFFOLFOX
OFFNAL/FU
20% 70% 10%
Got mFFX Got Gem-based
GemNAP
mFFXNAL/FUFOLFOX
OFFFOLFOXNAL/FU
mFFX = modified FOLFIRINOXNAP = nabpaclitaxelNAL = naliriOFF = oxaliplatin/5FU
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Molecular subtyping of pancreatic cancer: limited relevance to the clinic at this time, but room for improvement!
Stable Locally rearranged Scattered Unstable
Age-related Unknown etiology MMR DSB
Quasi-mesenchymal
Squamous
Basal-like
Exo-crine
ADEX
Classical
Classical
Immuno-genic
Pancreatic progenitor
Genomics
Transcriptomics
Le Large, TY et al, Seminars in Cancer Biology (2017), http://dx.doi.org/10.1016/j.semcancer.2017.03.008
Waddell et al
Connor et al
Collisson et al
Bailey et al
Moffitt et al
Birnbaum, Molecular Cancer, 16:168, 2017
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Conclusions
• Conventional cytotoxic drug combinations produced modest incremental improvements in survival of metastatic pancreatic cancer
• Treatment strategies to improve patient tolerance and allow prolonged exposure may improve outcome
• Radiational targeted therapies failed in the clinic and a shift of paradigm to targeting key biological events is under way
• Promising areas of progress are in DNA repair, stromal targeting and tumor metabolism
• Immunotherapy failed in its traditional single agent approach but combinations may hold promise
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Thank [email protected]