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New Agents in Pancreas Adenocarcinoma
Eileen M. O’Reilly, M.D.Associate Member
Memorial Sloan-Kettering Cancer CenterAssociate Professor
Weill Medical College of Cornell University
Cytotoxic Therapies
Gemcitabine
FOLFIRINOX
FOLFIRINOX vs Gemcitabine Overall Survival
Number at riskGemcitabine
FOLFIRINOX
171 134 89 48 28 14 7 6 3 3 2 2 2
171 146 116 81 62 34 20 13 9 5 3 2 2
1 .0 0
0 .7 5
0 .5 0
0 .2 5
0 .0 0
Pro
ba
bilit
y
Mo nths0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6
Median 11.1 mo
Median 6.8 mo
HR = 0.57P < 0.0001
Conroy, T. NEJM, 2011
FOLFIRINOX Development
• FOLFIRINOX superior to gemcitabine: – OS, PFS and RR
• Investigation ongoing in locally advanced, neoadjuvant/borderline, adjuvant settings
• Relative benefit/tox for 3 vs 2 drug unknown?• Sequential vs. concurrent therapy?• Ability to combine with novel agents?
Von Hoff, D. J Clin Oncol, 2011
Ph. I-II Gemcitabine + Nab-Paclitaxel• N= 67• Phase II doses:
– Gemcitabine 1,000mg/m2 + nab-paclitaxel 125mg/m2 day 1, 8, 15, q28
• DLT’s sepsis, neutropenia• N= 44 treated at MTD
– RR 48%, med OS 12.2 months, 1-Year survival 48%
Von Hoff, D. J Clin Oncol, 2011
Gemcitabine + Nab-Paclitaxel
• Correlative results– Ca 19-9 decline associated with RR, PFS– SPARC (in stroma) correlated with OS– Mice with human pancreas xenografts:
combination of gemcitabine + nab-paclitaxel• Depleted stroma• Improved drug delivery, improved tumor response
• Phase III – data awaited
Novel Targets
New Targets, New DrugsTarget Class of Drug Example of Drug
IGF-1R Antibody to IGF-1RTyrosine kinase inhibitor
AMG 479, MK-0646, IMC-A12OSI-906
RAS/ MEK Oncolytic viral agentsMEK inhibition
ReovirusGSK1120212 (trametinib)
mTOR/ P13K/ AKT mTOR inhibitorAKT, P13K
Everolimus, temsirolimusMK-2206, XL-765, BKM-120
C-MET HGF-MET inhibitors, TKI Tivantinib (ARQ 197), Cabozantanib
Hedgehog/Stroma
Notch
Small molecule HH inhibitorStromal depletionGamma-secretase inhibitor
GDC-0449, IPI-926, LDE-225, PEGPH20R04929097, Anti-notch Ab
PSCA Antibody to PSCA AGS-1C4D4
SRC SRC, bcr-abl inhibitor Dasatinib, AZD 0530
Immunity Anti-CTLA4Vaccines
Ipilimumab, tremilumimabGVAX, telomerase, CRS-207
PARP PARP inhibitor AZD 2281, ABT-888, rucaparib
Hypoxia/Metabolism DNA cross-linking, alkylator TH-302, HIF-1α
Actionable Targets (Potentially) in Pancreas Adenocarcinoma
• Methodology– IHC biomarkers, e.g., Cox2, SPARC– Whole genome expression analysis (HT-12v4
beadchip, Illumina)– FISH analysis, e.g., C-Myc, EGFR, Her-2– Mutation analysis (Sanger sequencing), e.g., KRAS
• N= 1,029 patients – heterogeneous population
Von Hoff, D. Proceedings ASCO, 2012 Abst #4013
Immunohistochemistry (29 Biomarkers)Biomarker Expression
RRM1 (decreased) 77%
COX2 (increased) 74%
Thymidylate synthetase (negative) 73%
TOPO1 (increased) 61%
ERCC1 (negative) 57%
PGP (negative) 47%
SPARC (increased) 44%
TOPO2A (increased) 30%
PTEN (negative) 27%
MRPI (negative) 22%
PDGFR (increased) 20%
MGMT (negative) 8%
Von Hoff, D. Proceedings ASCO, 2012 Abst #4013
FISH & Mutation AnalysesTarget % Amplified (FISH) N= 695C-Myc 33%Her-2/neu 10%EGFR 2%TOPO2A -Target % Mutated (Sanger) N= 783KRAS 73%PIK3CA 7%BRAF -C-Kit -
Von Hoff, D. Proceedings ASCO, 2012 Abst #4013
IGF-1R Targeting
Randomized Phase IIIGF-1R, TRAIL Targeting
Stratify PS 0 vs 11: 1: 1 randomizationPrimary endpoint: 6-month overall (24%↑ (45→69%) 80% p) survival
Kindler, HJ. J Clin Oncol, 2010 (abst # 4035)NCT00630552
Metastatic Pancreas Ca
N= 120
Gemcitabine + Placebo
Gemcitabine + AMG 655 10 mg/kg
RANDOMIZE
Gemcitabine + AMG 479 12 mg/kg
Results: Rand. Phase II (N= 125)Gemcitabine +
AMG 479(open-label)
Gemcitabine + AMG 655(blinded)
Gemcitabine + Placebo(blinded)
6-month OS 57% 59% 50%12-month OS 39% 20% 23%Median OS 8.7 mths 7.5 mths 5.9 mthsMedian PFS 5.1 mths 4.0 mths 2.1 mthsGd 3-4 ANC 18% 22% 13%Gd 3-4 Platelets 15% 17% 8%Gd 3-4 Fatigue 13% 12% 5%Hyperglycemia 15% 2% 35
Kindler, HJ. J Clin Oncol, 2010 (Abst #4035)
HR OS 0.67, p=0.12; HR PFS 0.65, p=0.07
NCT01231347
Phase III: Metastatic Pancreas Adenoca(GAMMA Trial)
Gemcitabine + Placebo
RANDOMIZE
Gemcitabine + AMG-479(12 mg/kg, 20 mg/kg)
UntreatedMetastatic
Pancreas CaN= 825
Primary endpoint: Overall survivalCorrelatives: IGF, IGF-BP levels and outcome
SWOG S0727Phase I- Randomized Phase II:
Value to IGF-1R + EGFR inhibition in PC?
• N= 10 dose determination of cixutumumab (IgG mAb) + gemcitabine, erlotinib
• Randomized phase II– Cixutumumab (IMC-A12) 6mg/kg, Gemcitabine
1000mg/m2, Erlotinib 100mg/daily– Gemcitabine, Erlotinib– Primary endpoint PFS
P. Philip. Proceedings ASCO, 2012 Abst #4019
SWOG S0727 ResultsGem/Erlotinib/Cixutumumab
N= 57Gem/Erlotinib
N= 59Median PFS 4 months 4 months
P= 0.96
Philip, P. Proceedings ASCO, 2012 Abst #4019
Despite strong preclinical synergy for IGF-1R and EGFR inhibition – clinical data negative
Biomarkers: Plasma [IGF], IGF mRNA predictive?
Prostate Membrane Stem Cell Antigen Targeting
Prostate Stem Cell Antigen (PSCA)
• AGS-PSCA fully human IgG1 mAb against PSCA
• PSCA: 87-100% of prostate tumors; ~60% of panc ca
• AGS-PSCA + gemcitabine inhibited tumor growth and metastases in orthotopic HPAC tumors in mice better than either alone
Gu, Z. Oncogene, 2000. Zhigang, Z. W J Surg Oncol, 2004. Kan, K-R. J Urol, 2004. Lam, J.S. Clin Can Res, 2005
Wolpin, B. J Clin Oncol, 2011 (Abst #4031). Hidalgo, M. World GI ESMO Congress, 2011
Randomized Phase II Gemcitabine +/- AGS-1C4D4
Stage IV Panc CaECOG 0-12: 1 RandomizationN= 165
Primary Endpoint6-month Survival Rate45% → 65%
Secondary EndpointsOS, PFS, RR, ToxicityEffect of PSCA on OS, PFS, RR
GemcitabineN= 68
RANDOMIZE
Gem + AGS-1C4D4N= 137
Randomized Phase II Gemcitabine +/- AGS-1C4D4
Gemcitabine(N= 63)
Gem + AGS(N= 133) P-Val
6-month Survival 44.4% 60.9% 0.016Median OS 5.53 mths 7.9 mths 0.06PSCA + (N= 66)6-month Survival
8.5 mths57%
10.3 mths79%
0.260.03
PSCA - (N= 57) 4.6 mths 4.5 mths 0.27
Wolpin, B. J Clin Oncol, 2011 (Abst #4031); Hidalgo, M. World GI ESMO Congress, 2011
Embryonic Pathway TargetingStromal Depletion
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
Trials Evaluating Hh Pathway Inhibition in Pancreas Adenocarcinoma
Phase N Regimen Stage NCTII ~80 Gem, Nab-Paclitaxel + GDC-0449 IV 01088815
IB-Rand. II 105 Gemcitabine + GDC-0449/ P IV 01064622IB- Rand II 122 Gemcitabine + IPI-926/ P IV 01130142IB- Rand II FOLFIRINOX + IPI-926 III-IV 01383538II (pre-op) 20 GDC-0449 I-II 01096732IB- Rand II 30+ Gemcitabine + LDE225/ P III-IV 01487785
P= Placebo. GDC-0449= Vismodegib. IPI-926= Saridegib
Preliminary data Gemcitabine +/- IPI-926 – Survival favors control arm
Rand. Phase II: Gem + Vismodegib/PInterim Analysis after 50% PFS Events
Gem/ Vismodegib (N= 53)
Gem/ Placebo (N= 56)
CR/ PR - / - 3%/ 11%Stable Disease 49% 31%Med. PFS (95% CI) 3.7 months (2.4- 4.6) 2.4 months (1.9- 3.2)
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% 24%
Catennaci, D. Proceedings ASCO, 2012 Abst # 4022
Correlatives: [Shh], CT perfusion
Phase IB, Randomized Phase IIGemcitabine + PEGPH20
• Pancreas cancers – high level of hyaluronan• Preclinical activity for PEGHP20
– Degrades hyaluronan– Facilitates drug delivery– Reduces interstitial fluid pressure– Improved effect with cytotoxics
• Ongoing dose-finding phase IB
Jacobeth, M. Gut, 2012. Hingorani, S. Cancer Cell, 2012. NCT01453153
Biomarker Driven Therapies
Biomarker Classification
• Prognostic– Classify patients into clinical subgroups with expected
distinct clinical outcomes
• Predictive– Identify patients who are likely to be sensitive and/ or
resistant to a specific agent
Biomarkers in Pancreas Adenoca
• Few and none validated…yet• Ca 19-9 most studied
– Tumor-associated antigen
• Candidate biomarkers include– Therapy: hENT-1, dCK, ERCC1, Topo-1, TS,
gemcitabine SNP’s– Tumor: Kras, SPARC, BRCA, SMAD4, S100A2, CXCR4
Gemcitabine Uptake & Metabolism
Adapted. Ko A, et al. Gastroenterol, 2009
ENT1: equilibrative nucleoside transporter
CNT: concentrative nucleotide transporters
DCK: deoxycytidine kinase (rate-limiting)
RRM 1/2: ribonucleotide reductase
DCTD: deoxycytidine monophosphate deaminase
CDA: cytidine deaminase
hENT1 – Preclinical Data
• Cell line data in PC indicate hENT1 major transporter of gemcitabine
• Pharmacologic inhibition of hENT1 renders cells gemcitabine resistant
• Correlation [hENT1] and chemosensitivity
Garcia-Manteiga J, et al. Clin Can Res, 2003. Mackey JR, et al. Can Res, 1998. Mori, R. Onc Rep 2007. Nakano Y. Br J Can, 2007. Achiwa H. Cancer Sci, 2004. Galmarini CM, Haematologica, 2006
hENT1 – Clinical Data
• Surgical series– hENT1 (+) PC had significantly longer survival compared to
hENT (–): 13 vs 4 months
• Retrospective (N= 83)– hENT1 mRNA in resected PC associated with ↑OS– hENT1 low vs high: 9.3 vs 25.7 mths, p<0.001
• Retrospective (N= 434)– High hENT1, dCK predicts benefit from gemcitabine
Spratlin J, et al. Clin Can Res, 2004. Giovannetti E, et al. Can Res, 2006. Marechal, R. World GI ESMO, 2011 (Abst # O-00008)
hENT1 is Predictive for Outcome after Gemcitabine; Not Prognostic
Farrell, J. Gastroenterol, 2009
N= 198 Adjuvant Gemcitabine or 5-FU + 5-FU/RT (RTOG 97-04)Overall Survival: Categorized by hENT1 level
NCT01124786; NCT01233375
CO-1.01 (CP-4126)
• Gemcitabine-5’-elaidate, hENT1 independent• Xenografts – Improved activity over gemcitabine• Randomized Ph II untreated metastatic PC (LEAP):
Gemcitabine vs CO-1.01– Primary: OS in hENT1 (low); all; hENT1 (high)– N= 360
• Single-arm 2nd-line: Gemcitabine-refractory disease (no hENT1)
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
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
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
Loss of Functional BRCA-1 or 2 Affects DNA Double-Strand Break Repair Pathway
Ashworth, et al. J Clin Oncol, 2008
Pt # StageBRCA
Mutation1st line Response 2nd line Response 3rd line Response
OS(mo)
1 T2N0M0 BRCA1Surgery & Adjuvant Gemcitabine
Relapse16.3 mo
AZD 2281/ GemPR 2 moPOD 4.5 mo
FOLFIRINOXAssessment pending
24.7, AWD
2 T3N0M0 BRCA2Surgery & Adjuvant GTX
Relapse 12.8 mo Pending 13.4, AWD
3 T3,N0, II BRCA 2*7535delA
Surgery & Adjuvant Gemcitabine
Relapse 11 moFOLFIRINOX – FOLFOX
CR 3 moRx d/c for toxicityLR 8mo
Cisplatin/5FU -CapecitabineRT
PR 38.4, AWD
4T3,N1,
IIBBRCA2
*4075DGT
Surgery & Adjuvant Gem/ Cisplatin
Relapse at 14 mo 14.7, AWD
5T3, N1
IIB BRCA2Surgery & Adjuvant Gem, 5FU/RT
Relapse at 13 mo Gem/oxaliplatinPRPOD 6 mo
AZD-2281 SD 6 mo 34.3, AWD
6 T4, III BRCA2Y1894X
GTX POD at 5 mo FOLFOX Response at 3 mo 8.8, AWD
7 T4, III BRCA2Gem/ Cisplatin→ Gem /RT→ gem
SD /minor responsePOD 11 mo
FOLFOX POD 2 mo 20.4,DOD
8 IV BRCA2*6174delT
Unknown POD at 7 mo 9.1, DOD
9 IV BRCA1*4603G->T
Gem/ Capecitabine
PR 3 mo FOLFOX POD 14 moFlavopiridol/ Docetaxel
POD 2 mo 27.6, DOD
10 IV BRCA1*187delAG
Gem + AZD2281PR 2 mo, POD 6 m
FOLFOX→ CPT-11/ Gem(Oxali d/c reaction)
POD 2.5 moABT-888 & Temozolomide (1 cycle)
POD 6 weeks13.7, DOD
11 IV BRCA2 No treatment 1.0, DOD
12 IV BRCA1*IVS8+7G>A
Gem & AZD 2281PRPOD 7 mo
Gem/ Capecitabine
POD 2 mo FOLFOX POD 11.5 ,DOD
13 IV BRCA2 Gem/ CisplatinPRPOD 9 mo
FOLFOX POD 2 mo MK 2206 POD 2 mo 15.2, AWD
14 IVBRCA2
IVS13 -2A>T, V211I (859 G>A)
Gem/ OxaliplatinPRSD 7 mo
9.2, AWD
15 IV BRCA2 Gem/ Oxaliplatin Pending 1.5, AWD
MSKCC: BRCA Mutation Carriers with Panc Adenoca
AWD: Alive with disease, DOD: Dead of disease, NED: No evidence of disease POD: Progression of disease, PR: Partial response, SD: Stable disease GTX: Gemcitabine, docetaxel, capecitabine
Key Observations:Activity to platinum-agentsActivity to PARP inhibitors
(Lowery, MA, O’Reilly, EM, The Oncologist, 2011)
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 + veliparibArm B: Cisplatin + gemcitabine
Gemcitabine + cisplatin d3+10, q 21Veliparib dosing day 1-12, BID, PO
Dosing veliparib from ongoing phase I (NCT01282333)
PI: E.M. O'Reilly (CTEP, Lustgarten Foundation)
Emerging Therapies in PC
• FOLFIRINOX– Active, increasingly integrated into practice– Feasibility of adding novel agents?
• New cytotoxic agents− Nab-paclitaxel/ gemcitabine; C0-1.01
• IGF-1Ri, Hh pathway inhibitors? • TH-302, PEGPH20, PARPi – early
• Increasing pre-clinical support• Randomized phase II trials – platform
The Future in Pancreas Cancer Therapeutics …
• Cytotoxics are here to stay• Improved molecular classification• Incremental therapeutic improvements• Profiling tumors e.g., BRCA/ PALB2, wild-type
ras, SMAD4 retained, ERCC1, hENT1?• Ongoing goals: enhanced understanding
tumor biology, preclinical models, biomarker development, validation and collaboration