New Agents in Pancreas Adenocarcinoma Eileen M. O’Reilly, M.D. Associate Member Memorial Sloan-Kettering Cancer Center Associate Professor Weill Medical College of Cornell University

Cytotoxic Therapies

Gemcitabine FOLFIRINOX FOLFIRINOX vs Gemcitabine Overall Survival Number at risk Gemcitabine FOLFIRINOX P r o b a b i l i t y Months Median 11.1 mo Median 6.8 mo HR = 0.57 P < 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?

Ph. I-II Gemcitabine + Nab-Paclitaxel N= 67 Phase II doses: – Gemcitabine 1,000mg/m 2 + nab-paclitaxel 125mg/m 2 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 Von Hoff, D. J Clin Oncol, 2011

Novel Targets

New Targets, New Drugs TargetClass of DrugExample of Drug IGF-1R Antibody to IGF-1R Tyrosine kinase inhibitor AMG 479, MK-0646, IMC-A12 OSI-906 RAS/ MEK Oncolytic viral agents MEK inhibition Reovirus GSK (trametinib) mTOR/ P13K/ AKT mTOR inhibitor AKT, P13K Everolimus, temsirolimus MK-2206, XL-765, BKM-120 C-METHGF-MET inhibitors, TKI Tivantinib (ARQ 197), Cabozantanib Hedgehog/Stroma Notch Small molecule HH inhibitor Stromal depletion Gamma-secretase inhibitor GDC-0449, IPI-926, LDE-225, PEGPH20 R , Anti-notch Ab PSCAAntibody to PSCAAGS-1C4D4 SRCSRC, bcr-abl inhibitorDasatinib, AZD 0530 Immunity Anti-CTLA4 Vaccines Ipilimumab, tremilumimab GVAX, telomerase, CRS-207 PARPPARP inhibitorAZD 2281, ABT-888, rucaparib Hypoxia/MetabolismDNA cross-linking, alkylatorTH-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) BiomarkerExpression 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 Analyses Target% Amplified (FISH) N= 695 C-Myc33% Her-2/neu10% EGFR2% TOPO2A- Target% Mutated (Sanger) N= 783 KRAS73% PIK3CA7% BRAF- C-Kit- Von Hoff, D. Proceedings ASCO, 2012 Abst #4013

IGF-1R Targeting

Randomized Phase II IGF-1R, TRAIL Targeting Stratify PS 0 vs 1 1: 1: 1 randomization Primary endpoint: 6-month overall ( 24%↑ (45→69%) 80% p ) survival Kindler, HJ. J Clin Oncol, 2010 (abst # 4035)NCT Metastatic Pancreas Ca N= 120 Gemcitabine + Placebo Gemcitabine + AMG mg/kg RANDOMIZERANDOMIZE Gemcitabine + AMG mg/kg

Results: Rand. Phase II (N= 125) Gemcitabine + AMG 479 (open-label) Gemcitabine + AMG 655 (blinded) Gemcitabine + Placebo (blinded) 6-month OS57%59%50% 12-month OS39%20%23% Median OS8.7 mths7.5 mths5.9 mths Median PFS5.1 mths4.0 mths2.1 mths Gd 3-4 ANC18%22%13% Gd 3-4 Platelets15%17%8% Gd 3-4 Fatigue13%12%5% Hyperglycemia15%2%35 Kindler, HJ. J Clin Oncol, 2010 (Abst #4035) HR OS 0.67, p=0.12; HR PFS 0.65, p=0.07

NCT Phase III: Metastatic Pancreas Adenoca (GAMMA Trial) Gemcitabine + Placebo RANDOMIZERANDOMIZE Gemcitabine + AMG-479 (12 mg/kg, 20 mg/kg) Untreated Metastatic Pancreas Ca N= 825 Primary endpoint: Overall survival Correlatives: IGF, IGF-BP levels and outcome

SWOG S0727 Phase 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/m 2, Erlotinib 100mg/daily – Gemcitabine, Erlotinib – Primary endpoint PFS P. Philip. Proceedings ASCO, 2012 Abst #4019

SWOG S0727 Results Gem/Erlotinib/Cixutumumab N= 57 Gem/Erlotinib N= 59 Median PFS4 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: % 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, Zhigang, Z. W J Surg Oncol, Kan, K-R. J Urol, 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 Ca ECOG 0-1 2: 1 Randomization N= 165 Primary Endpoint 6-month Survival Rate 45% → 65% Secondary Endpoints OS, PFS, RR, Toxicity Effect of PSCA on OS, PFS, RR Gemcitabine N= 68 RANDOMIZERANDOMIZE Gem + AGS-1C4D4 N= 137

Randomized Phase II Gemcitabine +/- AGS-1C4D4 Gemcitabine (N= 63) Gem + AGS (N= 133) P-Val 6-month Survival44.4%60.9%0.016 Median OS5.53 mths7.9 mths0.06 PSCA + (N= 66) 6-month Survival 8.5 mths 57% 10.3 mths 79% PSCA - (N= 57)4.6 mths4.5 mths0.27 Wolpin, B. J Clin Oncol, 2011 (Abst #4031); Hidalgo, M. World GI ESMO Congress, 2011

Embryonic Pathway Targeting Stromal 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, Thayer, S. Nature, Feldmann, G. Gut, Jimeno, A. Mol Can Ther, Oliver, K. Science, 2009

Trials Evaluating Hh Pathway Inhibition in Pancreas Adenocarcinoma PhaseNRegimenStageNCT II~80Gem, Nab-Paclitaxel + GDC-0449IV IB-Rand. II105Gemcitabine + GDC-0449/ PIV IB- Rand II122Gemcitabine + IPI-926/ PIV IB- Rand IIFOLFIRINOX + IPI-926III-IV II (pre-op)20GDC-0449I-II IB- Rand II30+Gemcitabine + LDE225/ PIII-IV P= Placebo. GDC-0449= Vismodegib. IPI-926= Saridegib Preliminary data Gemcitabine +/- IPI-926 – Survival favors control arm

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 Disease49%31% Med. PFS (95% CI)3.7 months ( )2.4 months ( ) Adjusted HR 0.92 ( ) Med. OS (95% CI)6.3 months ( )5.4 months ( ) Adjusted HR 0.97 ( ) One- Year survival24% Catennaci, D. Proceedings ASCO, 2012 Abst # 4022 Correlatives: [Shh], CT perfusion

Phase IB, Randomized Phase II Gemcitabine + 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, Hingorani, S. Cancer Cell, NCT

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, Mackey JR, et al. Can Res, Mori, R. Onc Rep Nakano Y. Br J Can, Achiwa H. Cancer Sci, 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, Giovannetti E, et al. Can Res, 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

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 2 nd -line: Gemcitabine-refractory disease (no hENT1) NCT ; NCT

Pancreas Cancer & BRCA Mutations Rare in general population – Increased prevalence in Ashkenazi population – Founder mutations BRCA 1 185delAG, 5832insC BRCA delT 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, 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 – Susceptible to alkylating agents Anecdotal clinical data in PC Friedensen. Med Gen Med, Couch. Can Epid Biom Prev, McCabe. Cancer Biol Therapeut, 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 #Stage BRCA Mutation 1 st lineResponse2 nd lineResponse3 rd lineResponse OS (mo) 1T2N0M0BRCA1 Surgery & Adjuvant Gemcitabine Relapse 16.3 mo AZD 2281/ Gem PR 2 mo POD 4.5 mo FOLFIRINOX Assessment pending 24.7, AWD 2T3N0M0BRCA2 Surgery & Adjuvant GTX Relapse 12.8 moPending13.4, AWD 3T3,N0, II BRCA 2 *7535delA Surgery & Adjuvant Gemcitabine Relapse 11 mo FOLFIRINOX – FOLFOX CR 3 mo Rx d/c for toxicity LR 8mo Cisplatin/5FU - Capecitabine RT PR38.4, AWD 4 T3,N1, IIB BRCA2 *4075DGT Surgery & Adjuvant Gem/ Cisplatin Relapse at 14 mo14.7, AWD 5 T3, N1 IIB BRCA2 Surgery & Adjuvant Gem, 5FU/RT Relapse at 13 moGem/oxaliplatin PR POD 6 mo AZD-2281SD 6 mo34.3, AWD 6T4, III BRCA2 Y1894X GTXPOD at 5 moFOLFOXResponse at 3 mo8.8, AWD 7T4, IIIBRCA2 Gem/ Cisplatin → Gem /RT→ gem SD /minor response POD 11 mo FOLFOXPOD 2 mo20.4,DOD 8IV BRCA2 *6174delT UnknownPOD at 7 mo9.1, DOD 9IV BRCA1 *4603G->T Gem/ Capecitabine PR 3 moFOLFOXPOD 14 mo Flavopiridol/ Docetaxel POD 2 mo27.6, DOD 10IV BRCA1 *187delAG Gem + AZD2281 PR 2 mo, POD 6 m FOLFOX → CPT-11/ Gem (Oxali d/c reaction) POD 2.5 mo ABT-888 & Temozolomide (1 cycle) POD 6 weeks 13.7, DOD 11IVBRCA2No treatment1.0, DOD 12IV BRCA1 *IVS8+7G>A Gem & AZD 2281 PR POD 7 mo Gem/ Capecitabine POD 2 moFOLFOXPOD11.5,DOD 13IVBRCA2Gem/ Cisplatin PR POD 9 mo FOLFOXPOD 2 moMK 2206POD 2 mo15.2, AWD 14IV BRCA2 IVS13 -2A>T, V211I (859 G>A) Gem/ Oxaliplatin PR SD 7 mo 9.2, AWD 15IV BRCA2 Gem/ OxaliplatinPending1.5, 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-agents Activity to PARP inhibitors (Lowery, MA, O’Reilly, EM, The Oncologist, 2011) Key Observations: Activity to platinum-agents Activity 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 + veliparib Arm B: Cisplatin + gemcitabine Gemcitabine + cisplatin d3+10, q 21 Veliparib dosing day 1-12, BID, PO Dosing veliparib from ongoing phase I (NCT ) 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; C 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