1. 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

2. Cytotoxic Therapies

3. Gemcitabine FOLFIRINOX FOLFIRINOX vs Gemcitabine Overall Survival Number at risk Gemcitabine FOLFIRINOX 171 134 89 48 28 14 7 6 3 3 2 2 2 171 146 116 816234201395322 1.00 0.75 0.50 0.25 0.00 P r o b a b i l i t y Months 0369121518212427303336 Median 11.1 mo Median 6.8 mo HR = 0.57 P < 0.0001 Conroy, T. NEJM, 2011

4. 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?

5. 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

6. 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

7. Novel Targets

8. 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 GSK1120212 (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 R04929097, 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

9. 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

10. 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

11. 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

12. IGF-1R Targeting

13. 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)NCT00630552 Metastatic Pancreas Ca N= 120 Gemcitabine + Placebo Gemcitabine + AMG 655 10 mg/kg RANDOMIZERANDOMIZE Gemcitabine + AMG 479 12 mg/kg

14. 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

15. NCT01231347 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

16. 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

17. 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?

18. Prostate Membrane Stem Cell Antigen Targeting

19. 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

20. 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

21. 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% 0.26 0.03 PSCA - (N= 57)4.6 mths4.5 mths0.27 Wolpin, B. J Clin Oncol, 2011 (Abst #4031); Hidalgo, M. World GI ESMO Congress, 2011

22. Embryonic Pathway Targeting Stromal Depletion

23. 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

24. Trials Evaluating Hh Pathway Inhibition in Pancreas Adenocarcinoma PhaseNRegimenStageNCT II~80Gem, Nab-Paclitaxel + GDC-0449IV01088815 IB-Rand. II105Gemcitabine + GDC-0449/ PIV01064622 IB- Rand II122Gemcitabine + IPI-926/ PIV01130142 IB- Rand IIFOLFIRINOX + IPI-926III-IV01383538 II (pre-op)20GDC-0449I-II01096732 IB- Rand II30+Gemcitabine + LDE225/ PIII-IV01487785 P= Placebo. GDC-0449= Vismodegib. IPI-926= Saridegib Preliminary data Gemcitabine +/- IPI-926 – Survival favors control arm

25. 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- 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 survival24% Catennaci, D. Proceedings ASCO, 2012 Abst # 4022 Correlatives: [Shh], CT perfusion

26. 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, 2012. Hingorani, S. Cancer Cell, 2012. NCT01453153

27. Biomarker Driven Therapies

28. 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

29. 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

30. 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

31. 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

32. 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)

33. 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

34. 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) NCT01124786; NCT01233375

35. 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

36. 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

37. 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

38. Loss of Functional BRCA-1 or 2 Affects DNA Double-Strand Break Repair Pathway Ashworth, et al. J Clin Oncol, 2008

39. 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)

40. 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)

41. 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

42. 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