Pancreatic cancer Challenges

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1 9/30/2015 Pablo del Pino VP Oncology Celgene Europe Public Private Challenges in Pancreatic Cancer Research II Pancreatic cancer Challenges 4th largest cause of cancer death <5% alive at 5 years Average survival ~6 months 80% die within a year Mortality unchanged for 50 years Surgery only cure (20% of 20% = 4%) Waddell et al. Nature 2015;518:

2 Projecting cancer deaths to 2030 INT-ABR Date of preparation July 2015 Rahib et al. Cancer Res 2014; 74: This was the beginning of OUR (Celgene) challenges in Pancreatic Cancer Therapeutic indication Abraxane in combination with gemcitabine is indicated for the first line treatment of adult patients with metastatic adenocarcinoma of the pancreas. 3 2

3 Clinical Benefit Unclear Patients Profiles Remaining Open Research Questions ABRAXANE + Gemcitabine Indicated for patients with advanced pancreatic cancer in the settings below Patient Settings Adjuvant Neoadjuvant/ Borderline Resectable Locally Advanced 1 st Line Metastatic 2 nd Line Metastatic Adjuvant Registration Study APACT Multiple Neoadjuvant studies Locally advanced MAST LAPACT Elevated Bilirubin Emerging new drugs Borderline resectable studies ABRAXANE + other combos Sequential ABRAXANE Long term Survivors ABRAXANE + other combination Celgene Sponsored Studies RT Sequential AG Other Open Research Questions/ Investigator Initiated Trials AG in Frail patients 5 3

4 Biomarkers identification Challenges Clinical Studies Evaluating SPARC Expression and nab Paclitaxel Activity First Author Disease Setting N for SPARC analysis High SPARC expression significantly predictive of nab P activity? SPARC IHC assessment Scoring/ antibody Von Hoff 1 Metastatic pancreatic cancer 36 Yes Stroma + tumor epithelia (association found for stromal SPARC only) 2 antibodies; z score transformation Alvarez 2 Hamilton 3 Yardley 4 Yardley 5 Desai 6 Neoadjuvant pancreatic cancer 10 No Stroma 1 antibody Metastatic breast 24 Yes Stroma + tumor epithelia NR cancer Neoadjuvant SMS score a ; 68 Yes SMS score breast cancer a 2 antibodies Neoadjuvant breast cancer Head and neck cancer a SMS, SPARC microenvironment signature, 24 No 12 No Stroma and tumor epithelial Stroma and tumor epithelia 2 antibodies evaluated separately and together 1 antibody, overall score 1. Von Hoff DD, et al. J Clin Oncol. 2011;29: Alvarez R, et al. Br J Cancer. 2013;109: Hamilton EP, et al. Poster presented at: ASCO 2010 [abstract Yardley DA, et al. Poster presented at: ASCO 2009 [abstract 527]. 5. Yardley DA, et al. Poster presented at: ASCO 2010 [abstract 10574]. 6.Desai N, et al. Transl Oncol. 2009;2: Biomarkers identification Challenges Findings from other studies suggest evaluation in the adjuvant setting is warranted 7 Hidalgo M, Plaza C, Illei PB, et al. SPARC analysis in the phase III MPACT trial of nab-paclitaxel plus gemcitabine vs Gem alone for patients with metastatic pancreatic cancer. Oral presentation at: 16th World Congress on Gastrointestinal Cancer; June 25-28, 2014; Barcelona, Spain [abstract O-0004]. 4

5 Mutational landscape of PDAC Promising pathways? Immune Therapy PD1 IDO inhibitors Vaccines Epigenetic modifiers Epigenetics Stromal Disruption Pegylated hyaluronan Pancreatic Cancer KRAS ERK JAK Molecular Signaling Stem Cells DLL4/VEGF bispecific DLL4 Notch/Wnt 9 Chemotherapy Abraxane combos PARP Liposomal irinotecan 5

6 97 novel agents are investigated across Pancreatic Cancer trials (39 are currently in combination with Abraxane gemcitabine) 10 The 39 novel agents currently investigated in combination with AG Drug Mechanism Drug Mechanism ADI PEG 20 Ariginine deaminase (starvation) OMP 18R5 (vantictumab) WNT pathway inhibitor Algenpantucel L hyperacute pancreatic vaccine OMP 21M18 Demcizumab Alisertib Aurora kinase inhibitor OMP 54F28 (ipafricept) WNT pathway inhibitor Azacitidine (oral) Hypomethylator y OMP 59R5 (tarextumab) Noth 2/3 BBI608 Apoptosis stimulant Paricalcitol (IV) Vitamin D agonist BYL719 (alpelisib) PI3K alpha inhibitor PEGPH20, Halozyme Hyaluronidase Ceritinib ALK receptor TKI PF gamma secretase inhibitor Pembrolizumab Immune checkpoint inhib (anti PD1) PLX7486 trka TKI Enzalutamide Androgen biosynth inhibitor Ruxolitinib JAK FG 3019 Connective tissue target Selinexor (Karyopharm) CRM 1 inhibitor GS 5745 (IV) Matrix metalloproteinase Sorafenib TKI INCB JAK1 TH 302 Hypoxia induced cytotoxix INCB JAK1 TS 1 Thymidylate Synthase inhibitor Indoximod Immunostimulant Vismodegib (oral) Hedgehog LDE 225 (erismodegib) ib) Hd Hedgehog pathway inhibitor Vorinostat HDAC inhibitor M402 (necuparanib) Apoptosis stimulant SGT 53 p53 function Gene Therapy MK 1775 Wee1 TKI MM 141 Anti EGFR3 TKI Nivolumab Immune checkpoint inhib (anti PD1) NovaCaps Cell therapy NPC 1C (ensituximab) MAB targets TAAs ODSH, ParinGenix Heparin stimulant OGX 427 (apatorsen) Anti HSP27 Source: citeline.com accessed 11/13/2014; novel agents are either unapproved (except erlotinib,ts 1) or not yet indicated in pancreatic cancer and trial should be intended for active therapy (not palliative) What is the best combination strategy with immune checkpoint inhibitor/other Agents? Immune checkpoint inhibitor(s) plus: CD40 agonist Vaccines Stroma targeting agent Stem cell inhibitor Hyaluronidase Nab-paclitaxel/gemcitabine Nab-paclitaxel/gemcitabine + RT 11 Vanneman & Dranoff. Nature Reviews Cancer 2012;12: Confidential Not to be Distributed 6

7 What is the Right approaches of Early Stage PC Treatment Strategy? Proposed pre operative strategies to integrate biomarkers into clinical trials Role of Regulatory Agencies? FDA & EMEA 12 In Celgene we want. Improve early Diagnosis and refine treatment to achieve 12 months of OS in patients with advance Pancreatic Cancer and doubling the survival rate 5% to 10% in all patients by

8 To address the high disease burden, pancreatic cancer should be a research priority involving multiple stakeholders Pancreatic Cancer research needs to be a multi-stakeholder effort Patient representatives Clinicians Academia Policy makers Industry INCREASING PUBLIC IS ESSENTIAL 2nd European Pancreatic Cancer Platform Meeting Toledo, June 2015 Patients Support Org Industry Clinicians Researchers Politicians Journalists 15 8

9 Puzzle strategy for co creation Some Deliverables Awareness Data Collection Diagnosis 9

10 Pancreatic Cancer patients need to have the same opportunities as other cancer patients I dream that the word cure will no longer be followed by the words it's impossible Patrick Swayze, died from pancreatic cancer 10