Download Free Medical Emerging Biology in Pancreatic Cancer PowerPoint Presentation

Emerging Biology in Pancreatic Cancer PowerPoint Presentation

DOWNLOAD MEDICAL POWERPOINT PRESENTATION

About This Presentation

Description : This medical presentation on cancer titled "Emerging Biology in Pancreatic Cancer" talks about pancreatic adenocarcinoma, a highly lethal tumor. The presentation discusses its risk factors, screening, and effective systemic therapies of pancreatic cancer.

Tags : Cancer, Aberrant Metabolism, Cause, Result, Pancreatic Carcinogenesis, Pancreatitis, Diabetes, Pancreatic Cancer, Obesity, Cellular Stress

Published on : May 03, 2021 | Views : 1377 | Downloads : 2

Shareable Url :

Embed Code :

Comment

Transcript

Slide 1-

Provided by MediCom Worldwide, Inc. Not an official event of the 2016 Gastrointestinal Cancers Symposium. Not sponsored or endorsed by any of the cosponsoring organizations of the 2016 Gastrointestinal Cancers Symposium. Supported by an educational grant from Celgene Corporation
Slide 2-

Emerging Biology in Pancreatic Cancer James L. Abbruzzese, MD, FACP, FASCO Professor of Medicine Chief, Division of Medical Oncology, Department of Medicine Associate Director for Clinical Research and Training Duke Cancer Institute Durham, North Carolina
Slide 3-

Pancreatic Adenocarcinoma Highly lethal tumor 3% of all cancer cases in the US 7% of all cancer deaths 4th leading cause of cancer death Lung Colorectal Breast Pancreas http://www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-041783.pdf
Slide 4-

Recent Translational Progress Initial histologic and molecular characterization of precursor lesions Initial descriptions of mutational profile of pancreatic cancer Development of GEMMs and patient-derived xenografts (PDX) Importance of tumor-related stroma, stellate cells, and immunocytes Recognition of the role of diabetes and obesity in pancreatic cancer risk and survival
Slide 5-

Recent Clinical Progress Initial screening efforts for patients with FPC or known germ-line mutations conferring risk Understanding the natural history of mucinous cystic neoplasms and development of initial criteria for surgical resection Recognition that development of targeted agents will require understanding pancreatic cancer cellular heterogeneity Development and FDA approval of nab-paclitaxel + gemcitabine Integration of currently available modalities (surgery, radiation, chemotherapy)
Slide 6-

Critical Questions - Areas of Greatest Need Can we identify cohorts of individuals at high risk? Can we screen patients deemed to be at high risk and identify pre-invasive pathologic precursors or very early cancer? Can we develop effective systemic therapies?
Slide 7-

Pancreatic Cancer: Scanning the Horizon for Focused Interventions March 13, 2013 National Cancer Institute (NCI). Division of Extramural Activities. CTAC Working Group Reports and Supplements. http://deainfo.nci.nih.gov/advisory/ctac/archive/0313/PCwgReport.pdf A Report to the Director of the National Cancer Institute The Pancreatic Cancer Working Group Clinical Trials and Translational Research Advisory Committee
Slide 8-

Four Initiatives Understand the biological relationship between PDAC and nutrient excess Develop and evaluate longitudinal screening protocols for biomarkers for early detection of PDAC and its precursors Develop new treatment approaches that interfere with KRAS oncogene-dependent signaling pathways Study new therapeutic approaches: Immunotherapy and stromal disruption National Cancer Institute (NCI). Division of Extramural Activities. CTAC Working Group Reports and Supplements. http://deainfo.nci.nih.gov/advisory/ctac/archive/0313/PCwgReport.pdf
Slide 9-

Four Initiatives Understand the biological relationship between PDAC and nutrient excess Develop and evaluate longitudinal screening protocols for biomarkers for early detection of PDAC and its precursors Develop new treatment approaches that interfere with KRAS oncogene-dependent signaling pathways Study new therapeutic approaches: Immunotherapy and stromal disruption National Cancer Institute (NCI). Division of Extramural Activities. CTAC Working Group Reports and Supplements. http://deainfo.nci.nih.gov/advisory/ctac/archive/0313/PCwgReport.pdf
Slide 10-

Pancreatic Cancer Risk Factors Environmental Cigarette smoking (~25%) Chronic pancreatitis Metabolic (>25%) Obesity Diabetes Genetic Pancreatic cancer families Hereditary syndromes Mucinous pancreatic cysts Mucinous cystic neoplasm Intrapancreatic mucinous neoplasm (IPMN) MORE CONTROL LESS CONTROL Decker GA, et al. Gastroenterol Hepatol (N Y). 2010;6(4):246-254.; Andersen DK, et al. Pancreas. 2013;42(8):1227-1237.; NCCN Guidelines Pancreatic Adenocarcinoma. Version 2.2015.; McWilliams RR, et al. Pancreas. 2015 Dec 5. [Epub ahead of print].
Slide 11-

Aberrant Metabolism is Both a Cause and a Result of Pancreatic Carcinogenesis Physiologic Metabolic Alterations Obesity Diabetes Effects on Pancreas Cells Germ line genetic modifiers Genotoxic Stress KRAS mutation Genomic Instability Altered Cellular Metabolism Hyperglycemia Metabolic Syndrome Nutrient Signaling Pathway Activation Cohen R, et al. Oncotarget. 2015;6(19):16832-16847.; Blum R, et al. Cell Death Dis. 2014;5:e1065.
Slide 12-

Nutrient Excess is a Risk Factor for Pancreatic Cancer Physiologic Metabolic Alterations Obesity Diabetes Effects on Pancreas Cells Germ line genetic modifiers Genotoxic Stress KRAS mutation Genomic Instability Altered Cellular Metabolism Hyperglycemia Metabolic Syndrome Nutrient Signaling Pathway Activation Cohen R, et al. Oncotarget. 2015;6(19):16832-16847.; Blum R, et al. Cell Death Dis. 2014;5:e1065.
Slide 13-

What are the observations linking alterations in whole-body energy metabolism to pancreatic carcinogenesis?
Slide 14-

Pancreatic Cancer Risk and Diabetes General Observations Pancreatic cancer induces the diabetic state Patients with new-onset diabetes 1/125 new onset diabetics develop pancreatic cancer in 2-3 years Diabetics with recent initiation of insulin Longstanding (type II) diabetes and insulin resistance influences pancreatic carcinogenesis Individuals with a history of diabetes >5 years have SRR of 2.0 (95% CI 1.2-3.2) Chari ST, et al. Gastroenterology. 2005;129:504–511.; Everhart J, Wright D. JAMA. 1995;273:1605-1609.; Hart PA, Chari ST. Pancreas. 2013;42(8):1207-1209.; Li D. Am J Cancer Res. 2015;5(10):3260-3269.
Slide 15-

Li D, et al. Gastroenterology. 2009;137(2):482-488. Diabetes and Risk of Pancreatic Cancer
Slide 16-

Pancreatitis, Diabetes, and Pancreatic Cancer Chronic Pancreatitis Type II Diabetes Pancreatogenic (T3cDM) DM Islet cell loss Pancreatic Cancer Pancreatogenic (T3cDM) DM (PC-DM) ? paraneoplastic “Diabetogenic” Pancreatic cancer Andersen DK, et al. Pancreas. 2013;42(8):1227-1237.
Slide 17-

Summary Whole-body energy metabolism: Diabetes New onset (or worsening) diabetes is a risk factor for pancreatic cancer Patients with long-standing diabetes are also at slightly increased risk Diabetic patients treated with insulin or insulin secretagogues were at higher risk; metformin-treated patients had a significantly lower risk of pancreatic cancer compared with those who had not taken metformin
Slide 18-

Obesity Overweight and obesity are associated with 14% of all cancer deaths in men and 20% of cancer deaths in women1 Obesity increases the risk of insulin resistance and overt diabetes2 1Calle EE, et al. N Engl J Med. 2003;348(17):1625-1638. 2Kahn SE, et al. Nature. 2006;444(7121):840-846.
Slide 19-

Obesity and Pancreatic Cancer Hospital-Based Case Control Study Goals: Examine the impact of excess body weight across life span and risk of pancreatic cancer Examine the influence of BMI on age of onset of pancreatic cancer Examine the influence of BMI on patient survival Design Case-control study (841 patients and 754 matched controls) Height and body weight collected by personal interview Li D, et al. JAMA. 2009;301(24):2553-2562.
Slide 20-

All Study Participants Association of BMI and risk of pancreatic cancer Li D, et al. JAMA. 2009;301(24):2553-2562.
Slide 21-

Normal weight Overweight Obese Age of Onset Overall Survival Normal weight Overweight Obese Obesity and Pancreatic Cancer Li D, et al. JAMA. 2009;301(24):2553-2562.
Slide 22-

Pancreatic Inflammation, Obesity, and Pancreatic Cancer Chronic Pancreatitis Obesity Pancreatogenic (T3cDM) DM Islet cell loss Pancreatic Cancer “Nutrient Excess -Related” Pancreatic cancer Andersen DK, et al. Pancreas. 2013;42(8):1227-1237.
Slide 23-

Summary Whole-body Energy Metabolism: Obesity Obesity is closely associated with increased risk and earlier age of onset of pancreatic cancer Obesity has a negative prognostic impact on survival for all stages of patients with pancreatic cancer
Slide 24-

These observations serve to emphasize the important relationship between pancreatic carcinogenesis, and whole-body energy metabolism
Slide 25-

What are the cellular genomic and metabolic consequences of hyperglycemia and obesity for pancreatic carcinogenesis?
Slide 26-

Cellular Impacts of Nutrient Excess Insulin resistance and hyperinsulinemia Increased signaling through nutrient sensing signaling pathways Hexosamine signaling pathway mTOR signaling pathway Increased ROS leading to genotoxicity Wellen KE, Thompson CB. Mol Cell. 2010;40(2):323-332.
Slide 27-

Nutrient Deficiency and Nutrient Excess Cause Cellular Stress Wellen KE, Thompson CB. Mol Cell. 2010;40(2):323-332.
Slide 28-

Aberrant Metabolism Is Also a Result of Pancreatic Carcinogens Physiologic Metabolic Alterations Obesity Diabetes Effects on the Pancreas Germ line genetic modifiers Genotoxic Stress KRAS mutation Genomic Instability Altered Cellular Metabolism Hyperglycemia Metabolic Syndrome Nutrient Signaling Pathway Activation Cohen R, et al. Oncotarget. 2015;6(19):16832-16847.; Blum R, et al. Cell Death Dis. 2014;5:e1065.
Slide 29-

Mutated KRAS Initiates Pancreatic Carcinogenesis Morris JP 4th, et al. Nat Rev Cancer. 2010;10(10):683-695.
Slide 30-

Pancreatic Inflammation Critical Mechanistic Link Between KRAS Mutation and Pancreatic Cancer Activation of KRAS in adult mice does not induce mPanINs and mPDAC Adult acinar cells are resistant to oncogenic insults Pancreatitis induces mPanINs and mPDAC in mutant KRAS expressing adult acinar cells Pancreatic inflammation contributes to mPanIN development by inhibiting oncogene induced senescence Pancreatic inflammation blocks senescence in human PanINs Guerra C, et al. Cancer Cell. 2007;11(3):291-302.; Guerra C, et al. Cancer Cell. 2011;19(6):728-739.
Slide 31-

What are the cellular metabolic consequences of activating KRAS mutations?
Slide 32-

KRAS Mutation Metabolic Reprograming Increased glucose uptake and metabolism (Warburg effect) Increased GLUT1, HK1, HK2 expression Differential channeling of glucose intermediates Hexosamine biosynthetic pathway Non-oxidative pentose phosphate pathway Reprograming glutamine metabolism Increased autophagy Mitophagy Increased macropinocytosis Locasale JW, et al. Cell. 2012;149(3):656-670.
Slide 33-

KRAS Mutation Metabolic Reprograming Increased glucose uptake and metabolism (Warburg effect) Increased GLUT1, HK1, HK2 expression Differential channeling of glucose intermediates Hexosamine biosynthetic pathway Non-oxidative pentose phosphate pathway Reprograming glutamine metabolism Increased autophagy Mitophagy Increased macropinocytosis Locasale JW, et al. Cell. 2012;149(3):656-670.
Slide 34-

Increased Rates of Macropinocytosis in Ras-transformed Cells Commisso C, et al. Nature. 2013;497(7451):633-637.
Slide 35-

Summary Metabolic alterations leading to hyperglycemia and hyperinsulinemia activate nutrient sensing pathways and increase ROS contributing to pancreatic carcinogenesis Obesity is an important risk factor with excess adipose tissue resulting in high levels of circulating adipokines and inflammatory mediators activating many pro-carcinogenic pathways Epidemiology and mechanistic studies suggest that chronic pancreatic inflammation is a common driver of pancreatic carcinogenesis
Slide 36-

Summary Mutations in KRAS activate canonical cancer-related pathways, but also contribute to extensive metabolic reprograming of pancreatic cancer cells A greater understanding of these metabolic alterations may lead to novel therapeutic strategies
Slide 37-

The Current Treatment Landscape of Pancreatic Cancer: Optimizing Outcomes through Individualized Therapy Philip A. Philip, MD, PhD, FRCP Professor of Oncology and Internal Medicine Dr. Kathryn Cramer Endowed Chair in Cancer Research Leader, GI & Neuroendocrine Multidisciplinary Team Vice President for Medical Affairs Barbara Ann Karmanos Cancer Institute Wayne State University School of Medicine Detroit, Michigan
Slide 38-

Spectrum of Pancreatic Cancer
Slide 39-

U.S. Food and Drug Administration (FDA). Increasing Availability of Therapies for Pancreatic Cancer
Slide 40-

Burris HA, et al. J Clin Oncol. 1997;15:2403-2413.; Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966.; Conroy T, et al. N Engl J Med. 2011;364:1817-1825.; Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703. Incremental Benefits With New Agents in Frontline
Slide 41-

R A N D O MI Z E Gemcitabine FOLFIRINOX Metastatic Good PS Good LFTs Primary endpoint = overall survival (11.8 vs 6.1, P < .0001) Doubling of RR, PFS, survivals at 6 and 12 months Conroy T, et al. N Engl J Med. 2011;364(19):1817-1825. FOLFIRINOX versus Gemcitabine in Metastatic Pancreatic Cancer
Slide 42-

Time Until Definitive Deterioration >20 Points in EORTC-QLQ C30 Global Health Status Gourgou-Bourgade S, et al. J Clin Oncol. 2013;31(1):23-29.
Slide 43-

Nab-Paclitaxel + Gemcitabine: Phase 3 Study (MPACT)1,2 Nab-P=Nab-paclitaxel 1Von Hoff D, et al. N Engl J Med. 2013;369:1691-1703. 2Von Hoff D, et al. ASCO GI 2013. Abstract LBA148. Nab-paclitaxel 125 mg/m2 Gem 1,000 mg/m2 QW 3/4 wk (n = 431) Gem 1,000 mg/m2 QW for 7 wk, then QW 3/4 wk (n = 430) Primary endpoint: OS Secondary endpoints: PFS, ORR R 1:1 (n = 431) (n = 430) Months
Slide 44-

Nab-P/Gem or FOLFIRINOX? a 29% by investigator and 23% by independent review (IR). b 44% of patients resumed therapy when neuropathy was ≤ grade 1. RR=response rate 1Von Hoff D, et al. N Engl J Med. 2013;369:1691-1703. 2Conroy T, et al. N Engl J Med. 2011;364:1817-1825. Cross-trial comparisons should be interpreted with caution
Slide 45-

Major Determinants of Treatment Choice in Advanced Pancreatic Cancer Performance status Age Major liver dysfunction/biliary stent Patient preference UGT1A1 Pre-existing neuropathy Albumin Platelet count Ascites ?? Biomarkers NCCN Guidelines Pancreatic Adenocarcinoma. Version 2.2015. Release date 3/6/2015.
Slide 46-

Deeper Responses with Combination Therapy Before After Courtesy Dr. P. Philip
Slide 47-

How to Improve on Current Gains Increasing cytotoxic power Rational sequencing of therapies Using maintenance therapies of biological value Changing cytotoxics Targeted therapy Immune modulation Exploiting biology to predict patient outcome Incorporating ablative/surgical strategies to treat residual disease Chiorean E, et al. Drug Des Devel Ther. 2015;9:3529-3545.
Slide 48-

Evolution of Frontline Regimens Over Next 5 Years Irinotecan 5-FU MM-398 Oxaliplatin Nab-paclitaxel Gemcitabine Cisplatin FOLFIRINOX Gemcitabine/nab-paclitaxel Gemcitabine Nab-paclitaxel/5-FU MM-398/5-FU MM-398/Nab-paclitaxel/5-FU Oxaliplatin/nab-paclitaxel/5-FU Oxaliplatin/MM-398/5-FU Gemcitabine/Cisplatin erlotinib Teague A, et al. Ther Adv Med Oncol. 2015;7(2):68-84.
Slide 49-

Nab-paclitaxel + mFOLFOX (FOLFOX-A) in Good PS Patients: Active and Safe Phase I trial from Brown University N = 15, previously untreated, PS 0-1 FOLFOX/Nab-paclitaxel (125-175 mg/m2/2w) Recommended phase 2 dose is 150 mg/m2 DLTs were nausea and fatigue Two patients with grade 3 neuropathy ≥10 cycles Objective response rate = 53% Phase II is underway Safran H, et al. GI Symposium, #258, 2014.
Slide 50-

Nab-P/Gem After FOLFIRINOX: Retrospective Review1 Retrospective review from Yale; 23 patients identified who received nab-P/Gem after a median of 12 cycles FOLFIRINOX; endpoints: dose, toxicity, ORR, TTF, OS 1Zhang Y, et al. Exp Hematol Oncol. 2015;4:29. Time to Treatment Failure and Survival Dose Reductions and Density Response Assessment
Slide 51-

Oxaliplatin Plus 5-fluorruacil (OFF) has Activity After Failure of Gemcitabine-based Therapies Failure on gemcitabine-based therapy RA N D O M I Z E OFF 5-FU Primary endpoint = 0S N = 168 KPS 90-100 in 50% Gem chemo ≥3 mo in 72% M0 in 12% Prior gem PFS median 4.6-5.0 mo Mets KPS Time first-line treatment Stratify CONKO-003 Oettle H, et al. J Clin Oncol. 2014;32(23):2423-2439.
Slide 52-

Oxaliplatin Added to 5FU Improved PFS and OS in Gemcitabine Failed Patients Oettle H, et al. J Clin Oncol. 2014;32(23):2423-2439.
Slide 53-

PANCREOX: Phase III Trial of mFOLFOX6 vs. 5FU/LCV in Second-line Setting in Advanced Pancreatic Cancer Gill S, et al. J Clin Oncol. 2014;32:5s: abstract 4022.
Slide 54-

mFOLFOX Second-line SWOG Experience Chung VM, et al. J Clin Oncol. 2015;33:(suppl; abstr 4119).
Slide 55-

MM-398, Nanoliposomal Irinotecan (nal-IRI) Is Different than Standard Irinotecan Novel nanoliposomal encapsulated irinotecan Increased and prolonged concentrations of irinotecan and active metabolite SN-38 in tumor tissues Single-agent activity in second line setting in patients with advanced pancreatic cancer failing gemcitabine ~80,000 irinotecan molecules/liposome Lipid membrane Internal aqueous space PEG-DSPE Irinotecan Carnevale J, et al. Future Oncol. 2015 Dec 21. [Epub ahead of print].; Ko AH, et al. Br J Cancer. 2013;109(4):920-925.
Slide 56-

Metastatic pancreatic cancer Prior gemcitabine therapy MM-398 80 mg/m2 5-FU 2,400 mg/m2/46 h LV 400 mg/m2 Q 2 weeks 5-FU 2,000 mg/m2/24 h LV 200 mg/m2 Weekly x 4 Q 6 weeks MM-398 120 mg/m2 Q 3 weeks Randomize Phase III trial N = 417 Primary endpoint = overall survival Wang-Gillam A, et al. Lancet. 2015 Nov 29. [Epub ahead of print]. NAPOLI-1: MM-398 (Nanoliposomal Irinotecan) + 5-FU/LCV Following Gemcitabine-based Treatment
Slide 57-

NAPOLI-1 Global trial Karnofsky PS 80-90 in 90% of patients Majority of patients had liver metastases Previously received chemo regimens Gemcitabine alone 45% Gemcitabine based combination 55% 5FU-based 42-46% Irinotecan-based 10-14% Platinum-based 30-36% Wang-Gillam A, et al. Lancet. 2015 Nov 29. [Epub ahead of print].
Slide 58-

NAPOLI-1: Overall Survival Wang-Gillam A, et al. Lancet. 2015 Nov 29. [Epub ahead of print].
Slide 59-

NAPOLI-1: Progression-free Survival Wang-Gillam A, et al. Lancet. 2015 Nov 29. [Epub ahead of print].
Slide 60-

NAPOLI-1: Selected Grade 3 or 4 Toxicities Wang-Gillam A, et al. Lancet. 2015 Nov 29. [Epub ahead of print].
Slide 61-

Sequencing Drugs in 2016 Gem-nabpaclitaxel Gem-nabpaclitaxel (if no neuropathy) mFOLFIRINOX MM-398/5-FU/LCV Gemcitabine mFOLFOX6/mFOLFIRINOX Capecitabine MM-398/5-FU/LCV
Slide 62-

Sunitinib Prolongs Survival in the Maintenance Setting Randomized phase II study Metastatic disease N= 55 No progression on chemotherapy for advanced disease at 6 months Observation vs. sunitinib 37.5 mg/day Primary endpoint = progression at 6 months PF6-6, 22.2% versus 3.5% OS at 2 years, 22.9% versus 7.1% Reni M, et al. Eur J Cancer. 2013;49(17):3609-3515.
Slide 63-

Maintenance Sunitinib Prolonged the Progression-free Survival and Survival Reni M, et al. Eur J Cancer. 2013;49(17):3609-3515.
Slide 64-

Spratlin JL, et al. Int J Mol Sci. 2011;12(9):5895-5907.; Waddell N, et al. Nature. 2015;518(7540):495-501.; Sultana A, et al. Clin Transl Gastroenterol. 2015;6:e130.; Greenhalf W, et al. J Natl Cancer Inst. 2014;106(1):djt347.; NCCN Guidelines Pancreatic Adenocarcinoma. Version 2.2015. (MS-11 – MS-13).; Takahara N, et al. Cancer Chemother Pharmacol. 2013;71(1):85-92. Potential Biomarkers for Metastatic Disease
Slide 65-

Exploiting DNA Repair Defects DNA repair defects Waddell N, et al. Nature. 2015;518(7540):495-501.
Slide 66-

BRCA Mutations May Predict Survival in Patients Treated with Platinum Compounds or PARP Inhibitors Olaparib Golan T, et al. Br J Cancer. 2014;111(6):1132-1138.; Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250.
Slide 67-

67 yo Male with Metastatic Disease: No Response on Gem/Nabpacli but a Prolonged Response to FOLFOX Disease progression After 2 cycles Gem-NabPacli mFOLFOIX6 BRCA2 mutated CA19-9
Slide 68-

Selected Studies in BRCA Mutated Pancreatic Cancers Choosing a biomarker for selection? Germline BRCA mutations Somatic BRCA mutations Homologous recombination deficiency (HRD) score www.clinicaltrials.gov
Slide 69-

Pancreatic Cancer: A Very Challenging Biology Frequent de novo drug resistance Stroma as a barrier to drug delivery Complex and poorly understood microenvironment Multiple gene mutations “Nondruggable” tumor suppressor genes No biomarkers
Slide 70-

Projected Cancer Deaths in 2030 (Thousands) Rahib L, et al. Cancer Res. 2014;74(11):2913-2921.
Slide 71-

Chemotherapy Platform for Current Clinical Trials Favors Gemcitabine/Nab-paclitaxel Gemcitabine/ Nab-paclitaxel + X FOLFIRINOX + Y
Slide 72-

Major Unmet Need: Unfavorable PS and Elderly Majority of patients with advanced pancreatic cancer have PS of 2-3 Clinical trials accrue PS 0-1 and median age 60-62 years Fatigue is the most important limiting factor with gem/nabpaclitaxel or FOLFIRIONOX National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results Program (SEER). SEER Stat Fact Sheets: Pancreatic Cancer. Who Gets This Cancer? http://seer.cancer.gov/statfacts/html/pancreas.html accessed January 8, 2016.
Slide 73-

Conclusions Advances have been in the development of cytotoxic therapies with modest benefits Standard second-line therapy is now available using the nanoliposomal irinotecan-based combination Sequencing of therapy with consideration of quality of life is very important Clinical trials must always be considered in newly diagnosed patients and those failing frontline or adjuvant therapy
Slide 74-

Pancreatic Cancer: Is a Systemic Disease from the Outset New cases = 49,000/year, deaths = 41,000 Disease diagnosed late in its natural history 5-year survival less than 6%! High frequency of systemic failures of disease even after curative resections Subclinical metastases present at the outset KRAS mutations in >90% TP53, SMAD4, CDKN2A inactivations in >50%
Slide 75-

Thank you! philipp@karmanos.org
Slide 76-

Looking Ahead: Where Do Future Opportunities Lie? Andrew H. Ko, MD Professor of Clinical Medicine Department of Medicine Division of Hematology/Oncology University of California, San Francisco San Francisco, California
Slide 77-

Novel Drugs in Development for Advanced PDAC X
Slide 78-

Novel Therapeutics May Defy Neat Compartmentalization and Cross Mechanistic Boundaries
Slide 79-

Stromal Depleting/Modifying Agents: A Physical Barrier that Impedes Effective Drug Delivery? Courtesy of Eric Collisson, MD.
Slide 80-

The Pancreatic Tumor Microenvironment: A Complex and Dynamic Interplay Between Multiple Cellular and Extracellular Components Evans A, et al. Front Physiol. 2012;3:270.; Quail DF, et al. Nature Med. 2013;19:1423-1437.
Slide 81-

Components of the PDAC Microenvironment PDAC=pancreatic ductal adenocarcinoma Pancreatic Cancer and Tumor Microenvironment. Grippo PJ, Munshi HG, editors. Trivandrum (India): Transworld Research Network; 2012.
Slide 82-

Stromal Targeting Agents Hedgehog inhibitors Recombinant human hyaluronidase: PEGylated-rHuPH20 Agonist CD40 monoclonal antibodies Vitamin D analogues Nab-paclitaxel? Olive KP, et al. Science. 2009;324:1457-1461.; Provenzano PP, et al. Cancer Cell. 2012;21:418-429.; Beatty GL, et al. Science. 2011;331:1612-1616.; Sherman MH, et al. Cell. 2014;159:80-93.; Alvarez R, et al. Br J Cancer. 2013;109:926-933.
Slide 83-

Hyaluronan Is a Major Component of the Extracellular Matrix Halloran is degraded by hyaluronidase Recombinant human hyaluronidase: PEGylated-rHuPH20 (Halozyme Therapeutics) Whatcott CJ, et al. Cancer Discov. 2011;1(4):291-296.
Slide 84-

In Mouse Models of Pancreatic Cancer, PEGPH20 Combined with Chemotherapy (1) Remodels Tumor Stroma; and (2) Re-expands Microvasculature Provenzano PP, et al. Cancer Cell. 2012;21:418-429. GEMCITABINE ALONE GEM + PEGPH20
Slide 85-

Clinical Trials of PEGPH20 in Pancreatic Cancer Phase I: PEGPH20 as monotherapy1 Doses ranging from 0.5 - 5.0 mcg/kg twice weekly Post-treatment biopsies (4 weeks) demonstrated 23-60% reduction in tumor hyaluronic acid (HA) Musculoskeletal events (pain, cramps) most common dose-limiting toxicity – mitigated by dexamethasone Phase Ib: Gemcitabine plus PEGPH202 RP2D: 3 mcg/kg twice-weekly ORR = 41%, including partial response rate of 67% (4/6) in tumors with high HA levels (vs 27% (3/11) in low HA) 1Ramanathan RK, et al. Cancer Chemother Pharmacol. 2011;67(3):503-509. 2Hingorani SR. Cancer Cell. 2015;28(2):151-153.
Slide 86-

Phase II HALO-109-202 Trial 1o endpoint = progression-free survival
Slide 87-

Phase II HALO-109-202 Trial Results (Preliminary) Hingorani SR et al. J Clin Oncol. 2015;33:(suppl; abstract 4006). Higher rate of thromboembolic events on PEGPH20-containing arm during first stage of enrollment (42 vs 25%); mitigated during second stage with addition of prophylactic enoxaparin
Slide 88-

Current/Future PEGPH20 Clinical Trials SWOG phase I/II trial (S1313): Modified FOLFIRINOX +/- PEGPH20 Planned phase III trial of gemcitabine/ nab-paclitaxel PLUS PEGPH20 Limited to patients with tumors exhibiting high levels of HA expression
Slide 89-

Caveats (Words of Warning?) Re: Stromal Depleting Strategies Lessons learned from Hedgehog story in pancreatic cancer The tumor stroma may be a physical barrier hampering drug delivery…but also may have protective effects in restraining tumor growth/progression Stromal depletion may result in more aggressive tumor phenotype Dense stroma reaction a/w improved DFS and OS in patients with resectable pancreatic cancer Rhim AD, et al. Cancer Cell. 2014;25(6):735-747.; Özdemir BC, et al. Cancer Cell. 2014;25(6):719-734.; Sinn M, et al. Br J Cancer. 2014;111(10):1917-1923.; Torphy RJ, et al. ASCO 2015; abstract 4021.
Slide 90-

What About Immunotherapies: How Immunogenic Is Pancreatic Cancer? Limited infiltrating effector T-cells seen in primary pancreatic tumor specimens Minimal clinical activity observed with anti-CTLA-4 and anti-PD-1 monoclonal antibodies Can pancreatic cancers be ‘primed’ to become more immunogenic? von Bernstorff W, et al. Clin Cancer Res. 2001;7(3 Suppl):925s-932s.; Clark CE, et al. Cancer Lett. 2009;279(1):1-7.; Royal RE, et al. J Immunother. 2010;33(8):828-833.; Topalian SL, et al. N Engl J Med. 2012;366(26):2443-2454.
Slide 91-

Immunotherapies Currently in Evaluation for Advanced/Metastatic Pancreatic Cancer
Slide 92-

CRS-207 in Pancreatic Cancer GVAX GM-CSF Dendritic Cell Antigen uptake & Activation T Cell Tumor antigens Deletion of virulence genes (actA, inlB) Insertion of mesothelin expression cassette – validated immune target ΔactA ΔinlB GVAX Pancreas Irradiated, whole-cell tumor vaccine CRS-207 (Aduro Biosciences) Live-attenuated Listeria monocytogenes Potent activation of innate and antigen-specific immune response Tumor Cell Destruction Le DT, et al. J Clin Oncol. 2015;33:1325-1333.
Slide 93-

Phase 2 Study of GVAX/CRS-207 vs. GVAX Alone in Metastatic Pancreatic Cancer Prior phase I trial of CRS-207 showed markedly improved survival (17 months) in 3 pancreatic cancer patients who had previously undergone ‘boost’ with GVAX vaccine Primary objective: overall survival Le DT, et al. Clin Cancer Res. 2012;18:858-868.; Le DT, et al. J Clin Oncol. 2015;33:1325-1333.
Slide 94-

Overall Survival (At Planned Interim Analysis) Median OS, Full analysis set: Arm A: 6.1 months Arm B: 3.9 months P = .02, HR 0.59 Median OS, Per-protocol set (subjects receiving at least one dose of CRS-207): Arm A: 9.7 months Arm B: 4.6 months P = .02, HR 0.53 Le DT, et al. J Clin Oncol. 2015;33:1325-1333. Toxicities related to CRS-207: transient fevers, rigors, lymphopenia
Slide 95-

Randomized Phase II ECLIPSE Trial Primary endpoint = overall survival ClinicalTrials.gov Identifier: NCT02004262
Slide 96-

STELLAR Randomized Phase II Study PRIMARY ENDPOINT: OVERALL SURVIVAL ClinicalTrials.gov Identifier: NCT02243371
Slide 97-

2. T cell transduction 1. T cell isolation by leukapheresis 3. T cell expansion Tumor specific CAR gene in lentivirus Native TCR CAR Courtesy of J. Lee. Chimeric Antigen Receptor (CAR) T-cells
Slide 98-

Pilot Study of Autologous T-cells Redirected to Mesothelin and CD19 with a Chimeric Antigen Receptor in Patients with Metastatic Pancreatic Cancer UCSF/U Penn collaboration; PI, Ko A. ClinicalTrials.gov Identifier: NCT02465983
Slide 99-

CAR-T Protocol Study Schema 4 WEEKS Intensive safety monitoring first 28 days; tumor staging @ months 1, 3, 6 ClinicalTrials.gov Identifier: NCT02465983
Slide 100-

Finally: What Other Signaling Pathways Are Currently Being Targeted in Pancreatic Cancer?
Slide 101-

JAK/STAT Inhibition: The RECAP Study Patients Histologically confirmed metastatic PDAC Karnofsky PS ≥60 Failed gemcitabine R A N D O M I Z E Ruxolitinib 15 mg BID, days 1-21 Capecitabine 1000 mg/m2 BID, days 1-14 Placebo BID, days 1-21 Capecitabine 1000 mg/m2 BID, days 1-14 1:1 n=64 n=63 Rationale: JAKs mediate inflammatory cytokine signaling through activation of STAT transcription factors; ruxolitinib (JAK 1/2 inhibitor) blocks this signaling Persistent activation of Stat3 is oncogenic and prevalent in many solid tumors Pancreatic cancer: clinical hallmarks of weight loss, cachexia, anorexia all reflect systemic inflammation; mouse models indicate pancreatic cancer-related cachexia is JAK2-dependent Hedvat M, et al. Cancer Cell. 2009;16(6):487-497.; Gilabert M, et al. J Cell Physiol. 2014;229(10):1437-1443.; Hurwitz HI, et al. J Clin Oncol. 2015;33(34):4039-4047.
Slide 102-

Med OS 136.5 v 129.5 days 6-mo surv 42% v 35% HR 0.79 (P = .25) Med OS 83 v 55 days 6-mo surv 42% vs 11% HR 0.47 (P = .01) Entire study population (n=127) C-reactive protein > 13 mg/L (n=60) (marker of systemic inflammation) Hurwitz HI, et al. J Clin Oncol. 2015;33(34):4039-4047. Ongoing JANUS-1 and -2 trials (registrational phase III studies) selected specifically for patients with high levels of C-reactive protein (biomarker-driven) – 2nd line setting
Slide 103-

Notch Signaling – Important in Maintenance of Stem Cell Populations Demcizumab (anti-DLL4, OMP-21M18) Tarextumab (anti-Notch2/3, OMP-59R5) Hernandez Tejada FN, et al. Front Pediatr. 2014;2:54.
Slide 104-

ClinicalTrials.gov Identifiers: NCT01647828 and NCT02289898
Slide 105-

Other First-line Studies of Interest in Metastatic PDAC All being studied in combination with gemcitabine/nab-paclitaxel Clinicaltrials.gov
Slide 106-

Novel Drugs in Development: Reason for Optimism? ?
Slide 107-

Case Study Presentation Philip A. Philip, MD, PhD, FRCP Professor of Oncology and Internal Medicine Dr. Kathryn Cramer Endowed Chair in Cancer Research Leader, GI & Neuroendocrine Multidisciplinary Team Vice President for Medical Affairs Barbara Ann Karmanos Cancer Institute Wayne State University School of Medicine Detroit, Michigan
Slide 108-

Case #1 73-year-old male No major comorbidities Epigastric discomfort, fatigue and weight loss of 10-20 lbs EGD normal CT scan of the abdomen = pancreatic tail mass and liver lesions
Slide 109-

Case #1 Continued CT guided biopsy of the liver = moderately differentiated adenocarcinoma, pancreaticobiliary type ECOG performance status = 1 CA19-9 = 82,704 Albumin = 3.0, AST/ALT/ALP = normal WBC = 14,000, platelets = 251,000 BRCA2 mutated
Slide 110-

Summary Was started on gemcitabine plus nabpaclitaxel Tolerated treatment relatively well CT scan after 2 cycles showed disease progression in the liver CA19-9 rising Neuropathy grade 1
Slide 111-

Case #2 61-year-old female Presents with obstructive jaundice CT scan of the abdomen = mass in head of the pancreas with no encroachment on vessels Further staging shows no distant metastases Underwent a Whipple procedure Pathology = moderately differentiated adenocarcinoma, pT3N0, margins clear
Slide 112-

Summary Received gemcitabine x 6 months and tolerated well CT scan 6 months after last chemo showed new liver metastases confirmed pathologically ECOG PS = 1 CBC, diff, platelets, SMA, lytes all normal
Slide 113-

Case #3 54-year-old male No comorbidities Hematuria being investigated CT scan done prior to cystoscopy Lung nodules Liver nodules Mass in the body of the pancreas
Slide 114-

Case #3 Continued Biopsy of the pancreatic mass (CT guided) revealed a moderately differentiated adenocarcinoma ECOG PS is 0 CA19-9 = 8, CEA = 47 Albumin = 4.2, AST/ALT/ALP = normal WBC = 9.2, platelets = 289,000
Slide 115-

Summary Started on FOLFIRONIOX plus pegfilgrastim Had a very good partial response Tolerated treatment very well
Slide 116-

Summary Continued After 5 months oxaliplatin was dropped because of worsening neuropathy (Grade 2) and fatigue After 9 months of treatment disease started to progress in the liver and developed small ascites CEA was rising ECOG PS was 1-2 Fatigue 5 out of 10 (still working) Neuropathy down to grade 1
Slide 117-

Thank You! Questions?
Slide 118-

Provided by MediCom Worldwide, Inc. Not an official event of the 2016 Gastrointestinal Cancers Symposium. Not sponsored or endorsed by any of the cosponsoring organizations of the 2016 Gastrointestinal Cancers Symposium. Supported by an educational grant from Celgene Corporation