The Fight AgainstPancreatic CancerApril 2016Efrat Dotan, M.D.Assistant ProfessorDepartment of medical oncologyFox Chase Cancer CenterOverview Epidemiology/Biology Diagnosis Early stage disease Surgical treatments Chemotherapy/Radiation treatments Advanced stage disease Chemotherapy treatments Future Research1

PancreasEpidemiologySiegel et al, 20162

Epidemiology Estimated 53,000 new cases diagnosedyearly in the US. Males- 27,670 Females – 25,400 Pancreatic CancerRepresent 3% of allnew cancer cases inthe U.S.3%Siegel et al, 2016SEER Cancer Statistics Review, 1975-2012, National Cancer InstituteEpidemiologyPancreatic Cancer is most frequently diagnosedamong people aged 65-74SEER Cancer Statistics Review, 1975-2012, National Cancer Institute3

Risk factors Smoking Overweight Personal history of diabetes Personal history of chronicpancreatitis – inflammation to thepancreas Family history of pancreatic cancer Hereditary conditionsSEER Cancer Statistics Review, 1975-2012, National Cancer InstitutePancreatic cancer staging4

Pancreatic cancer1975-19775 yearsurvival3%1987-19894%2005-20118%Siegel et al, 20165

DiagnosisChallenges in Early Diagnosis: Usually there are no symptoms orsigns in early stages of the disease. Many of the signs and symptoms arenot specific (weakness, abdominaldiscomfort, loss of appetite) The pancreas is hidden behind otherorgans and hard to examine.Siegel et al, 2016Signs & Symptoms Asthenia (weakness) – 86%Weight loss and Anorexia (no appetite)– 85%Abdominal pain – 79%Epigastric pain (stomach) – 71%Dark urine – 59%Jaundice – 56 %Nausea – 51%Back pain – 49%Diarrhea- 44%Vomiting – 33%Steatorrhea (fatty stools)– 25%Thrombophlebitis – 3%Hepatomegaly (large liver) – 39%Epigastric mass – 15%Ascites (abdominal fluid) – 5%6

DiagnosisBlood tests: Elevation of liver function tests. Elevation of tumor marker – CA19-9Imaging: Ultrasound CT Scan MRI PET-CT7

DiagnosisInvasive tests: ERCP EndoscopicUltrasound8

CT guidedbiopsy forpatients withmetastaticdisease.Pathology9

Treatment – Early stage Only curative option is surgicalresection. Removal of the gallbladder, bileducts, part of the duodenum andhead of the pancreas. Modification to the surgery havebeen developed to decreasemorbidity. Minimally invasive techniques arefeasibleAllen OldfatherWhipple (1881- 1963)10

Current peri-operative mortality is approximately 4%.Winter JM. et al. Annals of surgery 201211

Whipple surgeryBilimoria K. et al. Annals of surgery 2007Whipple surgeryBilimoria K. et al. Annals of surgery 200712

Pathologic FactorsWinter et al. 2006Postoperative CA 19-9Berger A. 200813

Adjuvant therapyCONKO study:Collaborative, multi-institutional, randomized,controlled trial have demonstrated benefit tochemotherapy with gemcitabine for 6 months aftersurgery.Oettle et al. JAMA. 2007Adjuvant therapyChemo-radiation:Multiple studies have shown some improvement withthe addition of chemo/radiation to the post operativetherapy.There is an ongoing debate regarding the benefit.In the US often used.Herman. JM J Clin Oncol. 200814

Adjuvant therapyMeta-analysis: Evaluation of all studied performed withchemotherapy with and without radiation, foundchemotherapy with Gemcitabine or Fluorouracil to bethe most effective in reducing mortality by about 1/3.Wei-Chih Liao et al. Lancet Oncology2013Adjuvant therapyOngoing clinical research: 135 studies listed in for adjuvanttherapy for resected pancreatic cancer. Large studies in Europe and the US using moreaggressive chemotherapy regimens in comparisonto single agent gemcitabine.15

Borderline resectable Definition varies – mostly in cases with largetumors in close proximity to local bloodvessels. Tumors encasing the vessel were in thepast considered unresectable. However,with vascular re-construction some of thesecases can go to surgery. Tumor shrinkage with chemotherapy orradiation before surgery used more often –Neoadjuvant therapy.Neoadjuvant therapy About 30-40% of patients are candidates. Optimal therapy is controversial. Goal – Shrink the tumor and allow for aresection.Study# patientsRegimen# of patients withsurgeryVasile E. 201215FOLFIRINOX RT5Gunturu K, 201316FOLFIRINOX2Marthey L, 201577FOLFIRINOX RT25Blazer M, 201543FOLFIRINOX RT19Mellon E, 2015159FOLFIRINOX Gem/Abraxane RT59Sadot E, 2015101FOLFIRINOX RT1616

Neoadjuvant therapyRadiation: Controversial results regarding the benefit ofradiation from clinical trials. Often added to the regimen. Benefit:– Local control– Good tolerance– Better chance of gettingThe treatment pre-op.Metastatic diseaseGoals:- Drug delivery to allsites.- Palliative therapy.- Prolonging survival.- Improving quality oflife.17

Available agents nOxaliplatinOnivydeClinical trialsAdvances 1985199019952000200520102015Best supportive care5-FUGemcitabineCapecitabineConclusion from multiple papers (1990s - early 2000s):“The only justification for subjecting a patient withadvanced pancreatic carcinoma to chemotherapy is theentry of such a patient into a clinical research trial that atleast provides the hope that something of value may beaccomplished.”18

Gemcitabine approved in 1997 for first-linetherapy of advanced pancreatic cancerClinical benefit: 23.8% vs. 4.8%The next phase .Phase IIDrugs testedGemcitabine /- cisplatin# patients192ResultsNo differenceGemcitabine /- oxaliplatin313No differenceGemcitabine /- 5-FU322No differenceGemcitabine /- capecitabine)533No differenceGemcitabine /- pemetrexedGemcitabine /- irinotecan565360No differenceNo differenceGemcitabine /- exatecan349No differenceNone demonstrated statistically significantimprovement in survivalBoeck and Heinemann, 2008.19

The next phase .Phase IIIDrugs tested# PatientsResultsGemcitabine /- Marimastat239No differenceGemcitabine /- Tipifarnib688No differenceGemcitabine /- Erlotinib569Gemcitabine /- Bevacizumab 602Minimalimprovement withErlotinibNo differenceGemcitabine /- Cetuximab735No differenceGemcitabine /- Axitinib632No differenceBramhall et al, 2002; Van Cutsem et al, 2004; Moore et al, 2007; Kindler et al, 2010;Philip et al, 2010; Kindler et al, 2011.PRODIGE4/ACCORD11Gemcitabine (n 171)1,000 mg/m2 weekly x 7 of 8, then weekly x 3 of 4MetastaticPancreatic CancerFOLFIRINOX (n 171)Oxaliplatin 85 mg/m2Irinotecan 180 mg/m2leucovorin 400 mg/m25-FU bolus 400 mg/m2, then 2,400 mg/m2infusional over 46 hoursConroy et al, 2011.20

Median survival- 11.1m vs. 6.8mConroy et al, 2011.CA 19-9 Trend while on FOLFIRINOX21

Pre - treatmentPost - treatmentImprovement in quality of life measures:- Improvement in symptoms – fatigue, pain, anorexia- Physical and cognitive function- Global Health ScoresGourgou-Bourgade et al, 2013.22

EventFOLFIRINOX(n 171)Gemcitabine(n 171)P valueNeutropenia45.7%*21.0% a 17.8%NSVomiting14.5%8.3%NSDiarrhea12.7%1.8% 0.001Sensoryneuropathy9.0%0.0% 0.001Conroy et al, 2011.MPACT studyPancreatic cancer(locally advancedor metastatic)N 861Gemcitabine1,000 mg/m2weekly x 7 of 8 (cycle 1),then weekly x 3 of 4 (cycle2 and subsequent cycles)Gemcitabine 1,000 mg/m2plusnab-paclitaxel 125 mg/m2weekly x 3 of 4Von Hoff et al, 2013.23

Von Hoff et al, 2013.Safetynab-P Gem(n 421)Gem(n 402)Grade 3 Hematologic AE, a 132716912Pts Who Received Growth Factors, %2615Febrile Neutropenia, b %31Grade 3 Nonhematologic AE in 5% Pts, %FatiguePeripheral Neuropathy cDiarrhea171767 11Grade 3 NeuropathyTime to Onset, median daysTime to Improvement by 1 Grade, median daysTime to Improvement to Grade 1, median daysPts Who Resumed nab-P, %14021294411329---Preferred TermbaBased on lab values; b Based on investigator assessment of treatment-related events;Von Hoff et al, 2013.cgrouped termVon Hoff et al., ASCO GI 2013 LBA148 4824

CA 19-9 Trend while on Gemcitabine/AbraxaneNanoliposomal IrinotecanWang-Gillam A. Lancet, 2015.25

Advances in 2 decades1985199019952000200520102015Best supportive care5-FUGemcitabineCapecitabineTarcevaIrinotecan 5FU - FOLFIRINOXOxalipatin GemcitabineNab-Paclitaxel 5FUOnivydeOlder patientsOverall survival by age at diagnosisOverall survival and number of chemotherapy agentsAge 65Age 65Vijayvergia, N. J Geriatr Oncol, 2015.26

Clinical trialsOngoing clinical research: Over 200 studies listed in formetastatic pancreatic cancer. Most studies involving combination ofGemcitabine/abraxane Drug X. At FCCC – 3 ongoing studies with Gemcitabine Abraxane Drug X. Wee Inhibitor AZ1775 Wnt inhibitor Vantictumab Wnt inhibitor IpafriceptImmunotherapyGVAX PancreasIrradiated, whole-cell tumor vaccineGVAXCRS-207 (Aduro Biosciences)Live-attenuated Listeria monocytogenes Dendritic CellGM-CSFPotent activation of innate and antigenspecific immune responseΔactAΔinlBTumor antigensAntigen uptake& ActivationTumor CellDestructionT CellDungLe et al. JCO 2014Le et al, T.2014.27

Phase 2 StudyCY/GVAXCRS-207Arm A, n 6024 months follow-upSubjects withmetastatic pancreaticcancer; failed orrefused chemotherapyRR20-wk treatment Course*: 6 doses, q3w2:1Arm B, n 30randomization* Additional coursesif clinically stable24 months follow-upo Prior phase I trial of CRS-207 showed markedly improved survival(17 months) in 3 pancreatic cancer patients who had previouslyundergone ‘boost’ with GVAX vaccine.o Primary objective: overall survivalCy cyclophosphamide; GVAX GVAX pancreas vaccine.DungT. Le et al. JCO 2014Le et al, 2014; Le et al, 2012.Overall SurvivalMedian OS, Per-protocol set (subjectsreceiving at least one dose of CRS-207):Arm A: 9.7 monthsArm B: 4.6 monthsp 0.0167, HR 0.5290Cy cyclophosphamide; GVAX GVAX pancreas vaccine.DungLe et al. JCO 2014Le et al, T.2014.28

Phase II ECLIPSE TrialMetastatic pancreatic cancers/p 1 prior lines of rx(Stratified: 2nd line vs. 3rd-plus line)GVAX/Cy (weeks 1, 4) CRS-207 (weeks 7, 10, 13,16)CRS-207 (weeks 1, 4,7, 10, 13, 16)Single-agentchemotherapy(Physician’s choice)Primary endpoint overall survivals/p status post; Cy cyclophosphamide; GVAX GVAX pancreas NCT02004262.Summary There is real optimism in the treatment of thisdisease!! Survival has clearly improved for metastaticdisease and localized disease. Renewed interest in drug development hasinvigorated clinical trials. Enrollment in clinical trials is highlyencouraged!29

Over 170 pancreatic cancer specific studies listed in Clinical Trial Finder. Over 115 pancreatic cancer specific studies listed in Clinical Trial Finder formetastatic pancreatic cancer.“We must engage an army of heroes in the fightagainst pancreatic cancer so that we can know it,fight it and end it”Lisa Niemi Swayze, Chief Ambassador of HopeThank you30