American Association For Cancer Research/ONS Bench To Bedside .

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American Association for CancerResearch/ONS Bench to Bedside:Immunotherapy: Think Smarter, Treat BetterJaruska Naidoo, MBBChAssistant Professor of OncologySidney Kimmel Comprehensive Cancer Centerjnaidoo1@jhmi.eduKey Session Takeaways1. The adaptive immune system, and in particular T cells,can be used as a powerful tool to elicit an immune response against tumor cells.Joanne Riemer, RN, BSNResearch Oncology NurseJohns Hopkins UniversityJriemer3@jhmi.edu2. Biomarkers for response, response evaluation, and kinetics, as well as side effects of immunotherapy are uniqueto this group of agents. With regard to immune-relatedtoxicity, points of consideration include (a) always suspectand autoimmune toxicity, (b) rule out competing diagnoses (e.g., infection, disease progression), (c) identify thetoxicity (e.g., diarrhea vs. colitis), and (d) grade the toxicity.3. Converting bench discoveries to clinical advances requires the conduct of a well-designed and efficiently runclinical trial. This requires the coordination of a strongteam, including providers, program managers, researchnurses, office staff, and data coordinators. Roles andresponsibilities overlap, and the quality of the research isaffected by all team members.PowerOncology Nursing Society 42nd Annual CongressMay 4–7, 2017 Denver, CO1

ONS 42nd Annual CongressImmunotherapy for Cancer:From Bench to BedsideJarushka Naidoo, MB BCH; Joanne Riemer, BSN RNDepartment of OncologySidney Kimmel Comprehensive Cancer Center at Johns Hopkins UniversityOncology Nursing Society 2017Plenary SessionDisclosures (JN)Disclosures (JR)Consulting:Bristol zenecaMerckHonoraria:Bristol l Myers-Squibb,Astrazeneca/MedImmuneMerckResearch otherapy: Bench to BedsideOutline Brief Introduction to Cancer Immunotherapy Bench Discoveries Bedside Applications Behind the Scenes of a Clinical Trial The Role of the Research Nurse A Bench to Bedside Story Future DirectionsPower1

ONS 42nd Annual CongressThe Human Immune SystemThe Ultimate Anti-cancer Therapy? Specificity: virtually infinite antigen recognition Adaptability: based on tumor genetic & epigenetic changes Memory: durable responses even after drug discontinuation Universality: potential anti-tumor effect regardless of tumor typeTumor Types with Objective Response to Anti-PD-1/PD-L1MelanomaNon-small cell lung carcinomaUrothelial carcinomaHead and Neck carcinomaRenal Cell carcinomaMerkel Cell carcinomaMSI-high Colorectal carcinomaBiliary Tract carcinomaOvarian carcinomaBreast carcinomaAnal carcinomaMesotheliomaGastric adenocarcinomaHogkins LymphomaHepatocellular carcinomaNaidoo et al, Ann Transl Med 2016Bedside ApplicationsAre all PD-L1 tests created equal?AssayPatient selectionCut-off’s used in TrialsNivolumab28-8noneTumor cells: 1%, 5%Pembrolizumab22C3Tumor cells 50%Tumor cells: 1%, 5%, 50%AtezolizumabSP142?Tumor cells; 1%, 5%, 10%Immune cells: 1%, 5%, 10%DurvalumabSP263?Tumor cells 25%Avelumab73-10?Tumor cells: 1%, 5%, 10%Immune cells: 10%Tsao et al, ESMO 2016Bedside ApplicationsNext Steps for PD-L1 TestingPD-L1 expression:- Core needle biopsy/Excisional biopsy/Resected tissue- FFPE tissue: at least 100 tumor cells- PD-L1 IHC 22C3 pharmDx (Dako)- Role for PD-L1 testing on cytologysamples unknownATLAS of PD-L1 testing in NSCLC- Blueprint phase 2 project- Validation of phase 1 in differentsample types(resection, biopsy, cytology)- inter-observer concordance among20 pathologists- Compare needle biopsy vs. resectionsample vs. cytology in same patientReck et al, N Engl J Med 2016; Tsao ESMO 2016Power2

ONS 42nd Annual CongressBedside ApplicationsUnique Response Kinetics with Immune Checkpoint BlockadeImmune-related Response Criteria (irRC)- Characterize atypical responses, seen in 5-10% cases- Patients with melanoma treated with ipilimumab (phase II program)- irRC (SD PR) had comparable outcomes to RECIST 1.1 (SD PR)- Suspected radiologic progression reassessed with CT 4weeks after initial CTKey DifferenceRECIST 1.1irRCTumor measurementUnidimensionalBidimensionalTarget lesionsMaximum 5Maximum 15New lesionProgressive disease10 visceral and 5 cutaneous lesions may be added to the sum of theproducts of the 2 perpendicular largest diameters of all index lesionsComplete ResponseDisappearance of all target and non-target lesions; no new lesions; LN 10mm short axisPartial Response 30% decrease frombaselineProgressive Disease 20% 5mm absoluteincrease in tumor burdenStable Disease 50% decrease from baseline 25% increase in tumor burden. New lesions added to calculationNeither progressive disease nor partial responseWolchok et al, Clin Cancer Res 2009Hodi et al, J Clin Oncol 2016Bedside ApplicationsUnique Response Kinetics with Immune Checkpoint Blockade Patients with melanoma on KEYNOTE-001 (2 or 10mg/kg pembrolizumab, n 655)Patients assessed by both RECIST 1.1 and central irRC, imaging 28 weeks (n 327) Early pseudoprogression: 25% in tumor burden at week 12, no PD at next scanDelayed pseudoprogression: 25% in tumor burden post week 12, no PD next scanHodi et al, J Clin Oncol 2016Bedside ApplicationsPseudoprogressionRegimen/TrialPrimary Response CriteriaORRResponse CriteriairRCEval Patients ORRTumor TypePatientsAddit. ResponsesMultipleMultipleMelanomaNSCLC (squam)Renal %RECIST 1.0RECIST 1.0mWHORECIST 1.1RECIST 1.1RECIST 1.1NRNRNRNR168NRNRNRNRNR23%NRNR8 additional4 additionalNRNR10 additionalMelanoma11738%RECIST 1.113537%NRMelanomaMelanoma41115740/28%*26%RECIST 1.1RECIST IST 1.1RECIST 1.1NRNRNRNRNRNRNivolumabBrahmer (2012)Topalian (2012)Wolchok (2013)Rizvi (2015)Motzer (2015)Weber (2015)LambrolizumabHamid (2013)PembrolizumabHodi (2013)Robert (2015)AtezolizumabHerbst (2013)Powles (2015)NR not reported, mWHO modified WHO criteria, squam squamous, eval evalUable, addit additional, ORR Objective ResponseRate, *Ipilimumab-naïve/pre-treated,Chiou et al, J Clin Oncol 2016Power3

ONS 42nd Annual CongressBedside ApplicationsManaging the Side Effects of ImmunotherapyThe patient continues therapy with subsequent shrinkage of all tumorlesions. After 3 months of pembrolizumab, he reports a new dry coughand shortness of breath. The chest CT scan is below.What is the possible causes of this clinical scenario?A.B.C.D.Lung infectionProgressive metastatic diseasePneumonitisAll of the aboveBedside ApplicationsManaging the Side Effects of Immunotherapy Inflammatory processes can affect anyorgan system Distinct from chemotherapy side effects Evaluation and management areunique May be exacerbated by underlyingautoimmune conditions/presence ofautoantibodies Patients with autoimmune conditionsnot requiring 10mg dailyprednisone/equivalent may receivetherapy1. Always suspect an autoimmunetoxicity2. Rule out competing diagnoses(?infection ?progression)3. Identify the toxicity(diarrhea vs. colitis)4. Grade the toxicityNaidoo et al, Ann Oncol 2015Bedside ApplicationsPneumonitis ChallengesHow do we diagnose pneumonitis?How do we manage it?Grade 1Close observationGrade 2Drug With-holdingOral Steroid Taper over 4-6 weeksGrade 3-4Discontinue ImmunotherapyIV Steroid, Oral Steroid Taper if improvesOther Immunosuppression if worsens, 48hrIs this: Infection? Progression? Pneumonitis?PowerWhat are the outcomes with treatment?4

ONS 42nd Annual CongressBedside ApplicationsPneumonitis ChallengesCOP-like(n 5)Ground-GlassOpacities (n 10)HyperSensitivity (n 2)NOS(n 4)Interstitial(n 6)Associated with: NSCLC histology (p 0.03), Immunosuppressive Therapy (p 0.06)Naidoo et al,J Clin Oncol 2016Bedside ApplicationsPneumonitis Management AlgorithmGrade1Asymptomatic,Radiologic changesonly Radiologicimaging(High resolutionCT chest)2 Microbialassessmentwhere necessaryMild/moderate newsymptoms3-4Severe/lifethreatening newsymptoms orworsening hypoxiaManagementInvestigations ConsiderPulmonary/Infectious DiseasesConsults andBronchoscopy Consider Holdimmunotherapy Monitor for symptoms every 3daysFollow-up Repeat CT every cycle If develops symptoms, treatas higher grade Withhold immunotherapy Monitor for symptoms daily Oral prednisone 1mg/kg/dayor equivalent If improves to Grade 1 within3 days of supportive care,resume immunotherapy atnext dose If persistent beyond 3 days,discontinue immunotherapy After symptoms improve,taper steroids over 1 month Discontinueimmunotherapy Hospitalization IV methylprednisolone2-4mg/kg/day or equivalent Prophylactic antibiotics After symptoms improve to Grade 1 or baseline, tapersteroids over 6 weeks If worsens in 48 hoursconsider additionalimmunosuppression (infliximab,cyclophosphamide,mycophenolate mofetil)Naidoo et al, Ann Oncol 2015Behind the Scenes of a Clinical TrialThe Stages of Drug Development Bench: pre-clinical phase Clinical phase: sponsor applies to FDA forinvestigational new drug (IND). The nextsteps are clinical phases that may take yearseach Manufacturer applies for new drugapplication. FDA approval: BedsidePower5

ONS 42nd Annual CongressBehind the Scenes of a Clinical TrialThe Clinical SettingSidney Kimmel Comprehensive Cancer Center at Johns Hopkins University Missions of a Comprehensive Cancer Center– Research– Education– Patient CareMain campus (Downtown Baltimore):– 8 In-patient oncology units/Oncology ICU– Outpatient infusion area treats 200 patients/day– Radiation Oncology– 25% of patient population participate in clinical trials– Access to specialist care in medical and surgical specialtiesOther Oncology Campuses: JH Bayview, JH GreenSpring Station; JH SibleyBehind the Scenes of a Clinical TrialThe Clinical Research TeamStudy Site Primary investigator Sub-investigators Program managers Lead Research Nurse Research Nurses Lead study coordinator Office support staff Administration Team- Infusion nurse- Phlebotomist- PharmacistSponsor: Pharmaceutical company,Cooperative Group,Government AgencyPrimary Institution– Medical Monitor– Study Monitors– Central Labs– Radiology– Pathology– Data managers– StatisticiansBehind the Scenes of a Clinical TrialOncology Research Teams at JHH By Disease-Specialty– Thoracic Oncology (Lung/Head and Neck)– Breast Cancer– Gastrointestinal Cancers– Genitourinary Cancers– Hematologic Malignancies– CNS Malignancies By Trial Type– Phase I– Tumor ImmunologyPower6

ONS 42nd Annual CongressRole of the Research NurseMissions of the Cancer CenterResearch Learn and interpret the study protocol Review and prepare key documents (e.g. lab manual)Education Educate patient on study schedule/protocolEducate administration team on study schedule/protocolConsent patient to the studyScreen patient eligibility for the studyPatient Care Manage patient while on study: toxicitiesCommunicate with patient, study team and sponsorDocument patient managementRole of the Research NurseLearning the ProtocolPurpose of the Study Phase of protocol: Phase I/II/III/IV Objectives Drugs to be evaluatedWhich Patients are Suitable for the Study Inclusion & Exclusion CriteriaStudy Schedule How often study drug(s) are givenSamples to be collectedTests & Imaging requiredData to be collectedRole of the Research NurseStages of a Clinical TrialStart of the Study Patient Recruitment Informed Consent Screening for Eligibility Study EnrollmentStudy Treatment Oversee treatment on scheduleFollow-up Phase/Completion Follow-up/Surveillance CommunicationPower7

ONS 42nd Annual CongressBench to Bedside StoryPhase I Trial CA209-001:Open-label multicenter, multi-dose, dose-escalation study BMS-936558/MDX-1106 in Subjects with Selected Advance or Recurrent Malignancies– Opened in 2008 to 5 disease group and evaluated 5 dose levels– 2011 Expanded NSCLC in 3 dose levels– Experience with monotherapyBench to Bedside StoryNSCLC Expansion Cohorts Enrolled & on study for 2 years Enrolled & progressed 4 months Enrolled & progressed 4months 2 yrs Died of pneumonitis at 1 monthBench to Bedside StoryManaging ToxicitiesNew SymptomDyspnea with activityGrade 2O2 sat 93% at rest, 90% withwalkingEvaluate: High resolution CT Consider:-Pulmonary consult,-Bronchoscopy(Other specialist or super user)Results: New GGO, tumor decreasedin size Bronchoscopy negative forinfection Grade 2 pneumonitis If improvement set up taperschedule over 4-6 weeks withfollow-up visits & repeat CT in2-3 weeksAlgorithmDifferential diagnosis Infection Pulmonary embolism Pneumonitis Disease progression OtherManagement PowerInitiate corticosteroids at 12 mg/kgConsider resuming I-OFollow up visit in 3-5 days.If no improvement consideradditionimmunosuppressant8

ONS 42nd Annual CongressBench to Bedside StoryProceeding to Phase IIIPhase III Trials: CA209-017 & 057:An Open-label Randomized Phase III Trial of BMS-936558 (Nivolumab)versus Docetaxel in Previously Treated Advanced or MetastaticSquamous & Non-squamous Cell Non-small Cell Lung Cancer– Opened in 2012– Quickly enrolled– Opdivo FDA approved for 2nd line NSCLC in 2015Bench to Bedside StoryToxicities in Phase III lated AEs:All & Grade Docetaxel88%54%Keynote010Pembrolizumab 63%2 mg/kg dose13%Docetaxel81%35%Most CommonTreatment-Related AEsFatigue – 16%Appetite – 11%Asthenia – 10%Neutropenia – 33%Fatigue – 33%Nausea 23%Fatigue – 16%Nausea – 12%Appetite – 10%Neutropenia – 31%Fatigue – 29%Nausea – 26%Fatigue – 20%Pruritis – 11%Appetite – 11%PneumonitisRateAll – 5%Gr 3/4 – 0%Fatigue – 25%Diarrhea 18%Appetite – 16%0%0%All – 3%Gr 3/4 – 1%0%All – 5%Grade 3-5 – 2%2 deathsBrahmer et al, NEJM 2015; Borghaei, et al NEJM 2015; Herbst, et al Lancet 2015; Naidoo, et al Ann Oncol 2015Bench to Bedside StoryToxicities in combination trialsTrialAgentKeynote 021 ChemotherapyAllTreatment-Related AEs:Grade 1-2: 65%Grade 3: 19%Grade 4:3%Most CommonGrade1-2Treatment-Related AEsFatigue 40%Nausea 44%Anemia 39%Grade 3-4Pembrolizumab Grade 1-2: 54% Chemotherapy Grade 3: 31%Grade 4:7%Fatigue 61%Nausea 56%Anemia 20%2%12%CheckMate012Nivolumab IpilimumabGrade 1-2: 38-45%Grade 3-4 : 33-37%Rash 13-24%Diarrhea 18-21%Elevated Amylase 13%Elevated lipase 8%Pneumonitis 3-5%3-5%3%3-5%3-5%VEM1-IpiVemurafenibfollowed byIpilimumabAnyGrade 3:Grade 4:Rash 28%Diarrhea 17%AST increase 9%9%5%3%43%27%3%Langer, et al Lancet 2016; Hellmann, et al Lancet 2017; Amin et al, JITC 2016Power9

ONS 42nd Annual CongressFuture DirectionsTranslating Research into Experience Efficacy of I-O is evidence-based, further trials ongoing Managing irAE’s based on experience; further study requiredLessons Learned: Pre-screen those not suitable for I-O irAE’s (immune related adverse events)– Recognizing– Grading Consider medical specialist consult to evaluate suspected irAE Educate patient and caregivers––––I-O targets the immune system to fight cancerAn activated immune system may cause inflammation in any organSide effects of I-O are different from chemotherapyIn emergency, recommend ED physician call oncologistFuture DirectionsEducating ProvidersFuture DirectionsEducating Patients and CaregiversPower10

ONS 42nd Annual CongressFuture DirectionsEducating Patients and CaregiversFuture DirectionsEducational Resources ONS.org– Immunotherapy in Cancer Treatment (4 hour online course)– Immunotherapy community: An opportunity to post questions Share resources Teach others SITC: Society for Immunotherapy of Cancer ICLIO: Institute for Clinical Immuno-OncologyFuture DirectionsThe Cancer Moonshot InitiativeVice President’s OfficeCancer MoonshotFederal Task ForceNCI/NIHNational Cancer Advisory Board“Blue Ribbon Panel”Working GroupsPower11

ONS 42nd Annual CongressFuture DirectionsBlue Ribbon Panel Working Groups 7 Groups (12-15 members: researchers, clinicians, industry, advocates):1. Cancer Immunology2. Clinical trials3. Implementation Science and Data Sharing4. Tumor Evolution5. Precision Medicine6. Prevention and Early Detection7. Pediatric cancer Aim: recommend 2-3 major scientific opportunities poised for acceleration Working Groups met weekly to discuss and formulate recommendationscancer.gov/brpBlue Ribbon Panel Report 2016Future DirectionsBlue Ribbon Panel Recommendations1. Directly Engage Patients2. Create a National Cancer Data Ecosystem3. Create a Human Tumor Atlas4. Developing of New Enabling Technologies5. Create a Cancer Immunotherapy Translational Network6. Identify Therapeutic Targets to Overcome Drug Resistance7. Fusion Oncoproteins in Pediatric Cancer8. Symptom Management Research9. Precision Prevention and Early Detection10. Retrospective biospecimen analysis in patients who received standard Txcancer.gov/brpBlue Ribbon Panel Report 2016Colleagues and CollaboratorsJHH Thoracic Oncology ProgramJulie R. Brahmer, MDDavid E. Ettinger, MDPatrick M. Forde, MDRonan J. Kelly, MDChristine L. Hann, MDJosephine Feliciano, MDKristen Marrone, MDGeorgeanne Jambeter, NPSarah Sagorsky, PAValerie Rowe, NPAmy Vance, NPClare Ferrigno, NPJHH Thoracic Oncology ResearchProgramJessica WakefieldRachel LevyCaitlin JoffeAngela LigginsChris HarrisPowerJHH Cancer Immunology ProgramElizabeth M. Jaffee, MD PhDEvan Lipson, MDTianna DausesJHH Bloomberg Kimmel Institutefor Cancer ImmunotherapyDrew M. Pardoll, MD PhDSuzanne Topalian MDLeisha Emens, MD PhDLei Zheng, MD PhDDung Le, MD PhDJHH Oncology Research NursingNancy Tsottles, RNAlice Pons, RNTrish Brothers, RNMatthew Lindsley, RNPawla Meikue, RNBarbara Coleman, RNPeggy Fitzpatrick, RNMikaela Olsen, RNJHH Oncology ResearchCoordinatorsPritish JohnRose SebreeKimberley BaytopsBhavika PatelRobert WagnerAnna SmithChanice Barkley-SomervilleIiasha BeadlesRobin StewartKai Pollard12

ATLAS of PD-L1 testing in NSCLC - Blueprint phase 2 project - Validation of phase 1 in different sample types (resection, biopsy, cytology) - inter-observer concordance among 20 pathologists - Compare needle biopsy vs. resection sample vs. cytology in same patient Reck et al, N Engl J Med 2016; Tsao ESMO 2016 Bedside Applications

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