Treatment Of Immunotherapy Toxicities
Treatment ofImmunotherapy ToxicitiesMallika P. Weant, PharmD, CPPAugust 3, 2018
DisclosureI have no disclosures to reportrelevant to the content of thispresentation
Objectives Describe the mechanism of action ofcheckpoint inhibitor therapies andlist the currently approved agents Recognize common and seriousimmune-related adverse events anddescribe management options
Timeline for Cancer TreatmentsSurgeryRadiationtherapyApproachCut outtumor cellsto stopgrowth andpreventspreadUse highlyconcentratedx-rays or radioactive isotopesto kill cancercellsUse cytotoxicdrugs to killor inhibitcancer cellgrowthSince1800sEarly 1900sLate 1940s2000s2010sHighly toxicand may noteradicate alltumor cells,leading tohighrecurrenceratesLimitedtumor typeseligible; Highefficacy butshortdurability notleading totumorrecurrenceVariableefficacy indifferenttumor types;differenttoxicityprofiles thanother agentsLimitationsInaccessibleLimited efficacytumorif metastaticlocation;spread; May beLimitedharmful toefficacy ifnearby apted from: erapyTargetedtherapyImmunotherapyUtilize theInterfere withimmunea mechanismsystem’srequired forinnate abilityor thatto recognizesupportsand eliminatetumor growthtumor cells
Types of ImmunotherapyNon-specific AntibodiesTargeting ImmuneSystem CheckpointsCancer VaccineTherapy IL-2 IFN-alpha Immunomodulating drugs Tumor infiltrating lymphocyte therapy Lymphokine activated killer cell therapy Cytokine induced killer cell therapy Dendritic cell cytokine induced killer cell therapy Genetically engineered T-cell therapy Naked Conjugated (radio-labeled, chemo-labeled) CTLA-4 PD-1 PD-L1 Tumor cell vaccines Antigen vaccines Dendritic vaccines Vector-based vaccinesCTLA-4: cytotoxic T-lymphocyte–associated antigen-4PD-1: programmed cell death protein 1PD-L1: programmed cell death ligand 1SRM J Res Dent Sci 2015;6:175-80.
Current PD-1and PD-L1 Inhibitors PD-1: trans-membrane protein on T cells,B cells and NK cells Nivolumab (Opdivo ) Pembrolizumab (Keytruda )PD-L1: PD-ligand which is found on thesurface of tumor cell Atezolizumab (Tecentriq ) Avelumab (Bavencio ) Durvalumab (Imfinzi )https://www.accessdata.fda.gov/scripts/cder/daf/
PD-1/PD-L1 Therapies andApproved IndicationsMelanomaMerkel alCancerRenal CellCarcinomaPD-1 der/daf/European Journal of Cancer 54 (2016) 139-148.Non-SmallCell LungCancerHead andNeckSquamousCell Cancer
Mechanism of Action:PD-1 and PD-L1 Inhibitors Tumor microenvironmentcontains overexpression ofimmunosuppressivemolecules PD-1 PD-L1 CTLA-4 Binding of PD-1 to PD-L1prevents T-cell activation Blocking binding of PD1/PD-L1 with a checkpointinhibitor, cytotoxic T cells arereactivated apoptosisNational Cancer Institute 2015Nat Rev Urol. 2016 July ; 13(7): 420–431.
Mechanism of PD-1 and PD-L1 zolizumabAvelumabDurvalumabNat Rev Urol. 2016 July ; 13(7): 420–431.
Physiological Implicationsof PD-1/PD-L1 Therapies PD-1/PD-L1 interaction between malignant cells andT cells allows tumor to evade immune response PD-1 and PD-L1 inhibitors bind to PD-1/PD-L1 immune response Reactivation of tumor-specific cytotoxic T lymphocytes Increased T cell proliferation and activity Pro-inflammatory reactionsGenerates atypical tumor responses resulting indysimmune toxicities Immune-related adverse events (irAEs)European Journal of Cancer 54 (2016) 139-148.Annals of Oncology 27 (2016) 559–574.
Immune-relatedAdverse Events (irAEs) Auto-immune toxicity to normal tissue due toimmune activation May affect any organ system Grade 1 - 2: mainly affect skin and gut Grade 3 - 4: mainly affect GI tractSafety profiles vary per tumor typeIncidence All grades: 70% Grades 3 - 4: 7 – 19%Discontinuation rate of PD-1/PD-L1 due to irAEs 3 – 8%European Journal of Cancer 54 (2016) 139-148.Asia Pac J Clin Oncol. 2017 Aug;13(4):277-288.
Immune-related Adverse Events(irAEs) Toxicities do not appear to be dose-related,cumulative No relationship between symptom onset andefficacy/disease regression Timeline of symptom onsetSkinToxicityWeeks2-4GIToxicityEuropean Journal of Cancer 54 (2016) 139-148.J Clin Oncol 21 (2012) 30: 2691-7.Asia Pac J Clin Oncol. 2017 / (accessed 9/2017)Weeks4-6HepatotoxicityWeeks8- 12EndocrineToxicitiesWeeks12-24
Immune-related Adverse Events(irAEs)Annals of Oncology 27 (2016) 559–574.
Organ Systems Affected byPD-1/PD-L1 Skin Gastrointestinal tract Enterocolitis, gastritis, pancreatitis, celiac diseaseEndocrine glands Maculopapular rash, vitiligo, psoriasis, toxic epidermalnecrolysis, drug reaction with eosinophilia and systemicsymptomsThyroid disease, hypophysitis, adrenal insufficiency,diabetesLungs Pneumonitis, pleural effusion, sarcoidosisEuropean Journal of Cancer 54 (2016) 139-148.
Organ Systems Affected byPD-1/PD-L1 Nervous system Liver HepatitisKidneys Peripheral neuropathy, aseptic meningitis, Guillain-Barrésyndrome, encephalopathy, myelitis, meningo-radiculoneuritis, myasthenia gravisGranulomatous interstitial nephritis, lupus-likeglomerulonephritisHematological cells Hemolytic anemia, thrombocytopenia, neutropenia,pancytopeniaEuropean Journal of Cancer 54 (2016) 139-148.
Organ Systems Affected byPD-1/PD-L1 Musculo-articular system Heart Arthritis, myopathiesPericarditis, cardiomyopathyEyes Uveitis, conjunctivitis, blepharitis, retinitis, choroiditis,orbital myositisEuropean Journal of Cancer 54 (2016) 139-148.
Common irAEs withPD-1/PD-L1 Inhibitors Incidence 10% Fatigue Rash, pruritus GI: Nausea, diarrhea, colitis Arthralgia Pneumonitis, pneumonia Hepatitis, increased liver enzymes EndocrinopathiesAnnals of Oncology 27 (2016) 559–574.Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Risk Factors for irAEs Personal/family history of auto-immune diseases Tumoral infiltration Focal immune reconstitution inflammatory syndromeOpportunistic pathogens Psoriasis, lupus, ulcerative colitis, diabetes, etc.Inflammatory reaction against a previous chronic pathogenConcomitant medications and job-related exposures Environmental exposures may increase risk of autoimmunediseasesAnnals of Oncology 27 (2016) 559–574.
How to Manage Patients witha History of Autoimmune Diseases? If autoimmune disease is controlled, provider mayconsider treatment with PD-1/PD-L1 therapy Case reports show autoimmune disease mayremain stable ie. vitiligo – no disease worseningEndocrine deficiencies which are controlled withsubstitutive treatment Treatment decision should weigh risk versusbenefit for individual patient Increased monitoring should occur to preventworsening of autoimmune diseaseAnnals of Oncology 27 (2016) 559–574.
Toxicity ManagementPREVENTMONITOR GI, Hepatic, Renal irAE rapid resolutionSkin, Endocrine irAE gradual improvementAnnals of Oncology 27 (2016) 559–574.ANTICIPATETREATDETECT PhysicalImagingLabs (CBC, CMP,CRP, Coags, TSH)Early onset 2 monthsLate onset 2 months
Immune-related AdverseEvent: Fatigue Most frequently reported irAE with PD1/PD-L1 inhibitor Incidence Anti-PD-1: 16 – 37% Anti-PD-L1: 12 – 24% Usually mild in severity Pathogenesis – poorly understood Rule out other causes – endocrine?Annals of Oncology (2015) 26(12): 2375-91.Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Immune-related Adverse Events(irAEs)Annals of Oncology 27 (2016) 559–574.
Immune-related AdverseEvents: Dermatologic Vitiligo Seen most in patients with melanoma Incidence: 8% of melanoma patients on antiPD-1/PD-L1 therapy Hua and colleagues prospectively followedmetastatic melanoma patients (n 67) onpembrolizumab therapy 25% developed vitiligo Objective response to treatment associated withincidence of vitiligo All patients who developed vitiligo were alive at analysis Median follow-up: 441 daysJAMA Dermatol 2016; 152: 45-51.Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Immune-related Adverse Events:Dermatologic Pruritus Incidence all grades: 13 – 20% Grades 3 and 4 (severe) incidence: 2.5%Management of PruritusMildContinue immunotherapyTreat with high-potency topical steroidsModerateConsider holding immunotherapyTreat with high-potency topical steroids, oral antihistamines(cetirizine, hydroxyzine); dermatology consultationSevereHold immunotherapyTreat with prednisone/methylprednisolone 0.5 – 1 mg/kg/day,GABA agonists (gabapentin, pregabalin);Urgent dermatology consultationNCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018
Immune-related AdverseEvents: Dermatologic Rash Proposed mechanism: blockade of antigen expressedon tumor surface and the dermo-epidermal junction Incidence: 15% of patientsTypes Maculopapular Lichenoid dermatitis Bullous pemphigoid Stevens Johnson Syndrome (SJS) Toxic Epidermal Necrolysis (TEN)JAMA Oncol. 2016;2(10):1346-1353.Annals of Oncology (2015) 26(12): 2375-91.Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Maculopapular Rash:Grading CTCAE Classification Grade 1: macules/papules covering 10% of BSAwith or without symptoms Grade 2: macules/papules covering 10-30% of BSAwith or without symptoms; limiting ADLs Grade 3: macules/papules covering 30% of BSAwith or without symptoms; limiting self-care ADLs Grade 4: papulopustular rash associated with lifethreatening superinfection; SJS or TEN covering 30% of BSA and requiring ICU admissionAnnals of Oncology 28 (2017) (suppl 4): iv119–iv142.CTCAE: CommonTerminology Criteriafor Adverse Events
Management of Skin RashMildContinue immunotherapyUse moderate potency topical steroids, oral antihistamines for itching;Use topical emollients; Avoid irritants, sun exposureModerateConsider holding immunotherapyUse high potency topical steroids and/or prednisone 0.5 – 1 mg/kg/day,oral antihistamines for itching, topical emollientsSevereHold immunotherapyTreatment with high potency topical steroids,Prednisone 0.5 – 1 mg/kg/day (increase if no improvement), treat untilgrade 1 then wean over 4 – 6 weeks;Urgent dermatology consultationNCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018
Immune-related Adverse Events(irAEs)Annals of Oncology 27 (2016) 559–574.
Immune-related AdverseEvents: Endocrinopathies Pituitary Hypophysitis – uncommon Acute symptoms: headaches, photophobia, dizziness,nausea/emesis, fevers or anorexia Non-acute symptoms: fatigue, possible weight lossThyroid Hypothyroidism Hyperthyroidism Proposed mechanism: mediated by T-cells Incidence: 5 – 10% Commonly Grade 1 or 2Routine monitoring, at baseline, then at least monthly (TSH, FT4)Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.NCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018
Immune-related Thyroid Dysfunction ManagementTSHFree T4 (normal) No symptoms, monitorIf symptoms, initiate thyroid replacement (normal) Repeat, if still elevated, refer to endocrinologist (normal) No symptoms, recheck; Check AM cortisol (mayindicate hypopituitarism) No symptoms, monitorIf symptoms, hyperthyroidism: beta-blockers,thyroid antibodies and uptake scan Check AM cortisol (may indicate hypopituitarism)No symptoms, monitorIf symptoms, consider replacement if TSH 10Hypothyroidism ( FT4 with TSH) OR (Normal FT4 with TSH 10) Treatment: levothyroxine 0.5 – 1.5 mcg/kg With hormone replacement, continue anti-PD-1/PD-L1 therapyAdapted from: Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Immune-related AdverseEvents: Endocrinopathies Diabetes mellitus Proposed mechanism: mediated by specific CD8T-cells as blockade of PD-1/PD-L1 pathway occurs Type 1 DM Type 2 DM Loss of beta cells of islets of LangerhansManagement: Steroids Unknown if steroid use can prevent loss of betacells Steroids will contribute to worsening control of bloodglucoseInsulin replacement/regulation of BG restartanti-PD-1/PD-L1 therapyAnnals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Management of HyperglycemiaNew onset hyperglycemia 200 mg/dLand/orHistory of Type II DM with lowsuspicion of DKANew onset fasting glucose 200 mg/dL orRandom BG 250 mg/dL orHistory of Type II DM with fastingBG 250 mg/dLPatient withDKAContinue immunotherapyMonitor serial BG with each dose, diet andlifestyle modifications (if needed, medicaltherapy); Consider endocrine consultationEvaluate patient for DKA If negative, manage as aboveIf positive for DKA workup, see belowHold immunotherapyInpatient management, per institutionalguidelines; Insulin management per inpatientteamEndocrine consultationDKA: diabetic ketoacidosisNCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018
Immune-related Adverse Events(irAEs)Annals of Oncology 27 (2016) 559–574.
Immune-related AdverseEvents: Hepatotoxicity Hepatitis Incidence: Grade5 – 10%3 accounts for 1 – 2% Typicallyasymptomatic Monitor liver enzymes Serumtransaminases, bilirubin atbaseline and prior to each treatment Ifelevated rule-out other causes Considera liver biopsy if necessary fordifferentialAnnals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Management of HepatitisMildIf AST/ALT ULN - 3x ULN, monitor with increased frequencyContinue immunotherapyModerateIf AST/ALT 3 – 5x ULN, hold immunotherapyRecheck AST/ALT every 3 – 5 days, if rising, considerprednisone 0.5 – 1 mg/kg/day, taper over at least 4 weeksSevereIf AST/ALT 5 – 20x ULN, permanently discontinue immunotherapyInitiate prednisone 1 – 2 mg/kg/day, taper over at least 4 weeks, monitorLFTs every 1 – 2 days, hepatology consultationLifethreateningIf AST/ALT 20 x ULN, permanently discontinue immunotherapy andinpatient admission for managementInitiate methylprednisolone/prednisone 2 mg/kg/day, taper slowly astolerated, monitor LFTs daily, urgent hepatology consultationNCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018
Management of Hepatitis Cont’dPatient worsening despite steroid managementIf on PO steroids Change to IV MethylprednisoloneIf on IV steroids Add mycophenolate mofetil 500 – 1000 mg PO bidIf worsens on mycophenolate mofetil Consider addition of tacrolimus* and consult hepatologyJAMA Oncol. 2016;2(10):1346-1353.J Clin Oncol. 2011; 29(9):e237-e240.* Use of infliximab is contraindicateddue to increased risk of hepatotoxicity
Immune-related Adverse Events(irAEs)Annals of Oncology 27 (2016) 559–574.
Immune-related Adverse Events:Gastrointestinal Toxicity CTLA-4 inhibitors anti-PD-1/PD-L1 therapyIncidence Colitis Symptoms Grade 3 – 4: only 1 – 2%Diarrhea nausea/vomiting abdominal painEndoscopic findings Normal mucosa Inflammation Mild erythema Severe inflammation (mucosal friability/ulceration)J Crohns Colitis 11 (2017) (suppl 1): S237.Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Management ofDiarrhea/ColitisGrade 1Consider holding immunotherapyMild: 4 liquid stools/day baseline, no symptoms of colitis;Symptomatic management (fluids, antidiarrheal agents), close monitoringGrade 2Hold immunotherapyModerate: 4-6 liquid stools/day baseline with colitis symptoms not interfering with ADLsInitiate IV methylprednisolone 1 mg/kg/day, convert to prednisone when toleratedIf no response in 2 – 3 days: Increase methylprednisolone to 2 mg/kg/day, consider infliximab*Grade 3/4Grade 3: Discontinue immunotherapy, consider resuming alternative agentGrade 4: Permanently discontinue immunotherapySevere: 6 liquid stools/day baseline with colitis symptoms interfering with ADLsInpatient admission: IV fluids, electrolytes, consult GI service, consider colonoscopyInitiate IV methylprednisolone 2 mg/kg/day, if no response in 2 days, consider infliximab*SteroidTaper For moderate and severe diarrhea: treat until symptomsimprove to Grade 1, then taper over 4 – 6 weeksNCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018JAMA Oncol. 2016;2(10):1346-1353.*Infliximab dosing: 5 mg/kg up to q2weeks
Immune-related Adverse Events(irAEs)Annals of Oncology 27 (2016) 559–574.
Immune-related AdverseEvents: Pulmonary Pneumonitis Anti-PD-1/PD-L1 therapy CTLA-4 inhibitors IncidenceAll grades: 2 – 4% Grade 3 or 4: 1 – 2% Incidence is similar across tumor types and withvarying doseSymptoms may include: new cough, upperrespiratory infection, shortness of breath orhypoxia Rule out disease progression or lung metastases CT Scan can help with differentialJAMA Oncol. 2016;2(10):1346-1353.J Clin Oncol 2015; 33: 2004-2012.Annals of Oncology 28 (2017) (suppl 4): iv119–iv142.
Management of PneumonitisGrade 1Hold immunotherapyAsymptomatic; Monitor and reassess in 1 – 2 weeksWork-up: Chest imaging (CT with contrast preferred or X-ray), pulse oximetryGrade 2Hold immunotherapyPresence of new/worsening symptoms (dyspnea, cough, chest pain); Monitor and reassess every 3 – 7 daysConsider infectious workup, bronchoscopy with BAL, chest imaging; Start antibiotics if infection suspectedInitiate methylprednisolone/prednisone 1 – 2 mg/kg/day, if no improvement within 72 hours, treat as grade 3Grade 3/4Permanently discontinue immunotherapySevere new symptoms, new or worsening hypoxia, life threatening difficulty breathing, ARDSInpatient admission: infectious workup, pulmonary and ID consultation, bronchoscopy with BAL,consider empiric antibioticsInitiate IV methylprednisolone 1 – 2 mg/kg/dayIf no improvement or worsening after 48 hours, add infliximab*, mycophenolate mofetil or IVIGSteroidTaperGrade 2: Treat until Grade 1, taper over 4 – 6 weeksGrade 3 – 4: Treat until Grade 1, taper over 6 weeksNCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018JAMA Oncol. 2016;2(10):1346-1353.*Infliximab dosing: 5 mg/kg up to q2weeks
General Principles ofImmunosuppressive Therapy Corticosteroid use to treat irAE has NOT been shown toreduce anti-tumor activity Routine premedication with steroids (nausea, infusion reactions) isnot recommended due to potential mitigation of anti-tumor activityin the prophylactic settingLonger steroid tapers may be required for some irAE Pneumonitis HepatitisProphylactic treatments should be considered Pneumocystis jiroveci pneumonia if on prednisone 20 mg/dayfor 4 weeks Fungal infections if on prednisone 20 mg/day for 6 weeksNCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018J Natl Compr Canc Netw 2018;16(5.5):594-596.
Sequelae of Prolonged roids use 4 er Treat Rev. 2016 Mar; 44:51-60.
Clinical Pearls of ProlongedCorticosteroid Use Insomnia Dosing in AM or if BID, PM dosing earlier in dayGI Upset Administer with meals Consider H2RB or PPI for reflux (especially in high risk patients: NSAID use,anticoagulation)Diabetes Routine blood glucose monitoring is recommended Consider initiation of oral agents/insulin for optimal control Endocrine consultationOsteoporosis Optimize Vitamin D levels Supplementation with calcium Provide education to minimize risk Greatest risk if patient on steroids 3 monthsJAMA. 2006 Mar 15;295(11):1300-3.Cancer Treat Rev. 2016 Mar; 44:51-60.NCCN Guidelines Management of Immunotherapy-Related Toxicities Version 1.2018
Conclusions for Management ofCheckpoint Inhibitor Toxicities Anti-PD-1/PD-L1 agents are relatively welltolerated (Grade 1 or 2 irAE) Every organ system can be affected Patient education of prompt reporting of symptomsis imperativeGrade 3 or 4 irAE are rare but possibly lifethreatening Urgent management with corticosteroids/immunomodulatory agents may be necessary
Self-Assessment Question1. Whichof the following is NOT a PD-1/PDL1 brolizumabe)Atezolizumab
Self-Assessment Question1. Whichof the following is true about irAE ofPD-1/PD-L1 inhibitors?a)Toxicities do not appear to be dose-relatedb)Incidence of all grades of toxicity is 70%c)No relationship exists between symptomonset and efficacyd)All of the above
Treatment ofImmunotherapy ToxicitiesMallika P. Weant, PharmD, CPPAugust 3, 2018
Types of Immunotherapy IL-2 IFN-alpha Immunomodulating drugs Non-specific Cancer Immunotherapy Tumor infiltrating lymphocyte therapy Lymphokine activated killer cell therapy Cytokine induced killer cell therapy Dendritic cell cytokine induced killer cell th
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