Pooja Patel PGR Final - Mayo Clinic Patel PGR Final.pdf · resume once daily prednisone ≤ 10 mg Proceed with therapy ©2018 MFMER | slide-37 Management LFTs: liver function tests

©2018 MFMER | slide-1

Checkpoint InhibitorsDiverse Side Effects, Unique Management

Pooja Patel, PharmDMayo Clinic Health System-Franciscan HealthcareLa Crosse, WI

Pharmacy Grand RoundsJune 12, 2018


Objectives• Identify the indication and mechanism of action

for common checkpoint inhibitors

• Discuss types of immune-mediated adverse effects of checkpoint inhibitors and their signs/symptoms

• Outline practical approaches to manage immune-mediated adverse drug effects


The Immune System


Role of Immune System

Finn O.J. Annals of Oncology. September 2012

Immunosurveillance Tumor rejection

Tumor Immunology

Innate and adaptive immune effectors

Immune System

Interactions

Tumor recognition and control


3 E’s of Immuno-Editing


Elimination Equilibrium Escape

Cancer

ImmuneCancer

Immune

Cancer

Immune


Goal of Immunotherapy• Strengthen the cancer patient’s immune system

• Improve ability to recognize the tumor• Provide a missing immune effector function

Immunotherapy


Cancer

Immune


Checkpoint Inhibitors


Targets of Checkpoint Inhibition


Cytotoxic T lymphocyte-

associated protein 4CTLA-4

Cell surface proteinExpressed by T-cells

Agents

Ipilimumab (Yervoy®)

IndicationUnresectable, metastatic or

adjuvant treatment for melanoma


CTLA-4 Inhibitor

MHC: major histocompatibility complexCTLA-4: cytotoxic T-lymphocyte associated protein 4


CTLA-4

Antigen Presenting Cell

B-7

CD-28


CTLA-4 Inhibitor

MHC: major histocompatibility complexCTLA-4: cytotoxic t lymphocyte associated protein 4


CTLA-4

Antigen Presenting Cell

B-7

CTLA-4 inhibitor

CD-28


Targets of Checkpoint Inhibition

NK: natural killer


Programmed cell death1/ ligand 1PD-1/ PD-L1

Expressed by T-cells, B-cells, NK cellsCell surface protein


PD-1 Inhibitors


Agents

pembrolizumab (Keytruda®)nivolumab (Opdivo®)

Indication

Metastatic melanomaMetastatic NSCLC

Classic Hodgkins disease

Agents

atezolizumab (Tecentriq®)avelumab (Bavencio®)durvalumab (Imfinzi®)

Indication

Metastatic urothelial carcinoma, metastatic NSCLC,

Merkel cell carcinoma

PD-L1 Inhibitors


PD-1 and PD-L1 Inhibitors

MHC: major histocompatibility complexPD-1/PD-L1: programmed death/ligand 1


PD-1 PD-L1


PD-1 and PD-L1 Inhibitors

MHC: major histocompatibility complexPD-1/PD-L1: programmed death/ligand 1


PD-L1 Inhibitor

PD-L1

PD-1 Inhibitor


Principles for Adverse Event Management


Mechanism Related Adverse Events• Mechanism of action explains the unique adverse

effects • PD-1/PD-L1 and CTLA-4 normally involved in

maintaining appropriate immune response• Blocking checkpoint pathways lead to increased T-cell

proliferation• Aim to target tumor cells but can target normal tissues

as well

Berman D. Pharmacol Ther. 2015


Incidence• Varying incidence of toxicity

• CTLA-4 inhibitor > PD-1/PD-L1 inhibition• Combination of therapy > monotherapy

• Types of immune-related adverse events may vary with tumor type and checkpoint inhibitor



Patient Assessment• Patients should be assessed prior to treatment• Risk factors

• History of autoimmune disease• Actively receiving treatment for autoimmune disease• Previous immune-mediated adverse events with

checkpoint inhibitors

• Patient education• Inform patient of potential adverse events• Report directly to treating physician or team• Prompt work-up and action

Haanen et al. Ann Oncol. 2017


Pattern of Toxicity

Skin Toxicity

3 weeks after initiation

Gastrointestinal Toxicity

After 1-3 dosesPresenting around

week 6

Hepatotoxicity

After 3-4 dosesAfter 8-12 weeks

Endocrinopathies

Between weeks 12-24

Weber, JS. J Clin Oncol. 2015Tarhini A. Scientifica. 2013


Potential Toxicity

Roberts K. Asia Pac J Clin Oncol. 2017

Most Common > 10%

ColitisDermatologicDiarrheaFatigue

Common 1 – 10%

AnemiaArthralgiaHepatitisHyper/HypothyroidismHypophysitisPneumonitisTransaminitis

Rare < 1%

EncephalitisNephritisPancreatitisType 1 Diabetes


Diagnosis

CTCAE: Common Terminology Criteria for Adverse Events

Roberts K. Asia Pac J Clin Oncol. 2017

Rule out other etiology

Rule out other etiology

Eliminate possibility of emergency

Eliminate possibility of emergency

Classify per CTCAE

guidelines

Classify per CTCAE

guidelines


(Broad) Classification of Severity

Kumar V. Front Pharmacol. 2017

Grade 1

Mild events

Symptomatic relief

Continued therapy

Grade 2

Moderate events

Symptomatic support

Low-dose corticosteroid

Withhold therapy

Grade 3 or 4

Severe or life-threatening event

High dose corticosteroid

Permanently discontinue

therapy

Common terminology criteria for adverse events (CTCAE)


Assessment Question 1Which of the following therapies would be most concerning and likely prompt assessment for immune-mediated adverse events?• A. Initiation of ipilimumab

• B. Second dose of durvalumab

• C. Week 3 of ipilimumab in combination with nivolumab

• D. First dose of pembrolizumab therapy

CTLA-4 inhibitor: ipilimumabPD-L1 inhibitor: durvalumab

PD-1 inhibitor: nivolumab, pembrolizumab


Immune-Mediated Skin Toxicity


Incidence• Most frequent adverse event of checkpoint

inhibitors• CTLA-4 Inhibitors: 45%• PD-1 Inhibitors: 34%• Rash, pruritus and vitiligo

• Serious skin adverse events are rare and usually do not require treatment discontinuation

CTLA-4 inhibitor: ipilimumabPD-1 inhibitor: nivolumab, pembrolizumab

Haanen J. Ann Oncol. 2017


Management

BSA: body surface area


Grade 1Macules/papules covering

< 10% BSA With or without symptoms

Avoid skin irritants and sun exposure

Topical emollients recommended

Topical mild strength steroid +/- oral or topical antihistamines

Grade 2Macules/papules covering

10-30% BSARash covering > 30% with or

without mild symptoms

Supportive management Topical moderate strength

steroid+/- oral or topical antihistamines

Proceed with

therapy

Proceed with

therapy


Management

BSA: body surface areaADL: activities of daily living


Grade 3Macules/papules covering > 30%

BSAModerate or severe symptoms

Limiting ADL

Topical treatments as previousInitiate steroids:

Mild: oral prednisone 1 mg/kg daily for 3 days; wean over 2 weeks

Severe: IV methylprednisolone 0.5-1 mg/kg daily; wean over 4 weeks

on response

Grade 4Macules/papules covering > 30% BSA requiring ICU

admissionLife-threatening superinfection

Urgent dermatology reviewIV methylprednisolone

1-2 mg/kg daily

Withhold,Recommence once improved

Discontinue


Immune-Mediated Gastrointestinal Toxicity


PD-1Inhibitors• Limited data on GI immune-mediated adverse

events• Grade 3-4 events in 1-2% of cases• Case series on 19 patients• Median time for symptom onset was 3 months

• Diarrhea and colitis are more frequent with CTLA-4 inhibitors




Incidence



Onset

GI symptoms may occur at any time during CTLA-4 inhibitor infusions 1-10Occur several months after last dose

Enterocolitis

Most common symptom is diarrheaAbdominal pain, hematochezia, weight loss, fever and vomiting

Differential diagnosisDifferential diagnosis

GI infection vs. tumor-related symptomsStool analysis for enteropathogens and Clostridium difficile toxin

• GI toxicity is well described for CTLA-4 Inhibitors


Management


WithholdRecommence once improved

Grade 1Diarrhea: Increase of < 4 stools

per day over baselineColitis: mild symptoms

Increase of 4-6 stools per day over baseline

Colitis: Abdominal pain, mucus or blood in stool

Symptomatic management:Fluids

Loperamide Avoid high fiber diet

Supportive management

Grade 2

Proceed with therapy

If symptoms persist > 3 daysPrednisone 1 mg/kg daily; wean

over 2-4 weeksIf no bloody diarrhea budesonide

9 mg dailyIf persists more than 14

days, prednisone 1 mg/kg daily; wean over 2-4 weeks


Management

ADL: activities of daily living


Grade 3 or 4 Diarrhea: 7 or more stools per day over baselineColitis: Severe abdominal pain, peritoneal signs

Hospitalization indicatedLimited ADL

Life-threatening consequences

Hospitalization for symptom managementSteroids: IV methylprednisolone 1-2 mg/kg daily

wean over 4-8 weeks

3: Withhold,Recommence based on risk/benefit ratio

4: Discontinue

Additional immunosuppression if no improvement over 72 hours:

Infliximab, mycophenolate mofetil, tacrolimus


Assessment Question 2What therapy is optimal for initiation for a patient with complaints of 6 bloody stools above baseline for the past 4 days despite loperamide use?• A. IV methylprednisolone 2 mg/kg daily

• B. Oral prednisone 1 mg/kg daily

• C. Oral budesonide 9 mg daily

• D. IV infliximab 5 mg/kg


Immune-Mediated Hepatotoxicity


Incidence• Occurs in 5-10% of patients with monotherapy

and 25-30% with combination therapy • 1-2% Grade 3 events with monotherapy • 15% Grade 3 events with combination therapy

• Usually asymptomatic and detected on routine blood monitoring

• Rule out disease-related causes, concomitant drug administration and infectious causes




Management


ALT or AST > ULN – 3X ULN

Repeat labs in 1 week

ALT or AST3-5X ULN

Re-check LFTs/INR/albumin every 3 days

Review medicationsConsider imaging for metastases or clotIf rising ALT/AST when re-checked start

oral prednisone 1 mg/kg dailywean over 2 weeks

Grade 2Grade 1

Withhold therapy, resume once daily

prednisone ≤ 10 mg

Proceed with therapy


Management

LFTs: liver function testsWNL: within normal limits


ALT or AST 5-20X ULN

ALT/AST < 400 and other LFTs WNLoral prednisone 1 mg/kg daily

ALT/AST > 400 or other LFTs not WNLIV methylprednisolone 2 mg/kg daily

Daily LFTs, INR, albumin

ALT or AST> 20X ULN

IV methylprednisolone 2 mg/kgHepatology consult

Consider liver biopsy

Grade 3

Withhold therapy Re-challenge per

consultant discretion

Discontinue therapy

Grade 4

Worsening despite steroids:Mycophenolate then tacrolimus

Once improved to Grade 2, wean over 4 weeks


Immune-Mediated Endocrinopathy


Thyroid Gland Disorders• Incidence of thyroid disorders increased

considerably with introduction of checkpoint inhibitors

• PD-1/PD-L1 therapy: 5-10%• Combination therapy: 20%

• Thought to be mediated by T cells




Thyroid Disorder Management• Hypothyroidism: supplementation with thyroid

hormone should be considered

• Hyperthyroidism: treatment with beta-blockers should be started in symptomatic patients

• Therapy with checkpoint inhibitors should be interrupted until recovery from symptoms



Hypophysitis• Before CTLA-4 inhibitors, incidence of

hypophysitis was rare• Incidence with ipilimumab increases from 1% to 16%

when dose increases from 3 mg/kg to 10 mg/kg• Still rare in patients treated with PD-1/PD-L1

inhibitors

• Headache and visual disturbances• Low TSH levels, adrenocorticotropic hormone

and/or follicle-stimulating hormone, luteinizing hormone occur

TSH: thyroid stimulating hormoneCTLA-4 inhibitor: ipilimumab

PD-1 inhibitor: nivolumab, pembrolizumab



Management


Mild

Vague symptoms(e.g. mild fatigue, anorexia)

no headache

Initiate appropriate hormone replacement therapy

Await pituitary axis to confirm diagnosis but warn patients to seek urgent review if unwell

Proceed with

therapy


Management


SevereSevere mass effect symptoms,

i.e. severe headache, any visual disturbance or

severe hypoadrenalism,i.e. hypotension, severe electrolyte

disturbance

Pituitary axis assessmentHormone replacement therapy

Initiate IV methylprednisolone 1 mg/kg daily; convert to oral and wean over 4

weeks to 5 mg dailyConsult endocrinologist

Withhold therapy

ModerateModerate symptoms; headache but

no visual disturbanceor

Fatigue/mood alteration but hemodynamically stable, no

electrolyte disturbance

Pituitary axis assessmentOral prednisone 0.5-1 mg/kg daily

Withhold therapy

If no improvement in 48h, treat as severe


Rare Immune-Mediated Adverse Effects


Rare Or Possibly Fatal• Neurological toxicity

• Polyneuropathy, facial nerve palsy, demyelination, myasthenia gravis

• Cardiac toxicity• Myocarditis, pericarditis, arrhythmias, cardiomyopathy

• Renal toxicity• Pneumonitis

• Acute interstitial pneumonitis, diffuse alveolar damage syndrome (DADS)

• High dose steroidsHaanen J. Ann Oncol. 2017


Assessment Question 3A patient receiving ipilimumab therapy presents with symptoms concerning for severe hypophysitis. Which treatment plan is most appropriate for the patient?• A. Oral prednisone 1 mg/kg daily weaned over 2 weeks and

discontinued

• B. IV methylprednisolone 1 mg/kg weaned over 4 weeks and discontinued

• C. IV methylprednisolone 1 mg/kg converted to oral therapy and then weaned down to 5 mg daily

• D. Await endocrinology consult


Pharmacist’s Role

Prevent

Anticipate

RecognizeManage

Monitor

Champiat S. Ann Oncol. 2016


Summary


Recognize adverse event Assess severity

Involve specialists

Symptomatic management

Withhold or discontinue therapy

Corticosteroids

Hormone replacement therapy


ReferencesO. J. Finn. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology. Volume 23(8); 1 September 2012.

Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. Journal of Clinical Oncology. 2015;33(18):2092-2099.

Ahmad Tarhini. Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management. Scientifica. 2013; 2013:1-19.

Berman D, Korman A, Peck R, et al. The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer. Pharmacol Ther. 2015;148:132-153.

Kumar V, Chaudhary N, Garg M, et al. Current Diagnosis and Management of Immune Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitor Therapy. Frontiers in Pharmacology. 2017;8:49.

Roberts K, Culleton V, Lwin Z, et al. Immune hcekpoint inhibitors: Navigating a new paradigm of treatment toxicities. Asia Pac J Clin Oncol. 2017;13:277-288.

Haanen JG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Gguidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2017;28(4):iv119–iv142


Checkpoint InhibitorsDiverse Side Effects, Unique Management

Pooja Patel, [email protected] Grand RoundsJune 12, 2018

Documents

Pooja Patel PGR Final - Mayo Clinic Patel PGR Final.pdf · resume once daily prednisone ≤ 10 mg Proceed with therapy ©2018 MFMER | slide-37 Management LFTs: liver function tests