managing patients on immune checkpoint inhibitors in the

Managing Patients on Immune Checkpoint Inhibitors in the COVID-19 Era

The Importance of Nurse–Pharmacist Collaboration

This activity is jointly accredited for nurses and pharmacists and is supported by independent educational grants from

Bristol-Myers Squibb and Merck & Company.

Faculty

Dr. Holle currently serves as Associate Clinical Professor, Pharmacy Practice at the University of Connecticut School of Pharmacy in Storrs, CT, and as an Oncology Pharmacy Specialist at the UConn Health, Carole and Ray NeagComprehensive Cancer Center Farmington. Dr. Holle received her PharmD from the University of Wisconsin–Madison and completed an Oncology Pharmacy Specialty Residency at The University of Texas MD Anderson Cancer Center in Houston. Dr. Holle is a board certified pharmacy oncology specialist.

Lisa M. Holle, PharmD, BCOP, FISOPPAssociate Clinical Professor, Pharmacy Practice UConn School of PharmacyStorrs, CTOncology Pharmacy SpecialistUConn Health Carole and Ray Neag Comprehensive Cancer CenterFarmington, CT

Faculty

Ms. Moran is a Lead Hematology Oncology Advanced Practice Registered Nurse who works closely with Dr. Holle at the UConn Health Carole and Ray NeagComprehensive Cancer Center. She has been an oncology nurse for 24 years, 15 of which as an Advanced Practice Registered Nurse. She is currently enrolled in the University of Connecticut, Doctor of Nursing program. Ms. Moran’s clinical interest include benign and malignant hematology, oral chemotherapy adherence, and treatment toxicity management.

Andrea Moran, MSN, APRNLead Hematology/Oncology Advanced Practice Registered NurseUConn Health Carole and Ray Neag Comprehensive Cancer CenterFarmington, CT

Dr. Holle and Ms. Moran have disclosed that they have no actual or potential conflict of interest in relation to this program.

The clinical reviewer, Megan May, PharmD, BCOP has no actual or potential conflict of interest in relation to this program.

Susanne Batesko, RN, BSN, Robin Soboti, RPh, and Susan R. Grady, MSN, RN-BC, as well as the planners, managers, and other individuals, not previously disclosed, who are in a position to control the content of Postgraduate Healthcare Education (PHE) continuing education activities hereby state that they have no relevant conflicts of interest and no financial relationships or relationships to products or devices during the past 12 months to disclose in relation to this activity. PHE is committed to providing participants with a quality learning experience and to improve clinical outcomes without promoting the financial interests of a proprietary business.

Disclosures

Accreditation StatementJoint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the

Postgraduate Institute for Medicine and Postgraduate Healthcare Education. Postgraduate Institute for

Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME),

the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center

(ANCC), to provide continuing education for the healthcare team.

Pharmacy: Postgraduate Healthcare Education, LLC (PHE) is accredited by the Accreditation Council for

Pharmacy Education (ACPE) as a provider of continuing pharmacy education.

UAN: 0430-0000-20-107-L01-P

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 1.5 contact

hours. Designated for 0.7 contact hours of pharmacotherapy credit for Advanced Practice Registered

Nurses.

• Discuss the current and emerging use of immune checkpoint inhibitors (ICIs) and ICI combination regimens for the treatment of cancer

• Demonstrate interventions to effectively prevent or manage toxicities of ICIs and ICI combination therapies

• Distinguish best practices for managing patients on ICIs during the coronavirus disease 2019 (COVID-19) pandemic

• Develop an interprofessional practice model aimed to improve outcomes in patients receiving ICIs

Learning Objectives

• March 11, 2020 – WHO declared pandemic

• COVID-19• Caused by severe acute respiratory syndrome coronavirus-2 (SARS

CoV-2)

• Mild to severe symptoms appearing 2–14 days after exposure• Fever/chills

• Cough, shortness of breath, or difficulty breathing

• Muscle/body aches

• Headache, sore throat, congestion, or runny nose

• Loss of taste/smell

• Nausea, vomiting, or diarrhea

A New Era: COVID-19

Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html.;World Health Organization. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020.

https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html

https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020

• Morbidity and mortality higher in:• Elderly

• Patients with comorbidities• Heart disease

• Cancer

• Chronic obstructive pulmonary disease

• Obesity (BMI ≥30 kg/m2)

• Sickle cell disease

• Solid organ transplant recipients (SOTRs)

• Type 2 diabetes mellitus

COVID-19

Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/evidence-table.html.

BMI, body mass index.

https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/evidence-table.html

• Early reports from Wuhan, China• 0.9% of cases of 1099 patients

• More severe presentation than general public (30% vs. 16%)

• Higher mortality than general public (5.6% vs. 2.3%)

• Larger studies now available• From United States, United Kingdom, and China

• Case-control and case series

COVID-19 and Cancer

Fung M, et al. Clin Infect Dis. 2020;ciaa863.;Guan W-J, et al. N Engl J Med. 2020;382(18):1708-20.;Wu Z, et al. JAMA. 2020;323(13):1239-42.

• Males > females

• Older (median age: 52–69 years)

• High rates of comorbidities

• Cancer type in line with most common in geographic region

• Similar presenting symptoms

• Healthcare exposure increased risk of infection

• Increased risk of severe outcomes

COVID-19 and Cancer

Fung M, et al. Clin Infect Dis. 2020;ciaa863.

• Did COVID-19 cause changes in the way you treated patients with cancer receiving ICIs?

• Yes

• No

ARS Question #1

Current and Emerging Use of ICIs and ICI Combination Therapy in Cancer

Treatment

• ICI therapies• Cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor

• Ipilimumab

• Programmed cell death-1 (PD-1) inhibitors• Cemiplimab-rwlc

• Nivolumab

• Pembrolizumab

• Programmed cell death ligand-1 (PD-L1) inhibitors• Atezolizumab

• Avelumab

• Durvalumab

Approved ICI Therapies

Bavencio (avelumab) [package insert]. 2019.; Imfinzi (durvalumab) [package insert]. 2020.; Keytruda (pembrolizumab) [package insert]. 2020.;Opdivo (nivolumab) [package insert]. 2020.; Tecentriq (atezolizumab) [package insert]. 2020.; Yervoy (ipilimumab) [package insert]. 2020.

• Acute lymphoblastic leukemia

• Breast cancer (triple negative)

• Cervical cancer

• DLBCL

• Endometrial cancer

• Esophageal cancer

• Head & neck cancer

• Hepatocellular

• High tumor mutational burden

• Gastric cancer

• Large B-cell lymphoma

• Melanoma

• Merkel cell carcinoma

• MSI-high solid tumors/colon cancer

• Non–small-cell lung cancer (NSCLC)

• Renal cell cancer

• Small-cell lung cancer (SCLC)

• Urothelial cancer

Indications for ICI Monotherapy

Bavencio (avelumab) [package insert]. 2019.; Imfinzi (durvalumab) [package insert]. 2020.; Keytruda (pembrolizumab) [package insert]. 2020.;Opdivo (nivolumab) [package insert]. 2020.; Tecentriq (atezolizumab) [package insert]. 2020.; Yervoy (ipilimumab) [package insert]. 2020.

DLBCL, diffuse large B-cell lymphoma; MSI, microsatellite instability.

• Chemotherapy and radiation therapy• Promote maturation of antigen-presenting cells

• Augment tumor antigen presentation

• Increase PD-L1 expression on tumor cells

• Increase CD8+ T-cells and macrophages

• Targeted therapy• Disruption of signal transducer and activator of transcription (STAT)

signaling pathways, decreasing immunosuppression

• Upregulation of PD-L1 expressions

• Inhibition of T-cell proliferation, shifting balance of antitumor immune response

Combination ICI Therapy

Apetoh L, et al. Ann Oncol. 2015;26(9):1813-23.; Esteva FJ, et al. Lancet Oncol. 2019;20(3):e175-86.; Lazzari C, et al. Ther Adv Med Oncol. 2018;10:1758835918762094.


• Combined ICI therapy• Ipilimumab + nivolumab: hepatocellular cancer, MSI-high colon

cancer, melanoma, NSCLC, and renal cell carcinoma

• Combined chemotherapy + ICI therapy• Atezolizumab + chemotherapy: triple-negative breast cancer,

hepatocellular cancer, NSCLC, SCLC

• Durvalumab + chemotherapy: extensive-stage SCLC

• Nivolumab + ipilimumab + chemotherapy: NSCLC

• Pembrolizumab + chemotherapy: head & neck cancer and NSCLC

Imfinzi (durvalumab) [package insert]. 2020.; Keytruda (pembrolizumab) [package insert]. 2020.; Opdivo (nivolumab) [package insert]. 2020.; Tecentriq (atezolizumab) [package insert]. 2020.; Yervoy (ipilimumab) [package insert]. 2020.


• Combined tyrosine kinase inhibitor + ICI therapy• Avelumab + axitinib: renal cell carcinoma

• Atezolizumab + cobimetinib + vemurafenib: melanoma

• Pembrolizumab + axitinib: renal cell carcinoma

• Pembrolizumab + lenvatinib: endometrial carcinoma

Bavencio (avelumab) [package insert]. 2019.; Keytruda (pembrolizumab) [package insert]. 2020.; Tecentriq (atezolizumab) [package insert]. 2020.

• Initial ICI approval: every 2- or 3-week dosing regimens

• Extended-interval dosing based on modeling studies• Atezolizumab q 4 weeks

• Nivolumab q 4 weeks

• Pembrolizumab q 6 weeks

• Optimal treatment duration: unknown (1–2 years)• Consideration of treatment holidays to minimize adverse events or

COVID-19 risk (after 1 year)

• Consider performance status (PS): little data in Eastern Cooperative Oncology Group (ECOG) PS > 2

Current and Emerging ICI Dosing Strategies

Friedlaender A, et al. Front Oncol. 2020;10:862.; Keytruda (pembrolizumab) [package insert]. 2020.; Opdivo (nivolumab) [package insert]. 2020.;Sehgal K, et al. Front Oncol. 2020;10:1193.; Tecentriq (atezolizumab) [package insert]. 2020.

• Retrospective, single-institution study (n=157)• NSCLC (31%), melanoma (25%), urothelial cancer (8%)

• Received ICI dose within 30 days of end of life: 27%• Lower hospice enrollment than those receiving ICI >30 days of end of life

(45% vs. 69%; P=0.007)• Higher rates of death in hospital than those receiving ICI >30 days of end of

life (56% vs. 29%; P=0.002)

• ECOG PS ≥3 at time of last ICI dose (26% vs. 8%; P=0.003)

• Considerations: • Benefits of palliative care vs. ICI therapy near end of life• Time to effectiveness of ICI, risks of ICI adverse events, cost of therapy,

impact of QOL/symptoms/performance status

ICI with Palliative Care

Glisch C, et al. Am J Hosp Palliat Care. 2020;37(3):179-84.

QOL, quality of life.

• Ongoing evaluation as single and combined therapies (>500 trials)

• Late-stage development: >10 new checkpoint inhibitors

• Novel checkpoint inhibitors• Lymphocyte activation gene-3 (LAG-3)

• T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)

• T-cell immunoglobulin and ITIM domain (TIGIT)

Emerging ICI and ICI Combination Therapies

Qin S, et al. Mol Cancer. 2019;18:1515.; U.S. National Library of Medicine. https://clinicaltrials.gov.

Management of Immune-Related Adverse Events (irAEs)

• The most common irAE is:

• Colitis

• Hepatitis

• Pneumonitis

• Rash

ARS Question #2

• Immunotherapy generally tolerated better than cytotoxic chemotherapy

• “Unbalance the immune system” leads to “autoimmune manifestations” also referred to as irAEs

• Onset and type of toxicities are quite different than with traditional mainstays of therapy

• irAEs can occur in up to 70%–90% of patients receiving immune therapy

• Typically manifest as inflammation and autoimmune response

• Can affect any organ, but most commonly affect the skin, GI tract, lungs, endocrine system, and liver

Management of irAEs

Michot JM, et al. Eur J Cancer. 2016;54:139-48.; Postow MA, et al. N Engl J Med. 2018;378(2):158-68.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

GI, gastrointestinal.

• Understanding timing of onset may help identify cause of adverse event (AE)• Chemotherapy AEs usually occur soon after administration, but irAEs tend

to have a later onset and more prolonged course

• Most irAEs occur within 3–6 months of initiation of therapy

• Onset depends on the agent used, dosing regimen, and underlying patient characteristics

• irAEs from CTLA-4 inhibitors usually present sooner than those from PD-1/PD-L1 inhibitors

• Dose dependent in anti-CTLA-4

• Cumulative toxicities not seen with PD-1/PD-L1 blockade

Timing of irAEs

Michot JM, et al. Eur J Cancer. 2016;54:139-48.; Postow MA, et al. N Engl J Med. 2018;378(2):158-68.;Topalian SL, et al. J Clin Oncol. 2014;32(10):1020-30.; Weber JS, et al. Cancer. 2013;119(9):1675-82.

• Combined immune therapy vs. monotherapy• Combined therapy → earlier onset, prolonged AEs

• Can occur months after start of therapy or even after therapy has been discontinued

• Extended follow-up is needed even after therapy discontinuation

Timing of irAEs

Medina P, et al. J Pharm Pract. 2020;33(3):338-49.

Timing of irAEs

Derm, dermatologic.

Weber JS, et al. Cancer. 2013;119(9):1675-82.

Monitoring Assessments for ICI’s(May vary for different agents and combination regimens)

Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

Assessment Baseline Frequency

Physical exam X Every visit

Neurologic exam X Every visit

Bowel habits (frequency/consistency) X Every visit

Imaging (CT scan) X Periodically

Complete blood count X Every 2–3 weeks

Comprehensive metabolic panel X Every 2–3 weeks

Exam of skin and oral mucosa X As needed

Pancreatic (amylase/lipase) As needed

Liver transaminases X Every 2–3 weeks

Oxygen saturation and PFTs (high-risk patients) X Based on symptoms

TSH, free T4, AM cortisol X Every 4–6 weeks

CT, computed tomography; PFTs, pulmonary function tests; T4, thyroxine; TSH, thyroid-stimulating hormone.

• Early recognition of irAEs is critical to proper management and prompt intervention

• Multiple sources available for patient education• ASCO, NCCN, ESMO, SITC

• Ongoing education from time of diagnosis, during treatment planning, and during therapy

• Standardized approach to patient education results in better outcomes

• Barriers• Time and commitment to organization of information

• Complex education

• Fear of being taken off therapy

Patient Education

ASCO, American Society of Clinical Oncology; ESMO, European Society of Medical Oncology; NCCN, National Comprehensive Cancer Network; SITC, Society for Immunotherapy of Cancer.

Wood LS, et al. Clin J Oncol Nurs. 2019;23(3):271-80.

• Explain how immunotherapy agents work• Parking brake/gas pedal analogy

• Describe expected response to therapy• May not be right away, as with chemotherapy

• List requirements for monitoring and managing side effects• Any changes should be reported

• Remind patient that therapy may not be interrupted, if treated early

• Clarify when to expect side effects

• Clarify when to call care provider• May occur after treatment has ended

Patient Education: Key Messages to Communicate

Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.; Wood LS, et al. Clin J Oncol Nurs. 2019;23(3):271-80.

• Goal: Control immune response without diminishing antitumor effect of therapy

• No prospective trials have defined strategies for effectively managing irAEs

• Management based on consensus guidelines

• Management guidelines based on severity of symptoms• ASCO

• NCCN

Management of irAEs

Jamal S, et al. J Rheumatol. 2020;47(2)166-75.; Postow MA, et al. N Engl J Med. 2018;378(2):158-68.

• Prompt evaluation and recognition is critical

• Proactive management, adequate patient education, and ongoing patient evaluation can minimize the need for therapy interruption or discontinuation

• Multidisciplinary approach to management• Nursing

• Pharmacy

• Medicine/specialist consultation

• Therapeutic intervention based on severity and organ involved

Management of irAEs


• Discontinuation of therapy

• Organ-specific therapy (e.g., thyroid replacement, antihistamines, topical preparations)

• Corticosteroids (first-line immunosuppression)

• Other immune-modulating therapies• Immune suppression (i.e., infliximab, mycophenolate, cyclosporine, etc.)

• IL-6 receptor antagonist

• Intravenous immune globulin (IVIG)

• Therapeutic plasma exchange

Overview of Therapeutic Options for Managing irAEs

Stroud CR, et al. J Oncol Pharm Pract. 2019;25(3):551-7.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

IL, interleukin.

• Corticosteroids• Generally, prednisone doses of 0.5–1 mg/kg/day up to 2 mg/kg/day

• Underlying infection should be ruled out, if possible, prior to initiation

• Require monitoring for adverse reactions• Hyperglycemia, edema, anxiety, and iatrogenic adrenal insufficiency

• Prolonged use of corticosteroids• Bone loss

• Opportunistic infections

• May need prophylaxis• Antiviral, PJP, skeletal-related events

• Taper may be needed once irAEs resolved

Management of irAEs


PJP, pneumocystis jirovecii pneumonia.

• Grading system using United States National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) • CTCAE version 5.0

• Standard grading system based on organ affected

• Grade 1-5• 1=mild

• 5=death from AE

Assessment of irAEs

National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0). Bethesda, MD, National Cancer Institute. 2017.

Management of irAEs Based on Grade

Grade 1:

Non-urgent

Continue therapy

Provide supportive care

Grade 2:

Non-urgent

Withhold therapy

Start corticosteroids at lower doses

Grade 3:

Urgent/consider hospitalization

Withhold therapy

Start or increase corticosteroids

Referral to specialist

Grade 4:

Urgent/hospital/ICU

Discontinue therapy

Start or increase dose of corticosteroid

Consider alternative immunosuppression

Champiat S, et al. Ann Oncol. 2016;27(4):559-74. ICU, intensive care unit.

• Varying presentation from pruritus only to mild maculopapular rash/vitiligo to DRESS/SJS • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

• Fever

• Rash

• Eosinophilia

• Liver dysfunction

• Stevens-Johnson Syndrome (SJS)• Erythematous rash, blisters, and skin sloughing

• Typically involves the oral mucosa

Management of irAEs: Dermatologic

Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-68.; Si X, et al. Thorac Cancer. 2020;11(2):488-92.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

• Evaluation• Thorough H&P (including examination of the oral mucosa)

• Medication review

• Skin biopsy

• Differential diagnosis• Primary skin disorder

• Medications/photosensitivity

• Infection (zoster)


Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-68.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

H&P, history and physical.

• Clinical findings• Mild rash → bullous formation/blistering, sloughing

• Vitiligo

• Fever

• Treatment• Topical emollients, antihistamines, topical steroids

• Treatment interruption

• Systemic steroids

• Dermatology input


Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-68.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

• Patient presents with diarrhea (watery/bloody), abdominal pain/cramping, fever

• Onset: 6–8 weeks from starting treatment

• Evaluation• H&P with attention to frequency/consistency of BMs• Grading based on # of BMs above normal• Stool testing (C diff, O&P)• Imaging (CT scan, ulceration/perforation)• Colonoscopy

• Differential diagnosis• Infection (C diff)

• Clinical findings• Diarrhea: <4 to >6 times more episodes than usual for patient• Dehydration

Management of irAEs: Colitis

BM, bowel movements; C diff, Clostrdium difficle; O&P, ova and parasites.

Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-68.; Hahn AW, et al. Urol Oncol. 2017;35(12):701-7.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

• Treatment• Antidiarrheal

• Hydration

• Bland diet

• Corticosteroids

• Additional immunosuppression if not responding• Infliximab

• Vedolizumab

Management of irAEs: Colitis

Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-68.; Hahn AW, et al. Urol Oncol. 2017;35(12):701-7.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

• Usually asymptomatic at presentation with abnormal LFTs

• Onset: 5–6 weeks from start of treatment

• Evaluation: LFTs (AST, ALT, bili)

• Differential diagnosis• Progressive disease• Viral hepatitis• Medication toxicity• Alcohol use

• Clinical findings• Jaundice• N/V• Right-sided abdominal pain• Fatigue• Early satiety• Dark urine

Management of irAEs: Hepatic

ALT, alanine aminotransferase; AST, aspartate aminotransferase; bili, bilrubin; LFTs, liver function tests; N/V, nausea/vomiting.


• Treatment• Continue therapy if mild (grade 1)

• Hold therapy

• Corticosteroids

• Frequent monitoring of LFTs (every 1–2 days)

• Consider additional immunosuppression with mycophenolate mofetilif not responding to steroids

• Referral to hepatologist/liver biopsy

• CONTRAINDICATED:• Infliximab

Management of irAEs: Hepatic


• Non-infectious inflammatory pulmonary process

• Predominately occurs with PD-1/PD-L1 therapy

• Incidence is low (2.5%–5% with PD-1/PD-L1 monotherapy)

• Outcome is poor if not recognized and treated early

• Generally presents with dry cough, dyspnea, hypoxia, and tachycardia

• Evaluation• H&P, vital signs, O2 sat

• CT scan, PFTs, ABG

Management of irAEs: Pneumonitis

Choi J, et al. Immune Netw. 2020;20(1):e9.; Eigentler TK, et al. Cancer Treat Rev. 2016;45:7-18.; Myers G. Curr Oncol. 2018;25(5):342-7.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

ABG, arterial blood gasses; O2 sat, oxygen saturation.

• Differential diagnosis• Disease progression• Pneumonia

• Treatment • Hold ICI• Pulmonary referral/bronchoscopy• Corticosteroids• Additional immunosuppression if not improving

• Infliximab• Mycophenolate• IVIG

• Empiric antibiotics until infectious process is ruled out

Management of irAEs: Pneumonitis

Eigentler TK, et al. Cancer Treat Rev. 2016;45:7-18.; Myers G. Curr Oncol. 2018;25(5):342-7.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

• Elderly → generally safe, no dose adjustments

• Renal/hepatic impairment →mild to moderate impairment (i.e., CrCl >15 mL/min or bili >1–1.5x ULN) did not impact clearance • Not evaluated in severe impairment

• Pregnant/breastfeeding → little data of use in pregnancy and breastfeeding but ICIs likely cross the placental barrier and are present in breast milk • NOT recommended

irAEs in High-Risk Patients

Keytruda (pembrolizumab) [package insert]. 2020.; Opdiva (nivolumab) [package insert]. 2020.; Yervoy (ipilimumab) [package insert]. 2020.

CrCl, creatinine clearance, ULN, upper limit of normal.

• Patients with prior irAEs• Based on severity of prior irAE

• Resolution of symptoms

• Risk–benefit analysis

• Underlying autoimmune disease

• Solid organ transplant recipients

Management of irAEs in Special Populations

Abdel-Wahab N, et al. Ann Intern Med. 2018;168(2):121-30.

• Patients with underlying autoimmune disease have historically been excluded from ICI studies

• CTLA-4 and PD-1 play critical roles in autoimmunity

• CTLA-4 agonists are used to treat some autoimmune disorders• Abatacept, belatacept

• Retrospective studies and case reports of use of immunotherapy in this population show that patients with autoimmune disease can benefit from immunotherapy and tolerate it well

• Decision to treat with ICI may be based on underlying autoimmune disease• i.e., Crohn’s disease vs. mild psoriasis

• Risk vs. benefit of toxicity vs. complications/death from cancer

• Multidisciplinary approach/co-management with rheumatologist

Management of irAEs in Special Populations: Autoimmune Disease

Abdel-Wahab N, et al. Ann Intern Med. 2018;168(2):121-30.

• Ongoing phase 1B study of patients with unresectable/advanced cancer and an autoimmune disease

• Nivolumab

• Primary endpoint: overall safety of PD-1 blockade in patients with autoimmune disease

• Secondary endpoints• Efficacy on ORR, PFS, and OS • Establish dosing recommendations• Evaluate impact on underlying autoimmune disease• Perform molecular profiling to see if any predictive/prognostic alterations

can be identified

• Estimated completion date: August 31, 2022

irAEs in Autoimmune Disease:NCI Clinical Trial NCT03816345

ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

U.S. National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT03816345.

• Long-term immunosuppression necessary to prevent rejection/infection

• Higher rate of malignancy in SOTR population

• Hodgkin lymphoma, NHL, and skin, liver, lung, and thyroid cancers

• Compared to general population, SOTRs have a 65–250-fold increased risk of developing cutaneous SCC

• Increased risk of developing cancer based on type and length of treatment with immunosuppressive used (cyclosporine/azathioprine) and other host risk factors

• Allograft rejection mediated by T-cell stimulation

• T-cell stimulation is upregulated with some immunotherapy

• In immunotherapy clinical trials, SOTRs were excluded

• Little data for safety and efficacy of immunotherapy in SOTRs

Management of irAEs in Special Populations: SOTRs

Bouwes Bavinck JN, et al. Transplantation. 1996;61(5):715-21.; Engels EA, et al. JAMA. 2011;306(17):1891-901.;Fisher J, et al. J Am Acad Dermatol. 2020;82(6):1490-500.; Smedman TM, et al. Acta Oncol. 2018;57(10):1414-8.

NHL, non-Hodgkin lymphoma; SCC, squamous cell carcinoma.

• Immunosuppression is necessary to prevent graft rejection

• Lack of data and conflicting literature for use of immunotherapy in SOTRs

• Systematic review of 57 SOTRs treated for metastatic cancers with immunotherapy • 57 cases reviewed (kidney, liver, heart, lung)• Ipilimumab, pembrolizumab, and nivolumab used• 37% (21 patients) developed graft rejection• 8 deaths were related to graft loss• 29 deaths were related to disease progression• No difference in rate of rejection based on immunotherapy used

• More data are needed to understand safety and outcomes in this population

• ICI therapy should be used with caution in SOTRs

• Risk may be reasonable in renal transplantation compared with other solid organ transplantation (dialysis)

Management of irAEs in Special Populations: SOTRs

Fisher J, et al. J Am Acad Dermatol. 2020;82(6):1490-500.

• Combined immunotherapy regimens are likely more effective, but toxicity may be greater than with single-agent therapy

• Most common toxicities: dermatological, GI, hepatic, pulmonary, endocrine• Dermatologic effects are most common irAE with combined-therapy:

frequency up to 62%

• Overlapping toxicities• Chemotherapy-ICI combinations (nausea/fatigue)• TKI-ICI combinations (diarrhea)

• Can be difficult to establish cause of toxicities• Chemo vs. immunotherapy vs. disease vs. other causes

• Understanding of timing of presentation can aid in appropriate treatment

Management of irAEs With Emerging Immunotherapy Combination Regimens

Hassel JC, et al. Cancer Treat Rev. 2017;57:36-49.; Thompson JA, et al. J Natl Compr Canc Netw. 2020;18(3):230-41.

TKI, tyrosine kinase inhibitor.

Management of Patients Receiving ICIs in the COVID-19 Era

• Are patients receiving ICI therapy more likely to have worse outcomes with COVID-19?

• Yes

• No

ARS Question #3

• Retrospective cohort study (n=928) from United States, Canada, and Spain

• Most common cancers• Breast: 21%• Prostate: 16%• Hematologic: 22%

• Active treatment: 39%

• COVID-19 resulted in:• Hospitalization: 40%• Intubation: 12%• Case-fatality rate: 13%

COVID-19 and Cancer – Largest Study

Kuderer NM, et al. Lancet. 2020;395(10241):1907-18.

• Risk factors associated with 30-day mortality• Older age (per 10 years, OR=1.84)

• Male (OR=1.63)

• >2 comorbidities (OR=4.5)

• ECOG PS ≥2 (OR=3.89)

COVID-19 and Cancer – Largest Study

Kuderer NM, et al. Lancet. 2020;395(10241):1907-18.

OR, odds ratio.

• 2035 patients with cancer tested (March 10–April 7, 2020)• Excluded patients with testing prior to surgery or HSCT

• Tests by nasopharyngeal swab

• 423 patients diagnosed with symptomatic COVID-19 (21%)• 40% hospitalized

• 20% severe respiratory illness

• 9% ventilated

• 12% died within 30 days

COVID-19 and Cancer – MSKCC Study

Robilotti EV, et al. Nat Med. 2020;26(8):1218-23.

HSCT, hematopoeitic stem cell transplant; MSKCC, Memorial Sloan Kettering Cancer Center.


Baseline characteristic % of patientsN=423

>60 years old 56

Cancer type

Breast cancer 20

Lymphoma 11

Colorectal cancer 9

Lung 8

Metastatic 56

Comorbid conditions (≥1) 59

Most common presenting symptom

Fever 78

Cough 82


• Risks associated with hospitalization• Non-white race• Hematologic malignancy• Chronic lymphopenia and/or corticosteroid use• ICI therapy

• Risks associated with severe respiratory illness• Age >65 years• ICI therapy

• Not associated with higher risk: chemotherapy within 30 days, surgery, and metastatic disease



Cancer Endpoint No. of non-ICI patients

No. of ICI patients

Lung Hospitalization 12/23 (52%) 10/12 (83%)

Severe respiratory illness

8/23 (35%) 7/12 (58%)

Others Hospitalization 82/216 (38%) 8/17 (47%)

Severe respiratory illness

34/221 (15%) 5/19 (26%)



• Rationale for ICI risk• ICI-related lung injury

• ICI-triggered immune dysregulation by T-cell hyperactivation leading to acute respiratory distress syndrome

• Corticosteroid use for irAEs

• MSKCC study• 1 in 31 patients treated with ICI had received corticosteroids

• 0 had ICI-related pneumonitis at time of COVID-19

COVID-19 and ICIs


• Should treatment be delayed in COVID-19–positive patient with cancer?

• Should anti-cancer therapy be held because of COVID-19?• Risk/benefit analysis

• When is it safe to resume therapy once recovered from COVID-19?• CDC has guidance for discontinuing transmission-based guidelines

(testing/timing after symptoms resolve) but does not have guidance for resuming/starting anti-cancer therapy

• National Institute for Health and Care Excellence (NICE) in the UK has prioritized anti-cancer therapy balancing immunosuppression, capacity issues, and risk/benefit of cancer vs. complications from COVID-19

Cancer and COVID-19: Q & A

American Society of Clinical Oncology. https://www.asco.org/asco-coronavirus-resources/care-individuals-cancer-during-covid-19/cancer-treatment-supportive-care.

CDC, Centers for Disease Control and Prevention.

• ASCO provides some guidance for management of cancer patients during the COVID-19 pandemic

• Limited data • MSKCC study found that patients with cancer and COVID-19 who

received an ICI had an increased risk of hospitalization (OR=2.84; 95% CI, 1.24–6.72)

• Based on this study, consider adjusting dosing intervals, delaying treatment if appropriate

• Consider COVID-19 testing prior to therapy• Immunosuppression for irAEs could increase risks associated with

COVID-19

Immunotherapy and COVID-19

American Society of Clinical Oncology. https://www.asco.org/asco-coronavirus-resources/care-individuals-cancer-during-covid-19/cancer-treatment-supportive-care.; Robilotti EV, et al. Nat Med. 2020;26(8):1218-23.

CI, confidence interval.

https://www.asco.org/asco-coronavirus-resources/care-individuals-cancer-during-covid-19/cancer-treatment-supportive-care

• Synergy with both COVID-19 and immunotherapy potentially causing immune hyperactivation (cytokine release syndrome)

• Shortage of immunosuppressive agents to treat both

• Exposure when in clinic for treatment

• When to treat/not treat?

• Overlap between COVID-19 and autoimmune pneumonitis

Issues with COVID-19 and Immunotherapy

Your patient presents to your office prior to their next ICI treatment. They report a mild cough and mild dyspnea on exertion. They may have been exposed to COVID-19 a week ago. You decide to hold their next dose of ICI. Should you also start corticosteroids?

• Yes

• No

ARS Question #4

Immune-Related (IR) Pneumonitisvs. COVID-19 Pneumonia

• Presentation may be similar• Fever/chills

• Cough, shortness of breath, or difficulty breathing

• Lower-than-normal O2 saturation

• What next?• Isolate the patient if symptomatic

• Mask, negative pressure room, proper PPE

• Imaging• CXR

• CT scan

• Invasive testing

Is it IR Pneumonitis or COVID-19 Pneumonia?

Naidoo J, et al. J Immunother Cancer. 2020;8(1):e000984

CXR, chest X-ray; PPE, personal protective equipment.

Typical CT findings for both are similar:

“Organizing pneumonia”

“Multifocal ground-glass opacities”

IR Pneumonitis vs. COVID-19 Pneumonia

Initial management may be the same for both conditions• Grade 1 toxicity • Mild COVID-19 symptoms• Close monitoring• Self-isolation

Progressive disease/toxicity • ARDS• Lung injury

Corticosteroid use is controversial• High doses may increase risk of secondary infection• Low to moderate doses in critically ill patients may decrease duration of

mechanical ventilation• Effect on survival is not clear


Naidoo J, et al. J Immunother Cancer. 2020;8(1):e000984.; Zhang J, et al. Brain Behav Immun. 2020;87:59-73.

ARDS, acute respiratory distress syndrome.

• Decision to treat with corticosteroids should be made on case-by-case basis• If not critically ill, wait for COVID testing to decide on use

• If critically ill, consider steroid use while waiting for COVID testing to result

• Alternative immunosuppression• Anti–IL-6 therapy

• IL-6 cytokine primarily responsible for cytokine release syndrome

• Studies show promise in both IR pneumonitis and COVID pneumonia

• Ongoing clinical trials to clarify the role of corticosteroids/anti–IL-6 agents in critically ill patients with COVID-19


Naidoo J, et al. J Immunother Cancer. 2020;8(1):e000984.

Interprofessional Collaboration in Managing Patients Receiving ICIs

• Know the irAE spectrum • Keep in mind timing of suspected irAEs and COVID-19 symptoms

• Identify risk factors• Be aware if patient is at high risk

• Review past medical history and concurrent medications

• Educate patients and caregivers• Provide information needed to report potential irAEs and COVID-19

symptoms

• Home- or local-based services (e.g., labs, port flush)

• Document treatment plan, progress, and symptoms

Interprofessional Collaboration


• Nurses• Training in use of ICI

• Understand and recognize toxicities (common and less common)

• Frequent patient evaluations/phone triage

• Patient education and re-education during and following ICI

• APPs• Thorough evaluation of patients with each cycle

• Understanding of management of irAEs

• Consistent assessment/documentation at each encounter

• Specialist referrals for suspected irAEs

Role of Nurses and Advanced Practice Practitioners (APPs)

• Provide support and monitor patients during ICI therapy

• irAE treatment as appropriate

• Educate patient and team about ICI and irAEs

• Assess patients for irAEs and identify irAEs

• Identify AEs of irAE treatments

• Review medications to determine cause of irAE

• Complete medication reconciliation

Role of Pharmacists


• Multidisciplinary ICI meeting

• Multidisciplinary ICI clinic

• Specialists identified with interest/expertise in irAEs

• Telecommunication

• EMR documentation

Models of Effective Collaboration

EMR, electronic medical record.

Patient Health and Safety Education

Patient Care

Team Support

Resources and Supplies

Interprofessional Collaboration with ICI During COVID-19

American Society of Clinical Oncology. https://www.asco.org/sites/new-www.asco.org/files/content-files/2020-ASCO-Guide-Cancer-COVID19.pdf.;Segelov E, et al. Med Onc Group Australia (draft). 2020.

https://www.asco.org/sites/new-www.asco.org/files/content-files/2020-ASCO-Guide-Cancer-COVID19.pdf

Questions & Answers

Thank You!

managing patients on immune checkpoint inhibitors in the

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