Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Effects in the Emergency Department

Daniel Pallin, MD, MPH, and Douglas B. Johnson, MD, MSCI, prepared useful practice aids pertaining to immune-related adverse events for this CME/MOC/CE activity titled "Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Effects in the Emergency Department." For the full presentation, monograph, complete CME/MOC/CE information, and to apply for credit, please visit us at http://bit.ly/2PRv8Ul. CME/MOC/CE credit will be available until November 20, 2019.

1. CTLA: cytotoxic T-lymphocyte–associated antigen; IFN-: interferon gamma; MHC: major histocompatibility complex; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; TCR: T-cell receptor.
1. Ribas A, Wolchock JD. Science .2018;359:1350-1355.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
They modulate T-lymphocyte responses against cancer by blocking
negative regulation of immune responses via immune checkpoints;
blockade of immune checkpoints CTLA-4, PD-1, and PD-L1 can induce
signicant antitumor responses in a subset of patients with certain solid
and liquid malignancies
How do immune checkpoint inhibitors work?
† Activated T cells circulate through the body to nd their cognate antigen presented by cancer cells
† Recognition triggering of the TCR expression of negative
regulatory receptor PD-1 production of IFN- reactive
expression of PD-L1 antitumor T-cell responses turned o
† This negative interaction can be blocked by anti–PD-1 or
anti–PD-L1 antibody therapies
† CTLA-4 is a negative regulator of costimulation that is required
for initial activation of an antitumor T cell in a lymph node after
recognition of its specic tumor antigen presented by an
antigen-presenting cell
† The activation of CTLA-4 can be blocked with anti–CTLA-4
antibody therapy
T cells
activated


Lymph node
T cell
Dendritic cell
TCR
MHC
Signal 1Signal 2
CD28
B7
CTLA-4
Anti–CTLA-4
(ipilimumab)
Via bloodstream
Tumor
T cell
Cancer cell
TCR
MHC
Anti–PD-L1 (atezolizumab, avelumab, durvalumab)
Anti–PD-1
(pembrolizumab,
nivolumab,
cemiplimab-rwlc) PD-L1
PD-1
Access the activity, “Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Eects in the Emergency Department,” at www.peerview.com/SBT40.
Immune Checkpoint Inhibitors as a New Class of Anti-Cancer Therapies
Blocking Negative Regulation of Immune Responses to Induce Antitumor Responses
1
PRACTICE AID

2. CRC: colorectal cancer; CSCC: cutaneous squamous-cell carcinoma; CTLA: cytotoxic T-lymphocyte–associated antigen; dMMR: mismatch repair deficient; HCC: hepatocellular carcinoma; HNSCC: head and neck squamous cell carcinoma; MSI-H: microsatellite instability high;
PD-1: programmed death 1; PD-L1: programmed death-ligand 1; RCC: renal cell carcinoma.
1. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Accessed August 21, 2018.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Access the activity, “Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Eects
in the Emergency Department,” at www.peerview.com/SBT40.
Immune Checkpoint Inhibitors as a New Class of Anti-Cancer Therapies
Timeline of FDA Approvals and Current Indications
1
PRACTICE AID
September
Pembrolizumab
(melanoma)
December
Nivolumab (melanoma)
March
Ipilimumab (melanoma)
2011 2014 2015 2016 2017 2018
May
Atezolizumab (bladder)
August
Pembrolizumab (HNSCC)
October
Pembrolizumab
(PD-L1+ NSCLC, first line)
Atezolizumab
(NSCLC, second line)
November
Nivolumab (HNSCC)
March
Nivolumab
(squamous NSCLC,
second line)
 October
Nivolumab
(nonsquamous
NSCLC, second line)
Pembrolizumab
(PD-L1+ NSCLC,
second line)
Nivolumab + ipilimumab
(melanoma, first line)
Ipilimumab
(melanoma, adjuvant)
 November
Nivolumab (RCC)
December
Pembrolizumab
(melanoma, first line)
January
Nivolumab (bladder)
March
Avelumab
(Merkel cell carcinoma)
May
Durvalumab, avelumab,
pembrolizumab (bladder)
Pembrolizumab
+ chemotherapy
(nonsquamous NSCLC,
first line)
Pembrolizumab
(MSI-H cancers)
August
Nivolumab
(dMMR/MSI-H CRC)
September
Pembrolizumab (gastric)
Nivolumab (HCC)
December
Nivolumab
(melanoma, adjuvant)
February
Durvalumab
(stage III NSCLC)
April
Nivolumab + ipilimumab
(RCC, first line)
June
Pembrolizumab
(PD-L1+ cervical)
July
Nivolumab + ipilimumab
(dMMR/MSI-H CRC)
August
Nivolumab
(SCLC, third line)
Pembrolizumab
+ chemotherapy
(nonsquamous NSCLC,
first line—full approval)
September
Cemiplimab
(CSCC)
Drug Ipilimumab Nivolumab Pembrolizumab Atezolizumab Avelumab Durvalumab
Mechanism Anti–CTLA-4 Anti–PD-1 Anti–PD -L1

3. aTTP: acquired thrombotic thrombocytopenic purpura; irAE: immune-related adverse effect; ITP: Immune thrombocytopenia.
1. https://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/2018-management-of-irAEs-summary.pdf. Accessed September 14, 2018.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Access the activity, “Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Eects
in the Emergency Department,” at www.peerview.com/SBT40.
Spectrum of Immune-Related Adverse Effects
Associated With Immune Checkpoint Inhibitors
Used to Treat Patients With Cancer
1
Immunotherapies used in oncology are associated with important
clinical benets, but general immunologic enhancement induced by
these agents can also lead to a unique spectrum of irAEs
Pneumonitis
Colitis Hepatitis
Myocarditis Pericarditis Arrhythmias Impaired ventricular function with heart failure and vasculitis Venous thromboembolism
Inammatory arthritis Myositis Polymyalgia-like syndrome
Rash/Inammatory dermatitis Bullous dermatoses Severe cutaneous adverse reactions
(SCAR)

Nephritis
Symptomatic nephritis
Autoimmune hemolytic anemia aTTP Hemolytic uremic syndrome Aplastic anemia Lymphopenia ITP Acquired hemophilia
Primary hypothyroidism Hyperthyroidism Hypophysitis Primary adrenal insuciency Diabetes
Transaminases Hepatitis
Uveitis/iritis Episcleritis Blepharitis
Neuropathy Meningitis Guillain-Barré syndrome Myasthenia gravis Encephalitis Transverse myelitis

Dier from toxicities of chemotherapies and other cancer therapies
Can aect any organ system, but most
commonly involve the GI tract, endocrine
glands, skin, and liver
Can have unpredictable onset (including
early or late)
Can be dicult to dierentiate from other
causes (diagnosed by exclusion)
PRACTICE AID

4. Access the activity, “Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Eects
in the Emergency Department,” at www.peerview.com/SBT40.
Answers to Common Questions Related to irAEs
That Can Occur in Patients With Cancer Treated
With Immune Checkpoint Inhibitors
1
• Pathophysiology unknown
• T-cell, antibody, and cytokine responses may be involved

• No prospective trials have dened the best treatments; recommendations based on consensus opinion • Immunosuppression used to excess temporary inammation • Glucocorticoids are usually the rst-line immunosuppressive agent • Additional immunosuppressants can be used if glucocorticoids are not initially eective • Side eects of glucocorticoid treatment can occur, and immunosuppression risk for opportunistic infections

• Can present at any time, but typically start within the rst few weeks to months after treatment initiation and can occur after
treatment discontinuation
• Dermatologic AEs typically occur rst

PRACTICE AID

5. CTLA: cytotoxic T-lymphocyte–associated antigen; irAE: immune-related adverse effect; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1.
1. Postow MA et al. N Engl J Med . 2018;378:158-168.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients. 
Access the activity, “Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Efects 
in the Emergency Department,” at www.peerview.com/SBT40.
Answers to Common Questions Related to irAEs 
That Can Occur in Patients With Cancer Treated 
With Immune Checkpoint Inhibitors
1
PRACTICE AID •  Clinical outcomes are similar between patients who do and do not require immunosuppression to treat irAEs
•  Benefcial responses can persist despite the use of immunosuppressive agents 
Does Immunosuppression to Treat irAEs Afect Response to Immune Checkpoint Blockade? 
•  irAEs associated with one type of agent (eg, anti–CTLA-4 antibodies) may not necessarily recur during subsequent treatment with another
  agent (eg, anti–PD-1/–PD-L1 antibodies) 
•  The safety of retreatment likely depends on the severity of the initial irAE
•  Patients who have had a favorable response to immune checkpoint blockade and then discontinue treatment because of irAEs generally
  maintain responses; prospective data are needed to address the necessity of restarting immunotherapy
Can Immunotherapy Be Safely Restarted After a Major irAE?
•  Patients with # risk for irAEs (eg, those with pre-existing autoimmune conditions) may still beneft from treatment
•  Age alone should not be used to exclude patients from treatment, since beneft appears to be similar regardless of age
Can Patients at an Increased Risk of irAEs Be Safely Treated With Immune Checkpoint Blockade?
•  Conficting data exist regarding whether the occurrence of irAEs is associated with # treatment efcacy •  irAEs not required for treatment beneft, although certain AEs (eg, vitiligo) are linked to # treatment response
Are There Associations Between irAEs and Treatment Efcacy?

6. CAR: chimeric antigen receptor; DDx: differential diagnosis; irAE: immune-related adverse effect; PMHx: past medical history.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
Access the activity, “Emergency Medicine and Immuno-Oncology Intersect: Recognizing and Managing Cancer Immunotherapy–Related Adverse Eects
in the Emergency Department,” at www.peerview.com/SBT40.
Managing Immune-Related Adverse Effects
in the Emergency Department

† Ask about history of cancer
† If positive, ask about cancer therapies
received within past year
– Does treatment history include
cancer immunotherapy
(eg, immune checkpoint
inhibitors, CAR-T cell therapy)?

† Almost any inammatory conditions, endocrinopathies from checkpoint inhibitors
† Cytokine-release syndrome,
neurotoxicity from CAR-T cell therapy

Change your
practice!




† Don't settle too early on any oncologic or nononcologic diagnoses
† Examples
Premature Closure on a Nononcology Diagnosis
Your Diagnosis
Sepsis
Depression
Benign headache
Cellulitis
Viral syndrome
Pneumonia
Real Diagnosis
Cytokine-release syndrome
Adrenal insuciency
Hypophysitis
Immune-mediated dermatitis
or radiation recall
Immune-mediated hepatitis
Immune-mediated pneumonitis
Premature Closure on an Oncology Diagnosis
Your Diagnosis
Immune-mediated colitis
Cytokine-release syndrome
Real Diagnosis
C. dicile colitis
Sepsis

† Immunosuppression used to reduce excessive
state of temporary inammation
† Glucocorticoids should typically be used as
rst-line immunosuppressive therapy
† Additional immunosuppressive agents
can be used if glucocorticoids are
not initially eective
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PRACTICE AID