James T. Kenney, RPh, MBA, and Michael B. Atkins, MD, prepared useful Practice Aids pertaining to cancer immunotherapies for this CME/MOC/CE/CPE activity titled "Incorporating Cancer Immunotherapies Into the Oncology Treatment Arsenal in Managed Care Settings: Navigating the Complexities of Value Assessment & Cost Optimization in the Era of Immuno-Oncology." For the full presentation, monograph, complete CME/MOC/CE/CPE information, and to apply for credit, please visit us at http://bit.ly/2Er15gR. CME/MOC/CE/CPE credit will be available until December 23, 2019.

1. CTLA: cytotoxic T-lymphocyte–associated antigen; IFN-γ: 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. 2. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Accessed September 25, 2018.
Access the activity,“Incorporating Cancer Immunotherapies Into the OncologyTreatment Arsenal in Managed Care Settings: Navigating the Complexities
of Value Assessment & Cost Optimization in the Era of Immuno-Oncology,”at www.peerview.com/XEB40.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice.
Immune Checkpoint Inhibition in the
Treatment of Cancer1,2
PRACTICE AID
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
significant antitumor responses in a subset of patients with certain solid
and liquid malignancies
How do immune checkpoint inhibitors work?
o Activated T cells circulate through the body to find their cognate
antigen presented by cancer cells
o Recognition " triggering of the TCR " expression of negative
regulatory receptor PD-1 " production of IFN-γ " reactive
expression of PD-L1 " antitumor T-cell responses turned off
o This negative interaction can be blocked by anti–PD-1 or
anti–PD-L1 antibody therapies
o 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 specific tumor antigen presented by an
antigen-presenting cell
o The activation of CTLA-4 can be blocked with anti–CTLA-4
antibody therapy
Lymph node
T cell
Dendritic cell
TCR
MHC
Signal 1 Signal 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
T cells
activated
A
Q

2. 1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol.2018;36:1714-1768.
Immune-Related Adverse Events
Associated With the Immune Checkpoint
Inhibitors Used in Oncology1,2
PRACTICE AID
Access the activity,“Incorporating Cancer Immunotherapies Into the OncologyTreatment Arsenal in Managed Care Settings: Navigating
the Complexities of Value Assessment & Cost Optimization in the Era of Immuno-Oncology,”at www.peerview.com/XEB40.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice.
• In general, checkpoint inhibitor therapy should be continued with close
monitoring, with the exception of some neurologic, hematologic, and
cardiac toxicities
(Minimalornosymptoms;diagnosticchangesonly)
Grade 1
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or lab values
revert ≤ grade 1
• Corticosteroids (initial dose of 0.5-1 mg/kg/day of prednisone or equivalent)
may be administered
Grade 2
(Mild to moderate symptoms)
(Severe or life-threatening symptoms)
Grades 3/4
Grade 3 toxicities:
• Hold checkpoint inhibitor therapy
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/day or
methylprednisolone IV 1-2 mg/kg/day)
• If symptoms do not improve with 48-72 hours of high-dose corticosteroid,
infliximab may be offered for some toxicities
• Taper corticosteroids over the course of at least 4-6 weeks
• When symptoms and/or laboratory values revert to ≤ grade 1, rechallenging
with immunotherapy may be offered; however caution is advised, especially in
those patients with early-onset irAEs; dose adjustments are not recommended
Grade 4 toxicities:
• In general, permanent discontinuation of checkpoint inhibitor therapy is
warranted, with the exception of endocrinopathies that have been controlled
by hormone replacement
Brahmer JR et al. Management of Immune-Related Adverse Events in
PatientsTreatedWith Immune Checkpoint InhibitorTherapy: American
Society of Clinical Oncology Clinical Practice Guideline.
J Clin Oncol. 2018;36(17):1714-1768.
For organ-specific assessment and management of irAEs, please see the ASCO guidelines:
Additional resources available on the ASCO website:
https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/
supportive-care-and-treatment-related-issues#/29866
General recommendations and management principles include the following:
IrAEs are often diagnosed by
exclusion; other causes
should be ruled out
(including AEs of other
therapies used), but
immunotherapy-related
toxicity should always be
included in the differential
There should be a high level
of suspicion that new
symptoms are treatment-
related; early recognition,
evaluation, and treatment of
irAEs plus patient education
are essential for best outcome
Depending on severity of
irAE, management may
require corticosteroid or other
immunosuppressive treatment
and interruption or
discontinuation of therapy
If appropriate
immunosuppressive
treatment is used, patients
generally recover from irAEs
Use of immunosuppressive
therapy to manage irAEs does
not impact response to
immunotherapy
How should irAEs be diagnosed and managed?Q
A
What is the spectrum of potential irAEs?Why do irAEs occur?
Any organ system can be affected; more commonly occurring are
pulmonary (pneumonitis), dermatologic (rash, pruritus, blisters,
ulcers, vitiligo), gastrointestinal (diarrhea, enterocolitis,
transaminitis, hepatitis, pancreatitis), and endocrine (thyroiditis,
hypophysitis, adrenal insufficiency) irAEs
The precise pathophysiology is unknown, but translational
studies have shown that T-cell, antibody, and cytokine
responses may be involved
Pancreatitis,
autoimmune diabetes
Colitis
Enteritis
Encephalitis, aseptic meningitis
Thyroiditis, hypothyroidism,
hyperthyroidism Dry mouth, mucositis
Hypophysitis
Uveitis
Pneumonitis
Thrombocytopenia,
anemia
Hepatitis
Adrenal insufficiency
Nephritits
Vasculitis
Arthralgia
Neuropathy
Rash, vitiligo
Myocarditis
Activated T cell
Antithyroid
antibodies
Increasing
levels of
inflammatory
cytokines
Increasing levels
of preexisting
autoantibodies
Enhancing
complement-
mediated
inflammation due
to direct binding
of an anti–CTLA-4
antibody with
CTLA-4 expressed
on normal tissue
Increasing T-cell
activity against
antigens that
are present in
tumors and
healthy tissue
Activated T cell
Anti–CTLA-4 antibody
CTLA-4 on pituitary Complement-
mediated
inflammation
Cytokines
Tumor with antigen
and activated T cells
Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic
enhancement can also lead to a unique spectrum of immune-related adverse effects (irAEs)
A
A
Q Q

3. 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; SCLC: small cell lung cancer.
1. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm. Accessed October 19, 2018.
Access the activity,“Incorporating Cancer Immunotherapies Into the OncologyTreatment Arsenal in Managed Care Settings: Navigating the Complexities
of Value Assessment & Cost Optimization in the Era of Immuno-Oncology,”at www.peerview.com/XEB40.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice.
Rapidly Evolving Immuno-Oncology Landscape
Immune Checkpoint Inhibitors and Biomarkers:
Solid Tumors1
PRACTICE AID
Drug Ipilimumab Nivolumab Pembrolizumab Cemiplimab-rwlc Atezolizumab Avelumab Durvalumab
Mechanism Anti–CTLA-4 Anti–PD-1 Anti–PD-L1
Current Immune Checkpoint Inhibitors: Classes and Agents
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)
February
Nivolumab (bladder)
March
Avelumab
(Merkel cell carcinoma)
May
Durvalumab, avelumab,
pembrolizumab (bladder)
Pembrolizumab
+ chemotherapy
(nonsquamous NSCLC,
first line)
Pembrolizumab
(dMMR/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-rwlc (CSCC)
October
Pembrolizumab + carboplatin + paclitaxel or
nab-paclitaxel (squamous NSCLC)
November
Pembrolizumab (HCC, 2nd line)
December
Atezolizumab + bevacizumab + chemotherapy
(nonsquamous NSCLC)
Current FDA-Approved Indications for Immune Checkpoint Inhibitors1
Clinically Relevant Predictive Biomarkers
Currently used predictive biomarkers in clinical practice
• PD-L1 expression
• MSI-H or dMMR
Next emerging predictive biomarker • TMB

4. ASCO: American Society of Clinical Oncology; ESMO-MCBS: European Society for Medical Oncology-Magnitude of Clinical Benefit Scale; HR: hazard ratio; ICER: Institute for Clinical and Economic Review;
MSKCC: Memorial Sloan Kettering Cancer Center; NCCN: National Comprehensive Cancer Network; OS: overall survival; PFS: progression-free survival; RR: response rate.
1. Kaufman HL et al. J Immunother Cancer. 2017;5:38.
Oncology Value Frameworks and Their
Limitations in Assessing the Benefits
and Costs of Cancer Immunotherapies1
PRACTICE AID
Access the activity,“Incorporating Cancer Immunotherapies Into the OncologyTreatment Arsenal in Managed Care Settings: Navigating
the Complexities of Value Assessment & Cost Optimization in the Era of Immuno-Oncology,”at www.peerview.com/XEB40.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice.
Current value models:
£ Overestimate the treatment costs necessary to achieve maximum benefit
– Eg, combinations of immunotherapy may be less expensive than monotherapy if they work faster
(require less drug) and last longer
£ Overestimate the impact of acute, but reversible toxicities
– Toxicities are often short-lived (4 weeks) and manageable
– Death from noncurative therapy is typically not counted as a toxicity in comparisons
– Opportunities exist to reduce toxicity
£ Underestimate the value of long-term survival and treatment-free survival
– Time horizons need to account for long duration of benefits, including treatment-free survival
» Benefits to patients, family, community, and colleagues
£ Do not give adequate consideration to societal factors
– Benefits of potential cures
– Improvements in health and quality of life
– Potential to use curative treatments as platforms on which to build
Framework Factors Considered Purpose
Costs
Measured?
Perspective
ASCO
Net health benefit: Clinical benefit
(OS, PFS, RR), toxicity,
extended survival
Comparison of two regimens
that have been reported in a
randomized clinical trial
No Patient
ESMO-MCBS
Magnitude of clinical benefit: Prognosis
of condition, clinical benefit (OS, PFS),
long-term survival (HR, RR), quality of life,
toxicity
Comparison of magnitude
of benefit of regimens
with reported comparative
research outcome
No Societal
NCCN
Evidence
Blocks
Efficacy, safety, quality of evidence,
consistency of
evidence, affordability
Visual representation of
key factors that provide
information about the value
of the recommendations
within the guidelines
Yes Patient
MSKCC Drug
Abacus
Efficacy, cost toxicity, treatment novelty,
costs of development, rarity of disease,
population burden of condition
Intended to provide
information regarding the
proper pricing of new drugs
in the market
Yes Societal
ICER Value
Incremental cost-effectiveness ratio:
Cost new
- Cost standard
Effectiveness new
- Effectiveness standard
Comparison of two
treatments based on efficacy
and cost
Yes Societal
Comparison of Current Value Frameworks Used in Oncology
Limitations of Current Oncology Value Frameworks Related to Immuno-Oncology