Roy H. Decker, MD, PhD, and Sarah B. Goldberg, MD, MPH, prepared useful practice aids pertaining to lung cancer for this CME activity titled "The Era of Immunotherapy in Stage III NSCLC: Exploring the Evidence and Practicalities of Integrating Checkpoint Inhibition Into the Multimodal Treatment Arsenal." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2PU3iaZ. CME credit will be available until December 6, 2019.

1. a
Time from randomization to the first documented tumor progression, or death in the absence of progression. b
ORR as measured from baseline scan post-CRT completion.
AE: adverse effect; BIRC: blinded independent review committee; cCRT: concurrent chemoradiation therapy; DOR: duration of response; NSCLC: non–small-cell lung cancer; ORR: objective response rate; PRO: patient-reported outcome; PS: performance status;
Q2W: once every two weeks; RECIST: Response Evaluation Criteria in Solid Tumors.
1. Paz-Ares L et al. 2017 European Society for Medical Oncology Congress. LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929. 3. Antonia SJ et al. IASLC 20th World Conference on Lung Cancer. Abstract PL02.01. 4. Antonia SJ et al for the PACIFIC Investigators.
N Engl J Med. 2018 Sep 25. Epub ahead of print.
IMMUNE CHECKPOINT INHIBITION AS A KEY TREATMENT STRATEGY IN STAGE III NSCLC
Current Evidence and Ongoing Trials
PRACTICE AID
Access the activity, “The Era of Immunotherapy in Stage III NSCLC: Exploring the Evidence and Practicalities of Integrating
Checkpoint Inhibition Into the Multimodal Treatment Arsenal,” at www.peerview.com/JXJ40.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
PACIFIC TRIAL1-4 The first phase 3 trial to test an immune checkpoint inhibitor as sequential treatment in patients with stage III NSCLC who had not progressed
following platinum-based chemotherapy concurrent with radiation therapy
Durvalumab
10 mg/kg Q2W up to 12 mo
n = 476
Placebo
10 mg/kg Q2W up to 12 mo
n = 237
• Stage III, locally advanced, unresectable NSCLC
• No progression following definitive platinum-based cCRT
(≥2 cycles)
• ≥18 years of age
• WHO PS score 0 or 1
• Estimated life expectancy ≥12 wk
All-comers population
Patients
Co-primary
• PFS by BIRC (RECIST v1.1)
• OS
Endpoints
Secondary
• ORR (per BIRC)
• DOR (per BIRC)
• Safety/tolerability
• PROs
Median PFSa
Durvalumab
Placebo
17.2 mo
(95% CI, 13.1-23.9)
5.6 mo (95% CI, 4.6-7.7)
P < .001
Stratified HR for disease progression or death
0.51 (95% CI, 0.41-0.63)
ORRb
Durvalumab
Placebo
30.0%
17.8%
P < .001
2:1 randomization stratified by age, sex, and smoking history
1-42 days post-cCRT
FDA Approved on February 16, 2018; Indicated for:
Patients with unresectable stage III NSCLC whose disease has not progressed following
concurrent platinum-based chemotherapy and radiation therapy
Recommended Dosage
10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until
disease progression, unacceptable toxicity, or a maximum of 12 months
NewSOC
Most Frequent AEs: Durvalumab vs Placebo
Cough
35.4% vs 25.2%
Pneumonitis/
radiation pneumonitis
33.9% vs 24.8%
Fatigue
23.8% vs 20.5%
Dyspnea
22.3% vs 23.9%
Diarrhea
18.3% vs 18.8%
Overall Survival
Durvalumab
Placebo
66.3%
(95% CI, 61.7-70.4)
55.6%
(95% CI, 48.9-61.8)
Two-sided P = .005
24-mo
OSrate
Durvalumab significantly prolonged OS vs placebo
(stratified HR for death, 0.68; 99.73% CI, 0.47-0.997; P = .0025)
(95% CI, 13.0-23.6)
(95% CI, 25.8-34.5)
Durvalumab Placebo
Grade 3/4 AEs
29.9% 26.1%
OTHER IMMUNOTHERAPY TRIALS IN STAGE III NSCLC
Design: Consolidation Therapy
Treatment Phase Primary Endpoint Name ClinicalTrials.gov ID
Nivolumab 3 OS/PFS RTOG 3505 NCT02768558
Pembrolizumab 2 Time to death or distant metastasis NCT02343952
Pembrolizumab 1 Safety NCT02621398
Atezolizumab 2 Safety/timing NCT02525757
Nivolumab 2 Safety NICOLAS NCT02434081

2. IMMUNE-RELATED ADVERSE EFFECTS ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITORS
Underlying Mechanisms, Spectrum of Presentation, and Management1,2
PRACTICE AID
Access the activity, “The Era of Immunotherapy in Stage III NSCLC: Exploring the Evidence and Practicalities of Integrating
Checkpoint Inhibition Into the Multimodal Treatment Arsenal,” at www.peerview.com/JXJ40.
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
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)
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
Q Q
A
A
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
Increasing T-cell
activity against
antigens that
are present in
tumors and
healthy tissue
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
Activated T cell
Anti–CTLA-4 antibody
CTLA-4 on pituitary Complement-
mediated
inflammation
Cytokines
Tumor with antigen
and activated T cells

3. 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 EFFECTS ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITORS
Underlying Mechanisms, Spectrum of Presentation, and Management1,2
PRACTICE AID
Access the activity, “The Era of Immunotherapy in Stage III NSCLC: Exploring the Evidence and Practicalities of Integrating
Checkpoint Inhibition Into the Multimodal Treatment Arsenal,” at www.peerview.com/JXJ40.
• 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
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 the
best outcome
Depending on the severity of the 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?
• Hold checkpoint inhibitor therapy for most grade 2 toxicities
• Consider resuming immunotherapy when symptoms and/or lab values revert to ≤grade 1
• Corticosteroids (initial dose of 0.5-1 mg/kg/day of prednisone or equivalent) may be administered
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 PatientsTreated
With Immune Checkpoint InhibitorTherapy: American Society of Clinical Oncology
Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-1768.
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
Grade 2
(Mild to moderate symptoms)
(Severe or life-threatening symptoms)
Grades 3/4
Q
A

4. 1L: first line; 2L: second line; CTLA: cytotoxic T-lymphocyte–associated antigen; IFN-γ: interferon gamma; MHC: major histocompatibility complex; mNSCLC: metastatic non–small-cell lung cancer;
NSCLC: non–small-cell lung cancer; 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.
Access the activity, “The Era of Immunotherapy in Stage III NSCLC: Exploring the Evidence and
Practicalities of Integrating Checkpoint Inhibition Into the Multimodal Treatment Arsenal,”
at www.peerview.com/JXJ40.
UNDERSTANDING IMMUNE CHECKPOINT INHIBITION
Use of Anti–CTLA-4, Anti–PD-1, and Anti–PD-L1
Inhibitors as a Treatment for NSCLC
PRACTICE AID
How do immune checkpoint inhibitors work?1
• 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
Timeline of checkpoint inhibitor approvals for NSCLC
2015 201820172016
Nivolumab
squamous
mNSCLC 2L
Pembrolizumab
PD-L1+
mNSCLC 2L
Durvalumab
stage III NSCLC
Atezolizumab
mNSCLC 2L
Nivolumab
nonsquamous
mNSCLC 2L
Pembrolizumab
+ pemetrexed/carboplatin
nonsquamous mNSCLC 1L
Pembrolizumab
PD-L1+
mNSCLC 1L
Anti–PD-1 Anti–PD-L1
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 PD-L1
T-cells
activated
PD-1
Anti–PD-1 (Pembrolizumab,
Nivolumab, Cemiplimab-rwlc)
Anti–PD-L1
(Atezolizumab,
Avelumab,
Durvalumab)
Nivolumab
nonsquamous
mNSCLC 2L
Pembrolizumab
+ carboplatin
+ paclitaxel or
nab-paclitaxel
squamous mNSCLC 1L