Jessica Donington, MD, Natasha Leighl, MD, MMSc, FRCPC, FASCO, and Brendon Stiles, MD, prepared useful practice aids pertaining to the role of immunotherapy in lung cancer for this CME/MOC/CNE activity titled, "The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons." For the full presentation, monograph, complete CME/MOC/CNE information, and to apply for credit, please visit us at http://bit.ly/2WibbtU. CME/MOC/CNE credit will be available until June 16, 2020.

1. Immune Checkpoint Inhibition
Harnessing the Immune System in the
Treatment of Cancer
Access the activity, “The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of
Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons,” at
PeerView.com/CPZ40.
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
APC: antigen-presenting cell; CD: cluster of differentiation; CTLA-4: cytotoxic T-lymphocyte associated antigen 4; IFN-γ: interferon gamma; MHC: major histocompatibility complex; NSCLC: non–small cell lung cancer; PD-1: programmed cell death protein 1; PD-L1: programmed death
ligand 1; TCR: T-cell receptor.
1. Adapted from: Soularue E et al. Gut. 2018;67:2056-2067.
• Proteins on T cells or cancer cells that need to be activated/inactivated
to start/stop an immune response
– Examples include PD-1, PD-L1, CTLA-4
PD-1/PD-L1 Checkpoint Inhibition1
Without
Immunotherapy
With
Immunotherapy
MHC
Antigen
TCR
PD-1
PD-L1
Anti–PD-L1
Anti–PD-1
Tumor
cell
Tumor escape
Inactivation
of T Cell
Activation
of T Cell
Elimination of
tumor cells
CTLA-4 Checkpoint Inhibition1
Without
Immunotherapy
With
Immunotherapy
MHC CD80/86
CTLA-4
Anti–
CTLA-4
antibody
APC
Antigen
TCR
Inactivation
of T Cell
Activation
of T Cell
Tumor escape Elimination of
tumor cells
• Serve as “brakes” that help keep immune responses in check and can prevent T cell
response against cancer cells
• Can be blocked by immune checkpoint inhibitors
– The “brakes” on the immune system are released and T cells are able to attack and
ill cancer cells
Immune Checkpoints
• Activated T cells recognize cognate antigen presented by cancer
cells  TCR triggered  negative regulatory receptor PD-1
expressed  IFN-γ produced  reactive expression of PD-L1
 antitumor T-cell responses turned off
This negative interaction can be blocked by anti–PD-1 or
anti–PD-L1 antibody therapies
– Examples of anti–PD-1 antibodies: nivolumab, pembrolizumab,
cemiplimab-rwlc
– Examples of anti–PD-L1 antibodies: atezolizumab, avelumab,
durvalumab
• CTLA-4 is a negative regulator of costimulation that is required for
initial activation of an antitumor T cell in a lymph node upon
recognition of tumor antigen
This negative interaction can be blocked by anti–PD-1 or
anti–PD-L1 antibody therapies
– Examples of anti–CTLA-4 antibodies: ipilimumab, tremelimumab

2. Current and Emerging Roles of
Immunotherapy in NSCLC1-4
Access the activity, “The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of
Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons,” at
PeerView.com/CPZ40.
PRACTICE AID
Timing, Dose, and Duration of Durvalumab Treatment
Dosing: 10 mg/kg IV infusion
over 60 min Q2W
Continue Q2W until unacceptable toxicity,
disease progression, or a max of 12 mo
Should be initiated within 42 days post-cCRT
• Starting treatment within 14 days post-cCRT
was associated with the best outcomes
A Multimodal Treatment Approach Involving Surgery, Radiation, Chemotherapy, and Immunotherapy
• Combining and/or sequencing PD-1/PD-L1 checkpoint inhibitors with chemotherapy and radiotherapy can produce synergistic treatment responses across the
NSCLC disease spectrum
• It is not yet known how, when, and where to integrate PD-1/PD-L1 checkpoint inhibitors into the treatment regimen to maximally benefit patients
• It appears likely that optimal strategies for combining and sequencing vary depending on whether or not the disease is resectable
• Significant unmet need in locally advanced NSCLC for novel therapies to improve outcomes beyond those achieved with cCRT
• Durvalumab significantly improved PFS and OS vs placebo in PACIFIC → first major advance in decades for unresectable stage III NSCLC
Indications
Patients must have a CT scan to confirm
no PD before initiating durvalumab
Durvalumab is an anti–PD-L1 checkpoint inhibitor FDA approved and indicated for patients with unresectable
stage III NSCLC whose disease has not progressed following cCRT
Patients should NOT receive durvalumab if they are
X Under 18 years of age
X Being treated for an autoimmune disease or have received an organ transplant
X Pregnant, planning to become pregnant, or breastfeeding
Patients may be
treated regardless
of PD-L1 expression
or EGFR mutation
status

3. Current and Emerging Roles of
Immunotherapy in NSCLC1-4
Access the activity, “The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of
Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons,” at
PeerView.com/CPZ40.
PRACTICE AID
Rationale for Neoadjuvant Immunotherapy in Resectable, Early Disease
Neoadjuvant treatment with PD-1/PD-L1 CPIs before tumor resection may provide several benefits that improve prognosis in patients with early-stage,
resectable NSCLC
• Reduction of tumor size to allow for a potentially less morbid resection
• Ability of patients to tolerate therapy better before surgery compared with afterward
• Earlier eradication of nodal and micrometastatic disease
• Introducing immunotherapy while the primary tumor is still in the body facilitates
expansion and activation of tumor-specific T cells that engage in systemic
surveillance to identify and attack future micrometastases
• Availability of pre- and post-treatment specimens provides opportunity to rapidly
assess treatment efficacy/pathologic response
• Opportunity to evaluate potential biomarkers for response and toxicity
• Several ongoing trials combine neoadjuvant CPI treatment with other
therapies or strategies in an attempt to maximize the treatment response
Selected Trials of Adjuvant Immunotherapy for NSCLC
PEARLS (NCT02504372): Phase 3
IMpower010 (NCT02486718): Phase 3
Atezolizumab BSCvs 1° endpoint: DFS
Active,
Not
Recruiting
• Complete resection (stage IB-IIIA)
• Resection 4-12 weeks prior to
enrollment
• Cisplatin eligible
• Planned N = 1,280
Pembrolizumab Placebovs 1° endpoint: OS, LCSS
Recruiting
• Complete resection (stage IB-IIIA)
• Specimen for PD-L1 expression
testing
• Any histology
• Patients with 2 synchronous
primary NSCLC cancers excluded
• Planned N = 1,080
ANVIL (NCT02595944): Phase 3
Nivolumab Observationvs 1° endpoint: DFS, OS
Recruiting
• Complete resection (stage IB-IIIA)
• CT ≤1 mo since randomization to
confirm no PD
• No prior checkpoint inhibitor
treatment
• Planned N = 903
BR31 (NCT02273375): Phase 3
PEARLS (NCT02504372): Phase 3
Durvalumab Placebovs 1° endpoint: DFS
Recruiting
• Complete resection (stage IB-IIIA)
• No neoadjuvant chemotherapy
• Prior postoperative adjuvant
chemotherapy is permissible
• Planned N = 1,360

4. Current and Emerging Roles of
Immunotherapy in NSCLC1-4
Access the activity, “The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of
Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons,” at
PeerView.com/CPZ40.
PRACTICE AID
Selected Trials of Neoadjuvant Immunotherapy for NSCLC
PEARLS (NCT02504372): Phase 3
J1772 (NCT03237377): Phase 2
Durvalumab
± tremelimumab + RT
1° endpoint: safety
Active,
Not
Recruiting
• Stage IIIA
• No prior checkpoint inhibitor
treatment or anticancer vaccine
• Planned N = 32
Nivolumab
± ipilimumab
1° endpoint: safety
Recruiting
• Squamous or nonsquamous stage
IB-IIIA
• No preoperative chemotherapy
or any other cancer therapy
• CT or MRI prior to enrollment to
confirm no brain metastases
• Planned N = 30
AAAQ3153 (NCT02716038): Phase 2
Atezolizumab
+ nab-paclitaxel
+ carboplatin
Historical
chemotherapy
responses
vs 1° endpoint: MPR
Recruiting
• Squamous or nonsquamous
stage IB-IIIA
• Specimen for PD-L1 expression
testing
• Planned N = 30
J1414 (NCT02259621): Phase 2CheckMate -816 (NCT02998528):
Phase 3
Nivolumab +
platinum doublet
or ipilimumab
Platinum doublet
chemotherapy
vs 1° endpoint:
OS, MPR, TTDM
Recruiting
• Stage IB-IIIA
• Available primary lung
tumor tissue
• No prior checkpoint inhibitor
treatment
• Planned N = 350
Pembrolizumab 1° endpoint: safety, tumor response,
pathologic response
Recruiting
• Stage II-IIIA
• No anticancer treatment within
30 days prior to enrollment,
including systemic therapy, RT,
or major surgery
• Planned N = 30
NEOMUN (NCT03197467): Phase 2

5. Current and Emerging Roles of
Immunotherapy in NSCLC1-4
Access the activity, “The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of
Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons,” at
PeerView.com/CPZ40.
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
BSC: best supportive care; cCRT: concurrent chemoradiotherapy; CPI: checkpoint inhibitor; CT: computed tomography; DFS: disease-free survival; EFS: event-free survival; EGFR: epidermal growth factor receptor; LCSS: lung cancer–specific survival; MPR: major pathologic response; MRI:
magnetic resonance imaging; NSCLC: non–small cell lung cancer; PD: progressive disease; PD-1: programmed death protein 1; PD-L1: programmed death ligand 1; Q2W: every 2 weeks; RT: radiation therapy; SBRT: stereotactic body radiation therapy; TTDM: time to death or distant metastases.
1. Durvalumab (Imfinzi) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf. Accessed April 17, 2019. 2. Carbone DP et al. J Thorac Oncol. 2015;10:974-984. 3. Owen D et al. J Thoracic Dis. 2018;10:S404-S411. 4. https://clinicaltrials.gov.
Accessed April 17, 2019.
Selected Trials of Neoadjuvant + Adjuvant Immunotherapy for NSCLC
LCMC3 (NCT02927301): Phase 2
Atezolizumab 1° endpoint: MPR
Recruiting
• Stage IB-IIIA or selected IIIB
• Adequate primary tumor biopsy tissue
• No prior therapy for lung cancer
• Planned N = 180
J1414 (NCT02904954): Phase 2
Durvalumab
± SBRT 1° endpoint: DFS
Recruiting
• Stage I (>2 cm), II, and IIIA
• No prior therapy for lung cancer
• Planned N = 60
SAKK 16/14 (NCT02572843): Phase 2
Durvalumab 1° endpoint: PFS
Active,
Not
Recruiting
• Stage T1-3N2M0, stage IIIA (N2)
• NSCLC irrespective of genomic
aberrations or PD-L1 expression status
• Planned N = 68
TOP 1501 (NCT02818920): Phase 2
Pembrolizumab 1° endpoint
surgical feasibility
Active,
Not
Recruiting
• Stage IB (≥3 cm), IIA/IIB, or IIIA
• No prior therapy for lung cancer
• Planned N = 32
GECP 16/03_NADIM (NCT03081689):
Phase 2
Nivolumab + paclitaxel
+ carboplatin
1° endpoint: PFS
Active,
Not
Recruiting
• Stage IIIA
• No EGFR or ALK mutation
• Planned N = 46
IMpower030 (NCT03456063): Phase 3
Atezolizumab
+ platinum-based chemo
1° endpoint:
MPR, EFS
Recruiting
• Squamous or nonsquamous stage II-IIIB (T3N2 only)
• No prior therapy for lung cancer
• No EGFR or ALK mutation
• Planned N = 374
Placebo +
platinum-based chemo
vs
KEYNOTE-671 (NCT03425643): Phase 3
Pembrolizumab + platinum
doublet chemo
1° endpoint:
EFS, OS
Recruiting
• Stage IIB or IIIA
• No prior therapy for lung cancer
• Planned N = 786
Placebo + platinum
doublet chemo
vs

6. Guidance for Immune-Related Adverse
Effects Associated With Immunotherapy1-4
Access the activity, “The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of
Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons,” at
PeerView.com/CPZ40.
PRACTICE AID
What Are irAEs?
• 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
• Any organ system can be affected, but 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
Nervous system
Cardiovascular
Pulmonary
Gastrointestinal
Musculoskeletal
Ocular
Endocrine
Dermatologic
Hematologic
Renal

7. Guidance for Immune-Related Adverse
Effects Associated With Immunotherapy1-4
Access the activity, “The Expanding Role of Immunotherapy in Locally Advanced and Earlier Stages of
Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Thoracic Surgeons,” at
PeerView.com/CPZ40.
PRACTICE AID
This Practice Aid has been provided as a quick reference to help learners apply the information to their daily practice and care of patients.
a
For irAE guidelines, please visit: https://www.asco.org/practice-guidelines/quality-guidelines/guidelines/supportive-careand-treatment-related-issues#/29866.
AE: adverse effect; irAE: immune-related adverse effect.
1. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1786. 2. Calabrese LH et al. Nat Rev Rheumatol. 2018;14:569-579. 3. Durvalumab (Imfinzi) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761069s002lbl.pdf. Accessed April 17, 2019.
4. Postow MA et al. N Engl J Med. 2018;378:158-168.
How Should irAEs be Diagnosed and Managed?
Minimal or No Symptoms; Diagnostic Changes Only
• In general, immunotherapy should be continued with close monitoring, with the exception of some neurologic, hematologic, and
cardiac toxicities
Mild to Moderate Symptoms
• 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
Severe or Life-Threatening Symptoms
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 considered; 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
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 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 appear to
impact response to
immunotherapy
Grade 1
Grade 2
Grade 3/4
Additional
resources are
available on the
ASCO website:a
www.asco.org