Chair, Jessica Donington, MD, David H. Harpole Jr., MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC/AAPA activity titled “Unleashing the Potential of Perioperative Immunotherapy in Resectable NSCLC: Leveraging Science, Enhancing Collaboration, and Improving Outcomes With Neoadjuvant and/or Adjuvant Checkpoint Inhibition.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/AAPA information, and to apply for credit, please visit us at https://bit.ly/3OtwGAh. CME/MOC/AAPA credit will be available until October 22, 2024.

1. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
What Are irAEs?1
• Immune checkpoint inhibitors are associated with important clinical benefits, but general immunologic enhancement
can also lead to a unique spectrum of immune-related adverse events
• 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
Endocrine
Hyper- or hypothyroidism
Hypophysitis
Adrenal insufficiency
Diabetes
Hepatic
Hepatitis
Renal
Nephritis
Dermatologic
Rash
Pruritus
Psoriasis
Vitiligo
DRESS
Stevens-Johnson
Hematologic
Hemolytic anemia
Thrombocytopenia
Neutropenia
Hemophilia
Ocular
Uveitis
Conjunctivitis
Scleritis, episcleritis
Blepharitis
Retinitis
Respiratory
Pneumonitis
Pleuritis
Sarcoid-like granulomatosis
Cardiovascular
Myocarditis
Pericarditis
Vasculitis
Gastrointestinal
Colitis
Ileitis
Pancreatitis
Gastritis
Neurologic
Neuropathy
Guillain Barŕe
Myelopathy
Encephalitis
Myasthenia
Musculoskeletal
Arthritis
Dermatomyositis
01 Prevention
02 Anticipation
03 Detection
04 Treatment
05 Monitoring
01
02
03
04
05

2. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
Guidance for Surgeons: Suspect, Detect, and Refer for Treatment2,3
• irAEs frequently occur in the perioperative setting, either before or after surgical intervention
• irAEs occurring during neoadjuvant immunotherapy are generally manageable and in most cases should not exclude
patients from surgery
• The onus is on the surgeon to have a high degree of suspicion for potential toxicities in patients treated with immunotherapy
• Vague symptoms should not be dismissed, because nonspecific ailments can be indicative of severe toxicity
– Rheumatologic toxicities and endocrinopathies are some of the most difficult to recognize, given their relatively
nonspecific presentation
» For example, fatigue, poor energy, and low mood could represent hypophysitis or adrenal insufficiency
– Other toxicities can be essentially asymptomatic
» For example, renal and hepatic toxicity are generally only detected on routine labs
– Pneumonitis is another relevant irAE requiring awareness by surgeons, as severe pneumonitis could potentially
exclude patients from operative therapy, but significant pneumonitis has been rare in trials to date
• A comprehensive workup for irAEs, with a thorough history specifically targeted to potential irAEs, should be conducted
• Coordinate and collaborate with oncologists and other multidisciplinary experts to optimally diagnose and manage irAEs
in patients who have received/are receiving perioperative immunotherapy
• The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) have issued
guidelines for recognition and management of immune-related adverse events

3. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
General Recommendations for Treating irAEs4-7
Increasing
intensity
of
treatment
required
Grade 2
Grade 1 Grade 3 Grade 4
Moderate
Mild Severe Very severe
Symptomatic & supportive therapy
Stop treatment
Oral steroids Intravenous steroids. ------------>
• Referral to specialist
• Strong immune suppressive treatment
Increasing grade of irAE
intravenous steroids
Steroids (PO/IV): 1-2 mg/kg/d
prednisone or equivalent,
slowly taper over 4-6 weeks
For some AEs, treatment can be
restarted after resolution (eg, rash);
generally, ICI can be continued
with endocrinopathies once managed
Managed in outpatient/
community setting
Generally requires
hospital admission

4. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
 Hold immunotherapy and reassess in 1-2 weeks
 Pulse oximetry rest and ambulation
 Consider chest imaging with CT (with contrast preferred)
 Repeat in 3-4 weeks
Moderate (grade 2): 25%-50%
lung involved
Severe (grade 3-4)
Grade 3: all lobes of lung or
>50% of lung parenchyma;
limited ADLs, oxygen requirement
Grade 4: life threatening
 Hold immunotherapy
 Infectious workup (nasal swab, sputum, blood)
 Consider bronchoscopy and BAL
 Chest imaging with CT contrast
 Repeat in 3-4 weeks
 Consider empiric antibiotics
 Refractory: methylprednisolone 1-2 mg/m2
/day; if no response in 3-4 days, treat as grade 3
 Permanently discontinue immunotherapy and move to inpatient care
 Infectious workup (nasal swab, sputum, blood)
 Pulmonary and infectious disease consultation
 Bronchoscopy with BAL
 Empiric antibiotics
 Methylprednisolone 1-2 mg/m2
/day; when grade 1, taper over 6 weeks
 Refractory: infliximab, mycophenolate, or IVIG
How Should Pulmonary irAEs Be Diagnosed and Managed?4,8
 Pneumonitis: focal or diffuse inflammation of the lung parenchyma (typically identified on CT imaging)
 Diagnostic work-up: CXR, CT, pulse oximetry; for grade ≥2, may include infectious work-up
Mild (grade 1): <25% lung
involved
Additional considerations
• GI and pneumocystis prophylaxis may be offered to patients on prolonged steroid use (>12 weeks)
• Consider calcium and vitamin D supplementation with prolonged steroid use
• Bronchoscopy and biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy
Supportive care: smoking cessation and vaccinations (influenza, pneumococcal)

5. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
1. Champiat S et al. Ann Oncol. 2016;27:559-574. 2. Helmink BA et al. Ann Surg Oncol. 2020;27:1533-1545. 3. Stiles BM et al. J Thorac Cardiovasc Surg. 2020;160:1376-1382. 4. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1786. 5. https://www.esmo.org/content/
download/124130/2352601/1/ESMO-Patient-Guide-on-Immunotherapy-Side-Effects.pdf. 6. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 7. Puzanov I et al. J Immunother Cancer. 2017;5:95. 8. Provided courtesy of Marianne Davies, DNP, ACNP,
AOCNP, FAAN, 2021; adapted from AIM with Immunotherapy, NCCN, and CTCAE. 9. https://ascopubs.org/doi/full/10.1200/JCO.21.01440. 10. https://www.esmo.org/content/download/124130/2352601/1/ESMO-Patient-Guide-on-Immunotherapy-Side-Effects.pdf.
11. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. 12. https://www.sitcancer.org/research/cancer-immunotherapy-guidelines/irae/immune-checkpoint-inhibitor-related-adverse-events.
Additional Guideline Recommendations for Treating irAEs9-12

6. The AATS 2023 Expert Consensus Recommendations
for the Management of Patients With Early-Stage NSCLC1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
Levels of Evidence2
C-EO (Expert Opinion)
C-LD (Limited Data)
B-NR (Nonrandomized)
B-R (Randomized)
A
• Randomized or nonrandomized
observational or registry
studies with limitations of
design or execution; meta-
analyses of such studies
• Physiological or mechanistic
studies in human subjects
• Consensus of expert opinion
based on clinical experience
• Moderate-quality evidence
from ≥1 well-designed, well-
executed nonrandomized
studies, observational studies,
or registry studies; meta-
analyses of such studies
• Moderate-quality evidence from
≥1 randomized controlled trials
• Meta-analyses of moderate-
quality randomized controlled
trials
• High-quality evidence from >1
randomized controlled trial
• Meta-analyses of high-quality
randomized controlled trials
• ≥1 randomized controlled trials
corroborated by high-quality
registry studies
Class of Recommendation2
III: Harm (Strong)
III: No Benefit (Moderate)
IIb (Weak)
IIa (Moderate)
I (Strong)
Benefit < Risk
Benefit = Risk
Benefit ≥ Risk
Benefit >> Risk
Benefit >>> Risk
Recommendations for Optimal Diagnosis and Staging
Level of
Evidence
Class of
Recommendation
Recommendations
B-R
I
B-R
I
A
I
Appropriate staging of patients with newly diagnosed lung cancer should include CT and PET imaging. In addition,
brain imaging and invasive mediastinal staging should be performed where clinically indicated.
Thorough lymph node assessment is imperative for accurate pathologic staging and optimal oncologic outcomes.
Intraoperative lymphadenectomy should include at least 3 mediastinal stations and 1 hilar nodal station.
Lobectomy remains the SOC resection strategy for operable patients. However, anatomic sublobar resection may be
acceptable for tumors determined to be low risk for nodal involvement based on size or radiographic/histopathologic
features. It may also be an acceptable approach for patients who are high risk for lobectomy.
A
I
Early initiation of molecular sequencing and other biomarker analyses is recommended to select optimal preoperative
and postoperative treatment regimens in locally advanced patients.

7. The AATS 2023 Expert Consensus Recommendations
for the Management of Patients With Early-Stage NSCLC1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
Levels of Evidence2
C-EO (Expert Opinion)
C-LD (Limited Data)
B-NR (Nonrandomized)
B-R (Randomized)
A
• Randomized or nonrandomized
observational or registry
studies with limitations of
design or execution; meta-
analyses of such studies
• Physiological or mechanistic
studies in human subjects
• Consensus of expert opinion
based on clinical experience
• Moderate-quality evidence
from ≥1 well-designed, well-
executed nonrandomized
studies, observational studies,
or registry studies; meta-
analyses of such studies
• Moderate-quality evidence from
≥1 randomized controlled trials
• Meta-analyses of moderate-
quality randomized controlled
trials
• High-quality evidence from >1
randomized controlled trial
• Meta-analyses of high-quality
randomized controlled trials
• ≥1 randomized controlled trials
corroborated by high-quality
registry studies
Class of Recommendation2
III: Harm (Strong)
III: No Benefit (Moderate)
IIb (Weak)
IIa (Moderate)
I (Strong)
Benefit < Risk
Benefit = Risk
Benefit ≥ Risk
Benefit >> Risk
Benefit >>> Risk
Recommendations for Neoadjuvant Therapy
Level of
Evidence
Class of
Recommendation
Recommendations
B-NR
IIA
For medically operable patients with oncologically resectable stage III NSCLC with N2 disease for whom surgery is
planned, preoperative systemic therapy without radiotherapy is recommended. For those patients with superior sulcus
tumors and no evidence of N2 disease, neoadjuvant concurrent chemoradiotherapy is preferred.
B-R
I
Platinum-based chemotherapy doublet in combination with immunotherapy is the preferred neoadjuvant regimen for
medically operable patients with resectable stage II and III NSCLC, lacking EGFR and ALK alterations, regardless of
PD-L1 status. Neoadjuvant platinum-based chemotherapy doublet alone is recommended for patients with a
contraindication to immunotherapy.
C-EO
IIA
For eligible patients with resectable and medically operable stage II and III NSCLC without EGFR or ALK alterations,
neoadjuvant platinum-based chemotherapy with immunotherapy is preferred over adjuvant therapy.

8. The AATS 2023 Expert Consensus Recommendations
for the Management of Patients With Early-Stage NSCLC1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
Levels of Evidence2
C-EO (Expert Opinion)
C-LD (Limited Data)
B-NR (Nonrandomized)
B-R (Randomized)
A
• Randomized or nonrandomized
observational or registry
studies with limitations of
design or execution; meta-
analyses of such studies
• Physiological or mechanistic
studies in human subjects
• Consensus of expert opinion
based on clinical experience
• Moderate-quality evidence
from ≥1 well-designed, well-
executed nonrandomized
studies, observational studies,
or registry studies; meta-
analyses of such studies
• Moderate-quality evidence from
≥1 randomized controlled trials
• Meta-analyses of moderate-
quality randomized controlled
trials
• High-quality evidence from >1
randomized controlled trial
• Meta-analyses of high-quality
randomized controlled trials
• ≥1 randomized controlled trials
corroborated by high-quality
registry studies
Class of Recommendation2
III: Harm (Strong)
III: No Benefit (Moderate)
IIb (Weak)
IIa (Moderate)
I (Strong)
Benefit < Risk
Benefit = Risk
Benefit ≥ Risk
Benefit >> Risk
Benefit >>> Risk
Recommendations for Adjuvant Therapy
Level of
Evidence
Class of
Recommendation
Recommendations
A
I
All patients with NSCLC with pathologic stage IB-III (eighth edition) should be referred to medical oncology for
discussion of adjuvant systemic therapy after lung resection.
C-LD
IIa/IIb
For resected patients with NSCLC without pathologic nodal disease, high-risk features (lymphovascular
invasion, visceral pleural invasion, larger tumor size, positive margin, inadequate nodal sampling) should
prompt consideration of medical oncology referral and adjuvant therapy.
A
I
All resected stage IB-IIIA lung adenocarcinomas should undergo comprehensive testing for molecular
alterations, and all patients with resected stage II-IIIA should undergo tumor PD-L1 staining.
A
I
All resected stage II-IIIA lung squamous cell carcinomas should undergo PD-L1 staining.
B-R
I
All patients with resected IB-IIIA lung adenocarcinoma and with EGFR mutations should be referred to
medical oncology for discussion of adjuvant osimertinib, whether or not adjuvant cytotoxic chemotherapy is
considered possible/desired.
B-R
I
All patients with resected II-IIIA NSCLC patients with PD-L1 staining ≥1% should be referred to medical
oncology for consideration of adjuvant immunotherapy after adjuvant chemotherapy.
A
I
Postoperative radiation therapy to the mediastinum should not be routinely given to resected patients with
NSCLC with incidental/unforeseen (ie, “surprise”) pathologic N2 disease.
1. Kidane B et al. J Thorac Cardiovasc Surg. 2023;166:637-654. 2. Bakaeen FG et al. J Thorac Cardiovasc Surg. 2017;153:999-1005.

9. Strategies
for
implementation
of
immunotherapy
in
resectable
NSCLC
Postoperative
setting
Preoperative
setting
Perioperative
setting
Biological Rationale for Immune Checkpoint Inhibitor (ICI)–Based Treatment
of Patients With Resectable NSCLC
Postoperative ICIs
Postoperative
chemotherapy
(optional)
Cancer
cell
T cell
Postoperative ICIs
Postoperative
chemotherapy
(optional)
Cancer
cell
T cell
Postoperative ICIs
Postoperative
chemotherapy
(optional)
Cancer
cell
T cell PD-L1
PD-1
TCR
MHC II
Cancer
cell
T cell
Postoperative ICIs
Postoperative
chemotherapy
(optional)
T cell
repertoire
A broad spectrum
of activated
T cells eliminate
micrometastatic
disease
T cell
repertoire
A broad spectrum
of activated
T cells eliminate
micrometastatic
disease
Cancer cells
T cell
Activated T cells
eliminate
micrometastatic
disease
CD8+ T cell
DC
Macrophage
NK cell
• The presence of the whole tumor
enables triggering of a broader
repertoire of antitumor CD8+ T cells
• Preoperative tumor shrinkage
facilitates complete resection
CD8+ T cell
DC
Macrophage
NK cell
• The presence of the whole tumor
enables triggering of a broader
repertoire of antitumor CD8+ T cells
• Preoperative tumor shrinkage
facilitates complete resection
Prostaglandins
Catecholamines
TNF
IL-6/IL-8/IL-10
TAM
Treg cell
MDSC
Activation and expansion
Postsurgical stress
Surgical resection
Neoadjuvant setting Adjuvant setting
Perioperative Immunotherapy for Resectable NSCLC:
Biologic Rationale, Outcomes, and Key Clinical Trials1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40

10. Perioperative Immunotherapy for Resectable NSCLC:
Biologic Rationale, Outcomes, and Key Clinical Trials1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
Main Outcomes of Clinical Trials Evaluating
Neoadjuvant Immunotherapy or Chemoimmunotherapy Strategies
ICIs Without Chemotherapy
ICIs With Chemotherapy
Nivolumab
CheckMate
-159
0
25
50
75
100 95
45
10
10
7 7
14
0
0
21
88
97
93
7
11
4
89
5
19
10
86
15
30
10
90
6
31
13
100
10
27
13
95
2730
17
95
0
50
25
92
19
38
29
81
22 22
9
96
20
41
11
93
19
9 7
LCMC3 PRINCEPS IONESCO Gao et al. NEOSTAR NEOpredict-Lung EAST
ENERGY
Pembrolizumab
+ ramucirumab
NeoCOAST
Atezolizumab Durvalumab Sintilimab Nivolumab Nivolumab
+ ipilimumab Durvalumab Nivolumab Nivolumab
+ relatlimab
Durvalumab
+ oleclumab
Durvalumab
+ monalizumab
Durvalumab
+ danvatirsen
Surgery
ORR
MPR
pCR
Nivolumab
+ chemotherapy
NADIM
0
25
50
75
100
89
83
63
76
4643
20
54
58
62
18
82
NR
33
17
81
NR
49
25
82
NR
30
18
82
63
57
33
87
54
37
24
83
74
52
36
91
NADIM II CheckMate -816 Shu et al. Neotorch
AEGEAN KEYNOTE-671
Pembrolizumab
+ chemotherapy
SAKK 16/14
Zhang et al.
Nivolumab
+ chemotherapy
Nivolumab
+ chemotherapy
Atezolizumab
+ chemotherapy
Sintilimab
+ chemotherapy
Toripalimab
+ chemotherapy
Chemotherapy
→ durvalumab
Durvalumab
+ chemotherapy
Surgery
ORR
MPR
pCR

11. Perioperative Immunotherapy for Resectable NSCLC:
Biologic Rationale, Outcomes, and Key Clinical Trials1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
Ongoing Clinical Trials Evaluating ICIs in Resectable NSCLC
Endpoints
Clinical Trial Evaluating Perioperative Immunotherapy
Phase
• pCR
• Safety
NeoCOAST-2
II
• EFS
CheckMate -77T
III
• EFS
IMpower030
• EFS
• MPR
RATIONALE-315
• pCR
NCT05157776
R
Chemotherapy + durvalumab + oleclumab
(4 cycles)
Chemotherapy + durvalumab + monalizumab
(4 cycles)
Durvalumab + oleclumab
(1 year)
Durvalumab + monalizumab
(1 year)
Surgery
R
Chemotherapy + nivolumab
Chemotherapy Q3W
(3 cycles)
Nivolumab
(1 year)
Placebo
(1 year)
Surgery
R
Chemotherapy + atezolizumab
Chemotherapy + placebo Q3W
(4 cycles)
Atezolizumab
(1 year)
Placebo
(1 year)
Surgery
R
Chemotherapy + tislelizumab
Chemotherapy + placebo Q3W
(3-4 cycles)
Tislelizumab
(8 cycles)
Placebo
(12 cycles)
Surgery
R
Chemotherapy + sintilimab Q3W
(2 cycles)
Chemotherapy + sintilimab Q3W
(4 cycles)
Chemotherapy + sintilimab Q3W
(2 cycles; optional)
Placebo
(39 weeks)
Surgery

12. Perioperative Immunotherapy for Resectable NSCLC:
Biologic Rationale, Outcomes, and Key Clinical Trials1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/HXS40
Ongoing Clinical Trials Evaluating ICIs in Resectable NSCLC
Endpoints
Clinical Trial Evaluating Adjuvant ICIs
• DFS
PEARLS
• DFS in PD-L1+ and overall populations
BR31
• DFS
• OS
ANVIL
• DFS in PD-L1+, stage II-IIIA and ITT populations
IMpower010
• Investigator-assessed DFS
CANOPY-Aa
R
Pembrolizumab
(1 year)
Placebo
R
Durvalumab
(1 year)
Placebo
R
Nivolumab
(1 year)
Observaation
R
Atezolizumab
(1 year)
Best supportive care
R
Canakinumab
(1 year)
Placebo
a
Patients had stage II-IIIB disease according to the eighth edition of the TNM classification.
1. Mountzios G et al. Nat Rev Clin Oncol. 2023;20:664-677.