Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “Can the Addition of Immunotherapy to Multimodal Management of Stage I-III NSCLC Help Break the Stalled Cycle of Poor Outcomes?” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3m1OV2m. CME/MOC credit will be available until February 27, 2023.

1. Immune Checkpoint Inhibition
Harnessing the Immune System in the Treatment of Cancer
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/CRA40
Tumor Microenvironment
Lymphoid Tissue
Immune checkpoint inhibitors modulate T-lymphocyte responses
against cancer by blocking negative regulation of immune responses
PD-1 pathway inhibits
signaling downstream of TCR
•
TCR triggered by antigen
presented by tumor cell
• Negative regulatory receptor
PD-1 expressed and PD-L1
reactively expressed
• PD-L1 binds to PD-1
T cell inactivated
T cell inactivated
T cell activated
T cell activated
Anti–PD-1 or anti–PD-L1
monoclonal antibodies
block the interaction and
negative regulation
Anti–CTLA-4 monoclonal
antibodies block negative
regulation by CTLA-4
CTLA-4 is a negative regulator
of costimulation required for
activation of an
antitumor T cell in a lymph
node upon recognition of
tumor antigen
PD-1/PD-L1
Checkpoint
Inhibition
CTLA-4
Checkpoint
Inhibition
FDA-Approved Therapies
FDA-Approved Therapies
GO
Tumor escape
Tumor escape
Tumor attack
Tumor attack
Anti–PD-1: Nivolumab
Pembrolizumab
Cemiplimab-rwlc
Anti–CTLA-4: Ipilimumab
Anti–PD-L1: Atezolizumab
Avelumab
Durvalumab
•
Proteins on T cells or cancer cells that need to be activated/inactivated to start/stop
an immune response (eg, PD-1, PD-L1, CTLA-4)
•
Serve as “brakes” that help keep immune responses in check; 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 kill cancer cells)
What Are
Immune
Checkpoints?
Tumor Microenvironment
Elimination of tumor cells
Tumor escape
With
Immunotherapy
Without
Immunotherapy
PD-1/PD-L1 Checkpoint Inhibition
Elimination of tumor cells
Tumor escape
CTLA-4 Checkpoint Inhibition
With
Immunotherapy
Without
Immunotherapy
Lymphoid Tissue

2. Expanding Role and Use of Neoadjuvant and Adjuvant
Immunotherapy in Resectable Solid Tumors
Rationale and Current Approvals/Indications
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40
Neoadjuvant immunotherapy is administered before surgery and can reduce the
size of the primary tumor as well as eliminate residual cancers cells left after surgery
Rationale:
• Lower disease burden and intact
immune system
• T-cell response generated against
in situ primary tumor with diverse
antigen load
• Fast endpoints to assess response
• Allows for translational research:
biologic and immunologic
correlative studies
Rationale:
• Lower disease burden and intact
immune system
• Immunological pathways are
disrupted by surgical stress
• No risk for delaying surgery with
adjuvant versus neoadjuvant
approach
• Prior chemotherapy or other
systemic/local therapies may help
augment immune responses
Adjuvant immunotherapy is administered after surgery and leads to an increase
in activated T cells that can eliminate residual cancer cells in the tumor bed
Comparison of adjuvant and neoadjuvant immunotherapy treatment approaches1
Immunotherapy
T cells
T-cell activation Resection surgery
Solid tumor Resection surgery Immunotherapy T-cell activation
and additional
immunotherapy
Tumor cells Artery Healthy cells Immunotherapy

3. Expanding Role and Use of Neoadjuvant and Adjuvant
Immunotherapy in Resectable Solid Tumors
Rationale and Current Approvals/Indications
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40
 Overall survival (OS) is the gold-standard outcome measure for phase 3 trials, but the protracted length of these
clinical trials in resectable cancers makes this research daunting and expensive
 One strategy to expedite clinical trials, including those assessing immunotherapies in early-stage cancer settings,
is the use of newer, innovative surrogate measurements for endpoints
 Because pathologic response reflects a therapy’s ability to eradicate tumor cells more directly than radiographic
evaluation using RECIST criteria, it may better correlate with clinically meaningful outcomes
 Several trials in different tumor types have correlated the novel endpoints with more traditional endpoints such as OS,
DFS, and RFS, but additional confirmatory studies are needed
 Many adjuvant approvals have been based on disease-free survival (DFS)
 Trials in neoadjuvant settings provide an opportunity to assess pathologic response as an early surrogate marker
for survival outcomes, and pathologic response criteria such as major pathological response (MPR) and pathologic
complete response (pCR) have been assessed in neoadjuvant immunotherapy trials; there are various definitions,
but generally:
 MPR: ≤10% of viable tumor in the treated tumor bed
 pCR: complete absence of viable tumor in the treated tumor bed
 Recently, immune-related pathologic response criteria (irPRC) have also been developed with the aim of assessing
the full spectrum of response to immunotherapy in resection specimens
 Different scoring systems exist or are in development for evaluating pathologic response in various tumor types
(eg, melanoma, lung cancer, bladder cancer)
Relevant endpoints for neoadjuvant and adjuvant immunotherapy clinical trials2-8

4. Expanding Role and Use of Neoadjuvant and Adjuvant
Immunotherapy in Resectable Solid Tumors
Rationale and Current Approvals/Indications
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40
 Adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing
radical resection
 Adjuvant treatment of patients with completely resected esophageal or gastroesophageal junction cancer with
residual pathologic disease who have received neoadjuvant chemoradiotherapy
 Adjuvant treatment of patients with melanoma with lymph node involvement or metastatic disease who have
undergone complete resection
Current perioperative approvals and indications of immunotherapies in solid tumors9
Nivolumab
 Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of
more than 1 mm who have undergone complete resection, including total lymphadenectomy
Ipilimumab

5. Expanding Role and Use of Neoadjuvant and Adjuvant
Immunotherapy in Resectable Solid Tumors
Rationale and Current Approvals/Indications
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40
 Neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer with chemotherapy adjuvant treatment
after surgery as a single agent
 Adjuvant treatment of patients with renal cell carcinoma at intermediate-to-high or high risk of recurrence following
nephrectomy, or following nephrectomy and resection of metastatic lesions
 Adjuvant treatment of patients with stage IIB, IIC, or III melanoma following complete resection
 Patients with BCG-unresponsive, high-risk, non–muscle invasive bladder cancer with carcinoma in situ with or without
papillary tumors who are ineligible for or have elected not to undergo cystectomy
Current perioperative approvals and indications of immunotherapies in solid tumors9
Pembrolizumab
 Adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II to IIIA non–small
cell lung cancer whose tumors have PD-L1 expression on ≥1% of tumor cells
Atezolizumab
1. Krishnamoorthy M et al. J Natl Cancer Inst. 2021;113:823-832. 2. Topalian SL et al. Science 2020;367:eaax0182. 3. Benitez JC et al. Clin Cancer Res. 2020;26:5068-5077. 4. Bilusic M, Gulley JL. J Natl Cancer Inst. 2021;113:799-800. 5. Krishnamoorthy M et al. J Natl Cancer Inst. 2021;113:823-
832. 6. O’Donnell JS et al. Clin Cancer Res. 2019;25:5743-5751. 7. Hellmann MD et al. Lancet Oncol. 2014;15:e42-50. 8. Cottrell TR et al. Ann Oncol. 2018;29:1853-1860. 9. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-
approval-notifications.

6. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant1-4
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40
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 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
Prevention Anticipation
Treatment
Monitoring Detection

7. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant1-4
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40
Guidance for Surgeons: Suspect, Detect, and Refer for Treatment5,6
• 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

8. 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 0.5-1.0 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
Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant1-4
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40

9.  Hold immunotherapy with radiographic evidence of pneumonitis progression
 May offer one repeat CT in 3-4 weeks; in patients who have had baseline testing, may offer a repeat
spirometry/DLCO in 3-4 weeks
 May resume immunotherapy with radiographic evidence of improvement or resolution; if no improvement,
should treat as grade 2
 Monitor patients weekly with history, physical examination, and pulse oximetry; may also offer CXR
Grade 2: Symptomatic; 1 lobe
of lung or 25%-50% of lung
parenchyma; medical intervention
indicated; limiting instrumental ADL
Grade 3: Severe symptoms
requiring hospitalization; involves
all lung lobes or 50% of lung
parenchyma; limiting self care
Grade 4: Life-threatening
respiratory compromise; urgent
intervention indicated (intubation)
 Hold immunotherapy until resolution to grade ≤1
 Prednisone 1-2 mg/kg/day and taper by 5-10 mg/week over 4-6 weeks
 Consider bronchoscopy with BAL
 Consider empiric antibiotics
 Monitor patients every 3 days with history, physical examination, and pulse oximetry; consider CXR; if no clinical
improvement after 48-72 hours of prednisone, treat as grade 3
 Discontinue immunotherapy
 Empiric antibiotics; methylprednisolone IV 1-2 mg/kg/day; if no improvement after 48 hours, may add infliximab
5 mg/kg, or mycophenolate mofetil IV 1 g 2x/day, or IVIG x 5 days, or cyclophosphamide
 Taper corticosteroids over 4-6 weeks
 Pulmonary and infectious disease consults if necessary
 Bronchoscopy with BAL +/- transbronchial biopsy
 Patients should be hospitalized for further management
How Should Pulmonary irAEs Be Diagnosed and Managed?
 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
Grade 1: Asymptomatic; confined
to 1 lobe of lung or 25% of lung
parenchyma; clinical or diagnostic
observations only
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 + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy
Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant1-4
Full abbreviations, accreditation, and disclosure information available at PeerView.com/CRA40
1. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1786. 2. Postow MA et al. N Engl J Med. 2018;378:158-168. 3. Gordon R et al. Clin J Oncol Nurs. 2017;21(suppl 2):45-52. 4. Champiat S et al. Ann Oncol. 2016;27:559-574. 5. Helmink BA et al. Ann Surg Oncol. 2020;27:1533-1545.
6. Stiles BM et al. J Thorac Cardiovasc Surg. 2020;160:1376-1382.