Transforming Care and Outcomes With Immunotherapy in Stage I-III Resectable NSCLC: A Case Exploration of New Standards and Emerging Approaches

Co-Chairs, Jessica Donington, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to lung cancer for this CME/MOC/AAPA activity titled “Transforming Care and Outcomes With Immunotherapy in Stage I-III Resectable NSCLC: A Case Exploration of New Standards and Emerging Approaches.” 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/3TxdcP5. CME/MOC/AAPA credit will be available until June 7, 2025.

1. NSCLC Treatment Algorithm
1

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Stage and associated workup
• cT1abc, N0: PFT, bronch, mediastinal staging, PET
• cT2a-4, N0-3, M0-1: PFT, bronch, mediastinal staging, PET, brain MRI, and biomarker/mutation testing
Surgical candidate?
Lobectomy
(preferred)
or
segmentectomy/
wedge resection
(in select cases)
SBRT
or
conventionally
fractionated RT
Surgical resection
Mutational testing (if not conducted earlier)
EGFR ex19del/ex21 L858R present?
Surgical resection
T1
N0
M0
Operable disease
Yes
Yes
Yes
No
No
No
Multidisciplinary discussion for
neoadjuvant candidacy
T1–2, N1–2, M0
T3–4, N0–1, M0
Neoadjuvant
chemoimmunotherapy
Neoadjuvant portion of
perioperative immunotherapy
Nivolumab + platinum-based
chemotherapy x 3 cycles
CheckMate -816: Nivo + chemo vs
chemo (see FDA approval)
mEFS: 31.6 vs 20.8 mo (HR, 0.63)
Pembrolizumab + platinum-containing chemotherapy x 4
cycles as neoadjuvant
KEYNOTE-671: Pembro + chemo vs placebo + chemo
(neoadjuvant) / pembro vs placebo (adjuvant)
(see FDA approval)
mOS: not reached vs 52.4 mo; mEFS: not reached vs 17 mo
Adjuvant chemotherapy
Platinum-based chemotherapy
LACE Meta-analysis: 5-y OS improvement
of 5.4% vs no chemo
Adjuvant immunotherapy (stage II-IIIA)
Atezolizumab x 16 cycles
Stage II-IIIA, PD-L1 ≥1% (see FDA
approval)
Atezolizumab x 16 cycles
IMpower010: Atezo vs BSC
mDFS: NR vs 35.3 mo (HR, 0.66)
Pembrolizumab x 1 y
Stage IB (T2a ≥4 cm), II, or IIIA, regardless
of PD-L1 expression (see FDA approval)
Pembrolizumab x 1 y
PEARLS/KEYNOTE-091: Pembro vs placebo
mDFS: 53.6 vs 42.0 mo (HR, 0.76)
Adjuvant targeted therapy
Osimertinib x 3 y
ADAURA: Osimertinib vs placebo
2-y DFS (stage II-IIIA): 90% vs 44% (HR, 0.17)
NSCLC treatment algorithm
Stage IB-IIIA
(resectable)Stage IA
Surgical resection
Adjuvant portion of perioperative immunotherapy
Pembrolizumab, up to 13 cycles
KEYNOTE-671: Pembro + chemo vs placebo + chemo
(neoadjuvant) / pembro vs placebo (adjuvant)
(see FDA approval) 
mOS: not reached vs 52.4 mo; mEFS: not reached vs 17 mo
Yes
1. Adapted from an algorithm created by Aakash Desai, MBBS, MPH, and Matthew Ho, MD, PhD, with recent updates from NCCN Guidelines Version 2, 2024. Used with permission from the authors.

2. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
1-15

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Immune Checkpoint Inhibitors (ICIs)
•Monoclonal antibodies against CTLA-4,
PD-1, or PD-L1
•ICIs have transformed the treatment of
many cancer types
•In some cases, ICIs are associated with
immune-related adverse events (irAEs) Management of irAEs
•Treatment depends on the affected organ
and severity of symptoms
•ICIs should be halted following irAE
diagnosis in most patients, except those
with very mild symptoms
•Glucocorticoids are the first-line therapy for
most severe irAEs, following which,
nonsteroidal synthetic immunosuppressive
agents or intravenous immunoglobulin can be
used if symptoms do not improve within
48-72 hours
•Monoclonal antibody therapy against, for
example, TNF or IL-6, or plasma exchange
can be used for some irAEs
•Deciding when to recommence ICI therapy to
continue cancer treatment should be
undertaken by a multidisciplinary team
comprising organ specialists and oncologists
•ICIs should be permanently discontinued in
individuals with grade 3 myocarditis,
pneumonitis, and hepatitis, among others,
and all grade 4 irAEs
Outlook
•Some studies have identified biomarkers
associated with a higher risk of irAEs, such
as pretreatment levels of serum
autoantibodies
•Further studies are required before
autoantibodies can be used to guide
management strategies in clinical practice
•Studies will be needed to characterize the
associated risk, frequency, and
manifestations of irAEs as new ICIs or
combinations are approved
DIAGNOSIS
Diagnostic
workup of
individuals
with suspected
irAEs depends
on the affected
organ
SYSTEMIC
Sicca syndr ome and v asculitis
irAEs can
range in
severity
and affect
almost any
organ
Polyneur opathy
Uveitis
Interstitial
lung
disease
Hepatitis
Vitiligo
Myalgia
and
myositis
Enterocolitis
Thyroiditis
Hypophysiti s
Myocar ditis
Adrenitis
Arthralgia
and
arthritis
Epidemiology of irAEs
•Onset generally occurs between 2 and 16
weeks after ICI initiation depending on the
affected organ
•Some reports of onset within a few days of
starting therapy and >1 year after completion
•In general, PD-1 and PD-L1 inhibitors are
tolerated better than CTLA-4 inhibitors
•ICI monotherapy is associated with fewer
irAEs than PD-1/PD-L1 and CTLA-4
combination therapy
Preexisting autoimmune disease is a
strong risk factor for developing irAEs
Mechanisms of irAEs
•CTLA-4 inhibitors: imbalance in ratio of
regulatory T cells (which dampen the immune
response) to type 17 T helper cells (which
promote the immune response), autoantibody
production, and complement-mediated
cellular damage
•PD-1/PD-L1 inhibitors: less well-understood,
but could be due to reduced regulatory T cell
numbers
ICIs targeting the CTLA-4 or PD-1/PD-L1
pathways facilitate T-cell activation and
survival, which induce an antitumor
immune response Monitoring organ function during ICI
therapy to enable early detection of
irAEs is warranted only for some
organs, such as thyroid and liver
Endocrine irAEs of all severities should be
treated with hormone supplementation

3. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
1-15

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Society for Immunotherapy of Cancer (SITC) Consensus Definitions for irAEs
Recurrent irAEs
•Occur in the same organ
•Occur at least twice after IO
discontinuation
Steroid-unresponsive irAEs
•No clinical improvement after a
standard timeframe of guideline-based
irAE-directed steroid therapy
•Steroid-refractory irAEs derived no
clinical benefit from steroids
Steroid-resistant irAEs
•Derived some clinical benefit without
resolution of the event
Steroid-dependent irAEs
•Some improvement with guideline-
based irAE-directed steroid therapy;
however, a taper is not possible
•irAEs requiring ongoing steroids for
≥12 weeks are “chronically
steroid dependent”
Delayed/late-onset irAEs
•Occur >3 months after ICI
discontinuation
Chronic irAEs
•Persist beyond 3 months of ICI
discontinuation
Two subtypes
1.Chronic + active: ongoing
inflammation, requires ongoing
immunosuppression
2.Chronic + inactive: absence of
ongoing inflammation, not requiring
ongoing immunosuppression
Natural History of irAEs
Multisystem irAEs
•Occur concomitantly with another irAE
or during treatment for the first irAE
•irAEs occurring in the same or
different organ system
•If occurring in the same system, they
affect different tissues
Patterns of irAEs Response to irAE Treatment

4. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
1-15

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Guidance for Surgeons: Suspect, Detect, and Refer for Treatment
• 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; 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

5. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
1-15

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Patterns and Duration of Various irAEs
Pneumonitis: most common fatal toxicity associated with PD-(L)1 monotherapy
Myocarditis: most common fatal toxicity associated with PD-(L)1/CTLA-4 combination therapy
Endocrinopathies: most common toxicities associated with PD-(L)1 monotherapy
Hepatitis: a common toxicity associated with immunotherapy and targeted therapy combinations
Cutaneous toxicities: earliest toxicity associated with PD-(L)1 monotherapy and combinations
Nephritis: a common toxicity associated with chemo-IO
4 6 8 10 12 14 >30
4 6 8 10 12 14 >30
4 6 8 10 12 14 >30
Duration of Treatment, wk Duration of Treatment, wk
CTLA-4 Inhibitor
PD-1/PD-L1 Inhibitor PD-1/PD-L1 + CTLA-4 Inhibitors
Duration of Treatment, wk
Toxicity Grade
Toxicity Grade
Toxicity Grade
Colitis Liver toxicity
Skin, rash, or
pruritus
Pneumonitis
Endocrinopathy Nephritis

6. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
1-15

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General Recommendations for Treating irAEsThe Principles of irAEs Management
Increasing intensity
of treatment required
Grade 2Grade 1 Grade 3 Grade 4
ModerateMild Severe Very severe
Symptomatic and suppor tive 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/
communi ty setting
Generally requires
hospital admission
01Preventio n
02Anticipation
03Detection
04Treatment
05Monitoring
01
02
0304
05

7. Immune-Related Adverse Events of Cancer Immunotherapies
Become Aware and Stay Vigilant
1-15

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1. Ramos-Casals M et al. Nat Rev Dis Primers. 2020;6:38. 2. Martins F et al. Nat Rev Clin Oncol. 2019;16:563-580. 3. O’Leary CL et al. J Thorac Oncol. 2023 Oct 23 [Epub ahead of print]. 4. Helmink BA et al. Ann Surg Oncol. 2020;27:1533-1545. 5. Stiles BM et al. J Thorac Cardiovasc Surg.
2020;160:1376-1382. 6. Champiat S et al. Ann Oncol. 2016;27:559-574. 7. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1786. 8. https://www.esmo.org/content/download/124130/2352601/1/ESMO-Patient-Guide-on-Immunotherapy-Side-Effects.pdf. 9. https://www.nccn.org/
professionals/physician_gls/pdf/immunotherapy.pdf. 10. Puzanov I et al. J Immunother Cancer. 2017;5:95. 11. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1786. 12. Provided courtesy of Marianne Davies, DNP, ACNP, AOCNP, FAAN, 2021; adapted from AIM with Immunotherapy, NCCN,
and CTCAE. 13. Naidoo J et al. J Immunother Cancer. 2023;11:e006398. 14. https://ascopubs.org/doi/full/10.1200/JCO.21.01440. 15. https://www.sitcancer.org/research/cancer-immunotherapy-guidelines/irae/immune-checkpoint-inhibitor-related-adverse-events.
Additional Guideline Recommendations for Treating irAEs