Chair and Presenters Sandip Patel, MD, Tina Cascone, MD, PhD, and John V. Heymach, MD, PhD, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “The “Immunosurge” Continues: Moving in Leaps and Bounds to Expand the Role and Impact of Immunotherapy in Metastatic, Locally Advanced, and Early-Stage NSCLC.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3u3mUP5. CME/MOC credit will be available until March 22, 2025.

1. Overview of Key Phase 3 Clinical Trials Investigating
Immunotherapies in Resectable NSCLC1,2
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
1. https://clinicaltrials.gov. 2. https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications.
SURGERY
SURGERY
Neoadjuvant Immunotherapy (Approved)
Study Neoadjuvant Regimen Adjuvant Regimen
Adjuvant Immunotherapy (Approved)
AEGEAN Durvalumab + chemo x 4 cycles Durvalumab ~1 year
CheckMate -77T Nivolumab + chemo x 4 cycles Nivolumab ~1 year
KEYNOTE-671 Pembrolizumab + chemo x 4 cycles Pembrolizumab ~1 year
CheckMate -816
IMpower010
KEYNOTE-091
Nivolumab + chemo x 3 cycles
Chemo  atezolizumab ~1 y (PD-L1 ≥1%)
Chemo (optional)  pembrolizumab ~1 year
FDA
approved
FDA
approved
FDA
approved
SURGERY

2. NSCLC Treatment Algorithm1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
Stage and workup based on stage
•
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

3. Stage IIIA (unresectable) or IIIB/C
Definitive chemoradiation → durvalumab
Concurrent platinum-based chemotherapy and radiation with
consolidation durvalumab
PACIFIC: Durvalumab vs placebo
mPFS: 16.8 vs 5.6 mo (HR, 0.52)
BRAF V600E
Dabrafenib + trametiniba
BRF113928: Dabrafenib + trametinib single arm
ORR: 64% (95% CI, 46-79)
Encorafenib + binimetiniba
PHAROS: Encorafenib + binimetinib single arm (see FDA approval)
Treatment-naïve patients, ORR: 75% (95% CI, 62-85); mDOR: NE (95% CI, 23.1-NE)
Previously treated patients, ORR: 46% (95% CI, 30-63); mDOR: 16.7 mo (95% CI, 7.4-NE)
Vemurafenib
AcSé: Vemurafenib single arm
ORR: 45%; mPFS: 5.2 mo; OS: 10 mo
2L: KRAS G12C
Sotorasib
CodeBreaK100: Sotorasib single arm
ORR: 37.1% (95% CI, 29-46); mPFS: 6.8 mo
Adagrasib
KRYSTAL-1: Adagrasib single arm (see FDA approval)
ORR: 43% (95% CI, 34-53); mDOR: 8.5 mo
ALK
Alectiniba
ALEX: Alectinib vs crizotinib
1-y PFS: 68.4% vs 48.7% (HR, 0.47)
Brigatiniba
ALTA-1L: Brigatinib vs crizotinib
mPFS: 24 vs 11.1 mo (HR, 0.48)
Lorlatiniba
CROWN: Lorlatinib vs crizotinib
mPFS: NR vs 9.3 mo (HR, 0.28); 1-y PFS: 78% vs 39%
Ceritinib
ASCEND-4: Ceritinib vs chemo
mPFS: 16.6 vs 8.1 mo (HR, 0.55)
Crizotinib
PROFILE 1007: Crizotinib vs chemo
mPFS: 7.7 vs 3 mo (HR, 0.49)
NTRK
Larotrecteniba
NCT02122913/SCOUT/NAVIGATE: Larotrectenib single arm (see FDA approval)
ORR: 75% according to independent review and 80% according to investigator assessment
Entrectiniba
ALKA/STARTRK: Entrectinib single arm (see FDA approval)
ORR: 70% (NSCLC)
RET
EGFR S768I, L861Q, and/or G719X
Selpercatiniba
LIBRETTO-001: Selpercatinib single arm (see FDA approval)
ORR: 64%; mDOR: 17.5 mo
Pralsetiniba
ARROW: Pralsetinib single arm (see FDA approval)
Treatment-naïve patients, ORR: 78% (95% CI, 68-85); mDOR: 13.4 mo (95% CI, 9.4-23.1)
Previously treated patients, ORR: 63% (95% CI, 54-71); mDOR: 38.8 mo (95% CI, 14.8-NE)
Cabozantinib
NCT01639508: Cabozantinib single arm
ORR: 28%
Osimertiniba
FLAURA: Osimertinib vs erlotinib/gefitinib
mPFS: 18.9 vs 10.2 mo (HR, 0.46)
Erlotinib
EURTAC: Erlotinib vs chemo
mPFS: 9.7 vs 5.2 mo (HR, 0.37)
Afatiniba
LUX-Lung 3: Afatinib vs cis/pemetrexed
mPFS: 13.6 vs 6.9 mo (HR, 0.47)
Gefitinib
IFUM: Gefitinib single arm
mPFS: 9.7 mo
Dacomitinib
ARCHER 1050: Dacomitinib vs gefitinib
mOS: 34.1 vs 27 mo (HR, 0.75)
Amivantamab + carboplatin + pemetrexed (nonsquamous)
MARIPOSA-2: Amivantamb + chemo ± lazertinib vs chemo
mPFS: 6.3, 8.3 vs 4.2 mo (HR, 0.48, 0.44); ORR: 64%, 63% vs 36% (P .001 for both)
EGFR (ex20)
Amivantamab
CHRYSALIS: Amivantamab single arm
CBR: 74% (95%CI, 63-83); mPFS: 8.3 mo
Amivantamb + carboplatin + pemetrexed (nonsquamous)a
PAPILLON: Amivantamab + chemo vs chemo
mPFS: 11.4 vs 6.7 mo (HR, 0.4); ORR: 73% vs 47%
ROS1
Crizotiniba
PROFILE 1001: Crizotinib single arm
ORR: 72% (95% CI, 58-84)
Entrectiniba
ALKA STARTRK: Entrectinib single arm
ORR: 67.1%; mPFS: 19 mo
Ceritinib
YONSEI: Ceritinib single arm
ORR: 67% (95% CI, 48-81)
Repotrectiniba
TRIDENT-1: Repotrectinib single arm (see FDA approval)
ROS1 TKI-naïve patients, ORR: 79% (95% CI, 68-88); mDOR: 34.1 mo (95% CI, 25.6-NE)
Prior ROS1 inhibitor, ORR: 38% (95% CI, 25-52); mDOR: 14.8 mo (95% CI, 7.6-NE)
Lorlatinib
NCT01970865: Lorlatinib single arm
ROS TKI-naïve patients, ORR: 62%; Crizotinib pre-treated patients, ORR: 35%
EGFR (ex19 del or L858R)
Osimertiniba
FLAURA: Osimertinib vs erlotinib/gefitinib
mPFS: 18.9 vs 10.2 mo (HR, 0.46)
Osimertinib + pemetrexed + cisplatin/carboplatin
FLAURA2: Osimertinib + chemo vs osimertinib (see FDA approval)
mPFS: 25.5 vs 16.7 mo (HR, 0.62)
Erlotinib
EURTAC: Erlotinib vs chemo
mPFS: 9.7 vs 5.2 mo (HR, 0.37)
Afatinib
LUX-Lung 3: Afatinib vs cis/pemetrexed
mPFS: 13.6 vs 6.9 mo (HR, 0.47)
Gefitinib
IFUM: Gefitinib single arm
mPFS: 9.7 mo
Dacomitinib
ARCHER 1050: Dacomitinib vs gefitinib
mOS: 34.1 vs 27 mo (HR, 0.75)
Erlotinib + ramucirumab
RELAY: Erlotinib + ramucirumab vs erlotinib
mPFS: 19.4 vs 12.4 mo (HR, 0.59)
Erlotinib + bevacizumab (nonsquamous)
ARTEMIS-CTONG1509: Erlotinib + bevacizumab vs erlotinib
mPFS: 17.9 vs 11.2 mo (HR, 0.55)
Amivantamab + carboplatin + pemetrexed (nonsquamous)
MARIPOSA-2: Amivantamb + chemo ± lazertinib vs chemo
mPFS: 6.3, 8.3 vs 4.2 mo (HR, 0.48, 0.44); ORR: 64%, 63% vs 36% (P .001 for both)
MET (exon 14)
Capmatiniba
GEOMETRY mono-1: Capmatinib single arm (see FDA approval)
mPFS: 12.4 mo; treatment-naïve patients, ORR: 68% (95% CI, 55-80); DOR: 16.6 mo
Previously treated patients, ORR: 44% (95% CI, 34-54); DOR: 9.7 mo
Tepotiniba
VISION: Tepotinib single arm
mPFS: 8.5-11 mo
Crizotinib
PROFILE 1001: Crizotinib single arm
ORR: 32%
2L: HER2
Trastuzumab deruxtecana
DESTINY-Lung02: T-DXd 5.4 mg/kg vs 6.4 mg/kg (see FDA approval)
ORR: 58% (98% CI, 43-71); mDOR: 8.7 mo (95% CI, 7.1-NE)
Trastuzumab emtansine
NCT02675829: Trastuzumab emtansine single arm
ORR: 44%
T1-2, N2–3, M0
T3, N1–3, M0
T4, N0–3, M0
Tx
Nx
M1
Actionable mutation detected
Mutation (broad NGS if possible) and PD-L1 testing
NSCLC treatment algorithm
Stage and workup based on stage
• cT1abc, N0: PFT, bronch, mediastinal staging, PET
• cT2a-4, N0-3, M0-1: PFT, bronch, mediastinal staging, PET, brain MRI, and biomarker/mutation testing
Please see the next page for recommendations if no actionable mutation is detected
Stage IV
• EGFR
• ALK
• ROS1
• BRAF V600E
• RET
• MET (ex14)
• HER2
• NTRK1/2/3
• KRAS G12C
NSCLC Treatment Algorithm1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40

4. a
Denotes NCCN-preferred regimens. b
For patients who have no contraindications to PD-1 or PD-L1 inhibitors and who have a PS 0-1.
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.
PD-L1 1%b
IMMUNOTHERAPY + CHEMOTHERAPY
SQUAMOUS:
• Pembrolizumab + chemotherapya
(carboplatin + paclitaxel/nab-paclitaxel)
KEYNOTE-407: Pembro + chemo vs chemo
mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64)
• Cemiplimab + chemotherapya
(paclitaxel + carboplatin/cisplatin)
EMPOWER-Lung 3: Cemi + chemo vs chemo (see FDA approval)
mOS: 21.9 vs 13 mo (HR, 0.7)
NONSQUAMOUS:
•
Pembrolizumab + chemotherapya
(carboplatin/cisplatin + pemetrexed)
KEYNOTE-189: Pembro + chemo vs chemo
mPFS: 8.8 vs 4.9 mo (HR, 0.52); 12-mo OS: 69% vs 49% (HR, 0.49)
• Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab)
IMpower150: Atezo + chemo vs chemo
mPFS: 8.3 vs 6.8 mo (HR, 0.62)
• Cemiplimab + chemotherapya
(carboplatin/cisplatin + pemetrexed)
EMPOWER-Lung 3: Cemi + chemo vs chemo (see FDA approval)
mOS: 21.9 vs 13 mo (HR, 0.7)
• Atezolizumab + chemotherapy (carboplatin + nab-paclitaxel)
IMpower130: Atezo + chemo vs chemo
mOS: 18.6 vs 13.9 mo (HR, 0.79); mPFS: 7.0 vs 5.5 mo (HR, 0.64)
DUAL IMMUNOTHERAPY + CHEMOTHERAPY
SQUAMOUS:
• Nivolumab + ipilimumab + chemotherapy (paclitaxel/carboplatin)
CheckMate -9LA: Nivo/ipi + chemo vs chemo
mOS: 14.1 vs 10.7 mo
• Durvalumab + tremelimumab + chemotherapy (carboplatin + nab-paclitaxel)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
• Durvalumab + tremelimumab + chemotherapy (gemcitabine + carboplatin/cisplatin)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
NONSQUAMOUS:
• Nivolumab + ipilimumab + chemotherapy (paclitaxel/carboplatin)
CheckMate -9LA: Nivo/ipi + chemo vs chemo
mOS: 14.1 vs 10.7 mo
• Durvalumab + tremelimumab + chemotherapy (carboplatin + nab - paclitaxel)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
• Durvalumab + tremelimumab + chemotherapy (pemetrexed + carboplatin/cisplatin)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
DUAL IMMUNOTHERAPY
Nivolumab + ipilimumab
CheckMate -227: Nivo/ipi vs chemo
mOS: 17.1 vs 14.9 mo
DUAL IMMUNOTHERAPY
Nivolumab + ipilimumab
CheckMate -227: Nivo/ipi vs chemo
mOS: 17.1 vs 14.9 mo
DUAL IMMUNOTHERAPY + CHEMOTHERAPY
Nivolumab + ipilimumab + chemotherapy (pemetrexed + carboplatin/cisplatin)
CheckMate -9LA: Nivo/ipi + chemo vs chemo
mOS: 14.1 vs 10.7 mo
Durvalumab + tremelimumab + chemotherapy (carboplatin + nab-paclitaxel)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
Durvalumab + tremelimumab + chemotherapy (pemetrexed + carboplatin/cisplatin)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
IMMUNOTHERAPY MONOTHERAPY
Pembrolizumab
KEYNOTE-042: Pembro vs plat-based chemo
mOS: 16.7 vs 12.1 mo (HR, 0.81)
DUAL IMMUNOTHERAPY
Nivolumab + ipilimumab
CheckMate -227: Nivo/ipi vs chemo
mOS: 17.1 vs 14.9 mo
DUAL IMMUNOTHERAPY + CHEMOTHERAPY
Nivolumab + ipilimumab + chemotherapy (pemetrexed + carboplatin/cisplatin)
CheckMate -9LA: Nivo/ipi + chemo vs chemo
OS: 14.1 vs 10.7 mo
Durvalumab + tremelimumab + chemotherapy (carboplatin + nab-paclitaxel)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
Durvalumab + tremelimumab + chemotherapy (pemetrexed + carboplatin/
cisplatin)
POSEIDON: Durva/treme + chemo vs chemo (see FDA approval)
mOS: 13.3 vs 11.7 mo (HR, 0.86)
PD-L1 1%-49%
IMMUNOTHERAPY + CHEMOTHERAPY
SQUAMOUS:
•
Pembrolizumab + chemotherapya
(carboplatin + paclitaxel/nab-paclitaxel)
KEYNOTE-407: Pembro + chemo vs chemo
mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64)
• Cemiplimab + chemotherapya
(paclitaxel + carboplatin/cisplatin)
EMPOWER-Lung 3: Cemi + chemo vs chemo (see FDA approval)
mOS: 21.9 vs 13 mo (HR, 0.7)
NONSQUAMOUS:
• Pembrolizumab + chemotherapya
(carboplatin + pemetrexed)
KEYNOTE-189: Pembro + chemo vs chemo
mPFS: 8.8 vs 4.9 mo (HR, 0.52); 12-mo OS: 69% vs 49% (HR, 0.49)
•
Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab)
IMpower150: Atezo + chemo vs chemo
mPFS: 8.3 vs 6.8 mo (HR, 0.62)
•
Cemiplimab + chemotherapya
(carboplatin/cisplatin + pemetrexed)
EMPOWER-Lung 3: Cemi + chemo vs chemo (see FDA approval)
mOS: 21.9 vs 13 mo (HR, 0.7)
PD-L1 ≥50%
IMMUNOTHERAPY MONOTHERAPY
Pembrolizumaba
KEYNOTE-024: Pembro vs platinum-based chemo
mPFS: 10.3 vs 6 mo (HR, 0.50)
Atezolizumaba
IMpower110: Atezo vs platinum-based chemo
mOS: 20.1 vs 13.1 mo (HR, 0.59)
Cemiplimaba
EMPOWER-Lung1: Cemi vs platinum-based chemo
mPFS: 8.2 vs 5.7 mo; mOS: NR vs 14.2 mo (HR, 0.57)
IMMUNOTHERAPY + CHEMOTHERAPY
SQUAMOUS:
•
Pembrolizumab + chemotherapya
(carboplatin + paclitaxel/nab-paclitaxel)
KEYNOTE-407: Pembro + chemo vs chemo
mPFS: 6.4 vs 4.8 mo (HR, 0.56); mOS: 15.9 vs 11.3 mo (HR, 0.64)
• Cemiplimab + chemotherapya
(paclitaxel + carboplatin/cisplatin)
EMPOWER-Lung 3: Cemi + chemo vs chemo (see FDA approval)
mOS: 21.9 vs 13 mo (HR, 0.7)
NONSQUAMOUS:
•
Pembrolizumab + chemotherapya
(carboplatin/cisplatin + pemetrexed)
KEYNOTE-189: Pembro + chemo vs chemo
mPFS: 8.8 vs 4.9 mo (HR, 0.52); 12-mo OS: 69% vs 49% (HR, 0.49)
•
Atezolizumab + chemotherapy (carboplatin + paclitaxel + bevacizumab)
IMpower150: Atezo + chemo vs chemo
mPFS: 8.3 vs 6.8 mo (HR, 0.62)
• Cemiplimab + chemotherapya
(carboplatin/cisplatin + pemetrexed)
EMPOWER-Lung 3: Cemi + chemo vs chemo (see FDA approval)
mOS: 21.9 vs 13 mo (HR, 0.7)
• Cemiplimab + chemotherapy (paclitaxel + carboplatin or cisplatin)
EMPOWER-Lung 3: Cemi + chemo vs chemo (see FDA approval)
mOS: 21.9 vs 13 mo (HR, 0.7)
No actionable mutation detected (stratify based on PD-L1 staining %)
NSCLC Treatment Algorithm1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40

5. Immune-Related Adverse Events of Cancer Immunotherapies1-17
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
Immune checkpoint inhibitors
(ICIs)—which are monoclonal antibodies
against CTLA-4, PD-1, or PD-L1—have
transformed treatment of many cancer
types. However, in some cases, these
treatments are associated with
immune-related adverse events (irAEs).
MANAGEMENT
Treatment of irAEs depends on the affected
organ and the 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. However, further studies are
required before these autoantibodies can be
used to guide management strategies in
clinical practice. Moreover, as new ICIs or
new combinations of therapies are approved,
studies will be needed to characterize the
associated risk, frequency, and
manifestations of irAEs.
MECHANISMS
For CTLA-4 inhibitors, an imbalance in the
ratio of regulatory T (Tregs) cells (which
dampen the immune response) to type 17 T
helper (TH17) cells (which promote the
immune response), autoantibody production,
and complement-mediated cellular damage
have been suggested to contribute to irAE
development. The mechanisms underlying
PD-1/PD-L1 inhibitor–associated irAEs are
less well-understood but could be due to
reduced Treg cell numbers.
DIAGNOSIS
Diagnostic
workup of
individuals
with suspected
irAEs depends
on the affected
organ
SYSTEMIC
Sicca syndrome and vasculitis
irAEs can
range in
severity
and affect
almost any
organ
Polyneuropathy
Uveitis
Interstitial
lung
disease
Hepatitis
Vitiligo
Myalgia
and
myositis
Enterocolitis
Thyroiditis
Hypophysitis
Myocarditis
Adrenitis
Arthralgia
and
arthritis
EPIDEMIOLOGY
Onset of irAEs generally occurs between
2 and 16 weeks after ICI initiation, depending
on the affected organ; however, some
reports have noted 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, and ICI monotherapy is associated
with fewer irAEs than PD-1/PD-L1 and
CTLA-4 combination therapy.
Pre-existing autoimmune disease is a
strong risk factor for developing irAEs
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

6. Immune-Related Adverse Events of Cancer Immunotherapies1-17
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
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

7. Immune-Related Adverse Events of Cancer Immunotherapies1-17
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
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

8. Immune-Related Adverse Events of Cancer Immunotherapies1-17
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
General Recommendations for Treating irAEs
The Principles of irAEs Management
Increasing
intensity
of
treatment
required
Grade 2
Grade 1 Grade 3 Grade 4
Moderate
Mild Severe Very severe
Symptomatic and 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
01 Prevention
02 Anticipation
03 Detection
04 Treatment
05 Monitoring
01
02
03
04
05

9. Immune-Related Adverse Events of Cancer Immunotherapies1-17
Become Aware and Stay Vigilant
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 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?
 Pneumonitis: focal or diffuse inflammation of the lung parenchyma (typically identified on CT imaging)
 Diagnostic workup: CXR, CT, pulse oximetry; for grade ≥2, may include infectious workup
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)

10. Immune-Related Adverse Events of Cancer Immunotherapies1-17
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
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

11. Immune-Related Adverse Events of Cancer Immunotherapies1-17
Become Aware and Stay Vigilant
Full abbreviations, accreditation, and disclosure information available at PeerView.com/JSU40
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.esmo.org/content/download/124130/2352601/1/ESMO-Patient-Guide-on-Immunotherapy-Side-Effects.pdf. 16. https://www.nccn.org/
professionals/physician_gls/pdf/immunotherapy.pdf. 17. https://www.sitcancer.org/research/cancer-immunotherapy-guidelines/irae/immune-checkpoint-inhibitor-related-adverse-events.
Additional Guideline Recommendations for Treating irAEs