CCO_Immunotherapy_in_NSCLC_Downloadable_2.pptx

Identifying the Evolving Role of Immunotherapy in
Advanced/Metastatic NSCLC
Supported by an educational grant from Bristol Myers Squibb.
Provided by Partners for Advancing Clinical Education (PACE) in partnership with
Practicing Clinicians Exchange, LLC and Clinical Care Options, LLC

Slide credit: clinicaleducationalliance.com:
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Program Chair
Marianne Davies, DNP, ACNP, AOCNP, FAAN
Program Manager, Care Signature
Oncology Service Line
Yale New Haven Health
Oncology Nurse Practitioner, Senior APP II
Smilow Cancer Hospital, Yale New Haven
Yale Comprehensive Cancer Center
Associate Professor
Yale University School of Nursing
New Haven, Connecticut

Faculty
Sam Vafadar, DHSc, PA-C
Physician Associate
Thoracic Medical Oncology
Moffitt Cancer Center & Research Institute
Tampa, Florida

Disclosures
Marianne Davies, DNP, ACNP, AOCNP, FAAN, has no relevant financial
relationships to disclose.
Sam Vafadar, DHSc, PA-C: consultant/advisor/speaker: Cardinal Health,
G1 Therapeutics, Guardant Health.

Learning Objectives
At the conclusion of this activity, learners should be able to:
 Describe the rationale for neoadjuvant immunotherapy in early-stage NSCLC and
considerations that can influence subsequent management of patients
 Formulate personalized therapeutic strategies for neoadjuvant and adjuvant
immunotherapy in patients with NSCLC, based on expert recommendations, current
indications, and available efficacy and safety evidence
 Apply clinical trial evidence, expert guidance, patient preferences, and predictive
biomarkers to create ICI-based treatment plans for patients with advanced or metastatic
NSCLC
 Implement evidence-based strategies to monitor and manage irAEs associated with
immunotherapy, including patient education on toxicities and strategies to address barriers
to optimal care

Biologic Rationale for Immune Checkpoint Inhibition
Adapted from Ribas. NEJM. 2012;366:2517.
Lurain. Curr HIV/AIDS Rep. 2020;17:547.
Priming Phase: Lymph Node
Effector Phase: Tumor Microenvironment
CTLA-4
B7
Dendritic
cell
T-cell
MHC
TCR
Antigen
Tumor
PD-L1
PD-1
Activated
T-cell
CD28
B7
Inhibitory signal blocked
by antibody binding
Activating signals
MHC
TCR Antigen
Negative regulation blocked
by antibody binding
Activation
Anti–CTLA-4:
Ipilimumab
Tremelimumab
Anti–PD-1:
Cemiplimab
Nivolumab
Pembrolizumab
Anti–PD-L1
Atezolizumab
Durvalumab
Patient Counseling Script
“ICIs release a natural brake on the immune system,
which then allows T-cells to recognize and attack tumors.”

Molecular and PD-L1 Testing at Initial Diagnosis to
Guide Treatment in NSCLC
Initial Diagnosis of NSCLC
Advanced
Early Stage
Broad NGS testing and PD-L1 IHC
(at diagnosis)
Adjuvant:
Molecular testing (EGFR/ALK) and
PD-L1 IHC
Neoadjuvant:
EGFR/ALK testing*
and
PD-L1 IHC
 Test for PD-L1 expression required for all cases of NSCLC
 Broad molecular testing for all cases of advanced nonsquamous NSCLC should include EGFR, ALK,
ROS1, BRAF V600E, NTRK, RET, METex14 skipping, KRAS G12C, and HER2 mutations
‒ For squamous NSCLC, consider testing in young, never/light smokers, and female patients, or if biopsy
specimen is of mixed histology
 Biomarker results should be obtained before starting checkpoint inhibitor therapy
*NSQ or young, never-smoker SQ
Pennell. ASCO Educ Book. 2019;39:351. Godoy. Biomark Res. 2023;11:7.

Evolution of Therapy in Lung Cancer
Traditional View
Present View
NSCLC
SCLC
Histologic Breakdown
(eg, SQ, NSQ, large cell,
adenocarcinoma)
Molecular Pathology
(eg, EGFR, ALK, ROS1) PD-L1 Expression Level
Lung
Cancer ≥50%
≥1%-49%
<1%
de Jong. Cancers (Basel). 2023;15:2855.

Targeted Therapy in Advanced NSCLC With Actionable
Driver Mutations (2024)
*Osimertinib is approved alone or in combination with pemetrexed and platinum-based CT, and as second-line therapy for EGFR T790M–positive disease after progression on/after prior EGFR TKI. †
Erlotinib
may be administered alone or in combination with ramucirumab or bevacizumab. Erlotinib also approved in the second-line or later setting after ≥1 prior CT regimen.
‡Amivantamab also approved as monotherapy in the second-line setting after progression on/after platinum-based CT .
Adagrasib PI. Afatinib PI. Alectinib PI. Amivantamab PI. Capmatinib PI. Ceritinib PI. Crizotinib PI. Dabrafenib PI. Dacomitinib PI. Entrectinib PI.
Erlotinib PI. Fam-trastuzumab deruxtecan-nxki PI. Gefitinib PI. Lorlatinib PI. Larotrectinib PI. Osimertinib PI. Pralsetinib PI. Ramucirumab PI.
Selpercatinib PI. Sotorasib PI. Trametinib PI. NCCN. Clinical practice guidelines in oncology: NSCLC. v.6.2024.
ALK
Progression
EGFR ROS1
Crizotinib,
entrectinib, or
repotrectinib,
(preferred) or
ceritinib
Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker (ie, chemotherapy ± immunotherapy)
Alectinib, brigatinib, ceritinib, or
lorlatinib (preferred) or crizotinib
dependent on previous therapy
Alectinib, brigatinib,
or lorlatinib
(preferred);
ceritinib or crizotinib
Osimertinib
(preferred),*
erlotinib,†
afatinib, gefitinib,
or dacomitinib
BRAF V600E
Dabrafenib/
trametinib or
encorafenib/
binimetinib
First
line
Second
line+
Entrectinib
or
larotrectinib
NTRK
Selpercatinib
or
pralsetinib
RET
Capmatinib
or
tepotinib
METex14
skipping
KRAS G12C
Sotorasib
or
adagrasib
Classical
(del19 or
21 L858R)
Uncommon
ex20ins S768I, L861Q,
G719X
Amivantamab‡
+
carboplatin and
pemetrexed Afatinib or osimertinib
(preferred); erlotinib,
gefitinib, or dacomitinib
HER2
Trastuzumab
deruxtecan
Advanced NSCLC
(Molecular Biomarker Positive)

Current Indications for ICI–CT Regimens
Atezolizumab PI. Cemiplimab PI. Durvalumab PI. Nivolumab PI. Pembrolizumab PI.
ICI–CT Regimen Indication (FDA Approval Date)
Early
Nivolumab + platinum-doublet CT
Resectable (tumors ≥4 cm or node positive) NSCLC in neoadjuvant setting
(March 2022)
Pembrolizumab + neoadjuvant platinum-based CT
then as adjuvant monotherapy
With neoadjuvant platinum-containing CT then continued as adjuvant monotherapy
for resectable (tumors ≥4 cm or node positive) NSCLC (Oct 2023)
Atezolizumab after adjuvant platinum-based CT
Adjuvant treatment after resection and platinum-based CT for stage II-IIIA NSCLC
with PD-L1 expression on ≥1% of tumor cells (Oct 2021)
NONSQUAMOUS
Advanced
Atezolizumab + bevacizumab + carboplatin + paclitaxel 1L for metastatic nonsquamous NSCLC, no EGFR or ALK aberrations (Dec 2018)
Atezolizumab + carboplatin + nab-paclitaxel 1L for metastatic nonsquamous NSCLC, no EGFR or ALK aberrations (Dec 2019)
Pembrolizumab + pemetrexed + platinum CT 1L for metastatic nonsquamous NSCLC, no EGFR or ALK aberrations (Aug 2018)
SQUAMOUS
Pembrolizumab + carboplatin + (nab-)paclitaxel 1L for metastatic squamous NSCLC (Oct 2018)
ANY HISTOLOGY
Cemiplimab + platinum-based CT 1L for locally advanced/metastatic NSCLC, no EGFR, ALK, or ROS1 aberrations
(Nov 2022)
Nivolumab + ipilimumab + platinum-doublet CT 1L for metastatic/recurrent NSCLC, no EGFR or ALK aberrations (May 2020)
Durvalumab + tremelimumab + platinum-based CT Metastatic NSCLC, no sensitizing EGFR or ALK aberrations (Nov 2022)

Guideline-Recommended Treatment of
Advanced/Metastatic NSCLC
 PD-L1 and molecular testing is
recommended regardless of histology
 First-line treatment of adenocarcinoma
with PD-L1 expression ≥50%,
preferred/category 1 regimens include:
‒ Pembrolizumab
‒ Platinum-based CT/pemetrexed/
pembrolizumab
‒ Atezolizumab
‒ Cemiplimab
‒ Cemiplimab/pemetrexed/platinum-based
CT
 Other category 1 regimens include:
‒ Carboplatin/paclitaxel/bevacizumab/
atezolizumab
‒ Nivolumab/ipilimumab/pemetrexed/
platinum-based CT
‒ Cemiplimab/paclitaxel/platinum-based
CT
 Nivolumab + ipilimumab may be useful in
certain circumstances
NCCN. Clinical practice guidelines in oncology: NSCLC. v.6.2024. nccn.org.

Factors Influencing Immunotherapy Response
 PD-L1 expression
 Tumor mutation burden
 Microsatellite instability
 Tumor microenvironment
‒ TILs and less immunosuppressive environment may enhance efficacy
 Genetic alterations
‒ EGFR and ALK typically considered with resistance to immunotherapy
Rolfo. J Immunother Precis Oncol. 2021;4:185. Gainor. Clin Cancer Res. 2016;22:4585. Palmeri. ESMO Open. 2022;7:100336.

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36 40
FDA-Approved ICI Monotherapies for PD-L1–High
Advanced or Metastatic NSCLC
 Pembrolizumab indication as monotherapy for metastatic NSCLC was expanded to tumors with PD-L1 TPS ≥1% based on KEYNOTE-042.3
IMpower1105
(n = 205‡
):
Atezolizumab vs CT
(PD-L1 ≥50% [TC] or ≥10% [IC])
EMPOWER-Lung 14
(n = 565†
):
Cemiplimab vs CT
(PD-L1 TPS ≥50%*)
KEYNOTE-0241,2
(N = 305):
Pembrolizumab vs CT
(PD-L1 TPS ≥50%*)
HR: 0.62 (95% CI: 0.48-0.81)
Pembrolizumab (n = 154) 26.3 (18.3-40.4)
CT (n = 151) 13.4 (9.4-18.3)
Median OS, Mo (95% CI) Median OS, Mo (95% CI)
26.1 (22.1-31.8)
13.3 (10.5-16.2)
Cemiplimab (n = 284)
CT (n = 281)
HR: 0.57 (95% CI: 0.46-0.71; P = .0001)
20.2 (17.2-27.9)
14.7 (7.4-17.7)
Median OS, Mo (95% CI)
Atezolizumab (n = 107)
CT (n = 98)
Stratified HR: 0.76 (95% CI: 0.54-1.09)
1. Reck. JCO. 2021;39:2339. 2. Reck. NEJM. 2016;375:1823 3. Castro. JCO. 2023;41:1986.
4. Ozguroglu. Lancet Oncol. 2023;24:989. 5. Jassem. J Thorac Oncol. 2021;16:1872.
*PD-L1 IHC by 22C3. †
712 patients enrolled in overall ITT population.
‡
572 patients enrolled in overall population; PD-L1 IHC by SP142.
Mo
100
80
60
0
40
20
OS
(%)
66
0 6 12 18 24 30 36 42 48 54 60 72
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1.0
0.8
0.6
0.4
0.2
0.0
OS
(%)
4 8 24 28
12 32 40
36
20
16
0 44 52
48 56
+
+
+
Mo
OS
(%)
Mo
0 4 8 12 16 20 24 28 32 48
44 56
52
0
20
40
60
80
100

Practical Considerations for IO in Advanced NSCLC
 For PD-L1–high disease, single-agent anti–PD-1 or PD-L1 are mainstay of treatment
‒ CT + IO may increase response, but survival is comparable to single-agent PD-1 blockade
 For PD-L1–negative disease: CT/IO or IO/IO/CT
‒ IO/IO combinations without CT can be considered for off-label use in select patients
 For PD-L1 1%-49% disease: either CT/IO, IO/IO, or IO/IO/CT are options
 Although long-term survival is possible, it is only realized in a subset of patients
 Sequencing of IO and CT remains an open question
Akinboro. ASCO 2022. Abstr 9000. Peng. Front Oncol. 2021;11:657545. NCCN. Clinical practice guidelines in oncology: NSCLC. v.6.2024. nccn.org.

TMB, MSI, and the Tumor Microenvironment
 CheckMate 227: This trial evaluated nivolumab + ipilimumab vs CT in
advanced NSCLC, regardless of PD-L1 expression; it found that patients
with high TMB had improved PFS with this ICI combination and a similar
OS benefit between high vs low TMB1
 CheckMate 568: This study also investigated nivolumab + ipilimumab
(low-dose) and showed improved outcomes in patients with high TMB,
regardless of PD-L1 status2
 KEYNOTE-158: This study explored pembrolizumab in various tumor
types and found that patients with previously treated MSI-H or dMMR
tumors had significant responses to pembrolizumab3
1. Hellmann. NEJM. 2019;381:2020. 2. Ready. JCO. 2019;37:992. 3. Marabelle. JCO. 2020;38:1.

NCCN. Clinical practice guidelines in oncology: NSCLC. v.6.2024. nccn.org.
Advanced NSCLC w/o
Actionable Mutation
PD-1/PD-L1i
PD-1/PD-L1i + CT
PD-L1i + VEGFi + CT
PD-1i + CTLA-4i + CT
PD-1i + CTLA-4i
PD-1/PD-L1i + CT
PD-1i + CTLA-4i
+ CT
PD-1i + CTLA-4i
PD-1/PD-L1i + CT
PD-1i + CTLA-4i
+ CT
PD-1i + CTLA-4i†
PD-L1 1%-49%*
PD-L1 ≥50% PD-L1 <1%
*Single-agent pembrolizumab also approved for ≥1% PD-L1 but not broadly recommended by experts; guideline recommended for PD-L1
1%-49% if contraindications to combining with CT. †
Not an FDA-approved indication but guideline recommended. ‡
Per histology.
Current first-line treatment paradigm
based on PD-L1 expression in TC and/or IC
Current Paradigm for Immunotherapy in Advanced
NSCLC Without an Actionable Mutation
 ICI monotherapy: pembrolizumab,* atezolizumab,
cemiplimab (SQ/NSQ)
 ICI + CT regimens:
‒ Pembrolizumab/platinum-based
CT/pemetrexed (NSQ)
‒ Atezolizumab/carboplatin/paclitaxel/
bevacizumab (NSQ)
‒ Atezolizumab/carboplatin/nab-paclitaxel (NSQ)
‒ Pembrolizumab/carboplatin/(nab) paclitaxel
(SQ)
‒ Cemiplimab/platinum-based CT‡
(SQ/NSQ)
‒ Nivolumab/ipilimumab + 2 cycles of platinum-
based CT‡
(SQ/NSQ)
‒ Durvalumab/tremelimumab + platinum-based
CT‡ (SQ/NSQ)
 ICI combination: nivolumab/ipilimumab (SQ/NSQ)

Turning Up the Heat on “Cold” Tumors
 Cold tumors lack immune cell infiltration
‒ Lack of tumor antigens
‒ T-cell exhaustion
 Converting “cold” to “hot” may enhance IO efficacy
 Possible therapeutic approaches to convert cold tumors
‒ Oncolytic viruses
‒ Adoptive cell therapy
‒ Chemo/radiation therapy
Liu. Theranostics. 2021;11:5365.

Key Takeaways for the Tumor Microenvironment
 Beyond PD-L1, TMB and MSI are emerging as important biomarkers for
predicting response to ICIs in advanced NSCLC
 High TMB and MSI-H tumors, even with low PD-L1 expression, can
demonstrate remarkable sensitivity to ICIs
 Ongoing research is exploring the potential of combining TMB and MSI
testing with PD-L1 assessment to create a more comprehensive
approach to biomarker-guided immunotherapy in NSCLC

Factors Influencing Immunotherapy Response
 Performance status (overall health status)
 Smoking history
 Active autoimmune diseases
 Prior therapies
‒ Type and number of prior treatments, especially chemotherapy, can affect
immunogenicity
Wu. Transl Oncol. 2022;15:101268. Han. JAMA Oncol. 2022;8:1352. Nyein. BMC Cancer. 2022;22:101.

Considerations for IO- vs CT-Based Therapy at PD on IO
 Length of time on IO
 “Rate” of disease progression
 PD-L1 status
 Performance score, ability to tolerate CT

Types of Immunotherapy Resistance
 Primary resistance: tumor doesn’t respond to immunotherapy
‒ Includes hyperprogression
 Acquired resistance: tumor initially responds to immunotherapy but
subsequently relapses or progresses
Bai. Front Oncol. 2020;10:1290.

Current SoC for PD on/After IO Monotherapy
 Clinical decision: continue the IO or stop it?
‒ Continue IO and add chemotherapy
‒ Discontinue IO and switch to chemotherapy
 Practice consideration:
‒ Primary resistance: discontinue IO, start chemotherapy
‒ Acquired resistance: continue IO, add chemotherapy

EA5163/S1709 INSIGNA: What Is the Optimal
Sequencing of IO and CT in Advanced NSCLC?
 Multicenter, open-label, randomized phase III trial
 Primary endpoint: OS
 Key secondary endpoints: PFS, ORR, PD-L1 positivity, safety
Pembrolizumab IV Q3W for
≤2 yr or until PD/toxicity
Pembrolizumab + PC IV Q3W
for 4 cycles or until
PD/toxicity
NCT03793179. https://www.kucancercenter.org/cancer-clinical-trials/find-trial/clinical-trial-results/nct03793179.
Pembrolizumab IV Q3W for
≤2 yr or until PD/toxicity
Pembrolizumab + pemetrexed IV Q3W for ≤2 yr or until PD/toxicity
PC†
IV Q3W for 4 cycles
or until PD/toxicity
Pembrolizumab + PC IV Q3W
for 4 cycles or until PD/toxicity
Adults with stage IV*
nonsquamous NSCLC;
PD-L1 TPS ≥1%; no
EGFR, ALK, ROS1, or
BRAF V600
mutations; no prior
systemic therapy for
advanced disease;
ECOG PS ≤1
(N = ~600)
*Stage IIIB/C allowed if patient is not a candidate for cCRT. †
PC: pemetrexed and cisplatin.
Pemetrexed IV Q3W
until PD/toxicity
Pembrolizumab + pemetrexed
IV Q3W for ≤2 yr or until
PD/toxicity

Role of Radiation: Arbitrary Definitions
 ≤3-5 metastatic lesions that include the primary malignancy at diagnosis
Oligometastatic Disease
 ≤3-5 metastatic lesions with localized PD in context of controlled widespread
disease
Oligoprogressive Disease
 ≤3-5 metastatic lesions that remain despite systemic therapy
Oligopersistent Disease
Yan. Semin Radiat Oncol. 2023;33:416. Wujanto. Front Oncol. 2019;9:1219.

CURB: Consolidative SBRT for Oligoprogressive
Metastatic NSCLC and Breast Cancer
 Multicenter, open-label, randomized phase II trial
 Primary endpoint: PFS
 Key secondary endpoints: OS, safety, quality of life
NCT03808662. Tsai. Lancet. 2024;403;171.
Adults with metastatic
NSCLC* or TNBC/high-risk
breast cancer†
; ≤5 progressive
lesions on PET-CT or CT after
1L systematic therapy;
no leptomeningeal disease
(N = 106)
Stratified by no. progressive mets sites, primary site, prior
systemic therapy, receptor/mutation status
SBRT to all progressive sites +
SoC systematic therapy
(n = 55)
SoC systemic therapy‡
(n = 51)
Follow-up at Wk 8,
then Q12W thereafter
until 12 mo after
randomization
‡
Per physician discretion; palliative radiotherapy considered if
clinically warranted.
*No known EGFR mutation or ALK/ROS1
rearrangement, unless PD on 1L TKI. †
TNBC or
high-risk MBC with PD after 1L therapy.

CURB: PFS by Primary Disease Site
Tsai. Lancet. 2024;403;171.
Lung Cancer Breast Cancer
P = .43
Mo
Probability
of
PFS
Patients at Risk, n
SBRT
No SBRT
SBRT
(n = 31)
No SBRT
(n = 28)
mPFS, mo 10 2.2
HR: 0.41 (95% CI: 0.22-0.75)
SBRT
(n = 24)
No SBRT
(n = 23)
mPFS, mo 4.4 4.2
HR: 0.78 (95% CI: 0.43-1.43)
1.00
0.75
0.50
0.25
0
0 3 6 9 12 15 18 21 24 27 30
31
28
24
11
21
6
17
5
5
3
1
0
1
0
>4-fold difference
Mo
Probability
of
PFS
Patients at Risk, n
SBRT
No SBRT
1.00
0.75
0.50
0.25
0
0 3 6 9 12 15 18 21 24 27 30
24
23
14
14
7
4
6
3
2
1
0
1
0
0
P = .0039

 Overcoming resistance:
‒ Overcoming resistance: Combination
regimens are promising for improving long-
term outcomes
‒ Cold tumors: Strategies are being developed
to convert cold tumors to hot, expanding the
potential reach of IO
 Future direction:
‒ Refine biomarkers and personalize treatment
‒ Novel combination strategies to maximize
efficacy and minimize toxicity
‒ Augmenting IO response
Key Takeaways for IO in Advanced NSCLC
 Precision medicine:
‒ Molecular testing (PD-L1, TMB, MSI, EGFR, etc) is
essential for tailoring immunotherapy to individual
patients
 Immunotherapy landscape:
‒ First line: IO + CT often preferred, but
monotherapy may be suitable in patients with high
PD-L1 expression
‒ Post-TKI failure (EGFR+): IO + CT can be
considered, but results vary by trial
‒ Beyond PD-L1: TMB and MSI are emerging
biomarkers for predicting treatment response
‒ Phenotypic factors matter: Performance status,
smoking history, autoimmune disease, and prior
therapies

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Coverage of Immunotherapy in NSCLC!
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