Illuminating the Path With Immunotherapy for Metastatic, Locally Advanced, and Early-Stage NSCLC: A Guide to Patient Assessment, Treatment Selection, and Multidisciplinary Collaboration Across the Disease Continuum

Chair and Presenter, Sandip Patel, MD, Tina Cascone, MD, PhD, and Jonathan D. Spicer, MD, PhD, FRCSC, discuss NSCLC in this CME/MOC/NCPD/AAPA/IPCE activity titled “Illuminating the Path With Immunotherapy for Metastatic, Locally Advanced, and Early-Stage NSCLC: A Guide to Patient Assessment, Treatment Selection, and Multidisciplinary Collaboration Across the Disease Continuum.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/4aESTEt. CME/MOC/NCPD/AAPA/IPCE credit will be available until July 1, 2025.

1. Illuminating the Path With Immunotherapy for
Metastatic, Locally Advanced, and Early-Stage NSCLC

A Guide to Patient Assessment, Treatment Selection,
and Multidisciplinary Collaboration Across the Disease Continuum

Tina Cascone, MD, PhD
Associate Professor
Department of Thoracic/Head and Neck
Sandip Patel, MD Medical Oncology
Professor, Medical Oncology, University of The University of Texas MD Anderson
California San Diego < Cancer Center
Leader, Experimental Therapeutics Houston, Texas

Deputy Director, Sanford Stem Cell Clinical Center a
Co-Leader, Solid Tumor Therapeutics Program Jonathan D. Spicer, MD, PhD, FRCSC
Medical Director, Clinical Research Informatics Associate Professor,
Division of Thoracic Surgery

La Jolla, California
Director, McGill Thoracic Oncology Network

McGill University

Montreal General Hospital

Montreal, Quebec, Canada

Go online to access full CME/MOC/NCPD/AAPA/IPCE information, including faculty disclosures.

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2. PeerView.com/ZUT827

Our Goals for Today

Enhance your understanding of the latest data on immunotherapies in stage IV,
stage Ill unresectable, and stage I-III resectable NSCLC

Augment your skills in integrating immunotherapies into individualized treatment
plans for patients with NSCLC throughout the disease continuum

Implement best practices for multidisciplinary collaboration to make the most
of immunotherapy advances and improve patient outcomes in NSCLC

3. LUNGevity as Our Partner: Access Survivorship and
Support Services for Your Patients and Their Care Partners

For Patients &
Caregivers

ZA wungeyity

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4. LUNGevity as Our Partner: Immunotherapy Resources

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5. Decoding Decision-Making in
Metastatic NSCLC: Navigating the
Multitude of Immunotherapy Options

Sandip Patel, MD

Professor, Medical Oncology, University of California San Diego
Leader, Experimental Therapeutics

Deputy Director, Sanford Stem Cell Clinical Center

Co-Leader, Solid Tumor Therapeutics Program

Medical Director, Clinical Research Informatics

La Jolla, California

Y

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6. Approvals for First-Line Immunotherapy
in Advanced NSCLC

EMPOWER:

Cemiplimab + platinum chemo
(No EGFRIALKIROS1)

ge ecole
52 Pembrolizumab [nn ezo

E E +pemetrexed Pembrolizumab + carboplatin + nab-paclitaxel Nivolumab Durvalumab
2:5 platinum chemo +nab-paciitaxel + bevacizumab + carboplatin + ipilimumab + tremelimumab
5 (nonsquamous, + carboplatin (nonsquamous, — (nonsquamous, + chemo x 2 + chemo x 4

5 © noEGFR/ALK) (squamous) noEGFR/ALK) noEGFR/ALK) (noEGFR/ALK) | (no EGFR/ALK)

| |

2020

u |

2021 2022

>
2

S . : Atezolizumab Nivolumab + .

i fae nt tee nn Get
3 no EGFR/ALK) no EGFR/ALK) 1C 210%, no EDI1EIR, no EGFR/ALK)
E EGFR/ALK) no EGFR/ALK)

E

E

KEYNOTE-042 IMpower110 CheckMate -227 | EMPOWER-Lung-1

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7. A Case to Consider

67-year-old man who quit smoking 30 years ago was found to have a 3.4-cm right middle lobe lung
mass on a coronary calcium scan

PET CT revealed 3.4 x 3.4 RML mass, right hilar and subcarinal adenopathy and L1, 12th rib,
and left scapular metastases

MRI of brain was negative for metastases
Comorbidities: HTN, gout, hyperlipidemia
ECOG 0 at diagnosis

He is now noting mild left upper back pain

Pathology: EBUS shows metastatic poorly differentiated carcinoma with both glandular and squamous
features (patchy positive TTF-1 and negative for Napsin-A and p40); KRAS G13D; PD-L1 TPS 60%

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8. Faculty Panel Discussion: Which Options
Would You Discuss and Recommend?

Monotherapy options

+ Pembrolizumab (PD-L1 TPS 21%)
+ Atezolizumab (PD-L1 TC 250% or IC 210%)
+ Cemiplimab (PD-L1 TPS 250%)

Combinatorial options

+ Durvalumab + tremelimumab + platinum-based chemotherapy (SQ and NSQ)
+ Nivolumab + ipilimumab + platinum-based chemotherapy (SQ and NSQ)
+ Nivolumab + ipilimumab (PD-L1 TC 21% approved indication; NCCN: any PD-L1; SQ and NSQ)
+ Pembrolizumab + pemetrexed/platinum chemotherapy (NSQ)
+ Pembrolizumab + carboplatin + paclitaxel or nab-paclitaxel (SQ)
+ Atezolizumab + bevacizumab/paclitaxel/carboplatin (NSQ)
+ Atezolizumab + nab-paclitaxel/carboplatin (NSQ)
* Cemiplimab + platinum-based chemotherapy (SQ and NSQ)
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9. Another Case to Consider

62-year-old female, a current smoker, presents to the ED with a 1-month history of progressive
confusion

MRI of brain is positive for a 3-cm frontal lobe metastasis

Neurosurgery took her to the OR

Pathology: adenocarcinoma; KRAS G12C, STK11, KEAP1 mutations detected

PD-L1 negative

CT scan revealed large left lung lesion eroding into the left chest wall and right rib metastasis
She is back to her baseline after surgery

Comorbidities: COPD and CAD

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10. Faculty Panel Discussion: Which Options
Would You Discuss and Recommend in This Case?

Monotherapy options

+ Pembrolizumab (PD-L1 TPS 21%)
+ Atezolizumab (PD-L1 TC 250% or IC 210%)
+ Cemiplimab (PD-L1 TPS 250%)

Combinatorial options

+ Durvalumab + tremelimumab + platinum-based chemotherapy (SQ and NSQ)
+ Nivolumab + ipilimumab + platinum-based chemotherapy (SQ and NSQ)

+ Nivolumab + ipilimumab (PD-L1 TC 21% approved indication; NCCN: any PD-L1; SQ and NSQ)
+ Pembrolizumab + pemetrexed/platinum chemotherapy (NSQ)

+ Pembrolizumab + carboplatin + paclitaxel or nab-paclitaxel (SQ)

+ Atezolizumab + bevacizumabjpaclitaxel/carboplatin (NSQ)

+ Atezolizumab + nab-paclitaxel/carboplatin (NSQ)

+ Cemiplimab + platinum-based chemotherapy (SQ and NSQ)
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11. Practical Considerations and Case Variations

+ How does your treatment selection change based on different PD-L1
expression levels?

+ What is the relevance of the KRAS G12C mutation? What about the STK11
or KEAP1 mutations?

+ What if the patient had presented with a surgically resectable lung tumor
and a solitary brain metastasis amenable to SRS?

Disease burden Y” History of autoimmunity
Symptom severity Y Comorbidities

Performance status “ Patient goals and preferences
Histology Y Other?

+ What other factors are relevant?

SIS

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12. Potential Role of Subcutaneously Administered
Immunotherapy in NSCLC

Phase 3 Studies Assessing SC ICIs Across Tumor Types
+ SC administration provides an

alternative with potential benefits IMscin00112
for both ans providers SC alezolzumab In NSCLC
ae January 2024: Approved in the EU for all indications*
+ SC dosing may
— Alleviate the need for IV CheckMate -67T45
vein ports SC nivolumab in RCC
May 2024: Under FDA review for

— Allow more patient flexibility

— Reduce dose preparation and
administration times

— Optimize occupancy in infusion
centers

CREST’
Cohort B: SC sasanlimab in NMIBC

RELATIVITY-127®

When might you use SC ICIs in NSCLC: SC nivolumab + relatlimab in metastatic melanoma

1. Buroto M et al. Ann Oncol 2023/34:593-702, 2. Nips:/cnicalials gov/stuoyNCTO3735121. 3 ps/rswwordoharma.comstory/5818570,
4. Nps.fcnicalril.go/studyiNCTO4810078. 5. George Se al. ASCO GU 2024. Abstract LBA.

6. hips zw businesswie.com/news/home/20240520859296\en/Bristol Myers-Squibb-Announces-Updated-Action Date-by the S -Food-and-Drug-Administraton a
{for-Subeutaneous-Nivlumab-ivelumab-and hyaluronidase, 7. Ntpsilassic cnicalirals. govie2/showNCTO4165317 8. ps /cinicalriae gow'stodyncTos62s300. Peer View.com

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13. CheckMate -9LA: 5-Year Outcomes With Nivolumab (N) +
Ipilimumab (I) + Chemotherapy (CT) vs CT in 1L mNSCLC*

1L N + | + CT maintained long-term, durable efficacy benefit vs CT in patients with
mNSCLC at this 5-year follow-up, including in patients with tumor PD-L1 expression
<1% or squamous (SQ) histology
— 5-y OS rates: all randomized, 18% vs 11%; PD-L1 <1%, 22% vs 8%;

SQ, 18% vs 7%
Ongoing responders at 5 years: all randomized, 19% vs 8%; PD-L1 <1%, 25% vs
0%; SQ, 11% vs 6%
Discontinuation of N + | + CT due to TRAEs did not negatively affect long-term survival
N + | + CT increased 5-year survivorship vs C alone; among 5-year survivors:
— Responses were maintained in 59% vs 46% of responders, respectively
— 72% vs 35% of patients, respectively, were treatment-free at 5 years

Clinical benefit was seen across all | dosing subgroups
Safety outcomes were consistent regardless of the number of | doses received

1. Reck Metal. ASCO 2024. Abstract 8560. PeerView.com

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14. Charting the Course of Immunotherapy
in Locally Advanced NSCLC:
Optimizing Multimodal Strategies

Tina Cascone, MD, PhD
Associate Professor, Department of Thoracic/Head and Neck

Medical Oncology
The University of Texas MD Anderson Cancer Center

Houston, Texas

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15. PACIFIC: Study Design’

Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Study

Durvalumab

10 mg/kg Q2W (up to 12 mo)
n=476

Stage III, locally advanced, unresectable
NSCLC

+ No progression following definitive
platinum-based cCRT (22 cycles)

+ 218 years of age

+ WHOPS score 0 or 1

+ Estimated life expectancy 212 wk
Patients enrolled irrespective of PD-L1 status

1-42 days
post-cCRT

2:1 randomization stratified by age,
sex, and smoking history

Placebo
n=237

Endpoints
+ Co-primary: PFS by BICR® (RECIST v1.1) and OS

+ Key secondary: ORR per BICR,” DOR per BICR, TTDM per BICR (RECIST v1.1), safety, and PROS

Updated OS and PFS analysis assessed ~5 y after last patient was randomized
(data cutoff Jan 11, 2021; exploratory, post hoc analysis)

+ Time trom randomization to the fest documented tumor progression or death in the absence of progression.
CORR as measured from basaine scan post CRT complaton 1 ni
1 Antonia J at al. N Engl J Med. 2017:377:1919-1929, PeerView.com

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16. PACIFIC: Updated OS and PFS (BICR) in the ITT Population’

Durvalumab vs Placebo x 1 Year After Chemoradiation

os PFS
AAA AS
= sae Traces
= Fe FR
me
nee caso u
qe Hanne, s
ii e a nos „Diane À 08 ER
Bos at es E CT
7 : Ba sou ROO
ge ga
a En i

Time, mo

Timo, mo.

hese TOON COOOWT STH AOATANGH C7 20h 2 6 M EE M MM MNT NS ANR NME M6 à 1 0
1. Spigel DR et al. Cin Oncol 202240: 1301-1311 PeerView.com
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17. PACIFIC: Updated OS by Prespecified
and Exploratory Post Hoc Subgroups’

+ Updated OS and PFS (BICR) for patient = SE wae vo ofen
subgroups were consistent with previous nn en EEE OY zusam
reports, supporting the use of the PACIFIC "=: u my nese were
regimen in a broad population E ueno seme 8 ana

EGFR or ALK aberration status
Positive 17/29 (58.6) 8114 (57.1) 0.85 (0.37-1.97)
Negative 166/317 (52.4) 109/165 (66.1) 0.66 (0.52-0.84)
Unknown 81/130 (62.3) 38/58 (65.5) 0.85 (0.57-1.24)
PD-L1 expression level
225% 51/115 (44.3) — 27/44 (61.4) H—>=——=+ 0.52 (0.32-0.82)
<25% 111/187 (59.4) 64/105 (61) 0.90 (0.67-1.23)
Unknown 102/174 (58.6) 64/88 (72.7) re 0.68 (0.50-0.93)
1%-24% (post hoc analysis) 52/97 (53.6) 29/47 (61.7) 0.73 (0.46-1.14)
21% (post hoc analysis) 103/212 (48.6) 56/91 (61.5) he 0.61 (0.44-0.85)
<1% (post hoc analysis) 59/90 (65.6) 35/58 (60.3) 1.15 (0.75-1.75)
02 04 06 08 12 14 16 18
= _—
Durvalumab better Placebo better

1. Spige DR ota. J Gin Oncol 2022:40:1301-1341 porel PeerView.com

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18. PACIFIC Exploratory Analysis: Treatment Benefit Confirmed
With Durvalumab After cCRT in Stage IIIA-N2 NSCLC‘

PFS in Patients With (A) or

Dunalumab
a
PFS events, 0 (8) 20 406)
10 Mean PFS (95% Cl, mo NR (MON)
os
08%
as 959% 61 523080
5 200%
3“ 95% Cl, 40.5507
Eos
Bos
Eos
Los
02 a
CET
es cr 22420 26%
een tases Oe 25%, 150985
o
013 6 0 2 6 6 à à
Time, mo
No. at Risk
Duvalumab 197 161 199 116 78 40 19 6 1
E:

Patients wi al other stage (including stages IIA-NOANT and IB)
1.Senan S et al. ESMO Open. 2022.-100410.

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ithout? (B) Stage IIIA-N2 NSCLC

Durvalumab Placebo

Placebo
(o=90) we sim
EN] PFS events, 0%) ET oo)
556792) ne Median PFS 95% Ch.mo__ 138(109173) 564282)
os
os
5 5%
gar 95% C146.6589
Bos 207%
ii Bos 95% C1, 313479
Eos Durvalumad
2
os
Pracebo En
01
o
=» 013 8 8 2 6 6 à À à ®
Time, mo
No. at Risk
1 0 Duralumab 279 216 168 148 83 46 25 15 3 0 0
oo Pace M7 100 6 6 2% 1 3 2 0 0

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19. PACIFIC Exploratory Analysis: Treatment Benefit Confirmed
With Durvalumab After cCRT in Stage IIIA-N2 NSCLC‘

OS in Patients With (A) or Without? (B) Stage IIIA-N2 NSCLC

Pico Dumalımab Pete
ara (mien
5 events 0%) 75681) 52678) ‘05 events. 00) CTA
Medan OS (95% CD mo MOGI2NE) 242183202) Medan OS (85% C.mo_ NRG22NE) 31 (229:NE)
10 us 10 21%
09 25% C1 780989 ry 25% 61770962
5 cos fs sun
5 gon chera7ss gon 99% 61580702
gor gor
Bos man de Dunalımab
Eos sx GK 663257 Duvatumab Los Placebo
Boa 1 g 04 586%
a 5 95% 61490062
$ x Pace Ces

03 95% C1. 40.610

02

01 01

o o

NIRO TIFT REBANATHHSHw AS
Time, mo Time, mo

No. at Risk No. at Risk
Durvalumab 197 194 181 175 162 155 160 196 118 93 48 24 7 1 0 0 Durvalumab 279 270 250 240 223 209 193 183 166 117 67 33 16 1 0 0
Placebo” 90 87 79 72 69 64 54 49 42 20 14 6 3 1 0 0 Placebo 147 133 119 108 101 91 87 81 75 50 28 15 6 2 1 0
ations vt ol ter stages (including stages INA-NOINT and IB). si
¡Senan S et al. ESMO Open. 2022:7:100410. PeerView.com

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20. Other Trials in Unresectable Locally Advanced NSCLC

(Nonexhaustive List)!

PACIFIC-2

EAS181

KEYLINK-012

KEYVIBE-006

CheckMate -73L

PACIFIC-9°

SKYSCRAPER-03*

LAURA®

CRT + durvalumab > durvalumab

CRT > placebo

CRT + durvalumab > durvalumab

CRT > durvalumab

CRT + pembrolizumab > pembrolizumab + placebo
CRT + pembrolizumab > pembrolizumab + olaparib
CRT > durvalumab

CRT + pembrolizumab + vibostolimab > pembrolizumab + vibostolimab
CRT > durvalumab

CRT + nivolumab > nivolumab + ipilimumab

CRT + nivolumab = nivolumab

CRT > durvalumab

CRT > durvalumab + oleclumab

CRT > durvalumab + monalizumab

CRT > atezolizumab + tiragolumab

CRT > durvalumab

CRT + osimertinib

CRT > placebo

N=328

N = 660

N= 870

N=216

NCT03519971

NCTO4092283

NCT04380636

NCTO5298423

NcT04026412

NCTO5221840

NCTO4513925

NCTO3521154

+ PACIFIC-22 and CheckMate -73L did not meet their primary endpoints of PFS

‘Randomized ator CRT.

1. MoghanokiD eta J Thorac Oncol 2028,18:1129-1133.2. Bradley Jet al. ELCC 2024. Abstract LEA.
3 ps. Jnows ms convnowsicerporate-fnancial202\Bstoh Myers Squid Provdos-Update-on-Phase-3-CheckMato-73l-Traldlaut aspx

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21. Updated Results From COAST: Durvalumab (D) + Oleclumab (O)
or Monalizumab (M) in Stage Ill Unresectable NSCLC"

+ D+0O and D +M increased ORR,

prolonged PFS, and trended toward D (n67) D+0 (n=60) )
improved OS vs D alone Confirmed ORR (95% Ch, % os Er e

+ Randomization was stratified by any UT
histology, but results should be a een (3) (20.9) UA) ss
interpreted with caution given Madlan duration of response OX arg 2907 2300020
imbalances in prognostic characteristics °”"° 7 2. _

+ Safety was similar across arms, with no Median prs (95% C0), mo 7240138) 309) 31.)
new safety signals a 0.59 (0.37, 0.63 (0.40,

+ Further investigation of D, D + O, and Je a

PS dana sf Median 05 (95% Ch, mo 409(22.6,NR) — NR(STO,NR) — NRBLANA)
D + Min this population is ongoing in non Fern
the phase PACIFIC-9 study RER) 1.20) 133)
(NCT05221840), which will stratify EE asus mama 721686,
patients by stage, histology, and a), =) S12)
PD-L1 status
1. Aggarwal Cet al. ASCO 2024, Abstract 8046. PeerView.com

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22. Another Case to Consider

65-year-old healthy woman with LUL adenocarcinoma

CT screening showed a 6.1-cm L hilar mass with vascular and pericardial invasion
Underwent a PET scan (SUV 17 in masses and 13 in LN)

Had a LUL CT-FNA which showed poorly differentiated adenocarcinoma

EBUS by IP 4L and 7 positive for adenocarcinoma; 4R negative

Biomarker testing: PD-L1 <1%, KRAS G12C and ATM mutated; TMB stable: 9.5 mut/MB
cT4N2MO

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23. u
©
3
©

5
=
o

(©)
o
7)
©

(©)

24. Faculty Panel Discussion: Which Options
Would You Discuss and Recommend?

Definitive chemoradiation therapy followed by consolidation durvalumab
Neoadjuvant chemotherapy followed by surgery followed by adjuvant ICI
Neoadjuvant ICI + chemotherapy followed by surgery

Something else?

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25. How Would You Manage This Case if the Patient
Had an EGFR L858R Mutation Instead?

en Press release: Positive high-level results from the phase 3 LAURA trial showed maintenance

Ve osimertinib demonstrated a statistically significant and highly clinically meaningful improvement in
Rae PFS for patients with unresectable stage Ill EGFRmut NSCLC after CRT vs placebo after CRT!

Treatment and follow-up

Post-CRT imaging: CR, PR, SD»

Gars
Optimal: postprogression,
- merino :
80 mg QD patients receiving
Lente) or A
with stage INA/IIBANC. Stratification

Post-progression

lowed
EOFRmUNSCLO + CORT vs sCRT prem TEST,
(ex! or ) u ¡MA vs por RECIST v1.1 TSST, and OS

Curative intent le ‘Optimal: postprogression,

+ China vs non-China Patients receiving placebo
may receive open-label
Primary endpoints: PFS by BICR per RECIST V1.1
atents wi a loca cabas® EGFR mutation test v2 issue postive resul rom a CLUAcartfed or accreted laboratory donot require par | screening. “Post CRT imaging partormad to assess
PR and SD up 1 28 days before randomizaton. Assossment of PES2 wil not be colectd arte primary PFS analyst 7
1.LuS et al. Clin Lung Cancer. 2021:22:371-375. PeerView.com

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26. Paving Paths to Cure: Assessing
Neoadjuvant, Adjuvant, and Perioperative
Immunotherapy in Resectable NSCLC

Jonathan D. Spicer, MD, PhD, FRCSC

Director, McGill Thoracic Oncology Network
McGill University

Montreal General Hospital iy?’ |
Montreal, Quebec, Canada

y
Associate Professor, Division of Thoracic Surgery f = |
hi

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27. Curative Therapy for Locally Advanced NSCLC

Surgery
A N Radiation Therapy li Al
Systemic therapy

‘Chemotherapy
Targeted Therapy
Immunotherapy

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28. Evolving NSCLC Treatment Strategies!

1 Resectable Locally Advanced ll and IA Unresectable IIIB/C
Resection alone ‘Surgery + (neo)adjuvant cancer immunotherapy Chemotherapy/AT + cancer
Consider sublobar or targeted therapy immunotherapy or
resection + chemotherapy + RT targeted therapy
TandN NO N1 N2 N3

Ti IA 118
T2alb HA/IIB. 118
T3 INA 118 e
T4 INA 118 MIC
Mialblc IVA/B/C IVA/B/C IVA/B/C IVA/B/C

IVA/B/C
Systemic therapy: cancer immunotherapy; targeted therapy; chemotherapy

1. ps nen orgprofessionas/physican_gls/pdtinscl pdt. PeerView.com

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29. Nodal Staging’

‘The America ‘Thoracic Surgery (AXIS) ¡Domos
2023 Expert Consensus Document: Staging and

multidisciplinary management of patients with early stage

non-small cell lung cancer

Recoumeniaton
per Conseil Kia MD: [propre sapin of tens with aly imo ng cancer ld nae
Hemet MD Nel Tend PET imapis La tion, aia imaging animate meas aging
Cathie Shu, MD i] shoul be performed where cal indicate.
| Thorough lymph node assessment is imperative for accurate pathologic staging and
optimal oncologic outcomes. Intraoperative lymphadenectomy should include at
Ica 3 mediastinal sation and | flr nodal sation.
obeciomy remains the andar resection sty for operable pain
owes naomi whoa resection may be aceptable fortunes termined
toe low rik for nodal involvement based on size r radiographic!
Bisopatolgi fetes may also be a acceptable approach or patients who
ae high ik for lobectomy,
En inion of molecular sequencing anche omar analyse is
recommended o select optimal pcopratve ad postoperative treatment
egimens in cally advanced patient

1. Kidane B et al. J Thorac Cardiovase Surg. 2029;106:637-654, PeerView.com

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30. Updates to Perioperative Lung Cancer Care

Better Agents

2010

Better Selection

E38 potro
:

Better Outcomes
immunotherapy
Neoadjuvant
chemofimmunotherapy Perioperative

chomolimmunotherapy

‘Adjuvant
ALK TKI

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31. Patient Selection: Surgical Evaluation for NSCLC

Staging
Physiologic Evaluation

CT Biomarker testing

PET PFTS
EBUS/med Cardiac eval
Brain MRI Exercise testing

Frailty assessment

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32. Sequencing Considerations

Early eradication ‘Adjuvant is standard of care ‘Allows for greatest amount
of micrometastatic disease for resectable stage IB and Il disease of systemic therapy
Healthier patients with improved 5 Early eradication
tolerance of drug toxicity Nosurgenldasye of micrometastatic disease
improved adherence Tumor biomarkers can guide ‘Opportunity for pre- and post-treatment
and higher drug exposure therapeutic decisions tissue to adjust treatment
‘Opportunity for pre- and posttreatment A ae A Tumor biomarkers can guide
tissue to adjust treatment No added hilar and mediastinal fibrosis therapeutic decisions
Neoadjuvant is the standard of care
for resectable stage Ill disease

Presence of whole tumor allows
activation of broader and more diverse
immune response

No risk of disease progression
resulting in missed opportunity
for curative surgery

Presence of whole tumor allows
activation of broader and more
diverse immune response

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33. Understanding Evidence:
The Perioperative Immunotherapy Landscape

Adjuvant
IMpower010
PEARLS/KEYNOTE-091

Neoadjuvant _ Perioperative
CheckMate -816 AEGEAN
Neotorch
KEYNOTE-671
CheckMate -77T
RATIONALE-315

ANVIL
BR31
ALCHEMIST chemo-1O
MERMAID

IMpower030

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34. Overview of Perioperative Immunotherapy Trials

IMpowero1o AEGEAN! Checkiate 77
Timing Adam Advent Nemduan Foimenbe Fuiaue PetoperatvePetkpersive — Pefopentive
sie 1005 17 ase +02 500 791 ai 453
tuo Aezoizumab Pembralzumeb Nidumeb Duyalmab © Toeimb Pembrokzumeb Nialmab Tellzunab
hows ou on) (eos) Pout) on on) von von
No, cycles 6 1 o 1 ” A 1 2
pe Complet Conte) resgibleB Resectabe IIB. Resecabe Resecable LA
(edem)illA (79) (>dem)Ana (zn) (4em-IlA(7®) (8*) by lobectomy (er) em)
Stage Boum, % a 72/28 20/04 am 20/80" 20/70 25/65 41150
a ors
pr DFS hierarchical DFS PCR, EFS PCR, EFS MPR, EFS EFS, OS EFS EFS, MPR
mae (PD-L1 250%)
Chemotrerapy ip dower PH SD Peay doublet Planumbosed Platnumbased Caplan doublet Paioum doublet Planum cout
rence No EGER,
EGFR/ALK Included (15%) — Included (7.4%) ‘mutation aa WT Included (7%) no documented WT
(WT: Asia) Lien! ALK

1. Felipe E at al Lancet. 2021398: 1344-1357. 2. OBrien M et al. Lancet One. 202223-1274-1286, 3, Forde P otal. N Engl J Med, 2022;386:1073-1085.
4! Heymach Jot al AACR 2023. Abstract CTOOS. 5. Lu Set al. ASCO 2023, Abstract 8501. 6, Wakolee H et al. N Eng! Med, 2023:389:491-503. 7. Cascone T
ESMO 2023, Abstract LBAT. 8. Yue Det al. ELCC 2024. Abstract 1080

+: PeerView.com

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35. Understanding Evidence: Pathologic Response Results!-5

60
50 | 3 cycles 4 cycles
æ 40 pCR
A 30 24 Pathologic Complete Response
Sos 172 A 1 (No Viable Tumor at Resection)
ll &
o
CheckMate -816 AEGEAN Neotorch JE CheckMate -7T
60
485
e | we sea MPR
2° 33.3 30.2 Major Pathologic Response
E 30 (10% Viable Tumor at Resection)
2 2.3 11 12.1
do 8.9 8.4
o
CheckMate -816 AEGEAN Neotorch KEYNOTE-671 CheckMate -77T
|: Fort Pol N EL Me 2022908 072-1088 2 HoymachJetal AACR 2023 Abc TODS 3. LS ela ASCO 202 sta 501 À
4! Wakeloe Het a. N Eng! J Med. 2023,389:491-503. $. Cascone Tet al. ESMO 2023. Abstract PeerView.com

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36. CheckMate -77T Exploratory Analysis: Improved Efficacy With
Perioperative Nivo vs Placebo With 4 or <4 Neoadjuvant Cycles!
pCR by Number of Completed Neoadjuvant Treatment Cycles

4 Cycles <4 Cycles
All patients dents with
Difference
2138
50
40 x
# 30 267 É
E 20 ©
& 10 A" 2
LE,
Nivo — Placebo
WN Ste 117205

Of 7 patients who had a pCR in the nivo arm, 3 received
3 neoadjuvant cycles, and 4 received 2 neoadjuvant cycles

+ pCR rates similar among patients who underwent definitive surgery regardless of the number of neoadjuvant nivo + chemo cycles
Follow-up, median (ange): 25.4 (157-442) months,
599% Cb te za. 808-896, +27 DA TIT 4299, 0 251-402,123-11,4,929-334,277-442,.0-12,125-507,*154-592,10-008,

1. Awad MM et al. ELCC 2024. Abstract LBA2, PeerView.com

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37. Understanding Evidence: 2-Year EFS/DFS Results”

00 Adjuvant Neoadjuvant Perioperative
90 | HR, 0.81
66 HR, 0.76 HR, 0.68 HR, 0.68 HR, 0.40 HR, 0.58
FS 714 ge
5 70 3.6 65 633 Sur 624
L 60 59
a 152.4
@ 50 47 16.1
inf 10.6
wo
5
* 30
SS 20
10
o
IMpower010 KEYNOTE-091 CheckMate -816 AEGEAN Neotorch KEYNOTE-671 CheckMate -77T

1 ELCO 2023 Ant 04, 4 Heymach seta
7. Cascone Total, ESMO 2023.

A felon eta Lancet 2021 298-144-1967. 2. Been M a Local Cnel 202228-2741288 3 Fone
23. Abstract CTOOS. 5 Lu S ot al ASCO 2023. Abstract 8501. 6. Wakoloo Hat al. N Engl J Mod. 202:
rene

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38. Understanding Evidence: 3-Year OS Results!

100 Adjuvant® Neoadjuvant Perioperative
90 81 dora (038-106) (ie
P=.012 ee
80 775 78
71
x 70 64 64
g 60
z 50
$ 40
La
e 30
20
10
0
IMpower010 CheckMate -816 KEYNOTE-671
SFR aa Ann Oncol 229 80 918 2 Forte Pet of ELCG 2028 Anse 40.3. per ESMO 2023. Abstact LEAS. PeerView.com

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39. Our Resectability Criteria

+ Patient wishes and risk tolerance (highly variable)

+ Surgeon experience and risk tolerance (highly variable)

Baseline physiology to achieve accurate risk assessment (PFTs, VO2 max, 6-min walk test,
quantitative V/Q, ECOG, nutritional status, overall exercise tolerance, lifestyle,
comorbidities, etc.)

+ Predicted postoperative functional reserve/QoL based on extent of pulmonary resection
required for RO

+ Feasibility of RO at baseline and based on expected response (guided by biomarker profile,
functional reserve, type of neoadjuvant regimen employed, surgical experience)

+ How does risk/benefit profile of a surgical course compare with alternatives and their
risk/benefit profiles? Patient preference?

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40. Technical Challenge: Neoadjuvant Immunotherapy

Moderate/major
fibrosis in nICI cohort
20% with cN-
59% with oN+

Patients, %

None/Minor ” Moderate Major

nici M nc
Cornell

+» 44% induction IO cases with
moderate to severe fibrosis

+ Similar to induction chemo

PeerView.com/ZUT827

Complexity of Surgical Resection
40% of operations judged to be “more difficult’ than usual (scale 23)

wo pe
Oy 5. Pare
E ES
n
# ©
7
E%
E
E
ñ
°
Median HT 128 150 24 Modan 0 m 25 10
A u Zu Zu 1 2 8 HP

MD Anderson: NEOSTAR trial
+ 36% induction IO cases with moderate to severe fibrosis
+ Correlated with length of resection but not response

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41. Technical Challenge: Neoadjuvant Therapy

Intraoperative Challenges After Induction Therapy for NSCLC:
Effect of Nodal Disease on Technical Complexity

+ MD Anderson 2010-2020

+ 124 N+ patients treated
with neoadjuvant therapy

+ 86% chemotherapy

+ cN1 disease and treatment
response associated
with greater need for complex
intraoperative maneuvers,

1. Feldman Het a. JTCVS Open. 2022:12:372-384, PeerView.com

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42. Technical Challenge: Neoadjuvant Therapy

Initial CT

Post-Induction CT Post-induction planning

+ Discuss MIS and possible open
resection

+ MIS and open instruments in room
+ Strong assistant
+ Allot adequate time

+ Start MIS, assess for pleural
metastasis and begin dissection

* Continue MIS until feels unsafe
or cannot get tumor out

+ Convert if needed

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43. Radiological and Histopathological Features
of Abnormal Nodes Following Neoadjuvant ICI!

Nodal Immune Flare (NIF) Nodal PD (No-NIF)
> nn nie h pm

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44. Neoadjuvant/Periopera

Resolving Controversies:

ive Chemo-lO by Stage?!

Statistically
significant EFS

benefits are not
limited to stage III

1. Sorin et a. JAMA Oncol 2024:10:521-633,

PeerView.com/ZUT827

Stage It
Forde 2022% Stage It
Wakolee 2023 Stage It
Heymach 2023 Stage It
Cascone 2023 Stage It

Random effects model
Hetergenoty: 7 =0%, 7 = < 04, p = 0.68

Stage lt
Forde 2022 Stage lt
Wakelee 20238 Stage Il
Wakeiee 20230 Stage I
Hoymach 20232 Stage ill
Heymach 20230 Stage tll
Provencio 2023 Stage I
Lu 2023 Stage Il
Cascone 2023 Stage I

Random effects model
Hetergenoty: 7 = 0%, 7 = < 04, p=0.47

65
ns
104

er

1
217

62
173

57
202
146
1058

62
121
mo
a
Ed

ns
224

ss
165

202
149
1097

ms 087 (0.48; 1.56)
+ 0.59 (0.40; 0.88)
—# 0.76 (0.43; 1.34]
aa 081 (0.46; 1.43]
- 071 1055092]
En 054 (0.37;0.80)
- 057 [0.44:074]
—— 057 [0.38:0.90]
aa 057 (0.39: 0.83)
+ 0.83 (0.52:1.32]
—— 0.47 1025:0.88]
== 039 [027.057]
—- 051 (0.36;0.72}
> 0.54 (0.48;0.62]
02 0s 1 2 5

Favors Creme. Favor Chemo

PeerView.com

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45. Resolving Controversies:
Neoadjuvant/Perioperative Chemo-lO by PD-L1?1

pou aim
Forde 2022 pour as n m ES oe 154: 152
Mao 2020 POLI west = 025 106: 1011
Mean 20æ POL mw | 030 pam
Lazos PDU <a E 70 059 (039: 10]
Cwone2029 POLY et se a “a! om warum
Random eects model wo +
a on <0, 9 2001
Statistically significant POLI 149%
EFS benefits present Forde 2022 Pou 149% 5 at
We 2008 PDU 148% w ss +
across all PD-L1 strata Heymach 2023 POLI 149% 135 142 EL.
5 Jonh Laza Pou 148% oe
with relationships Carmen POLY 40% 78 Es
proportional to ee. = “8 =
magnitude of effect ee
POL 0%
Forde 2022 POL: or se e —— 025 10:10:00
Wine 2023 POL 0% mo om Ae 048 1033:0711
oyrach2023 PDL 350% wo tor —- 00 1038-1001
tw202s POL sor “ e. —— cas 15:06
Cascone 2029 POLY 350% as 2 — 026 1012:059
Random eects model mm — 040 (020;0.56)
any: Pm: =<0,p=021
oz os 1 2 5
Favor Chemo 10 Favors Chemo
1. Sorin eta JAMA Oncot2028:10:621-635, PeerView.com

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46. AEGEAN: Outcomes With Perioperative Durvalumab in
Resectable NSCLC and Baseline N2 Lymph Node Involvement!

+ Among patients with baseline N2 nodal status, perioperative D + neoadjuvant CT prolonged
EFS and increased pCR rate vs neoadjuvant CT alone, similar to that observed in the
mITT population
- EFS HR = 0.63 (95% Cl: 0.43-0.90), with benefit in both single- and multi-station disease
(HR = 0.61 and 0.69)
— Difference in pCR rate = 11.7% (95% Cl: 5.6-18.4)
+ In the N2 subgroup, the approach, type, and timing of surgery were similar between arms and
consistent with the overall trial
— The proportion of patients who completed surgery was slightly lower in the N2 subgroup vs
the mITT population (72.7% vs 77.2%)
- Ofthose that completed surgery, RO resection rates were numerically higher in the
D vs placebo arm (94.7% vs 91.7%)
+ Inthe N2 subgroup, the perioperative regimen had a manageable safety profile, similar to that
with neoadjuvant CT alone and consistent with the overall trial

Conclusion: With clinically meaningful improvement in efficacy, no adverse impact on surgical outcomes,
and a manageable safety profile, the addition of perioperative durvalumab to neoadjuvant CT remains a
potential new treatment option for patients with N2 R-NSCLC

1. Heymach J et al. ASCO 2024. Abstract 8011, PeerView.com

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47. 4-Year Update From CheckMate -816: Neoadjuvant Nivolumab
+ Chemotherapy vs Chemotherapy in Resectable ©

+ In this 4-year update, neoadjuvant N + CT demonstrated durable, long-
term EFS benefit and a clinically important OS improvement trend vs CT er
— N+CT improved lung cancer-specific survival vs CT (HR = 0.62)

+ OS improvement trend was seen with N + CT regardless of platinum
backbone or extent of surgical resection

+ Presurgical ctDNA clearance was prognostic for OS

+ Safety profile was consistent with previous reports

Conclusion: These 4-year results provide the first understanding of
the long-term benefits of neoadjuvant immunotherapy + CT and
reinforce nivolumab + CT as SOC for patients with resectable NSCLC

1. Spier J et al, ASCO 2024. Abstract LBABO1O. PeerView.com

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48. CheckMate -77T: Clinical Outcomes With Perioperative
Nivolumab by Nodal Status in Stage Ill Resectable NSCLC‘

+ Inthis exploratory analysis, perioperative nivolumab demonstrated clinical benefit vs placebo
in patients with clinical stage Ill N2 and stage Ill non-N2 NSCLC
— EFS was improved: HR = 0.46 (N2); 0.60 (non-N2)
+ Patients with N2 NSCLC had similar surgical feasibility as patients with non-N2 NSCLC after
neoadjuvant nivolumab + CT, and 86% of surgeries were complete (RO); after surgery:
— 67% of patients with N2 had nodal downstaging, and 57% had ypNO
- pCR rate was 29% among resected patients with N2, 38% among those with multi-
station N2
+ Patients with N2 and without pCR had improved EFS after surgery with nivolumab vs placebo:
HR = 0.48
+ Perioperative nivolumab showed similar safety outcomes between N2 and non-N2 subgroups

Conclusion: These along with previous results from CheckMate -77T support
perioperative nivolumab as a potential new treatment for patients with resectable
NSCLC, including those with poor prognosis such as stage III N2

1.Cascone T et a. ASCO 2024. Abstract LBA8007. PeerView.com

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49. Another Case to Consider

61-year-old ex-smoker with LUL mass;
ECOG PSO

Path: adenocarcinoma, PD-L1 0%,
KRAS G12C mutation

cT3N1MO after chest CT with IV contrast,
CT of head and PET scan

FEV1 79%, DLCO 100%

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50. Case Continues

Enrolled on neoadjuvant
chemoimmunotherapy trial

Received 3 doses of carboplatin
+ pemetrexed and ICI

Developed mildly symptomatic
COVID-19 after second dose

Restaging CT performed

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51. Case Continues

YeT2BN1, adenocarcinoma, solid predominant, POLA
10%, RVT 61%, RO

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52. Faculty Panel Discussion:
Multidisciplinary Decisions

+ What would be your preferred approach to the treatment of this patient?
+ What would you do if pCR had been achieved?

+ What are your key considerations for use of neoadjuvant, perioperative,
or adjuvant immunotherapy based on different factors?

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