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, discuss lung cancer in 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. Transforming Care and Outcomes
With Immunotherapy in Stage I-Ill
Resectable NSCLC

A Case Exploration of New Standards
and Emerging Approaches

Jessica Donington, MD Jonathan D. Spicer, MD, PhD, FRCSC Li
Professor of Surgery Associate Professor, Division of Thoracic Surgery | 1
Chief, Section of Thoracic Surgery L Director, McGill Thoracic Oncology Network Ff
The University of Chicago Medicine McGill University ve
À

Chicago, Illinois Montreal General Hospital

» Montreal, Quebec, Canada À
A N

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

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2. PeerView.com/WFQ827

Our Goals for Today

Enhance your understanding of the latest evidence supporting
the use of immunotherapy in resectable NSCLC

Augment your skills in identifying candidates for neoadjuvant,
adjuvant, or perioperative immunotherapy

Improve multidisciplinary collaboration to optimally integrate
immunotherapies into individualized treatment plans for patients
with resectable NSCLC

3. Immunotherapy in Resectable NSCLC:
Essential Evidence and Modern
Practice Principles

Jessica Donington, MD
Professor of Surgery

Chief, Section of Thoracic Surgery
The University of Chicago Medicine
Chicago, Illinois

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4. US | MB Luing-Cuncerinckenceant Morale — Cancer Incidence and Mortality’

238,340 127,070
diagnosed with lung died from lung
cancer in 2023 cancer in 2023
Estimated Cases by Tumor Type Estimated Deaths by Tumor Type
127,070

300,590 288,300
wi 550 o 550 = a

238,340
U u | i [|
10 = 0

Prostate Lung Colorectal Skin Lung Colorectal Pancreas Breast Prostate

1. nips iwi cancer orgiresearehleancerfacte-statetes/al-cancerfacts-fgures/2022-cancer-facts-igures hi, PeerView.com

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5. US Lung Cancer Incidence and Mortality’

1 of every 4 cancer deaths is a lung cancer death

1. ps wu: cancerorgiresearehieancerfacte-statetcsal- cancer facts-fgures/2023-cancer-facte-igures hm, PeerView.com

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6. Resectable Lung Cancer: Poor Prognosis’

5-y OS
Stage IB: 71%
Stage IIA: 64%
Stage IIB: 55%
Stage IIIA: 37%

0 6 12 18 24 30 36 42 48 54 60 66 72
Time, mo
4. Chanshy K et al. J Thorac Oncol, 2017:12:1109-1121. PeerView.com

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7. Curative Therapy for Locally Advanced NSCLC

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8. Curative Therapy for Locally Advanced NSCLC

7 À

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9. Curative Therapy for Locally Advanced NSCLC

©

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Local Therapy

Surgery
Radiation Therapy

6

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10. Curative Therapy for Locally Advanced NSCLC

Local Therapy

Surgery y
Radiation Therapy

Systemic therapy

‘Chemotherapy
Targeted Therapy
Immunotherapy

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11. Evolving NSCLC Treatment Strategies!

1 Resectable Locally Advanced II and IA Unresectable IIIBIC
Resection alone ‘Surgery + (neoJadjuvant cancer immunotherapy Chemotherapy/RT + cancer
Consider sublobar or targeted therapy immunotherapy or
resection chemotherapy + RT targeted therapy
TandN NO N1 N2 N3
Ti A 118
T2alb HA/IIB 118
T3 INA NIC
T4 INA 118 e
Mialblc IVA/B/C IVA/B/C IVA/B/C IVA/B/C

IVAIBIC
‘Systemic therapy: cancer immunotherapy; targeted therapy; chemotherapy

tps ww nen orgirotessonas/physician_ol/pinscl pat. PeerView.com

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12. Updates to Perioperative Lung Cancer Care

2000 2005 2010 2015 2020 2025

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13. Updates to Perioperative Lung Cancer Care

Better Agents

2000 2005 2010 2015 2020 2025 ;

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14. Updates to Perioperative Lung Cancer Care

Better Selection

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15. Updates to Perioperative Lung Cancer Care

Better Agents
: Inbilon

2000 2005 2010 2015 2020 2025

Better Selection
Better Surgery

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16. Updates to Perioperative Lung Cancer Care

therapy

Better Selection
Better Surgery
Better Outcomes

EES ‘Adjuvant EGFR TKI Adjuvan

immunother

y
Neoadjuvant
chemo/Immunotherapy Perloperative
chemolimmunotherapy
Adjuvant
ALK TKI

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17. Incorporating Immunotherapy
Into Resectable NSCLC Management

Select appropriate patient

© J
@ Determine sequence of therapies
© Appropriate pre- and intraoperative nodal staging
© Understand the evidence
@ Plan for potential technical challenges

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18. Patient Selection: Immune Checkpoint Inhibitors
and Targeted Therapies

k ?
A O

PD-1/PD-L1 Inhibitors Biomarker-Directed Therapies
Inhibit interactions between PD-1 Inhibit oncogenic drivers,
and PD-L1, which activates T cells so they which are present in ~64%
can recognize and eliminate cancer cells of patients with NSCLC

Atezolizumab (PD-L1)
Durvalumab (PD-L1) Osimertinib (EGFR)
Nivolumab (PD-1) Alectinib (ALK)
Pembrolizumab (PD-1)

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19. Patient Selection: Surgical Evaluation for NSCLC

Staging

Physiologic Evaluation

ar Biomarker testing

PET PFTs
EBUS/med Cardiac eval
Brain MRI Exercise testing

Frailty assessment

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20. Sequencing Considerations

Neoadjuvaı Adjuvant Sandwich
Early eradication ‘Adjuvant is standard of care ‘Allows for greatest amount
of micrometastatic disease for resectable stage IB and II disease of systemic therapy
Healthier patients with improved 4 Early eradication
tolerance of drug toxicity OEM EIS Ee 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 post-treatment | [ No added hilar and mediastinal fibrosis Tumor biomarkers can guide
tissue to adjust treatment 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

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

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21. Nodal Staging’

‘The America ‘Thoracic Surgery (AATS)
2023 Expert Consensus Document: Staging and
multidisciplinary management of patients with early stage
non-small cell lung cancer

Recommendation
Biniam Kidane, ND: th new lung cancer should inc
nam Kidane: MD. Appropriate staging of patients with newly diagnosed lung cancer should include

Espert Consensus
Panel:

should be performed where clinically indicated.

Thorough lymph node assessment is imperative for accurate pathologic staging and
‘optimal oncologie outcomes. Intraoperative lymphadenectomy should include at
least 3 mediastinal stations and 1 hilar nodal station,

Lobectomy remains the stndard-of care resection strategy for operable patients
However, anatomic sublobar resection may be acceptable for tumors determined
to be low risk for nodal involvement based on size or radiographic!
histopathologic features It may also be an acceptable approach for patients who
are high risk for lobectomy.

Earl initiation of molecular sequencing and other biomarker analyses is.
‘recommended to select optimal preoperative and postoperative treatment
‘regimens in locally advanced patients.

1. Kidane B etal J Thorac Cardiovase Surg, 2023;168:637-654 PeerView.com

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22. Understanding Evidence:
The Perioperative Immunotherapy Landscape

Adjuvant Neoadjuvant Perioperative
IMpower010 CheckMate -816 AEGEAN
PEARLS/KEYNOTE-091 Neotorch
KEYNOTE-671
CheckMate -77T
RATIONALE-315

ANVIL
BR31
ALCHEMIST chemo-IO
MERMAID

IMpower030

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23. Overview of Perioperative Immunotherapy Trials1-3

IMpowerot _ KEYNO ATIONALE-318
Timing ‘Adwont Ara Neue Peipenie — Pareperavo — Paoperatvo — Perperaive — Perkperlvn
Sus 1005 wn 8 802 500 726 a 483
Agent vO Atezolizumab Pembrolzumab — Nivolumab Dumalımab Torpalimab Pembrolzumab Nvoumab Tislelizumab
ou) won) von pouty von on) von von
No. cyces 6 1 3 1 ” 1 1 u
zu eel ese ie es ie es tesectable
Inclusion med _ecateain, (tel Rebelle Aesecabi HIB Resaca Resecable LA
(edema (79) — (>4cmpana (7m) O4CMPNA (7%) (8%) by | sd La sd
stage, % sort rie 20/64 21/13 20/00 20/70 29/65
= Fs,
Primary DS nercncal Dre PRES -MPREFS MPREIS Ers,os ers EFS, poR
(Pot 80%)
chemotherapy PLA amu Cot Patnumdased Piknumbased Caplan out Piknum dowel Planum cout
No documented No EGFR
IN no mn Excluded
(WT: Asia) sk ALK
1. Fede NEM 202.2 Heymac AMR 2028 2. Lu 5, ASCO 2028 4 ale H, NEM 2023.8 Caton T, ESMO 02. 0. Fee E Lancet 2021 Puetviéion:

7. frien M, Lancet One 2022. 6. Yue D, ESMO 2024,

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24. Understanding Evidence:

Treatment Length and Median Follow-Up in Months’?
IMpower010
KEYNOTE-091
CheckMate -816
AEGEAN
Neotorch
KEYNOTE-671
CheckMate -77T

o 6 12 18 24 30 36 42
Treatment length #æm Median follow-up

1.Forde P.NEIM 2022.2, Heymach J, AACR 2023, 3. Lu 5, ASCO 2023. 4. Wakelee H, NEJM 2023. 5 Cascone T, ESMO 2025 6, Felpe E, Lancet 2021 View.
7. OBrien M, Lancet One 2022.8. Yue D, ESMO 2024. PeerView.com

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25. Understanding Evidence: Pathologic Response Results'®

60

“0 3 vs 4 cycles
nu AT LT PCR
24

&
we 30 24.8 25.3 Pathologic Complete Response
Lo 172 18.1 (No Viable Tumor at Resection)
. = | : | 8 a
0
CheckMate -816 AEGEAN Neotorch KEYNOTE-671 CheckMate -77T
60
=. MPR
ae Major Pathologic Response
a 3 (10% Viable Tumor at Resection)
= >
10
0
CheckMate -816 AEGEAN Neotorch KEYNOTE-671 CheckMate -77T
4. Forde P, NEJM 2022. 2. Heymach J, ACR 2023, 3. Lu S, ASCO 2023. 4. Wakelee H, NEJM 2023, 5, Spice J, ESMO 2023. 6. Cascone T, ESMO 2023. PeerView.com

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

Pe Adjuvant Neoadjuvant Perioperative

90 | HR,0.81

pa HR, 0.76 HR, 0.68 HR, 0.68 HR, 0.40 HR, 0.59 HR, 0.58
x 714 70
a ee 63.6 er, m 65 633 Sur 624
e
S e Lea

50 47 16.1
Im} 40.6
3 40
£ 2
S 20

10

o 7
IMpower010 KEYNOTE-091 CheckMate -816 AEGEAN Neotorch KEYNOTE-671 CheckMate -77T

1. Feipe E, Lancet 20212. OBrien M, Lancet One 202.3. Forde P, NEJM 20224. Heymach J, NEM 2023. 5. Lu 5, ASCO 2028.6. Watelee H.NEIM2023. Peer View.com

7. Cascone T, ESMO 2023,

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27. Understanding Evidence: 3-Year OS Results!

100 Adjuvant Neoadjuvant Perioperative
90 89.1 60m (038.108) peed
P=012 pie
80 775 78 ñ
x 70 64 64
g 60
= 50
El
> 40
e 30
20
10
0
IMpower010 CheckMate -816 KEYNOTE-671

1.Füpe E, WCLC 2022. 2 Forde P, NEJM 2022. 3. Spicer J, ESMO 2023. PeerView.com

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28. Technical Challenge: Neoadjuvant Immunotherapy

Complexity of Surgical Resection

40% of operations judged to be “more difficult’ than usual (scale 23)
Moderate/major Pr

so ng P= 0 My, E pra
e 5 20% with cN- sm : 80 ¿E
E 59% with cN+ £20 aR
g 4 Eso i Eso
5 8 D %0
don Emo] 2%
& 2 E E
10 2 7
© "HoneftMinor " Moderate" Major wen TR Re + en
nici M nc
Cornell MD Anderson: NEOSTAR trial
+» 44% induction lO cases with + 36% induction IO cases with moderate to severe fibrosis

moderate to severe fibrosis
+ Similar to induction chemo

+ Correlated with length of resection but not response

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29. 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 H et al. J Thorae Carciovase Surg. 2024:167:1444-1453 04. PeerView.com

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30. 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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31. Resolving Controversies
in Neoadjuvant/Perioperative
Immunotherapy

Jonathan D. Spicer, MD, PhD, FRCSC

¥
Associate Professor, Division of Thoracic Surgery p = |
Director, McGill Thoracic Oncology Network e

McGill University fi
Montreal General Hospital MS
Montreal, Quebec, Canada y

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32. Statistically
significant EFS

benefits are not
limited to stage III

1. Sorin Met a. JAMA Oncol, 2024:10:621-633.

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Resolving Controversies:
Neoadjuvant/Perioperative Chemo-IO by Stage?!

Stage 1
Forde 2022% Stage It
Viakoleo 2023 Stage It
Heymach 2023 Stage It
Cascone 2023 Stage It

Random effects model
Hoterogenoty: 7 =0%, 7 = < 0.4, p = 0.68

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

Random effects model
Hotrogenoty: 7 = 0%, À = € 04, p = 0.47

65
ns
104

er

13
217

62
173

57
202
146
1058

62
121
mo
a
sn

15
224

ss
165

202
149
1097

—a— 0.87 10.48; 1.56)
- 0.59 10.40:0.88)
+ 0.76 (0.43: 1:94)
o 0.81 (0.46; 1.43}
- 071 0.55; 0.92]
- 0.54 (0.97;0.80)
- 0.57 10.44:074]
=| 0.57 (0.36;0:90)
~~ 0.57 (0.39; 0.83),
ce 083 (0.52; 1.82]
—— 047 10.25:0.88]
LR 0.39 (0.27,0.57]
== 051 0.36; 0.72}
> 0.54 (0.48; 0.62]
02 05 1 2 5

Favors Ohemo10 Fevers Chemo

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33. Resolving Controversies:
Neoadjuvant/Perioperative Chemo-IO by PD-L1?!

pou aim
Forte 2022 pour » ” - 084 pa
oo 2023 Bou a se 1st 075 18:10
Neyracn 2023 POLIS ve 125 076 Bam
Luzoz PDU <a a 7 59 1039: 1.0]
Cascne 2020 POLY ett ES ss 073 par.)
Random eects model wo
Haga Pon <0, 9 2091
Statistically significant ui.
EFS benefits present Forte 2022 Pou 149% s a
Vaio 2025 POLY 148% 7 ra
across all PD-L1 strata Heyrach 2029 POI 140% 138 142
i fonehi Laza Pou 148% a
With relationships Carson 2029 POLY 40 ze L
proportional to ter re 8 “.
magnitude of effect ARE
POL 0%
Forde 2022 Pou: or e a 025 1010.00
Mae 2023 POL 2% 12 m 048 03507
Hoyracn20zo PDL 350% 10 vor Geo 1035:1.001
Las POL soe ma “ a 15:08
Cascone 2029 POLY 350% “ 52 026 10:12:09]
Random eects model ss 389 040 (028;0.56)
any: =D À = 401 p 2021
oz os 1 2 5
Favor: Chemo-0. Favors Chemo
1. Som Metal. JAMA Oncol 2026:10:621-633, PeerView.com

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34. Resolving Controversies:
Neoadjuvant/Perioperative Chemo-IO for OS?!

All patients

Forde 2022 All patients
Wakelee 2023 All patients
Provencio 2023 All patients
Lu 2023 All patients

Random effects model
Heterogeneity: 1? = 0%, Y =<0.1, p =0.57

179

179 En
400 -
29 ——
202 o.
810 +
177%

02 05 1 2 5
Favors Chemo-1O Favors Chemo

0.57 (0.38; 0.87]
0.72 (0.56; 0.93]

Neoadjuvant/perioperative chemo-IO improves OS in ITT population (N = 1,645);

adjuvant studies have not yet provided such data

1. Sorin M et a. JAMA Oncol. 2024:10:821-633.

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35. Resolving Controversies: Neoadjuvant/Perioperative
Chemo-IO and PD-L1 Expression Level!

PD-LI<I%
Forde 2022 POLI <1%
Wakelee 2023 POLI <1%
Provencio 2023 POLI <1%
Random effects model

Heterogeneity: 1? = 0%, Y =<0.1, p = 0.83

POLA 21%
Forde 2022 POLI 21%
Wakelee 2023" POLI 21%
Wakelee 2023" POLI at%
Provencio 2023 POLI 21%
Random effects model

Heterogeneity: 1? = 48.5%, Y = <0.1, p=0.12

PI eg

logy not matched to treatment, lack of matuı

78
138

89
127
132

378

0.81 (0.48; 1.36]
0.91 (0.63; 1.32]

8 —— 131 (0.27; 6.41]

0.89 (0.66; 1.19]

8 0.38 [0.20;0.71]
15 = 0.69 [0.44; 1.07)
134 +. 0.55 [0.33; 0.92]
15 —— 0.17 [0.05;0.57]
353 > 0.49 [0.33; 0.73]
Si

02 05 1 2

5

Favors Chemo-IO Favors Chemo

patients yet to see OS benefits

or both?

1. Sorin Met al JAMA Oncol, 2024;10:621-633.

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36. KEYNOTE-671: Post Hoc Analysis of EFS
in Surgically Relevant Subgroups’

Baseline Characteristics Post-Randomization Factors
‘Subgroup EventsParticipants Hazard Ratio (85% ch | subgroup EventsParticipants Hazard Ratio (95% CH
Pembrolizumab Placebo Pembrolizumab Placebo
Am Am An um
Overa! 174n97 2481400 059 048072) Overall Warner 2484600 059 (048.072)
Hauts Surgery performed
a si eae dia Yes sms 10207 053 (042067)
nt zu som 058 (35091 se oe ieee em
on ones 12667 063 (048.082) re
Lobectomy or
Clinical stage re 102282 1427264 088 045075)
u a man Preumonectomy wor ——Á 040 (020077)
1 06 sa02 059 038092) Surgical completeness
ma 100217 185224 057044074) Ro 10220 144207 053 041008)
us ae ass 057 (036.090) Rtorrz um 26 1.06 054209
y 1 3
os F3 CES 7
Pembroizumab Placebo Pembroizumad _ Piacabe
ambeter amer ambeter am beter
1. Spice set al, STS2024, Oral presentation PeerView.com

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37. Modern Practice Principles in Action:
Real-World Cases and Contextual
Guidance for Decision-Making

wy |
e

nt > A

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38. Case 1

63-year-old former smoker with RUL mass found on CXR as part of cardiology workup

Follow-up CT demonstrated a 3.5-cm central mass

Brushing and biopsy on outside bronchoscopy negative for malignancy

PET positive at right perihilar mass, no uptake in mediastinal LNs or distant sites

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39. Case 1

Patient sent for repeat bronchoscopy with EBUS

Lymph node stations 4R, 11R, 7, 4L negative
for malignancy

RUL mass positive for squamous cell
carcinoma, PD-L1 60%

Tumor 4.4 cm in cranial-caudal view
Stage cT2bNO (IIA)

Cardiac workup was unremarkable

PFTs: FEV1 70% pred, DLCO 111% pred

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40. Case 1

Initial CT Post-Induction CT

aN

Patient underwent 3 cycles of carbo/gem/nivo

Tolerated well, but was seen in ED for anemia,
required RBC and PLT transfusion

Repeat imaging demonstrated increase in size
of R perihilar mass

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41. Case 1: Next Steps and Outcome

OR: RVATS, lysis of adhesions, RULobectomy and MLND
Pathology: tumor bed with extensive necrosis and fibrosis
no residual viable tumor
0/7 N1 nodes involved with tumor
0/8 N2 nodes involved wit tumor
ypTONO

Postop course complicated by chyle leak, managed conservatively
D/C POD 7 on low-fat diet

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42. Case Discussion

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43. Case 2: Incorporating Science Into Practice

Q 60-year-old female with history of pancreatitis

Q Active smoker (50 pack-years)

Q FEV1 95% and DLCO 68%

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44. Case 2: Incorporating Science Into Practice

Tumor description
AVATS BLL wedge, no Drop Tumor site: lower lobe
node dissection was performed Histotype: invasive adenocarcinoma, solid predominant
resulting path is pT2ANX Acinar pattern component: 25%

Micropapillary pattern component: 5%
Solid pattern component: 70%
PD-L1 100% Grade 3, poorly differentiated
STAS: yes
Invasive tumor size, greatest dimension: 1.2 cm
Lymphovascular invasion: present (multiple lymphatic and arterial)
Visceral pleural invasion: present (PL2)

NGS negative

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45. |

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46. tte

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47. Evolutionary Characterization of Lung Adenocarcinoma
Morphology in TRACERx!

nature medicine

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48. Evolutionary Characterization of Lung Adenocarcinoma
Morphology in TRACERx!

STAS and Preoperative ctDNA
1
E 075 STAS- and
El SONA:
E STAS+ and
E NA:
2 05 STAS- and s
E DNA S
E pen i
Y mean en co E
2 sus acon Saar) 2
a IAS done E
025 E as 2
STAS+ and
NAS
o
o 500 1000 1500 2000
Time, d
STAS-and ONS: 37 5 50 2 2
STAStandctONA- 54 a a a 2
STAS- and DNA 18 2 9 8 1
STAS+ andcONAt 26 8 3 1 o

1.KarasakiT eta. Nat Med, 202320:833-04. PeerView.com

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49. Case 2: Incorporating Science Into Practice’

High-grade patterns

Pathological features

Genomic features

Relapse site

1. KarasakiT et al. Nat Med, 2025 29:833-845.

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Micropapillary Solid/cribriform
Necrosis+
STASS High Ki-67
LI AAA)
Preop eiDNAF
High clonal diversity (lack of large High CIN

recent clonal expansion)
\ nn nn

Low clonal diversity (presence of large

recent clonal expansion)

Intrathoracic

Ó O

Extrathoracic

a”

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50. Case 2: What Did We Do?

Given high-risk feature for more locally advanced disease than suspected on imaging

Given the presence of PD-L1 100%: potential access of adjuvant IO with proven OS
benefit, in addition to potential survival gains from chemotherapy alone if proven to have
nodal upstaging

Given the patient's general good condition and lung function tests

Acompletion lobectomy was offered

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51. Copyright © 2000-2024, PeerView

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53. Case 2: Incorporating Science Into Practice’

OS: PD-L1 TC 250% (stage IIA)
Excluding EGFR/ALK+

Atezolizumab

Q Final path: pT2aN2, stage IIIA NSCLC 7

x
Q Eligible for adjuvant chemo with OS g
gain of 10%-15% in stage III and an
additional -17% gain is OS from
adjuvant immunotherapy

me
Rosso oazozs078

o
0 3 8 0 1215 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 65 60 72
és Time, mo

Ame 106104104%04109103101100 99 96 96 63 90 87 83 69 58 41 32 2019 6 2 1 NE
BSC 10310198 96 95 $2 90 87 B4 80 77 7675 71 64 62 45 35 A 14 8 4 3 2 NE

1.Felp E et al WCLC 2022. Abstract PLO3 00

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54. Case 3: Biology Trumps Anatomy v1.0

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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55. Case 3: Biology Trumps Anatomy v1.0

Q Enrolled on neoadjuvant
chemo-immunotherapy trial

Q Received 2 doses of carbopaclitaxel
+ anti-PD-1

Q Developed mildly symptomatic
COVID-19 after second dose

Q Restaging CT performed

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56. Case 3: Biology Trumps Anatomy v1.0

ypT2BN1, adenocarcinoma, solid predominant,
PD-Lt RO

10%, RVT 61%,

FU

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57. Case 3: Biology Trumps Anatomy v1.0

Q 18 months later, presents with headache and found to have an isolated brain metastasis
treated with surgery and SRS

Q Subsequently started on sotorasib for KRAS G12C

O Remains NED with ECOG 0 now 36 months since first diagnosis

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58. Case 4: Biology Trumps Anatomy v2.0

— —

Q 60-year-old male former smoker
with LUL mass; ECOG PS 0

Q Path: adenocarcinoma, PD-L1 100%,

NGS negative for alterations » |

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

Q FEV1 68%, DLCO 65%

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59. Case 4: Biology Trumps Anatomy v2.0

Q 60-year-old male former smoker
with LUL mass; ECOG PS 0

Q Path: adenocarcinoma, PD-L1 100%,
NGS negative for alterations

Q cT3N1M0 after chest CT with IV contrast,
EBUS, CT of head and PET scan

Q FEV1 68%, DLCO 65%

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60. Case 4: Biology Trumps Anatomy v2.0

Q Elected to participate in phase 3 blinded RCT comparing neoadjuvant chemo
to chemo-immunotherapy followed by excellent radiological response on contrast-infused CT

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61. Case 4: Biology Trumps Anatomy v2.0

Underwent VATS converted to open LUL with en bloc superior segmentectomy
and bovine pericardial patch angioplasty

Final path: ypTONO

Completed adjuvant therapy portion of trial

Returned to work during adjuvant and functionally very well recovered

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62. Case 5: Biology Trumps Anatomy v3.0

80-year-old male with s/p VATS RUL for stage |
adenocarcinoma 6 years prior

Known for atrial fibrillation on apixaban, GERD,
prior right hemocolectomy for dysplastic polyp

Presents with hemoptysis and new LUL mass

Endobronchial biopsy: squamous cell carcinoma
with PDL1 TPS 5%

FEV1 89% and DLCO 70%

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63. Case 5: Biology Trumps Anatomy v3.0

80-year-old male with s/p VATS RUL for stage |
adenocarcinoma 6 years prior

Known for atrial fibrillation on apixaban, GERD,
prior right hemocolectomy for dysplastic polyp

Presents with hemoptysis and new LUL mass

Endobronchial biopsy: squamous cell carcinoma
with PDL1 TPS 5%

FEV1 89% and DLCO 70%

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64. Case 5: Biology Trumps Anatomy v3.0

Q Seen in multidisciplinary clinic and assessed by colleagues
for CRT vs neoadjuvant chemo-immunotherapy followed
by surgery

Q Decision made to proceed to neoadjuvant

OD Referred back to me for surgery

Q Now what?

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65. Case 5: Biology Trumps Anatomy v3.0

Q Undergoes open LUL with en bloc S6 segmentectomy

Q Required pulmonary angioplasty and bronchoplasty

Q Densely adherent lymph nodes extending along the ongoing
PA confirmed to be malignant by frozen

Course complicated by bronchopleural fistula, managed
with drainage and abx

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66. Case 5: Biology Trumps Anatomy v3.0

Final pathology: adenosquamous carcinoma ypT3N2 R1 with positive margin
on perivascular soft tissue and due to lymphatic extension on bronchus

Q N2 positive at level 6 (adeno), 10 (squamous) and 12 (adeno)
30% RVT

NGS sent from both squamous and adenocarcinoma components
— MET exon 14 skipping mutation identified

PD-L1 TPS 1%

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67. Three Patients With Similar TNM Staging and Treatment
Plan, But Very Different Surgical Effects

>> <> <i

+ Surgery provided minimally invasive durable locoregional control, but the
treatment plan did not mitigate distant metastasis

A

+ Surgery confirmed pCR, which predicts high rate of cure, but may not have been
necessary!

IO >> << : <<

+ Surgery was complicated and provided incomplete resection, but it revealed
important tumor vulnerability that may significantly prolong this patient's life

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68. Key Takeaways

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69. Current State of Immunotherapy in Resectable NSCLC

+ 10 brings benefit over chemotherapy alone in neoadjuvant and adjuvant settings
+ Neoadjuvant chemo-IO associated with significant improvement EFS

Promising OS improvement (statistically significant in ITT for perioperative only)
Contribution of adjuvant component remains to be determined
+ Appears safe, but significant attrition through treatment

+ Unmet needs

Improved detection of micrometastatic disease

Improved consistency of comprehensive biomarker testing
Clarifying limits of resectability and surgical safety
Improved tailoring of systemic therapy to disease biology

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70. Conclusions: 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, VO, mex, 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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71. Audience Q&A Co