Elevating Care in Resectable Stage I-III NSCLC: Targeted Therapy and Immunotherapy at the Forefront of Multimodal Treatment Strategies

Chair and Presenters Roy S. Herbst, MD, PhD, Tina Cascone, MD, PhD, and Tetsuya Mitsudomi, MD, PhD, discuss NSCLC in this CME/MOC activity titled “Elevating Care in Resectable Stage I-III NSCLC: Targeted Therapy and Immunotherapy at the Forefront of Multimodal Treatment Strategies.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/4cx4975. CME/MOC credit will be available until October 9, 2025.

1. Elevating Care in Resectable Stage I-Ill NSCLC

Targeted Therapy and Immunotherapy at the Forefront of
Multimodal Treatment Strategies

Roy S. Herbst, MD, PhD Tina Cascone, MD, PhD
Ensign Professor of Medicine Associate Professor, Department of

Professor of Pharmacology x Thoracic/Head and Neck Medical Oncology
Chief of Medical Oncology Director of Translational Research

Deputy Director The University of Texas
Yale Cancer Center and Smilow Cancer Hospital MD Anderson Cancer Center
Assistant Dean for Translational Research Houston, Texas
Yale School of Medicine
New Haven, Connecticut Tetsuya Mitsudomi, MD, PhD
President
Izumi City General Hospital
Distinguished Invited Research Professor
Faculty of Medicine
Kindai University
Osaka, Japan

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

Copyright © 2000-2024, PeerView

2. Our Goals for Today

Augment your knowledge of the latest evidence on
targeted therapy and immunotherapy in resectable NSCLC

Equip you with strategies for identifying patients with
resectable NSCLC who are candidates for targeted therapy
or immunotherapy approaches

Improve multidisciplinary strategies for integration of
targeted therapy and immunotherapy into multimodal
treatment plans for patients with resectable NSCLC

Copyright © 2000-2024, Peerview

3. Gaps and Opportunities for Improvement
in Multidisciplinary Patient Evaluation and
Treatment Planning in Stage I-III NSCLC

Tetsuya Mitsudomi, MD, PhD
President

Izumi City General Hospital
Distinguished Invited Research Professor
Faculty of Medicine

Kindai University

Osaka, Japan

Copyright © 2000-202.

4. 5-Year DFS and OS by Pathologic Stage
Patterns After Complete Resection of NSC

100
90
80
70
60
50
40
30
20
10

0

DFS and OS, %

Stage: IA

Complete Resection in 2010

DFS N = 15,117; OS N = 16,430

er

os

E

er
|

IB IA IIB IIIA

18

MA,

1. Okamı Jet al. J Thorae Oncol 2019:14:212-222. 2. Pstes K Le Chevalier T. J Cin Oncol. 2005:23:3270-3278,

PeerView.com/CGJ827

TANOMO

T2NOMO

TINIMO

T2N1MO
T3NOMO

T3N1MO
T1-3N2MO

55

39
38

25
23

10 15

10 30

12 40

15 760)
PeerView

Copyright © 2000-2024, PeerView

5. LACE Meta-Analysis (Lung Adjuvant Cisplatin Evaluatio:

Deaths/Person Years

Period Control Chemotherapy
Years 0-3 966/5,155 857/5,181
Years 4-5 239/1,668 203/1,817
Years 26 49/720 76/790
Chemotherapy
454%
N = 4,584 No chemotherapy
HR 0.89
1 2 3 4 5 26

Time From Randomization, Y

1. Plonon JP ea. Gin Oncor. 200828 3552-3569 PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

6. Treatment Strategies for Resectable NSCLC in 2024

a> Y

Driver Gene-Negative
Adjuvant

IMpower010, KEYNOTE-091 !

1
a- Wee

sd AA

CheckMate -816 SSSR
MN oy

AEGEAN, KEYNOTE-671, CheckMate -77T,
Neotorch, RATIONALE-315

MMM VY

PeerView.com/CGJ827

Driver Gene-Positive (EGFR, ALK)

ADAURA

A- Vii, COCOS-

ALINA

h- 00000--

PeerView

Copyright © 2000-2024, PeerView

7. How to Select Best Strategy?

Staging
T: size, invasion
N: multiple, bulky, extranodal?
M: oligo?

Planned op procedures
Pneumonectomy
Angio-/bronchoplasty

Histology/Biomarker
Histologic type, grading

Driver gene... EGFR, ALK, other
PD-L1

ctDNA

PeerView.com/CGJ827

Anatomic Extent of the Disease

Multidisciplinary Team (MDT)

© tosca

‘oncologist

moy
gm:
x x
* x

Patient preference

horacio
ae Radiation
oncologist

d Pathologist

Patient Condition
General
PS

Organ reserve

Surgical tolerability
Cardiopulmonary function

Immunotherapy tolerability
ILD
AID

Targeted drug tolerability
ILD
QT prolongation

Radiation tolerability

PeerView

Copyright © 2000-2024, PeerView

8. MDT Discussion Results in Survival Benefit’?

PLOS ONE

Multidisciplinary team discussion results in
survival benefit for patients with stage Ill non-
small-cell lung cancer

Does presentation at multidiscplinary team meetings improve lung cancer —
survival? Findings from a consecutive cohort study om

yee Sep Bee u.

1.00

È =

3 3 z

gue Eos mor

Los Al

3 §

E 5

Ens 8 02 Non-MOT

CR o

° a2 0 0 0.

e pr u = “ee m CR as m m» 1 7
tor = ie is io ES wor ES ES a E i
1. Stone Ee al Lung Concer 2018 128:198-204 2. Hung HY ela. PLOS One, 2020.15:00236803, PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

9. How Do Biomarkers Matter?

Driver Gene Mutation'2
ADAURA (EGFR+)

PD-L1 Expression*5

ALINA (ALK+) IMpower010 (Adjuvant Atezolizumab)

m rame
E mu a amas
O pe + He
HE mo — esoo
E] E j Neoadjuvant/Perioperative IO Trials
TT Ze
— me

Histology/Biomarker
Histologic type, grading

drogas

Driver gene... EGFR, ALK, other
PD-L1

ctDNA?

dresse

LUN JM ann ATLAS 2. Yt Hg 226012081270 FA El Lona 201-137 à
À Has Rot oN Engl JM 2020.38 1328-1958 8. Son ea. JAMA Oncol. 20241082 PeerView
PeerView.com/CGJ827

Copyright © 2000-2024, PeerView

10. a % ee Driver Gene-Negative

Adjuvant
IMpower010, KEYNOTE-091

YN

Neoadjuvant
CheckMate -816

MONA,

Perioperative

AEGEAN, KEYNOTE-671, CheckMate -77T,
Neotorch, RATIONALE-315

MANNY VY

PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

11. vant/Perioperative vs Adjuvant Immunotherapy’

Neoadjuvant/Perioperative

jh efficacy due to the presence of tumor antigens.
and lymph nodes for the priming immune cells
Better drug delivery due to preserved blood vessels
Smaller tumor facilitates complete with safety

High compliance rate

Prognosis predictable by pCR

Earlier intervention for micrometastatic cancer cells
Short total treatment time (neoadjuvant)

Greatest amount of systemic therapy (periop)
Opportunity to de-escalate adjuvant (periop)

Adjuvant

Treatment plan after accurate staging and
biomarker testing
No delay in surgery

15% to 20% cancellation of surgery
Increased complications, possible surgical difficulty
Needs preoperative biopsy for exclusion of driver gene-
positive cases and for PD-L1 expression

Risk of chronic irAE (periop)

inancial toxicity (periop)

30% of the patients after surgery never reach
adjuvant IO treatment

50% to 65% compliance after 1 year

Risk of chronic irAE

1. Mountzios Geta. Nature Rev Gun Oncol, 2023:20:684-877.

PeerView.com/CGJ827

PeerView

Copyright © 2000-2024, PeerView

12. + Immunotherapy is not recommended for patients with NSCLC harboring EGFR/ALK alterations

+ Neoadjuvant chemo IO is preferred to upfront surgery for patients
with NSCLC that is

— Stage IIIA-IIIB (94% agreement) irrespective of PD-L1 expression
— Stage Il (65% agreement) irrespective of PD-L1 expression

+ Immunotherapy after complete resection of the stage II-III NSCLC
followed by chemotherapy

— Discourage (PD-L1 <1%)
— Consider (PD-L1 1%-49%)
— Recommend (PD-L1 250%)

1. Spier et al J Morac OncoL 2024 Jun 18 [Epub shad ol pen. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

13. Cardiopulmonary Assessment of Surgical Candidates?1+

Patient Condition
General
PS
Age
Organ reserve

Surgical tolerability
Cardiopulmonary function

Immunotherapy tolerability
ILD
AID

Targeted drug tolerability
ILD
QT prolongation

Radiation tolerability

1 Bret ot Chest. 2013143 1685-01808, 2, rel A ot a Ann Tore Surg 201010150203. .
3 Brunell tal. Ann Thorac Surg. 201192445448. 4, Flasher LA ell Oria. 2014.190:0278-339. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

14. What Are the Borders Between Resectable
and Unresectable Disease?

Various types of N2 disease

j Technically resectable
Staging ‘Oncologically resectable
+ T:size, invasion
ö Et iS L 5 4,

+ N: multiple, bulky, extranodal? . L
+ M: oligo?

Planned op procedures
+ Pneumonectomy
+ Angio-/bronchoplasty co Zone.dierete zonewihlmaeent mulplezane

Single station, Multiple station, single Multiple station, single Muliple station,

Technically resectable Technically difficu
+ Contrast-enhanced CT =
+ PET
+ Invasive mediastinal staging (EBUS) i d. L ” L =
+ Brain MRI
Single station, Single station Single station, ute zone,
‘scree, ky Pancoast infiraive, buky _infratve, coalescent

PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

15. International 10 Guidelines on Stage IIIA-N2 NSC

urgery or Radiotherapy?

10 guidelines: AccP BTS ESMO NICE NCCN SEOM German Chinese Irish Australian

CEE Zen ON 1 1 ER

LN resectability LNextent LNvolume Consensus

Non-bulky

1 Non-bulka
Potentially resectable y

stage IIIA-N2

Non-bulky

Bulky =

PeerView

1. Putor Metal. ERJ Open Res. 2020:6.00159-2019.

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

16. International 10 Guidelines on Stage IIIA-N2 NSC

urgery or Radiotherapy?

10 guidelines: ACCP BTS ESMO NICE NCCN SEOM German Chinese Irish Australian

Emil
LN resectability LN extent LN volume Consensus

Non-bulky — 60% S or RT

270% RT
Potentially resectable Nonny, Non consensus
stage IIIA-N2
% RT
Non-bulky Ar MZ 50% RT
Bulky = 80% RT
1. Putora Metal ERY Open Res. 2020:8001592019. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

17. japan, September 2022!

ot 10 ne OSO 8 Op->adj = CRT->Op = CRT->IO m Other

NC (7-00) eg
Ed
ET

1. Courtesy of Dr. Heto Hornouch PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

18. in Name) args MIO->0p MOp->adj = CRT->Op = CRT->IO m Other

pe)
wenn ge Me N2 Ne

gs "m.
CR rn gm

1.Couesy ol Dr. ento Hornouch. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

19. “uma ao Neoadjuvant 1O—Op-

in Mama) a Gs MIO->Op M Op->adj = CRT->Op = CRT->IO m Other

Ce ————
a Ba) no 40 28 NO

1. Courtesy of Dr. Het Hornouch. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

20. ocally Advanced NS

japan, September 2022!

u an == Op > Adjuvant Oo ===
le Lu 7 Neoadjuvant 100p

A o

mn EEES

in Man) args MIO->Op MOp->adj = CRT->Op = CRT->10 m Other

pes)
wenn me Me N2 Ne

o A a!
A NN

1. Courtesy ol Dr. HgentoHormouch. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

21. Treat These Pa

How N2 Disease

Single N2

1. Pictures kom: Authors case Or. Yosine GCba Universty, ACCP guideline for non-invasive mediastinal staging, 2007 PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

22. Treat These Pa

How s With N2 Disease

Single N2 Single, bulky N2

1. Pictures om: Author case, Or. Yoshino @Chibe University, ACCP guideline for nonnvaste mediastinal staging, 2007. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

23. Treat These Pa

How s With N2 Disease

7
22

Single N2 Single, bulky N2 Multiple, bulky,
invasive? N2

1. Pictures rom: Author’ case, D. Yoshino @Chibe University, ACCP guideline for noninvasive mediastinal staging, 2007. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

24. 27
BE
Single N2 Single, bulky N2 Multiple, bulky, Coalescent, invasive,
invasive? N2 and multiple N2

iew

1. Pictures om: Authors case, Or. Yoshino @Chiba University, ACCP guideline for non-nvasive medistnal staging, 2007

63827 Copyright © 2000-2024, PeerView

25. VA
GE

Single N2 Single, bulky N2 Multiple, bulky, Coalescent, invasive
invasive?
cms16 invasive? N2 and multiple N2
6Y NED

iew

1. Pictures om: Authors case, Or. Yoshino @Chiba University, ACCP guideline for non-nvasive medistnal staging, 2007

jew.com/CGJ827 Copyright © 2000-2024, PeerView

26. VA
GE

Single N2 Single, bulky N2 Multiple, bulky, Coalescent, invasive
i ive?
cM816 cM816 invasive? N2 and multiple N2
6Y NED 5Y9M NED

iew

1. Pictures kom: Authors case, Dr Yoshino @Chiba University, ACCP guideline for non-nvasive medistnal staging, 2007.

jew.com/CGJ827 Copyright © 2000-2024, PeerView

27. Treat These Patients With N2 Disea:

Single N2 Single, bulky N2 Multiple, bulky, Coalescent, invasive
invasive? itiple N2
éusié a invasive? N2 and multiple
6Y NED 5Y9M NED CRT—Surg
8Y NED
1. Pictures from: Authors case, Dr. Yoshino @Chiba University. ACCP guideline for non-invasive mediastinal staging, 2007. erview

6827 Copyright © 2000-2024, PeerView

28. Treat These Patients With N2 D

LD
PA
Single N2 Single, bulky N2 Multiple, bulky,
i ive?
CM816 CM816 tnveeve UNA
6Y NED 5Y9M NED CRT—Surg
8Y NED

1. Pictures om: Authors case, Or. Yoshino @Chiba University, ACCP guideline for non-nvasive medistnal staging, 2007

Coalescent, invasive
and multiple N2

222

iew

Copyright © 2000-2024, PeerView

29. A Little Less Than Half of Surgery After Neoadjuvant

Immunotherapy Is Difficult?

on of Hilar Fibrosis Between Neoadjuvant ICI NEOSTAR: Comparison of Surgical Complexity Between
and Neoadjuvant CT With PS Matching Neoadjuvant Nivolumab and Neoadjuvant Nivolumab + Ipilimumab
100
Hilar Fibrosis
70
60 i lerate/major 1 75 m
| fibrosis in nICI cohort: | ~40% more difficult than
= I 20% witheN- | ordinary lobectomies
40 7 ga?
30 22
20 25
0+ o

None/Minor Moderate Major 1 2 3 4
Surgical Complexity Rating"
"Neoadjuvant ICI (n = 32). = Neoadjuvant CT (n =32) = Nivoumab (9 =23) = Nivolumab + ipilmumab (n=21)

+ Sage complxty sal: = easier han normal suo datecon: 2 = neral Sse secon:
3 dtu tee cssecton because of ntammnaton: voy comple er secon A
1. Brendon Metal ARTS 2018, 2. Sepesi Bet lJ Thorac Cordovose Surg, 2022:164 1527-1357. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

30. CheckMate -816: Comparisons Regarding AE

and Surgical Difficulty"?

MM Nivo + CT
mCT =)
100%) 100%) 217
00.3
82 90 83 83 200
80 80 75 za =
70 70
150
60 60
50 gee 50
40 3437 40 100
= 30
30 a 35 25
20 ais 20 18 17 50
° oe |
0 0 0
TRAE TRAE Surgical Surgical Dota many Oye ue Mr Poamendeny Romain PEER
263 AE AE2G3 surgery Time, min
1. Forde Pot al. Engl J Me. 202586: 1975-1985. 2. Speer Jt a ASCO 2021. Abstract 8503. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

31. Technically Demanding Surgery May Be Necessary After
ant Immunochemotherapy!

TOY M, cT3N2aM0, Sq, PD-L1 1%

à
|

/
\ &
N

1. Images courtesy of Ds. Tsutani Chiba, Fukami ind Unes. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

32. Technically Demanding Surgery May Be Necess
Neoadjuvant Immunochemotherapy!

70Y M, cT3N2aM0, Sq, PD-L1 1% ycT2bN1Mo

ON

Nivo + CT x1 À
Nivo x2

1. mages courtesy of Dr. Tsutani Chiba, Fuxam ind Unveriy PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

33. Technically Demanding Surgery May Be Necessary After
Neoadjuvant Immunochemotherapy!

70Y M, cT3N2aM0, Sq, PD-L1 1% ycT2bN1Mo Right upper lobectomy with
= carinal resection

N Trachea

Nivo x2

1. mages courtesy of Ds. Tata, Chiba, Fukam @kind Unversity. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

34. Tak

lome Messages

Gaps and Opportunities for Improvement in Multidisciplinary Patient
Evaluation and Treatment Planning in Stage I-III NSCLC

Multidisciplinary Team (MDT) + Patients with resectable NSCLC should undergo a
multifaceted evaluation that considers biomarkers,
TNM status, proposed surgical procedures and
technical requirements, the patient's physical function,
and patient preference...

+ These patients should be evaluated by MDT for
the treatment

+ Surgery after neoadjuvant immunotherapy could be
difficult; surgeons skilled in advanced surgical
procedures should operate

PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

35. Discussion and Questions

Copyright © 2000-2024, PeerView

36. Mastering the Integration of Targeted
Therapy in Resectable Stage I-III NSCLC

Roy S. Herbst, MD, PhD
Ensign Professor of Medicine

Professor of Pharmacology

Chief of Medical Oncology

Deputy Director

Yale Cancer Center and Smilow Cancer Hospital
Assistant Dean for Translational Research

Yale School of Medicine

New Haven, Connecticut

100-2024, PeerView

37. ADAURA: Phase 3 Double-Blind Study’

Patients with completely
resected stage? IB, Il, NA NSCLC,
with or without adjuvant chemo*

Key inclusion criteria

‘Aged 218 years (Japan/Taiwan, aged

220 years)

WHO PS 0/1

Confirmed primary nonsquamous NSCLC

Ex19del/L858RS

Brain imaging, if not completed

preoperatively

Complete resection with negative margins®

Maximum interval between surgery and
randomization: 10 weeks without adjuvant
chemo; 26 weeks with adjuvant chemo

( Planned treatment N

Stratified by où de CAE
+ Stage ee Treatment continues until
(8 vs Il vs IA) + Disease recurrence
+ EGFRmut + Treatment completed

(ext9del vs LESER)
+ Race
(Asian vs non-Asian)

+ Discontinuation criterion met
Follow-up
+ Uni recurrence: week 12 and 24,
then every 24 weeks for 5 years,
then yearly
+ After recurrence: every 24 weeks
Ksor:5 years, then year

Placebo
Once daily

FS, by investigator assessment, in stage IVINA patients; designed for
superiority under the assumed DFS HR of 0.70

Secondary endpoints: DFS in the overall population’; DFS at 2, 3, 4, and 5 years; OS;
safety; HROOL

Following IDMC recommendation, the study was unblinded early because of efficacy (an unplanned interim analysis is reported);
at the time of unblinding, the study had completed enrollment and all patients were followed for at least 1 year

‘NCT0251106; ADAURA data ctf: January 17, 2020.» AJCC, Th ation. € PA, pot and planed racoeray was not alowed. Cntalycontmod in sue.
«Parents received a CT afer resecton and wit 2 cay blor estimen. Sage IB .
1. Herbst RS ot al ASCO 2020. Abstract LAS. 2. WU Y Ll. Eng Med. 2020.383:1711-1723. PeerView

PeerView.com/CGJ827

Copyright © 2000-2024, Peerview

38. Stage II/IIIA Disease (Primary Endpoint)"

Median DFS, mo (95% Cl)

1.0
09 65.8 (54.4-NC)
de Placebo (n = 237) 21.9 (16.6-27.5)

E HR (95% CI) 0.23 (0.18-0.30)
S 07 FLA
2 Maturity: 51%
Ss 06 Osimertinib: 32%
305 Placebo: 70%
E
a of Osimertinib
E
a 03 Placebo
02
01
0
0 6 12 18 24 30 36 42 48 54 60 66 72
Time, mo
No, at Risk
Osimertinib 233 222 216 202 196 192 174 138 90 45 20 E o
Placebo 297 191 141 124 106 9 74 61 41 23 11 1 0
rabat et teow 2022 Absact eur PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

39. the Overall Population (Stage IB/II/IIIA Disease)!

1.0
09
08
0.7
06
05
04
03
02
01

DFS, Proportion

No. at Risk

Median DFS, mo (95% CI)
we Osimertinib (n = 339) 65.8(61.7-NC)
Placebo (n = 343) 28.1 (22.1-35.0)
HR (85% Cl) 0.27 (0.21-0.34)

73%

Maturity: 45%
úOsimertinib: 28%
Placebo: 62%
Osimertinib
Placebo
12 18 24 30 36 42 48 54 60 66 72
Time, mo
Osimertinib 339 316 307 289 278 270 249 201 139 73 33 5 0
Placebo 343 288 20 205 181 162 137 115 84 48 25 4 0
PeerView

1. Tsuboi et a, ESMO 2022. Abstract LBAAT.

PeerView.com/CGJ827

Copyright © 2000-2024, PeerView

40. ADAURA: Subgroup Analysis of DFS in Patients With

and Without Adjuvant Chemotherapy by Disease Stage’

‘Subgroup HR 95% Cl
Overall Stratified log-rank Fe 020 015027
(N = 682) Unadjusted Cox PH he 019 013027
Stage ‘With adjuvant chemo (n = 352) i 0.14 0.08-0.23
ma Without adjuvant chemo (n = 118) E 015 0.06:0.30
Stage IB» Without adjuvant chemo (n = 154) HE] 03 015088

A ‘With adjuvant chemo (n = 166) 1 0.15 0.06-0.32
ns Without adjuvant chemo (n = 70) ——4 020 0.07-0.52

HA With adjuvant chemo (n = 186) he 013 006023
> Without adjuvant chemo (n=48) HA 010 002-029
+ Overall population HR for DFS (95% CI) 025 05 10

‘© Patients with adjuvant chemo
+ Patients without adjuvant chemo.

Favors osimertinib Favors placebo

+ Subgroup eatgorie with <20 event, sch as patents wth tage 18 disse wih adora! chomotreapy (15 avants toa patas in omer arm
and 11 he pacabo am) were exchided fom Ins anal. ;
TW VC Gta J Thorac Oncol 2022:17 423-43, PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

41. ADAURA: Updated DFS A

in the Overall Population’

Subgroup 95% Cl
= ‘Stratified log-rank == 0.21-0.
Overall 2) Unadjusted cox PH A 0.25-0.40
— — 0.20-0.48
Sex — 0.23-0.42
A <65 y (n = 380) AA 0.22-0.42
ES 265 y (n = 302) —— 023-048
Yes (n = 194) nn a 0.16-0.40
‘Smoking history No (n= 488) —— 0.26-0.45
Race UI) > 025-045
Non-Asian (n = 248) SS 0.18-0.43
IB (n= 212) —_._ — 041 0.23-0.69
Stage” — |.) 0.34 0.23-0.52
—— 020 014029
024 017-033
EGER mutation ee 045 0.31-0.64
Adjuvant chemotherapy ——i 038 02088
*AJCCIUICO MH edition reno) 4
1 Tas a oral. ESMO 2022. Abstract LAAT, „Er osimortinio Favors placebo, PeerView

PeerView.com/CGJ827

Copyright © 2000-2024, PeerView

42. ADAURA: Updated DFS by Stage’

10 Stage IB

el | Stage | Stage IIA

Osimertinib

Eon

Bee Osimertnib 80 (69-87) 75(65-83) 66(55:75)

oe Placebo 60 (49-69) — 43(34-52) — 16 (10-24)

© 02

a Overall HR 0.44 0.33 0.22

0 6 2 18 24 © % 42 48 5 00 06 72 (95% Cl) (0.250,76) (0.21-0.50) (0.15-0.31)

No. atRisk Time, mo
Osimorinlo 101 so 87 83 78 75 72 $9 47 2% 12 3 0

Placebo 98 92 82 76 70 67 89 82 42 2514 3 0

10 Stage IIIA

10 Stage Il
08
os
04
02

o

Osimertinib

DFS, Proportion

of Rem D % Om © & À

0 8 2 #8 À © % TE © & À

ans Time, mo rasen mm en aie 22 co
Osimertin 113 105 101 98 94 90 81 64 42 22 13 0 a tem omen M D 7 à 0

Paso 119 109 04 77 69 58 59 48 30 1 7 10
+ Rostagng based on data capurd in ho Parley at Diagross AICCIUICC Bl ation manual per investor assessment requested belore he primary ana .
Y o ota, ESMO 2022, Abstract LBAAT. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

43. ADAURA: Patterns of Disease Recurrence

Overall Population’:

In the overall population, fewer patients in the osimertinib group (n = 339) had disease recurrence (93; 27%)
‘compared with those in the placebo group (n = 343) who had recurrence (205; 60%)

Lung 26
Lymph nodes
CNS _ \
Bone Most common first sites of recurrence
Pleura
Liver + Osimertinib: lung (12%), lymph nodes (6%),
Pleural effusion and CNS (6%)
Adrenal
Head and neck + Placebo: lung (26%), lymph nodes (17%),
Breast and CNS (11%)
Renal y
Peritoneum A - >
Pancreas 0
Ovary Ofer MM Osimertinib
Other 1h I Placebo
Missing 180
50 40 30 20 10 O0 10 20 30 40 50

Patients With Disease Recurrence, %
* Distant recurrence only: osimerinb 482339 (13%), placebo 107/343 (31%) loca/regional en: osimortiib 422390 (12%), placebo 78/343 (23%);

iscavegonal and dart osmarin 6799 (PH) Pacede 20043 (0) E
Tudor ESMO 2022 Abstract LA47. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

44. ADAURA: CNS DFS in Patients With Stage II/IIIA Disease!

+ Overall, 63 patients (osimertinib, n = 22; placebo, n = 41) had CNS-DFS events*
- 18 (8%; osimertinib) and 32 (14%; placebo) patients had CNS recurrences.

40 98% 97%
Median CNS DFS, mo (95% Cl)
02 Osimertinib Osimertinib NR (65.8-NC)
2 oe Placebo NR (NC-NC)
207 HR (95% CI) 0.24 (0.14-0.42)
qe Placebo
É Maturity: 13%
05 Osimertinib: 9%
Los Placebo: 17%
a
9 03
2
6 02
01
o
0 6 12 18 24 30 36 42 4 84 60 66 72
ie. Time From Randomization, mo
Oümerinb 29 222 216 22 198 192 15 19% 90 45 2 2 0
Placebo” 27 m 142 m MT MOM 61 41 2 1 1 0
+ Dana 28 CNS events as CNS disease rumamc or deat by any cause .
Y Hors R tal. Cin Oncol 2023.41.1830-1640 ds PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

45. ADAURA: Overall Survival in Patients With Stage II/III[A Disease’

+ Adjuvant osimertinib demonstrated a statistically and clinically significant improvement
in OS vs placebo in the primary population of stage II-IIIA disease
m 5yOSRate,%
(95% Cl)
Osimertnib 233 85(79-89)
85% Placebo 237 73(66-78)
Osimertinib
Overall OS HR 0.49 (0.33-0.73)
2 (05.03% Cl); P 0004
a Maturity: 21%
3 Osimertinib: 15%
Placebo: 27%
&
8 Median follow-up for OS
(censored patients)
+ Osimertinib: 61.7 mo
+ Placebo: 60.4 mo
of 4 \
0 6 À em © % ew mw!
Time Since Randomization, mo
No. at Risk
Osimertnib 223 229 224 224 221 214 208 205 200 170 115 69 33 9 0
Placebo 237 232 226 221 210 202 190 182 171 138 9% 53 25 8 2 0

PeerView

1. Herbst Fetal. ASCO 2023, Abstract LAS

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

46. ADAURA: Overall Survival in Patients With

Stage 1B/II/IIIA Disease!

+ Adjuvant osimertinib demonstrated a statistically and clinically significant improvement

in OS vs placebo in the overall population of stage IB-IIIA disease 5-y OS Rate, %
(95% cl)
‘Osimertinib 33988 (83-91)
a Sah Placebo 34378 (73-82)
os Osimertinib
de Overall OS HR 0.49 (0.34-0.70)
En (95.03% Ch; P <.0001
Eo Maturity: 18%
ae Osimertinb: 12%
E Placebo: 24%
0%
80 | Median follow-up for OS

0 6 2 0 À D % 2 © MO O À 7 à ©
Time Since Randomization, mo
No. at Risk

Osimerind 339 332 325 324 319 311 304 301 204 252 176 108 50 15 0
Placebo 243 398 202 320 14 304 200 201 207 223 10% 97 4 17 3 0

1. Herbst R et al. ASCO 2023. Abstract LAS

PeerView.com/CGJ827

(censored patients):
+ Osimertinib: 61.5 mo
+ Placebo: 61.5 mo

PeerView

Copyright © 2000-2024, PeerView

47. ADAURA: Overall Survival in Patients With and Wi

pulation (Stage IB/II/111A)!

With Adjuvant Chemotherapy Without Adjuvant Chemotherapy

87% Osimertinib Osimertnib

Placebo

OS Probability, %
OS Probability, %
ee

Overall HR (95% Cl)
= 0.49 (0.30-0.79)

Overall HR (95% Cl)
= 0.47 (0.25-0.83)

o o
os RM TEE E EE © & À % À D
‘Time From Randomization, mo Time From Randomization, mo
Mo. m.
Arte Wax
ninerin 210 200 197 197 195 192 188 105 182 165 100 58 25 7 0 Oum 136 132 128 127 123 119 118 106 112 97 72 50 25 8 0
Paco 207 204 200 107 109 102 178 166 150 139 02 48 19 7 2 0 Pomo 196 1M 132 129 125 122 518 115 108 90 72 49 28 10 1 0

Ono! arar 2,202 Orr gus Sie A. Tk ata td cnc at Un aqua homer tr onto
a lona te manta, acca a aan and patas tr aten .
1. Herbst Ret al ASCO 2023, Abstract PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

48. ADAURA: All Causality AEs (210% of Patients)'?

Diarrhea + Interstitial lung disease (grouped terms)
Paronychia reported in 11 (3%)* patients in the
Dry skin osimertinib arm (all grade 1/2)>
+ QTc prolongation reported in 30 (9%)
Prurttis patients in the osimertinib arm vs 8 (2%)
Cough patients in the placebo arme
Stomatitis ————E
URTI + Any AE leading to treatment discontinuation:
Nasopharyngitis 13% in the osimertinib arm vs 3% in the
Decrease appetite \ placebo arm
Dermatitis acneiform
Mouth losration Hlosimertinib, all grades
Nausea grades 3/4
SH dress Placebo, al grades
Arthralgia I Placebo, grades 3/4

100 90 80 70 60 50 40 30 20 10 0 10 20 30 40 50 60 70 80 90 100
Patients With AE, %
1 Goma wn Jano 17, 2020, dt co ona ana plant opor LD (grapa te neuron, ra 2. Ga n= 692,0 rade 3, 0

À Gamme grace m=: grace 2: n= 10: grace = 4 Paco: grade }
1. Tsuoi eto ESMO 2022 Abstract 18447. 2 Horts Reta Jin Oncol, 202341 1830-1840, PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

49. Biology Has Spoken!

Best therapies earlier in
disease course, for the most
enhanced patient benefit

Surgery — Adjuvant Therapy
ES g
—
surgery chemother
FE

Prevent Metastasis
Brain Liver Bone
1. Herbst, Fale COR 2000, PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

50. ADAURA: ctDNA-Based MRD Detection’

Patients with completely
resected stage® IB, I, MA NSCLC,
with or without adjuvant chomo®
Koy inclusion criteria,

‘Aged 218 years (Japan/Taiwan,
‘aged 220 years)

WHO PS on

Confirmed primary nonsquamous.
NSCLC

ExigcelL 858

Brain imaging, ifnot completed
preoperatively

‘Complete resection with negative
margins’

‘Maximum interval between surgery
‘and randomization: 10 weeks.

without adjuvant chemo; 26 weeks
with adjuvant chemo,

Strates by _, Osimertinib
+ Stage 80 mg, onc
(Bs Il vs INA) ‘Treatment continues until
+ EGFRmut Disease recurrence
(ex19del vs LESBR) Treatment completed
+ Race

Discontinuation criterion
(Asian vs non-Asian) = at

ey
Exploratory endpoint: Evaluate the feasibility

of ctDNA-based MRD detection to predict disease CiDi/randomization 3 years 5 years
recurrence during adjuvant osimertinib treatment (baseline)

and post-treatment follow-up

+ NCT0251106; ADAURA data cute January 17, 2020. AJCC, Th adn. < Pro, post, and planned radothorapy was not alowed. + Central contemad in issue
‘Patents received a CT after resection and within 28 days bore treatment Colectad uni disease recumance or study end,

1. Joh Teta, ASCO 2024, Abstract 8005.

PeerView.com/CGJ827

PeerView

Copyright © 2000-2024, PeerView

51. ADAURA: MRD Events Were Detected More Frequently Wi
Placebo vs Osimertinib!
7 y

+ MRD events were detected
in 68 patients

- 13% (15/112) occurred
in osimertinib group

- 49% (53/108) occurred
in placebo group

ed pact fo vp 108 mons
Plate otal Aso 2008 Aca

PeerView.com/CGJ827

2
:

TE

ae
IO
N
ill)
julia

ee sz

PeerView

Copyright © 2000-2024, PeerView

52. ADAURA: Detected MRD at Baseline Was Associated
With Poor Outcomes’

Clearance of Baseline MRD Patients With Detected MRD at Baseline
ven +00000000000
z e PAN «00000000000
Se settee ten
E TERETE -
po coo Treatment
E um a =o
=“
= ns
ma
Time, mo a
© Distant

+ Of 18 patients with detected MRD at baseline
— 4/5 patients receiving osimertinib cleared MRD

- 0/13 patients receiving placebo cleared MRD. ° PL. = a
DS hese PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

53. ADAURA2: Adjuvant Osimertinib vs Placebo in Completely

Resected Stage IA EGFRmut NSCLC‘

Patients with stage IA2 or 1A3 (Sth edition) NSCLC Osimerti
+ Post complete (RO) resection 80 mg PO, or
+ Exon 19 deletion or L8S8R EGFR mutation SEEN
+ Tumor sample submission for central pathology + High risk vs low risk =
assessment of à FPE G-year treatment duration)
— Invasive tumor size Grech 41
= + Rave (Chinese Asian,
Lymphovascular invasion Bare (Chee. Ani: ESO

— Tumor histology
PS 0-1

No pre/postoperative RT or systemic therapy
Not eligible for any local SOC treatment

vs non-Asian)
Placebo

+ Primary endpoint: DFS per investigator in + High risk is defined as the presence of 21 of the following factors

high-risk stratum ~ Invasive tumor size >2 cm
* Secondary endpoints: DFS in ITT, OS in high-risk =" Lymphovasailer Invasion
stratum, OS in ITT, HR-QoL, safety/tolerability, and PK — 220% micropapillary, solid, or complex gland
adenocarcinoma histology

ss Exploratory Engel MND + Low risk is defined as the absence of any high-risk factors

+ Estimated prevalence of high risk is ~60%
+ Enrich high risk to 67% of ITT population (33% cap on low risk)

1. Mos Ice govet2showNGTOS 120549 PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

54. TARGET: 5-Year Adjuvant Osimertinib in Completely Resected

EGFRmut Stage II-IIIB NSCLC Post-Complete Resection’

Patents with EOETRTA stage IIe Single treatment arm; cohorts defined by EGFR mutation status

(8th edition)? NSCLC Radiographic scans.
+ Aged 218 years (Taiwan ‘Common EGFR mutations (Ex19del or L858R) cohort (n = ~150) ire aed
220 years) ” u
oe onsuemous, : * Primary endpoint: DF: al
Ea Adjuvant ats years baseline and for
| chemotherapy disease recurrence
+ EGFR mutations (common per investigator + Secondary endpoints: at 12 and 24 weeks
‘or uncommon*) and patient DFS* at 3 and 4 years; OS | and then every 24
+ WHOPS 04 thoice 8135 years; safely: type | esta hereafter
+ MRI or contrast CT brain scan ot recurence: CNS mets completion, disease
required a? or recurrence, or
re-enrollment u ‘ath. In addition to
erie Uncommon EGFR mutations (G719X, L861Q, 57681) cohort (n = -30) Drm
margins CERES - secondary endpoints: Castel
+ Max interval between surgery and Eee 80 mg PO QD DS ot 35 yeas; salty, | atte bain scans
randomization ocios for 5 y or until type of recurrence: recumence and as
= 10 weeks without adjuvant eats recurrence, CNS mets inicaly indicated
chemotherapy Gb ontinuation, ‘during treatment
— 26 weeks with adjuvant sata leath ue
chemotherapy

+ AJCC th ation staging eter, staging was clase posoparavely. ® Fur amendment to ag 218 years. For patent wit umo hong both common and
“common másters te paten wi bo ase o ho commen EGFR muatons coker + nvestgaor assessed PeerView
1 Soo RA otal Cin Lung Cancer 2024.25 8084

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

55. NeoADAURA: Neoadjuvant Osimertinib + Chemotherapy

vs Chemotherapy Alone for EGFRmut NSCLC‘

Resectable

+ Stage IIIB . Adjuvant
NSCLC
+ EGFRmut ice

NSCLC (optimal care)

(exi9deVL858R) Osimertinib
€ )

/ Double-blind treatment arms I (Adjuvant therapy and follow-up
1. Placebo QD + investigator's choice of pemetrexed
500 mg/m? plus carboplatin AUC 5 an + Patients will be followed for OS until 5 years from
or cisplatin 75 mgim? surgery, with evaluation at 12 and 24 weeks post

surgery, then every 23 weeks, until disease

2. Osimertinib 80 mg QD + investigator's choice een

of pemetrexed 500 mg/m? plus carboplatin

AUC 5 mg/mL/min or cisplatin 75 mg/m? Osimertinib will be red to all patie
. offer patients who
‘Open-label (sponsor-blind) treatment arm complete surgery (+ post-surgery chemotherapy)
\\ 3. Osimertinib 80 mg QD / N forup to 3 years or until recurrence

+ Primary endpoint: centrally assessed major pathological response at the time of resection

1. Tsuboi etl Future Oncol 202117 404-4085. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

56. LEADER Screening and LCMC4 Trials: Evaluation of Neoadj
Targeted Therapy in Resectable NCLC Wi

‘ecindivemurafin + cobimetiniy
entrecinb/prasetnb.

ALKBRAFNTRKIROSURET |
NAUTIKAT - NCTO4302025

EGER
(Osimerini + chemotherapy

MET Mut + MET Amp
3
NOGADAURA - NCTO4351555

¡Geometry -NCTOA920831

DE TN en
nekzwasion || xrascızc ||waäscizc || een
2 cancer Denmecan _)ncrosmmessı
E MOTATIÓN i .
& CONSORTIUM (pCR and MPR assessment ri FE =
tune cancen |% RVT in resection specimen Le Le
RESEARCH |Correlates in persister cells ER
FOUNDATION adjuvant therapy—per protocol or investigator's choice ) = =
Se courtes o Bor Sapesi PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

57. AURA: Phase 3 Double-Blind Study Design’

Patients with locally advanced,
unresectable EGFRmut stage I (th
edition) NSCLC with no progression
during/following definitive CRT#
‘Aged 218 years (Japan 220 years)

Osimertinib
80 mg once daily

assessed progression (per RECIST
v1.1), toxicity, or other
discontinuation criteria

Open-label osimertinib after

with confirmed locally advanced,

unresactable stage Ill NSCLC

WHO PS 0-1

ExtodelL858R> Placebo Tumor assessments:

Max interval between last dose of CRT daily + Chest CT/MRI and brain MRI

and randomization: 6 weeks + Atbaseline, every 8 weeks to
week 48, then every 12 weeks until
BICR-assessed progression

BICR-confirmed progression
offered to both treatment arms*

Stratification
+ Concurrent vs sequential CRT
+ Stage IIA vs stage IIBANC
+ Race (China vs non-China)

+ Primary endpoint: PFS assessed by BICR per RECIST v1.1
(sensitivity analysis: PFS by investigator assessment)

+ Key secondary endpoints: OS, CNS PFS, safety

* Concuront or sequential CRT comprising 22 cycles of patinum-basod chemothorapy (or dosos of week lainum-based chemotherapy) anda total ose of radiation of 60 Gy + 10%.
* Cental or FDA-approved oca esting (rom a CLIA-approved laboratory. or accredited local laboratory for stos outside of USA) based on tissue.

« doing cinical Bont (osimerinib arm); bythe judgement of rating physician (placebo am)

1. Ramalngam S et al. ASCO 2024, Abstract LBAS.

PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

58. AURA: Progression-Free Survival by BICR‘2

os

ia Osimertinib
7 Placebo
=o 7
Er H PFS HR (95% Cl);
3 H +
Bos H Osimertinib
& i
go
= i
03 i
02 +
os H +
00 + i. oo
ct ee hoe MMH D HED à à HN à à © à
Dors Time From Randomization, mo
AE
Tun ow 8 6 6 4 ee o...

+ Data cut January 5, 2024. Median folew-up for PFS (al paints): osimerinid 22.0 mo, placebo 56
mean folowup or PFS (censored patents}: osimerinb 27.7 mo, placebo 19.5 mo.

1. Ramalngam S et al. ASCO 2024. Abstract LEAS.

PeerView.com/CGJ827

Median PFS, mo
(95% Cl)
39.1 (31.5, NC)
56(37,7.4)
0.16 (0.10, 0.24);
<.001

Maturity: 56%
Osimertinib: 40%
Placebo: 86%

PeerView

Copyright © 2000-2024, PeerView

59. AURA: Interim Analysis of Overall Survival

+ In the placebo arm, 81% of patients with BICR-confirmed progression crossed

over to osimertinib Median OS, mo
5 (95% Ch
. Osimertinio 540 (46.5, NC)
aa Placebo NR (42.1, NC)
Osimerinib OSHR(S%CH; 0.81 (0.42, 1.56);
ET P 530°
B ce
Eos Matuñy: 20%
& Osimertinib: 20%
= Placebo: 21%
as
02
on H
SIA
re a mann
No ats Time From Randomization, mo
One 145 142 138 135 133 100 187 NS 100 #6 7 ze
nme

+ Dat et anun 5,2024. Median fon fer OS (al pation): iman 295 mo, psc 224 mo; mac fun fo OS (censor patenta; martin 309 mo, placebo 2.1
no Foren Sgnicance sita term ans, a Posie € 00006 was wur A
Y Ramaingam S etal: ASCO 2024, Abstract LEAS PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

60. ALINA: Randomized Phase 3 Study Design!

Adjuvant alectinib vs chemotherapy in early stage, resected ALK+ NSCLC

Patients with resected
stage 1B-IIIA (7th edition)
ALK+ NSCLC.

Ale
600 mg BID

Eos Stratification
Eligible to receive + Stage: IB (24 om) Further treatment
plalaumrbmsed chemo vs Ive IA Recurrence {investigator's choice)
‘Adequate end-organ eo Race hee and survival follow-up
odon non-Asien Platinum-based

No prior systemic chemotherapy*

cancer therapy — 4

Disease assessments (including brain MRI or CT scan if MRI unavailable) were conducted at baseline, every 12 weeks for year 1-2, every 24 weeks for year 3-5, then annually.

+ Primary endpoint: DFS? per investigator, tested hierarchically—stage II-IIIA — ITT (stage IB-IIIA)
+ Other endpoints: CNS DFS,” OS, and safety
+ Clan + pomotesad, plan + vinordbine or isla gometabin; cisplatin could be swiched to carla in cas oil,» DFS defined as na mo fom randonizatn to

Ana tet docenas recone of Cease or new primary NSCLC as Sterne by he Imestgaor or Seth wom any cause, where xcs à
1 Solomon Bet al ESMO 2023 Abarat LB? PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

61. INA: DFS of Adjuvant Alectinib vs C

in Early-Stage Resected ALK+ NSCLC!

DFS: Stage II-IIIA*
Pr

Data cut-off June 26, 2021; me m last patent In othe data cut-off was ~18 mo,

+ Median survival fou:
alectini, 27.8 mo. (9
chemotherapy, 284 ra o

«Por UICCIAICC 7 edita.» Staifed log rank. +2 events in ho alecii arm, 4 events in ho chemo am, one adétional patent inthe chem arm ded but was consored due to incompleto
date of death recordad; DFS define as the timo rom randomization to th fst documented recuranca of disease or new primary NSCLC as determined by the investigate, or death om

‘any cause, whichevor occ fest
1 Solomon B ot al ESMO 2023. Abstract LBA2.

PeerView.com/CGJ827

PeerView

Copyright © 2000-2024, PeerView

62. Let’s Consider a Case

Patient Presentation

67-year-old woman, never smoker, presents with persistent cough
Chest CT showed a 3.4-cm LUL mass

PET scan demonstrates 3.0- x 2.6-cm, solid-appearing LUL mass (SUV
5.3); pleural is normal, 1 hilar LN, no distant disease

EBUS confirmed hilar nodal involvement
Transbronchial biopsy LUL mass: invasive lung adenocarcinoma

PeerView.com/CGJ827

63. Let’s Consider a Case

Next Steps

She undergoes biomarker testing and the NGS panel reveals EGFR
exon 19 deletion

L VATS upper lobectomy reveals a 3.4-cm invasive adenocarcinoma,
moderately differentiated; multiple lymph nodes involved (one level 7,
one 11 L, two peribronchial)

Stage Illa (pT2aN2)

PeerView.com/CGJ827 Copyright © 2000-2

64. Let’s Consider a Case

Adjuvant Treatment and Outcomes

+ She was referred to a medical oncologist
+ Underwent four cycles of adjuvant cisplatin/pemetrexed

+ Undergoing 3 years of adjuvant osimertinib and doing well

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

65. Navigating Decisions About Neoadjuvant,
Adjuvant, or Perioperative Immunotherapy
in Resectable Stage I-lll NSCLC

Tina Cascone, MD, PhD

Associate Professor, Department of Thoracic/Head and Neck Medical Oncology
Director of Translational Research

The University of Texas MD Anderson Cancer Center

Houston, Texas

Copyrigh

66. Regulatory Status of Immunotherapy Approaches

in Resectable NSCLC

Neoat

vant Immunotherapy
CheckMate -816 _Nivolumab + chemo x 3 cycles

Re Adjuvant Immunotherapy

IMpower010 Chemo > atezolizumab ~1 y (PD-L1 21%)
SN KEYNOTE-091 Chemo (optional) > pembrolizumab ~1 year

Neoadjuvant Regimen mp ET TVA mam) Adjuvant Regimen

‘AEGEAN Durvelumab + chemo x 4 cycles Durvalumab ~1 year CEE
KEYNOTE-671 Pembrolizumab + chemo x 4 cycles Pembrolizumab ~1 year ES
CheckMate -77T Nivolumab + chemo x 4 cycles Nivolumab ~1 year

Neotorch Toripalimab + chemo x 3 cycles Tonpallmeb = neo x 1 cycle

Maintenance Toripalimab up to 13 cycles
RATIONALE-315 Tislelizumab + chemo x 3-4 cycles Tislelizumab <8 cycles

PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

67. Comparing the Differ

nt Immunotherapy Trials

in Resectable NSCL

AEGEAN Neotorch CheckMate -77T RATIONALE:
Timing Perioperative Perioperative Peroperaive Parioparatve
Size 802 500 a 453
a Atozokzumab Pambrotzumab Nwckmab Dumalumab Torpalmab Pambroizumab Nvolmab Tisakzumab
(PDL) Po) (D4) (POL) (PD-1) (D4) (PD) eo)
No. eye 16 18 3 16 7 8 16 2
iw Comet Completely eseiable 8 Reseciabe IIB. Resetable HIB Resecable IIIB. Resecabe MIB. Resectbl ILIA
lan) Cima m) CFOMHIIA (Ti). (tn) by lobectomy (eh) (em) (eth) en)
Stage Bei, 50/41 72128 ares 29/71 20180 30/70 35/65 41/50
Fs,
Dee Dröhemial DIE MORE MORE PES EFSLOS as ero Men
(Pout 250%)
Chemotherapy Cspatn doublet Pina GO ana doublet Plalnumbased Platnum-based spin double Platnum Goubet Platinum doublet
No documented yo documentos No EGFR
EGFRIALK Included (16%) — Included (74%) mutation wr Included (7%) no documented wr
(WT: Asia) Veni ALK
PeerView

PeerView.com/CGJ827

Copyright © 2000-2024, PeerView

68. Understanding Evidence: Pathologic Response Results1*

50 | 3eycles Up to 4 cycles
50 407
ze 40 pcR
§ 30 24 248 253 Pathologic Complete
a 20 17.2 18.1 Response
A (no viable tumor at
” = L: 1 | ul = is
0
CheckMate-516 AEGEAN Necorch — KEYNOTES71 CheckMate-77T RATIONALE-315
60 56.2
so us MPR
® 36.9 354 Major Pathologic
g 49 293 30.2 Response
= % (10% viable
20 23 aa 15 tumor at
a0 8.9 84 Hi resection)
0
CheckMate-816 AEGEAN Neotorch KEYNOTES7I CheckMate-77T RATIONALE-315
1 Ford Pat a Eng J Med, 2022386 1879-1985, 2 HymacJetal. AACR 2023 Absrac CTDOS 3. Lu Set al ASCO 2023. Abo! 801 .
À Wilco Metal Engl) Med. 2023 38949103. 6. Cosommo Tat al. ESMO 2023, Absvecl LEAT 8 Yue DS etal ESMO Val era, AbsuacavP1202. Peer View

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

69. Can ctDNA Supplement What We Can Learn From Tissue?

AEGEAN: Association of ctDNA Clearance With pCR/MPT and Its Predictive Utility

+ Among patients who were cIDNA positive at baseline (C1D1), all patients achieving pCR and >90% of all patients achieving
MPR had ctDNA clearance at C4D19

pcr? MPR?
Fw #
$
Treatment arm
q isis am E DNA tracks
En athological response À well with
5 por 3 completeness
5 Non por E
£ E
LE 3
DI Gt Cat Presurgery
Predictive Value of ctDNA Clearance at Different Timepoints for pCR
+ Patients without ctDNA clearance were unlikely to avian am per a =
achieve pCR (PBV >84.0% at C2D1 in both arms) un lo
+ Patients who achieved ctONA clearance in the = — = a
durvalumab arm vs the placebo arm were more likely
to achieve pCR (PPV = 50.0% vs 14.3% at C2D1) car bad ba Lol ue Led
reser ss 1 Prosper sa wo

2 mo BE. PCR (256% 86.9%) and MPR (4% u 168%) we gern he am pie am snd a ram pater tech Um. .
“Rook Met a, ESMO 2023. Anaract LBASO. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

70. Understanding Evidence: EFS/DFS Results!”

ia Adjuvant Neoadjuvant Perioperative

90 4-Year 4-Year 2-Year 4-Year
. © HR, 0.40
= 70 | mor HR 81 HR 0.66 63 667
D o HR, 0.59
ra) 53.2 524 1524
Go 49 484 50
D 50 Br 7 6.1
im} 38 40.6

40

30

20

10

o

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

1 Wales HA ot a ASCO 2024. Abstract LRABOSS 2. Bosse 8 tl. ESMO Inmuno-Oncology Congress 2023 Abstract 1200.
3 Sort ai ASCO 2024 Ansa 8010 4 Heymach Jet AACR 2020. Ale 67003 3 Lu tal ASCO 2023 Abstract 501 N
5. Spicer Je al ESNO 2023. LBASE. 7. Cescone Tet al ESMO 2023, Abstract LBAT. PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

71. tanding Evidence: OS Results!

Adjuvant? Neoadjuvant Perioperative
1 = 5-Year 4-Year 4-Year
HR,077 HR,071 HR, 0.72
80 748 (0561.06) nx wo
70 66.3 67.1
e 60 = 51.5
uy 50
S 40
30
20
10
0
IMpower010 CheckMate -816 KEYNOTE-671
No tl ASCO 202 Ro LEADS 2 Speer etal ASCO oe DRA 010.3 Spore al ESMO 2023 sec LAS PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, Peerview

72. A

/
CONFERENCE UPDATES & HIGHLIGHTS | #WCLC24 | 204 WCLC }

Abstract OA13.03. Presenter: J.V. Heymach
Perioperative Durvalumab for Resectable NSCLC: Updated Outcomes From the Phase 3 AEGEAN Trial

+ EFS benefit in favor of the durvalumab arm remained consistent compared with previously reported data
- Updated EFS HR = 0.69 (95% Cl: 0.55-0.88)

~ EFS benefit was maintained across predefined subgroups, including the planned neoadjuvant
platinum subgroups

- In separate exploratory analyses, EFS benefit in the durvalumab arm was more pronounced in
patients who received adjuvant treatment and favored the durvalumab arm regardless of pCR status

+ Clinically meaningful DFS improvement and an OS trend favoring the durvalumab arm were observed

— In separate exploratory analyses, the magnitude of DFS benefit with durvalumab was larger in
patients with pCR and improvement in lung cancer-specific survival also favored the durvalumab arm
+ Perioperative durvalumab + neoadjuvant chemotherapy was associated with a manageable AE profile,
with no new safety signals observed at this update

These findings, with additional follow-up, further support FDA-approved perioperative
durvalumab as a new treatment option for patients with resectable NSCLC

PeerView.com/CGJ827 Copyright

73. CONFERENCE UPDATES & HIGHLIGHTS | #WCLC24

Abstract PLO2.07

Neocoast-2: Efficacy and Safety of Neoadjuvant je RSCLO (D) + Novel Anticancer Agents
+ CT and Adjuvant D + Novel Agents in Resectable

ISCLC

PLO2: Presidential Symposium 1
Presenter: T. Cascone

NeoCOAST-2: Open-Label, Multi-Arm Platform Study in Perioperative NSCLC
Neoadhvant for cycles OSM ‘Adjuvant ee upto 1 year

em oleclumab + durvalumab +
platinum-doublet CT", Oloelumab + durvalumab

Key Evigiblty Criteria
+ Stage WANE resectable =72)

NSCLC (AICC 8h edtion) R >
+ EGFRIALK wap Am 3 volrustomig +
2 ECOGPS0ar1 7 er

reverted.
"Te par nt was ok promi far saa by calc OR rats

Squamous tumor histology. pemetrexed + esplatn or carboplatin or nonsquamous tumor histology. » Physician's choice of carboplatin or cisplatin, «Mitin 40 days of tho
ent «Proportion a th no viabo tumor cols and <10% residual viable tumor cos, rospectvaly, n recocted tumor specimen and sampled nodos at surgery

Copyright © 2000-2024, PeerView

74. INFERENCE UPDATE:

Abstract PLO2.07

Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D) + Novel Anticancer Agents
+CT and Adjuvant D + Novel Agents in Resectable NSCLC

PLO2: Presidential Symposium 1
Presenter: T. Cascone

NeoCOAST-2: pCR and mPR Rates Across Treatment Arms

Arm 1 Arm 2
Oleclumab + durvalumab + CT Monalizumab + durvalumab + CT

100 + miITT® 100 mirra
n=60 4
80 | 80

3

60 |

40

or centrall®

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

75. INFERENCE UPDATES & HIGHLIGHTS

Abstract PLO2.07

Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D) + Novel Anticancer Agents
+CT and Adjuvant D + Novel Agents in Resectable NSCLC

PLO2: Presidential Symposium 1
Presenter: T. Cascone

pCR Rates Across Baseline PD-L1 Expression Subgroups

Arm 1 Arm 2
Oleclumab + durvalumab + CT Monalizumab + durvalumab + CT

Overall pOR: 20% Overall PCR: 26.7%

325
(1340)

PCR Rate, %

soi uns cr |

Overall pCR: 34.1%

375
(12732)

aPO-LI TPS <1%
POLI TPS 21%

PeerView.com/CGJ827

76. INFERENCE UPDATE:

Abstract PLO2.07
Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D) + Novel Anticancer Agents

+ CT and Adjuvant D + Novel Agents in Resectable NSCLC

PLO2: Presidential Symposium 1
Presenter: T. Cascone

pCR Rates Across Baseline PD-L1 Expression Subgroups

lumab + durvalumab + CT Monaliz

Overall pCR: 20%

Overall POR: 26.7% Overall pCR: 34.1%
412

ann
35 33

32
(1825) a = (515)
(620) 25 mPD-LI TPS <1%

(ata) mPD-LI TPS 1%-49%
PD-L1 TPS 250%

176 r
it?)
cud (3120)

56
ana)

PCR Rate,

Copyright © 2000-2024, PeerView

PeerView.com/CGJ827

77. CONFERENCE UPDATES & HIGHLIGHTS | #WCLC24

Abstract PLO2.07
Neocoast-2: Efficacy and Safety of Neoadjuvant Durvalumab (D) + Novel Anticancer Agents
+CT and Adjuvant D + Novel Agents in Resectable NSCLC

PLO2: Presidential Symposium 1
Presenter: T. Cascone

+ In perioperative NSCLC, novel combinations demonstrated providing promising efficacy, with
numerically higher pCR and/or mPR rates compared to historical benchmarks
— Oleclumab + durvalumab + CT: pCR rate 20%; mPR rate 45%
— Monalizumab + durvalumab + CT: pCR rate 26.7%; mPR rate 53.3%
— Dato-DXd + durvalumab + CT: pCR rate 34.1%; mPR rate 65.9%
+ Treatments in all arms demonstrated a manageable safety profile and surgical rates
comparable to currently approved regimens

This is the first global phase 2 study showing encouraging efficacy and manageable
safety profile of an antibody-drug conjugate in the neoadjuvant setting for patients
with resectable NSCLC

Copyright

PeerView.com/CGJ827

78. INFERENCE UPDATE:

Abstract PLO2.08

Perioperative vs Neoadjuvant Nivolumab for Resectable NSCLC: Patient-Level Data
Analysis of CheckMate 77T vs CheckMate 816

PLO2: Presidential Symposium 1
Presenter: PM. Forde

Methods: Perioperative NIVO vs Neoadjuvant NIVO + Chemo : Analysis Populations*

Pony Patent Popa
ale a
EcoG rss »
- Endpobt Donate sage

658 (CR) ancmarend rm eo surgery ‘Ste ea. as

e e en led Span so
Te nenn pas debate
AS E

Check 77 Patents vb had apr ade

‘Subgroup analyses were no whe de to sale amo sizes
see characteris brtnoen pants who reed paraperave NVO r eondhvat NNO +

Median duration of tom 20 mo [Chacao B16) nd 533 mo (Creche 77T) fame were gara rend ai propensity scare weighing ATT ang ATE

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

79. ERENCE UPDATES | swercz

Abstract PLO2.08

Perioperative vs Neoadjuvant Nivolumab for Resectable NSCLC: Patient-Level Data
Analysis of CheckMate 77T vs CheckMate 816

PLO2: Presidential Symposium 1
Presenter: PM. Forde

Landmark EFS (BICR) From Definitive Surgery

ry 2 E]
Fees Time From Surgery, mo

+ HR (95% Cl): ATTY weighted analysis, 0.56 (0.35-0.90); unweighted analysis, 0.59 (0.38-0.92)
+ Median follow-up: CheckMate 816, 29.5 mo; CheckMate 77T, 33.3 mo

ro appbed to patents inthe ne

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

80. CONFERENCE UPDATES &

Abstract PLO2.08

Perioperative vs Neoadjuvant Nivolumab for Resectable NSCLC: Patient-Level Data
Analysis of CheckMate 77T vs CheckMate 816

PLO2: Presidential Symposium 1
Presenter: PM. Forde

Landmark EFS? (Analysis Population) by pCR Status?
pcre No pCR

Perioperative AIVO
Perioperative NIVO

HR 6% CD) 080 (014240) HR (5% Ch 065 (040-406),

6 à » 5 6 290 %

PeerView.com/CGJ827

Time From Surgery, mo

Time From Surgery, mo

Copyright © 2000-2024, Peer

81. UPDATES

Abstract PLO2.08

Perioperative vs Neoadjuvant Nivolumab for Resectable NSCLC: Patient-Level Data
Analysis of CheckMate 77T vs CheckMate 816

PLO2: Presidential Symposium 1
Presenter: PM. Forde

Landmark EFS? (Analysis Population) by Tumor PD-L1 Expression?”
PD-L1 <1% PD-L1 21%

Perioperative NIVO

Perioperative NIVO

Pereperatve NNOM Neoadfurant MIO + Chemo Poroperatve NNO“ Neoadhuvant VO + Chemo
LE vn ono) we
HR 05% CH 051 028093) 098 044-170)
2 8 À » © à 4

Time From Surgery, mo Time From Surgery, mo

mo.» Patents with ches. ® Unwoighiog an
3%. 33 patents (62 51 patents (68%). Modan number of doses (rango): <1%

PeerView.com/CGJ827

82. CONFERENCE UPDATES &

Abstract PLO2.08

Perioperative vs Neoadjuvant Nivolumab for Resectable NSCLC: Patient-Level Data
Analysis of CheckMate 77T vs CheckMate 816

PLO2: Presidential Symposium 1
Presenter: PM. Forde

Landmark EFS? (Analysis Population) by Clinical Stage”
Stage IB-II Stage Ill

Perioperative NIVO
Peroperatve N

“= 4 © %
Time From Surgery, mo Time From Surgery, mo

PeerView.com/CGJ827 Copyright , PeerView

83. CONFERENCE UPDATES & HIGHLIGHTS | #WCLC24

Abstract PLO2.08

Perioperative vs Neoadjuvant Nivolumab for Resectable NSCLC: Patient-Level Data
Analysis of CheckMate 77T vs CheckMate 816

PLO2: Presidential Symposium *
Presenter: P.M. Forde

Safety Summary”: Analysis Populations

Perioperative VO | Neoadjuvant NIVO + Chemo
(a= 139) {n= 167)

Patents, %)

Try Grade» | Grade 3a | Any Gade

ET ETE To

wm en m os
NAS osóngtoiceniuaten 200 1) WM 86)
TRAEsleadngodeconinstion 220 86) 16 a)
ANSAES 57 (41) 37 (27) 23(16) 16 (11)
‘Treatment-related SAES 23116) 14610) 1702) 130)
Suenos AES CRETE TL
Trostmant read death

+ AEs por CTCAE v4 and ModORA v24.0 (ChockMato 816) oF 26.1 (ChockMato 777)" Includes events reported betwoon ho st dose and 30 days ater the last dose of study treatment.

View.com,

adjuvant dose and 30 days ater tha lst dose of neoadjuvant study treatment. 4 includas events reported within 90 days atar Gene
er tho fst dose of neoadjuvant sud treatment.

Copyright © 2000-2024, PeerView

84. Let’s Consider Another Case

OA Patient Presentation

57-year-old man, former smoker (20 y); 50-pack-year history * Asymptomatic 6-cm diameter
FEV1: 58% suprahilar mass

DLCO: 90%

Zubrod/ECOG 1

PeerView. Copyright © 2000-2024, PeerView

85. Let’s Consider Another Case (2)
GE 720109

86. Let’s Consider Another Case

Additional Testing Results

+ Head MRI (-), PET otherwise (-)

Invasive mediastinal staging

+ EBUS FNA: AR (-), 7 (-), 4L (-),
TIR (+)

Bronchoscopy: tumor in upper lobe;
adenocarcinoma T3 N1

Biomarker testing: negative for EGFR
and ALK, PD-L1 <1%

PeerView.com/CGJ827

Copyright O 2000-2024,

87. cussion: What Would

Faculty Panel Recomme

+ Definitive concurrent chemoradiotherapy + consolidation ICI
+ Neoadjuvant chemotherapy + radiation followed by surgery
+ Neoadjuvant chemotherapy followed by surgery

+ Neoadjuvant chemotherapy + ICI followed by surgery

+ Surgery followed by adjuvant chemotherapy + ICI

+ Something else?

PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

88. Our Case Continues

Additional Testing Results

Patient received neoadjuvant chemotherapy + ICI

Taken to the OR

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView

89. Faculty Panel Discussion: What Would You Recommen

Following surgery, for which patients would you consider adjuvant
immunotherapy?

+ Patients with pCR
+ Patients with residual viable tumor in the resected specimen
+ Both

+ Neither

PeerView

PeerView.com/CGJ827 Copyright © 2000-2024, PeerView