Opportunity Knocks in AML: Guidance on Achieving Truly Personalized Care in Challenging Populations with Modern Therapeutics

Co-Chairs, Naval Daver, MD, and Tapan Kadia, MD, discuss acute myeloid leukemia in this CME/MOC/NCPD/CPE activity titled “Opportunity Knocks in AML: Guidance on Achieving Truly Personalized Care in Challenging Populations with Modern Therapeutics.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/CPE information, and to apply for credit, please visit us at https://bit.ly/3RQYjFU. CME/MOC/NCPD/CPE credit will be available until October 5, 2025.

1. Elevating Expectations, Broadening Impact

How to Leverage Immunotherapy and EGFR-Targeted Therapy
to Improve Outcomes in Unresectable Stage III NSCLC

Suresh S. Ramalingam, MD, FACP, Kristin Higgins, MD

FASCO Chief Clinical Officer

Executive Director po Professor of Radiation Oncology
Winship Cancer Institute City of Hope Cancer Center Atlanta
Roberto C. Goizueta Chair Newnan, Georgia

for Cancer Research

Emory University School of Medicine

Atlanta, Georgia

Jarushka Naidoo, MB, BCH, MHS
Professor of Medical Oncology
Consultant Medical Oncologist
Beaumont RCSI Cancer Centre
Dublin, Ireland

Adjunct Professor of Oncology
Johns Hopkins University
Baltimore, Maryland

Copyright © 2000-2024, PeerView

2. Elevating Expectations, Broadening Impact

How to Leverage Immunotherapy and EGFR-Targeted Therapy
to Improve Outcomes in Unresectable Stage III NSCLC

Suresh S. Ramalingam, MD, FACP,
FASCO

Executive Director

Winship Cancer Institute

Roberto C. Goizueta Chair

for Cancer Research

Emory University School of Medicine
Atlanta, Georgia

Jarushka Naidoo, MB, BCH, MHS
Professor of Medical Oncology
Consultant Medical Oncologist
Beaumont RCSI Cancer Centre
Dublin, Ireland

Adjunct Professor of Oncology
Johns Hopkins University
Baltimore, Maryland

Kristin Higgins, MD

Chief Clinical Officer

Professor of Radiation Oncology
City of Hope Cancer Center Atlanta
Newnan, Georgia

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

Copyright © 2000-2024, PeerView

3. Our Goals for Today

Augment your knowledge of clinical evidence on
immunotherapy and targeted therapy in unresectable
stage III NSCLC

Equip you with strategies to foster multidisciplinary
collaboration to improve outcomes in unresectable
stage III NSCLC

Improve your skills in integrating immunotherapy and
targeted therapy into individualized treatment plans for
patients with unresectable stage III NSCLC

Copyright © 2000-2024, PeerView

4. Answer This Question

Reflect on your practice and indicate which of the following currently
represent challenging areas in your clinical care of patients with stage III

NSCLC (select all that apply):

‘ls
2
3.

Differentiating between resectable and unresectable locally advanced NSCLC
Determining the optimal radiation strategy

Implementing and using biomarker testing to guide clinical decisions (eg, PD-L1,
EGFR mutations, and other genomic alterations)

. Establishing the best multidisciplinary treatment plan for individual patients,

including when/how to integrate ICI and EGFR-targeted therapy

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5. Multidisciplinary Patient Evaluation
and the Role of Chemoradiotherapy
in Unresectable Stage Ill NSCLC

Kristin Higgins, MD

Chief Clinical Officer

Professor of Radiation Oncology
City of Hope Cancer Center Atlanta
Newnan, Georgia

Copyright © 2000-2024, PeerView

6. Stage III NSCLC: A Heterogeneous Group!"

‘or any size inthe presence of 21
‘ofthe ctra of extent

Main bronchus (regardless of distance

No extension proximal car) vs atelectasis or obstructive
to the lobar bronchus peumontis extending to the num
(entro or par of ung)
None: tho tumor
8 sumounded by lung Visooral pleura
‘or visceral pleura
Absent Abren

1. Adopted kom Rami-Porta et aL CA Cancer J Cin, 2017:87:138-155,

>5ems7 om or any si inthe >7emoranysizoin the
presence oft ofthe cetera, presence of 21 of he crteria
Of extent ‘of extent

- Carina ortrachen

‘Chest wall including superior Diaphragm, mediastinum, heat,
subs). phrenic nerve, parietal great vessels, recurrent laryngeal

lu, andlor parta! ‘are, esophagus, andlor
pericardium vertebral body
Present the same lobe Presentin a erent
ofthe primary tumor ipsiateral lobe

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7. Key Questions in Managing Stage Ill

Patient
Factors

Performance status

Weight loss </>15%
Comorbidities

Pulmonary function (FEV, 21.0)
Cardiac function

Patient preferences

Social, financial factors

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Staging: IIIA vs IIIB/C

N2 bulk, no. of stations

Is it technically resectable?

Can radiation be delivered to

curative dose?

PD-L1 and genetic alterations
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8. Differentiating Between Resectable
d Unresectable Locally Advanced NSC

... Ask a surgeon!

+ Patients with locally advanced disease make up a heterogeneous population with varying degrees
of tumor resectability'

— N1 vs N2 vs N3 disease
= Small (<1.5 cm) versus bulky (>3 cm) N2 disease
— Single versus multistation N2 involvement
+ Resectability status may change after CRT!
+ There is no universally accepted definition of “unresectable” stage III disease!

+ Determination is made on a case-by-case basis! with an experienced thoracic surgeon as part of a
multidisciplinary team?

+ Two RCTs in resectable stage III (N2) did not demonstrate a significant OS benefit when surgery was
added to CRT versus CRT alone, but subgroups may benefit

Li sna, cha 0010985942 NN ane tes es may Non Sal a en en .
Taps tn ne oo ya Jal pl Aon KS eh al Lane” 2000874 018.808 à Fiss Metal J clr Oncol Solsona 67603. PET VIEW

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9. Patient Evaluation

Staging

Physiologic evaluation
CT

PET PFTs
+ EBUS/Med + Cardiac eval + EGFR

Brain MRI

Biomarker testing

+ Exercise testing + ALK

+ Frailty assessment

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10. rent Role of Che

Standard approach
is 60 Gy concurrent
chemotherapy with

IMRT technique

+ Multiple acceptable
chemotherapy
regimens

Based upon results
of RTOG 0617
showing no benefit
to dose escalation to
74 Gy

Concurrent RT alone
yields 5-year OS
of 32%

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Copyright © 2000-2024, PeerView

11. Grade 23 Adverse Event

erm Results From RTOG 0617:

Severe Long-Term Toxicity Profile!

Radiation Technique

Comparison, %

Univariate Logistic Regression

Pneumonitis
Esophagitis
Weight loss
Cardiovascular
Neurologic
Hematologic

1.Chun SO et al. JAMA Oncol 2024:10:1111-1118,

PeerView.com/BVU827

3.9

5.3

5.7

58.8

3.1

8.2

5.9

50.2

Lung V5Gy
OR: 1.02 (95% Cl, 0.99-1.05)
P=.13

OR: 1.01 (95% Cl, 0.996-1.03)
=.15

OR: 1.01 (95% Cl, 0.98-1.04)
P=.52

OR: 1.00 (95% Cl, 0.98-1.02)
P=.99

OR: 1.00 (95% Cl, 0.98-1.03)

P=1.00

OR: 1.00 (95% Cl, 0.99-1.01)
P=.66

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12. Results: Overall Survival by Heart V40Gy!

Median Survival,
Heart Dose A P
= V40Gy 20% 252.181
3 75 Y 2130 <o1
E V406y220% 1.701520)
3
17)
= 5
5 Heart V40Gy <20%
6
Heart V40Gy 220%
25 is
0
0 1 2 3 4 5
Time, y
Heart V40Gy <20% 242 184 138 106 86 62
Hear VA0Gy 220% 201 148 a 56 2 a

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1.Chun SO ot a. JAMA Oncol 2024:10:1111-1118,

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13. Results: Multivariable Analysis of Overall Survival!

Covariate Comparison _Fail/Total RL Sue HR (95% Cl) P
V40Gy <20%

Heart V40Gy (RL) vs 1571241 1641201 1.34 (1.06-1.70) 01
V40Gy 220%

Radiation dose °° en bi 1741254 1471188 1.28 (1.03-1.60) .03

PTV volume Continuous 321/442 NIA 1.000 (1.000-1.001) .02

Lung V5Gy Continuous 321/442 N/A 1.006 (0.998-1.014) — .13

Age Continuous 321/442 N/A 1.009 (0.997-1.022) 14

1. Ghun SO et al. JAMA Oncol 2024:10:1111-1115. PeerView

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14. IMRT vs Proton Bea

y
Radiation Dose, Gy

Lungs

3
Ë

Radiation Dose, Gy

PeerView

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15. RTOG 1308: Phase 3 Randomized Trial Comparing OS After
Photon vs Proton Chemoradiotherapy for Stage II-IIIB NSCLC

Completed
Photon (highest achievable dose accrual 9/2023!!
between 60-70 Gy at 2 Gy) once daily 330/330

+ platinum-based doublet
chemotherapy

Stratification factors
+ Stage: IIIA vs IIIB
+ GTV: £130 ce vs >130 cc

+ Histology: squamous vs
nonsquamous

Durvalumab or
consolidation
chemotherapy

Protons (highest achievable dose
between 60-70 Gy [RBE] at 2 Gy
[RBE]) once daily + platinum-based
doublet chemotherapy

+ Plan must meet dose and volume constraints of all OARs (very different from other trials)

PE Xing iso 5
lp he rgoncegyoriCinicaTralPrtocliog-19087Hcato-130. PeerView

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16. Phase 3 LU008 Trial NRG

SBRT (primary) Chemoradiation

+ Locally advanced || Stratification factors (mediastinum)
stage II (node + Stage (INIA vs Maintenance
positive) or Ill MIBANIC) immunotherapy
(NSCLC) x 12 months

LE CCC (CS) Chemoradiation

(primary + mediastinum)

+ Primary endpoints: OS and PFS
+ Control arm: chemoradiation to the primary and mediastinal disease (60 Gy/2 Gy) > immunotherapy maintenance x
12 months
+ Experimental arm: SBRT to the primary (standard BED 2100 Gy dose regimen) > chemoradiation to mediastinal disease
(60 Gy/2 Gy) > immunotherapy maintenance x 12 months
— SBRT to primary tumor
> 3 fractions to 54 Gy (BED10 of 151.2 Gy) [peripheral]
> 4 {fractions to 50 Gy (BED10 of 112.5 Gy) [peripheral or central]

> 5 fractions to 50 Gy (BED10 of 100 Gy) [central] or to 60 Gy (BED10 of 132 Gy) [peripheral or central]
PI: Or, Chuck Simone PeerView

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17. NRG LU008: SBRT to Primary

+ Total volume of lung receiving 40 Gy = 332 cc (compared with 590 cc, 44% reduction)
122 cc (compared with 1,300 cc, 29% reduction)
2,168 cc (compared with 2,360, 8% reduction) eerView

+ Total volume of lung receiving 40 G;

+ Total volume of lung receiving 10 G;

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18. nmet Needs in Unresectable Stage III NSC

Median PFS (95% C)_ In unresectable stage III NSCLC.

lA N Curva 123202) following CRT without progression,
08 Riecebo 1020229 SOC is consolidation durvalumab

Hazard ratio (95% Cl) 0.91 (0.39-213)

+ Benefit of consolidation durvalumab in
EGFR-mt NSCLC is uncertain based

PFS Probability
o
o

= on PACIFIC post hoc subgroup

Durvalumab N
01 analysis

0
13 6 9 12151821242730333630424548515457 « Currently, there are no approved
Time From Randomization, mo targeted therapies for unresectable
Mad 9 3 6 9 wis wa massa ar as ass sr Stage Ill NSCLC
num D À 1 1 8 6 3 ee LE TT TT TI 0
Pato M0 5 5443 222222111000
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1. Naidoo Jet al. J Thorac Oncol 2028:18:657-663

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19. Making the Most of Immunotherapy
in Unresectable Stage III NSCLC

Jarushka Naidoo, MB, BCH, MHS
Professor of Medical Oncology
Consultant Medical Oncologist
Beaumont RCSI Cancer Centre
Dublin, Ireland

Adjunct Professor of Oncology
Johns Hopkins University
Baltimore, Maryland

100-2024, PeerView

20. ocally Advanced NSC.

72-year-old woman

9-cm lung mass invading the mediastinum and N3 LN on PET/CT that are biopsy-proven
adenocarcinoma (T4N3, stage IIIC)

PD-L1 score of <1%
ECOG PS is 1

Molecular testing results: negative for EGFR mutations

PeerView

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21. Answer This Quest

What treatment would you recommend for this patient?

. Definitive chemoradiation followed by maintenance durvalumab

. Definitive chemoradiation alone

1
2
3. Thoracic radiation alone
4. Chemotherapy alone

5:

. I'm not sure

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22. PACIFIC: Durvalumab Post cCRT in Stage Ill
Unresectable NSCLC’

+ Unresectable stage III NSCLC without
progression after definitive platinum-based
CCRT (22 cycles)

+ Aged 218 years

+ WHO PS score 0 or 1

+ If available, archived pre-cCRT tumor tissue
for PD-L1 testing

+ Patients enrolled irrespective of PD-L1 status

N = 713 randomized

Durvalumab 10 mg/kg Q2W for up to 12 months
(n = 476)

2:1 randomization stratified by age, sex,

and smoking history

o 12 months

+ Primary endpoints: PFS (BICR) using RECIST v1.1 and OS

+ Key secondary endpoints: ORR, DOR, and TTDM (BICR) using RECIST v1.1; safety; and
patient-reported outcomes

+ Coprimary endpoints: OS and PFS

1. Antonia Sa. Engl J Med. 2017377:1919:192. PeerView

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23. PACIFIC: PFS Benefit!

EventsPatients, nA (%) — Median PFS, mo (95% Ct)

Duras ZORATE 63) 169190239)
Placebo 1757237 738) 584877)
0 Siraiiod HR = 0.55 (05% Gl, 0454.68)

‘Strattied HR from the primary analysis = 0.52 (85% CI, 0420.65)
os

“ 55.7%
E 07 (95% Ci, 51.0.602) Durvalumab vs
os 45%
3 es (95% Cl. 40.1-49.8) 39.7% aK ss placebo x
© oe REN TEN) (95% 1, 29.9-40.1) (95% Cl, 28.0-382) 1 year after
Los chemoradiation
$e 254%
o. cos cit
o
OTS 6 8 12 15 18 21 24 2 90 33 96 99 a2 45 as 61 G4 67 6) 63 08 69 72
No, at Risk Time Since Randomization, mo

Durvalumad 476 377 301 267 215 190 165 147 137 128 119 110 103 97 82 85 8% 78 67 ST M 22 1 S 0

Placebo 237 164 105 87 68 56 48 41 37 35 30 27 25 25 24 2 22 21 19 19 14 6 4 1 0

1-Spigol DR ota. J Cin Oncol. 2022.40:1301-1311

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24. PACIFIC: OS Benefit!

Events/Patients, UN (%) Median OS, mo (95% Ci)
Durvalumab 2641478 (55.5) 475 681-529)
Placebo 1551237 (65.4) 291221351)
‘Stratified HR = 0.72 (95% Cl, 0.59-0.89)
10 23.1% ‘Stratiied HR trom the primary analysis = 0.68 (95% Cl, 0.53-0.87)

09
os
or
os
os
04
os
02
o.

(95% Cl, 79.4-86.2)

66.3%
(95% Cl, 61.8-70.4)

OS, Probability

(95% cit
27323964

O13 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 S1 54 57 60 63 66 69 72 75

No, at Risk Time Since Randomization, mo
Durvalumab 476 464 431 414 385 364 343 319 208 289 273 264 252 241 296 227 218 207 196 183 134 91 40 18 2 0

Placebo — 237 220 199 179 171 156 143 133 123 116 107 99 97 93 91 83 78 77 74 72 56 33 16 7 2 0

1-Spigol DR ota. J Cin Oncol. 2022:40:1301-1311.

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Durvalumab vs
placebo x

1 year after
chemoradiation

PeerView

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25. PACIFIC: 5-Year OS and PFS Subgroup Analysis!

41. Spigot DR eta. J Cin Oncol. 2022:40:1301-1811

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26. PACIFIC: 5-Year OS and PFS PD-L1 Subgroups’

No. of Events!
No.of Patients (%)

pacte
Se

Au patents sun N
ass sms arena)
pr inner) eanos 61
Coon warme) sanear)
pes “iso 52187 (53.6) 2947 (61.7)
Taba vr
ars cate U) soon)
Aion ae ans

La

072(059-087)

0521032082)

0.90 (067-423)

0.68 (050-083)

0730461.

061044035)

4.18 (075-1.75)

Unstratiied HR

20070 (66) 1792970738) el 038048070)
sn) 3175) 04020007)
Hosen (664) 770633) 064 040006)
100174 (586) és (739) 060,044.02)
sor (S15) 3647 786) 081 033.078)
1212520) com (758) 04703504)
ss 41188 702) 080 059-120)

+ 42 cays post CRT
= POLI alone

E
+ 42 day pest OR
POLI 21% ony

EMA

4. Spigel DR eta, Gin Oncol. 2022:40:1301-1311

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92

92 06 1 14 13

GE cotas
PeerView

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27. Let’s Come Ba

Case: Locally Advanced NSC

72-year-old woman What is the most appropriate treatment?

9-cm lung mass invading the
mediastinum and N3 LN on PET/CT that
are biopsy-proven adenocarcinoma

Definitive chemoradiation,
followed by maintenance durvalumab

(T4N3, stage IIIC)

Definitive chemoradiation alone
PD-L1 score of <1%

ECOG PS is 1 Thoracic radiation alone

Molecular testing results: negative for

EGFR mutations Chemotherapy alone

PeerView

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28. PACIFIC-R: Real-World PACIFIC—Expanded Access Program!

Un le,
stage III NSCLC, Index date

regardless of Y
tumor PD-L1

Start
expression sant observation to evaluate diseas:

No evidence (10 mg/kg IV
of progression Q2W) through | Dec 201810 July to Oct Sept
following the EAP Aug 2020 2020 to Nov 2021 04 2023

definitive, (Sept 2017
nd of 5th
ear

Platinum-based to Dec 2018)
CRT

(Optional)

Primary endpoint: investigator-assessed PFS and OS

Key secondary endpoints: demographics, disease characteristics, prior therapy, PFS/OS
by subgroups, and AESIs

1. Gras N. Trace Oncol. 200817:1067-1080 PeerView

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29. PACIFIC-R: Patient Characteristics and PFS!

Median age at EAP inclusion, y (ange)
‘Age category at EAP inclusion, n (%)
my
7075y
>T5y
Sun)
Men
Women
‘Smoking status at EAP inclusion,» (%)
Never
Current
Former
ECOG or WHO PS at EAP inclusion, (6)
o
1
20r3

Full Analysis
Set (= 1399)

66 (26-8)

958 (68.5)
2950212)
145104)

944 (67.5)
45525)

mos
458025)
832505)
n=951
489614)
443 468)
192)

4. Girard N. J horacio Oncol. 2022;17:1067-1068.

PeerView.com/BVU827

Disease stage at intial NSCLC
agnosis, (%)

twos
ir
WB or tC

Hope hype a singe
ETS

Squamous
Nonsquamous
PO-LA status, n (4)
21%
1%
Inconsistent
EGER status, (4)
Mio
ws typo
Inconclusive or union

Full Analysis
Set (N= 12399)
1202
1453)
604 (43.4)
714619)
n=1378

49600)
882 64)
n= 067

700 (72.4)
ac)
ET)
n=s82
450.9)

517 (@88)
1989)

BFS ovens, nO)
Median PFS, mo (85% Cl)

737 (62.7)
217 (19.1248)

622%
(ORC. 54.1%

ge LEO asc ge
z (erect.
jo SEU

0 6 2 © E E
‘Time From Index Dato, mo

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30. PACIFIC-R: Treatment Discontinuation and Safety’?

Reasons for and Timing AESIs Leading to Interruption and
of Durvalumab Treatment Discontinuation Permanent Discontinuation of Durvalumab

Set (N = 1,399) Full Analysis Set (N = 1,399)

Median Time to AESI Category Temporary
Discontinuation, Interruption,
mo (range) n(%)
Completed E Ar 156 (11.2 231 (16.5)
Hraakmenk 659 (47.1) 11.9 (5.5-28.5) ny (11.2) (16.5)
Pneumonitis or ILD. 73 (6.2) 133 (9.5)
Diese 377 (26.9) 49 (0-302) — =
progression i "
Diarrhea or colitis and 180.0 1519
Adverse event 233 (16.7) 2.8 (0-19.6) intestinal perforation
Hepatitis or transaminase
Death 21 (1.5) 1.9 (013.6) ses LA) wc)
Patient decision 20(1.4) 6(0-19.5) Endocrinopathies 18 (1.3) 10 (0.7)
Other 68 (4.9) 5.9 (0-28.2) Other 33 (2.4) 51 (3.6)
1. Gard NY Thorac Oncat 2022:17:1067-1089. 2. OLeary CL eta. J Thorac Oncol 2024 19:96-408, PeerView

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31. PACIFIC-2: Does Co
Stage Ill Unresectable NCLC?1

Locally
advanced,
unresectable
(stage III)
NSCLC

ECOG/WHO
performance
status 0 or 1

Stratification

rrent ICI With RT Improve Outcomes

10 + CRT Consolidation
CR, PR, or SD

at 16 weeks

Durvalumab 1,500 mg IV
Q4W + SOC CRT:

Durvalumab

factor (n = 219) until progression
Age (<65 vs
pea ri CR, PR, or SD
Stage (IIIA lacebo IV Q4W po
vs oe + SOC CRT? has 7 tale
(n = 109) until p

+ Primary endpoint: PFS by BICR per RECIST v1.1

+ Key secondary endpoints: OS, ORR, and OS24; OFS2, DOR, TTDM, DCR,
pharmacokinetics, and health-related QOL; and safety and tolerability

+ Pratnun.

ns include: Je, carbopltinipacitaxel, pemetrexedlcsplatn(nonsquamous only, or pemetrexedicarbopatin

“based chemotherap splatinitopos
(nonequam or) longed rada Dra Miam lr & weeke 28 days, EL 60 Oy)

1. Bradley JD et at ELOC 2024, Abetract LA

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32. PACIFIC-2: Patient Characteristics’

Durvalumab + CRT Placobo + CRT

(n=219) (n= 109)
Age group (4), n CR)

<0 1862) ay
25010 <5 107 (48.9) 50 (459)
265 10 75 75 (42) 40 667)
275 sen 764
Median age (range). y 65 (36-84) 63 (36-84)
Son

Men 166758) 20034)
Women 530242) 29088)
Race, n (%)

vie. 141 (644) 821589)
Back 209 o
Asian es an) 39358)
‘American Indian or Alaska Nate 762) 7164)
Other 4013) 109)
ECOGAVHO PS, n (%)

0 normal acy) 98 447) 53496)
1 (rostictod activi) 121653) 56 (514)
Histology type, n (%)

Saumous 2G a
Nonsauamous van SE
POI status, C6)

<1% (negar) >

21% (post) 1616) st
Lingen 204) EE

* PD: testing was retrospective and performed
4. Bradley JD otal ELOC 2024, Abstract LBA

PeerView.com/BVU827

EGFR mutation, 1%)
Poste
Negative
Unknown
AICC stage, n CP
ma
iB
Ic
v
TM class at sereoning, n (%)
Primary tumor
Tx
1
n
nm
1
Regional mph nodes
No

M
N2
NB

Distant metastasos.
mo
Mio

central. ® Per the 8th adn ofthe AJCC Cancer Staging Manual

Dur:

umab + CRT Placebo + CRT
219) 109)

762 005
mn 1
E)
nun em
ww sie
mast) zo)
105) 109)
209 109
son 1062)
ares) 191149)
38 (17.8) 32 (29.4)
2
25010 104
“aD 14020)
mi 0060)
saa) 26
zus 108,908)
105 109
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33. PACIFIC-2: PFS"

Durvalumab+CRT Pla

o + CRT

a 147/219 (67.1) 801109 (73.4)
MPFS, mo (95% Cl) 13.8 (9.5-16.9) 94 (75-166)
HR (95% CI) 0.85 (0.65-1.12)

Pp 247

Durvalumab + CRT

Placebo + CRT

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66
Time, mo

1. Bradley JD et a LOC 2024 At LBA PeerView

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34. PACIFIC-2: OS'

Placebo + CRT

1.0 Events/randomized
patients (%) 142/219 (64.8) 69/109 (63.3)
u. MOS, mo (95% CI) 364(262456) 29.5(23.2451)
Ñ HR (95% CI) 1.03 (0.78-1.39)
2 P 0823
5 06
3 Durvalumab + CRT
A
© 04
a
°
02
AAA AAA

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66
Time, mo

1. Bray AD eta ELO 2024. AtatactLOAS PeerView

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35. PACIFIC-2: Does Concurrent ICI With RT Improve Outcomes

in Stage Ill Unresectable NSCLC?"

Durvalumab + CRT Placebo +

AE Category, (%) Et CS
Any AE 216 (886) 108 (100)
Maximum grade 3 or + 117634) 64683)
Outcome of dath san 11002)
SAE 108 (47) 56 (519)
Any AE leading to discontinuation of durvalumabyplacebo™ 56 (258) 1302)
9:0 24 mo om start of voatmont (approximates the duration of IO + ORT and ends at tho lt postbasaine scan) ENCE 568)
>41 516 mo from start of treatment (approximates the uration of consolidation of 10 inthe SOG PACIFIC regimen) 12155) 86e)
216 mo tom start of treatment (approximates treatment beyond the duration of consoldation O inthe SOC PACIFIC regimen) 1369) 109)

+ The most common treatment-emergent AEs with durvalumab + SOC CRT were
= Anemia (42%), pneumonitis (28.8%), neutropenia (27.4%), and nausea (25.6%)

+ The most common treatment-emergent AEs with placebo + SOC CRT were
= Anemia (38%), constipation (28.7%), pneumonitis or radiation pneumonitis (28.7%), and neutropenia (25.9%)

+ Combined rates of pneumonitis or radiation pneumonitis were similar in the durvalumab arm (28.8%) and placebo arm (28.7%)
= Grade 23 pneumonitis or radiation pneumonitis occurred in 10 patients (4.6%) in the durvalumab and 6 (5.6%) in the placebo arm

+ exclaes any patents who axparencas any AE of maximum CTCAE grado 5, At any ie, regards of continuation CRT. A
Bradley JD el al ELEC 2024 Abat LEA PeerView

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36. PACIFIC-2: Does Concurrent ICI With RT Improve Outcomes

in Stage Ill Unresectable NSCLC?! (Cont’d)

Any Er n (4) Es of Maximum Grade 2/4, n (4) [AEs Leading to Death, (%)

Time to Onset Durvalumab + CRT Durvalumab + CRT Placebo + CRT Durvalumab + CRT

19) 08) (2219)

0 to 54 mot 216 (98.6) 107 (99.1) 125 (57.1) 57 (52.8) 15 (6.8) 546)
ns se”
SS

From 01054 mo, nfecton was the primary driver of diference I fatal AEs
Patients wih mule events inthe same category are counted only once in that category. Patents wih events in 21 category are counted once in each of those

canst RE O aan AE eue oly rato dlls end
tray 0 cs eon ot nn an veran sap ote een ote uen ep eve oss eh

Sebi pu mene soy sues rs ta tc de na an class os pred esa ne eek ae
een

Sn ann one SOL PRÉ ar pn hmm cones D) per beat oma One

PE oa LCC 200. Ara At PeerView

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37. Future Directions: Is It Better to Resect or Radiate
in Stage Ill After Neoadjuvant “Induction” Wi

Durvalumab + Surgit Durvalumab

+ Resectable or “borderline
x 1 year

resectable” NSCLC chemo x 1-2
+ Stage IIB-IIIB AJCC v.8 Durvalumab +
+ EGFR/ALK WT chemo x 2
+ PET/mediastinal staging Definitive chemo RT Durvalumab
for nodal status x 6 wk x 1 year

+ Primary endpoint: safety MOT OSA Role teseciatle ya Not

+ Secondary endpoints: OS and PFS
1. ReckM eta. Ci Lung Cancer 2024:81525-57904 [Epub ones of pr PeerView

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38. Conclusions

The PACIFIC regimen is SOC for this population, excluding those with
EGFR/ALK alterations

PACIFIC-R shows similar outcomes to PACIFIC-1

PACIFIC-2 demonstrates no benefit for addition of concurrent ICI with RT

Definition of “unresectable” is evolving

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39. Assessing the Potential of EGFR-Targeted
Therapy in Unresectable Stage III NSCLC

Suresh S. Ramalingam, MD, FACP, FASCO
Executive Director

Roberto C. Goizueta Chair for Cancer Research
Emory University School of Medicine
Atlanta, Georgia

» 7" Winship Cancer Institute

Copyright © 2000-2024, PeerView

40. Let’s Consider a Variati ur Case

72-year-old woman

9-cm lung mass invading the mediastinum and N3 LN on PET/CT that are biopsy-proven
adenocarcinoma (T4N3, stage IIIC)

PD-L1 score of <1%
ECOG PS is 1

Molecular testing results come in: EGFR L858R mutation is detected

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41. Answer This Ques‘

What treatment would you recommend for this patient?

1. Definitive chemoradiation, followed by maintenance durvalumab
2. Definitive chemoradiation, followed by maintenance osimertinib
3.

4. I’m not sure

Definitive chemoradiation alone

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42. PACIFIC: 5-Year OS and PFS Subgroup Analysis!

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1-Spigol DR ota. J Cin Oncol. 2022.40:1301-1311

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PeerView

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43. Is There a Benefit to Durvalumab in Stage III EGFR-mt NSCL

+ 37 patients with stage Ill
EGFR-mt NSCLC

— 13 treated with durvalumab

CRT + EGFRTHI

— 24 not treated with durvalumab

(16 CRT alone, 8 TKI 2 ga
induction/consolidation) 3 3
E
+ mPFS: 10.3 mo with durvalumab vs LS Ew
6.9 mo with CRT vs 26.1 mo with TKI £ £
(P=.023)
+ 46.2% grade 23 irAEs; ica Le
25% pneumonitis
. D
+ 6 patients had osimertinib at MNAE
progression Time, mo
Series Be ow © 6 2 4 4 4
+ 1 had grade 4 pneumonitis | ee aa
A Ado IV ea. 3 Thor Oncol 2024: 1618041000, PeerView

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44. Post ORT imaging: CR, PR, and SD

‘Open-label osimertinib
ccRT+| = Optimal: post progression,

+ Patients 218 years patients receiving

mg QD

(220 years in Stratification osimertinib may continue
iii Pe Ma ER un, S22 label osimertinb
(ex19del or L858R) Me po iio

2 Soot + China vs non-China Se

scrTo| a patients receiving placebo

may receive open-label
osimertinib

+ Primary endpoint: PFS by BICR per RECIST v1.1

1. Ramsingam 8S etal ASCO 2024. Astra LAA PeerView

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45. AURA: PFS by BICR!

10

oe Osimertinib

Median PFS, mo (95%

cn

39.1 (31.5-NC)
oe, Placebo 566774)
PFS HR (95% Cl) = 0.16 (0.10-0.24)
P<.001
5 Maturity 56%:
Bos osimertinib 40%, placebo 86%
à
po Osimertinib
a 03
02
01
o
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Time From Randomization, mo
No. at Rik
Osimerinto 1 127 0 MET 6 1 4 37 25 16 9 8 4 2? 2 2 1 0
en OS OO 2 1 10 8 6 4 4 3 3% $ 2 1 1 0 0 6 0 0
1. Ramaingom SS et al. ASCO 2024. Abstract LBAA, PeerView

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46. AURA: PFS by Investigator Assessment!

19 Median PFS, mo (95% Cl)

09 Osimertinib 38.9 (26.7-NC)
08 aK Placebo 7365-103)
07 62% PFS HR (95% Cl) = 0.19 (0.12-0.29)
2 P< 001
3% Maturity 58%:
El 66 osimertinib 43%, placebo 86%
E
pos
à 03 Osimertinib
02
Placebo
on
o
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Time From Randomization, mo
No. atRisk

Osimerind 143 131 112 108 99 9 87 7B 67 56 45 35 26 16 9 6 4 2 2 2 1 0
A 63 36 M 18 16 10 6 5 4 4 3 3 3 3 2 2 1 1

1. Ramalngom SS etal ASCO 2024. Astra LAA PeerView

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47. LAURA: PFS by BICR Across Subgroups’

‘Overall (= 216)

Unadjusted Cox PH 1207216 —— 023 016053
sex Men 5084 a 02 015046
Women ronse ae 021 013034
Ago, y 5 sonzo DZ 016 010026
266 Sans —— 033 049057
Race Asian sure —— 020 013023
Non-Asian 2208 0204.18
‘Smoking history ‘Gurrentormer (yes) 4265 — 02 0140.48
Never (no) zansı —— 022 0140.94
Stages a 4278 — 028 0150.52
114 reno eS 021 013023
EGFR mutation® Extodol Ea m 017 04002
Löser 5508 —— 032 019056
China cohort Chinese 1840 Ne NC None
Non-Chinese 102178 a 026 047030
Chemoradiotherapy Concurant 107/198, —— 025 047028
Sequential 1323 Ne NC NONC
Response te prior CRT Complete response Ed Ne NC None
Part response sum De — 02 011034
Stable disease 58/08 —— 018 0,100.30

Nosovalus if

3 05 10 so

HR for Progression-Free Survival (95% Cl)

Favors osimertinib Favors placebo
AA es

Data euof January 5, 2024
Stage pros to ORT by AJCCIUICO staging (En ein). Central test of tumor tissue at screening, r local pre-existing test result patient in the osimertni arm hag
missing EGFR mutation information. mn
1. Ramatingam SS ot al. ASCO 2024. Abstract LEAS. PeerView

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48. LAURA: Tumor Response by BICR!

2 10 Osimertinib he
& 80 80

8g 60 8g 60
Sn ao
25 40 25 40 Mero
ES ES
£8 20 $520 mso
go go
8220 $2 20 mPR
2 2
38% 35% mon
SF 60 SE 60 =
Be Ge
a -80 © 30

4100 100

b (n = 143) Placebo (n = 73)

Objective response rate, % (95% Cl) 57 (49.0-66.0) 33 (22.0-45.0)

Disease control rate, % (95% Cl) 89 (83.0-94.0) 79 (68.0-88.0)

Median duration of response, mo (95% Cl) 5 (3.6-8.3)
maine a ASCO 202, Att LOMA PeerView

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49. AURA: Sites of New Lesions by BICR!

Patients with new lesions

Brain

Lung
Liver

Lymph nodes

Bone

Adrenal
Peritoneum/omentum
Pelvis

Spleen

Other

70 60 50 40 30 20 10 0 10 20 30 40 50 60 70
Patients With New Lesions, %

‘sacl: Janay 3,224, Percentages ase number pars in each sina’ nm Paten co have moe han oe new leon se Based on BIR.
Sencar easier fe tea rm da oy don dn semen HE pr retin bos ose. ;
Fan te ASCO 202 Ave At PeerView

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50. AURA: Interim Analysis of OS!

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

OS Probability

Median OS, mo (95% CI)

Osimerinib 54 (46.5.NC)

Placebo NR (42.1-NC)

(OS HR (95% CI) = 0.81 (0.42-1.56)
P= 530"

Maturity 20%:
Placebo osimertinib 20%, placebo 21%

Osimertinib

0 3 6 9 1215 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63
Time From Randomization, mo

oat Risk
De us ue de tas 139 130 tar NS 100 8 71 so 4 7 we 4 2 1 0
rar SARS ee Se NS NS UNS TST

1.Romaingam 88 eta ASCO 202, sn LA, PeerView

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51. AURA: Exposure and Safety Summary

‘Median duration of exposure, mo* ze: ae Fr

AE, any cause, n (%)
Any AE 140 (98) 64 (88)
Any AE grado 23 50 (25) 92)
Any AE leading to death 3) 26)
Any serious AE 55 (28) 1115)
Any AE leading to discontinuation 18(13) 46)
‘Any AE leading to dose reduction 12(8) 10
Any AE leading to dose interruption 80 (56) 18 (25)

AE, possibly causally related». n (%)
Any AE 115 (80) 30 (41)
Any AE grade 23 1913) 26)
‘Any AE leading to death 10) o
Any serious AE 1218) 10

Dala culo! January 5,2024
‘Total exposure was calculated using the dates of ho frst and last doses of study treatment (excluding crossover) in months: actual exposure was calculated as for total

‘exposure and excludod treatment intaruptons. ® Patents wih mutipl events in the same category wore counted only once in that category. Patios wth events in

‘mare than one category were counted once in each of those categories. Includes AES wih an onset date on or after the date of fest dose and up o and incusing

28 days folowing tho discontinuation of study treatment and before staring subsequent cancer therapy. «As assessed bythe investigator, .

1. Ramalingam SS et al ASCO 2024. Abstract LBAG. PeerView

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52. AURA: All-Causality AEs (210%)1

+ The most common AE in both arms was radiation pneumonitis; the majority were low grade (no grade
4/5), nonserious, and manageable

Ratan reuse

Dares

ash

cono

Parma
Er Interstitial lung disease (grouped term) was

Dacoased set reported in 11 (8%) patients in the
Dy sn
Prats The majority were grades 1/2; grade 5 n =1
Stati

WC cout cased
Preorona
Anemia
scubstltchstpin

aa, 10 © © 7 © © 0 OOOO 50 6 7 8 9 100
"ES with incidence of 210% in either treatment arm aro shown. Patients with mulipe evens nthe same category counted only once in that category. Patients with

‘events in >1 category are counted once in each of nose categories. Includes AEs wth an onset date on or after the date of fst dose and up to and including 28 day

{long the discontinuaton of study treatment and before staring subsequent cancer therapy. > One grade 5 AE of pneumonia was reported inte osimetint arm.

“Interstiial lung dsoase (Grouped term) was aportas int patent (1%) in placobo arm, AE was peumenits, grado 1. ï

1. Ramalngam SS etal ASCO 2024. Abstract LEM. PeerView

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53. Conclusions

In LAURA, osimertinib demonstrated a statistically significant and clinically meaningful improvement In PFS versus
placebo by BICR in unresectable stage Ill EGFR-mt NSCLC following definitive chemotherapy

+ Median PFS was 39.1 months (95% Cl, 31.5-NC) with osimertinib, 5.6 months (95% Cl, 3.7-7.4) with placebo;
HR = 0.16 (95% Cl, 0.10-0.24), P< .001

+ PFS benefit was consistent across subgroups

Interim OS data showed a positive trend in favor of osimertinib, despite a high proportion of patients crossing over to

osimertinib in the placebo arm (81%)

Safety profile of osimertinib post chemoradiotherapy was as expected and manageable

EGFR mutation testing is critical in stage Ill disease to ensure optimal outcomes for patients with EGFR-mt NSCLC

Osimertinib will become the new SOC for patients with unresectable stage Ill EGFR-mt NSCLC who have not

progressed after definitive chemotherapy

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54. SS HIGHLIGHTS | AWCLC24 and BESNO24

Abstract OA12.03.

Title: Osimertinib After Definitive CRT in Unresectable Stage Ill EGFR-mutated NSCLC: Safety
Outcomes From the Phase 3 LAURA Study

'OA12: Advancing Multimodal Therapies in Stage II NSCLC; Monday, September 9, 2024 at 2:00 PM PDT/ UTC -7
Presenter: T. Kato

Abstract conclusions:
+ The safety profile of osimertinib after CRT was as expected and manageable. Dose interruptions due to AEs had limited
impact on exposure. The majority of radiation pneumonitis (RP)/pneumonitis events were mild to moderate in severity and

were managed effectively per protocol mandated guidelines, with most patients able to continue or restart treatment
without recurrence of RP.

Abstract 1241MO.
Title: Osimertinib After Definitive CRT in Unresectable Stage Ill EGFR-mutated NSCLC:
Analyses of CNS and Distant Progression From the Phase 3 LAURA Study

Mini Oral Session, Monday, 16 September, 2024 at 2:45 PM
Presenter: S. Lu

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55. Let’s Discuss Our Case

72-year-old woman

9-cm lung mass invading the
mediastinum and N3 LN on PET/CT that
are biopsy-proven adenocarcinoma
(T4N3, stage IIIC)

PD-L1 score of <1%
ECOG PS is 1

Molecular testing results come in: EGFR
L858R mutation is detected

PeerView.com/BVU827

cally Advanced

What is the most appropriate treatment?
Definitive chemoradiation,
followed by maintenance durvalumab
Definitive chemoradiation, followed by
maintenance osimertinib

Definitive chemoradiation alone

What are some of the other practical
considerations related to incorporating
EGFR-targeted therapy in this setting?

PeerView

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56. Audience-Faculty =?)
Q&A