Unleashing the Innovation Era in AML: Practice Principles and Precision Medicine With Innovative Therapeutics

Co-Chairs, Naval Daver, MD, and Gail J. Roboz, MD, and presenters Amir T. Fathi, MD, and Eunice S. Wang, MD, discuss acute myeloid leukemia in this CME/MOC/NCPD/AAPA/IPCE activity titled “Unleashing the Innovation Era in AML: Practice Principles and Precision Medicine With Innovative Therapeutics.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/4cMgVzz. CME/MOC/NCPD/AAPA/IPCE credit will be available until July 1, 2025.

1. Unleashing the Innovation
Era in AML

Practice Principles and Precision Medicine With Innovative Therapeutics

Naval Daver, MD Amir T. Fathi, MD
Director, Leukemia Research Alliance Program Program Director, Center for Leukemia
Professor Massachusetts General Hospital Cancer Center

Department of Leukemia, Division of Cancer Medicine Associate Professor of Medicine
The University of Texas MD Anderson Cancer Center Harvard Medical School
Houston, Texas Boston, Massachusetts

Gail J. Roboz, MD Eunice S. Wang, MD
William S. Paley Professor of Medicine Chief, Leukemia/Benign Hematology Service

Director, Clinical and Translational Leukemia Programs Professor of Oncology, Dept. of Medicine
Weill Cornell Medicine Department of Medicine

The New York Presbyterian Hospital Roswell Park Comprehensive Cancer Center

New York, New York Buffalo, New York

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

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2. Multiple Regulatory Approvals Have Led to Meaningful
Changes in AML Management Since 2017
+ Pre-2017: The 7 +3 era

Approvals Glasdegib Venetoclax;

4 a F ies Quizartinib (FLT3i)
since 2017 Gilteritinib (FLT3i) oral azacitidine

2018 2019 2020 2022

| | |

Midostaurin (FLT3i) Ivosidenib (IDH1i) Olutasidenib (IDH1i)
CPX-351

Enasidenib (IDH2i)
Go

In 2024 and beyond
+ Targeted, chemotherapy-sparing combinations?
+ More FLT3i maintenance options?

* Menin inhibitors? PeerView.com

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3. ... Leading to Increasing Treatment Complexity

MDACC algorithm
integrating newer
treatment options,
HCT, and precision
medicine in AML*

Where does MRD
‘monitoring fit?

Can we offer potentially
curative HCT to more
patients?

1. Davee N et a. Blood Cancer J. 2020:10:107.

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Bram.
int t6) 182

(Fira (70 ana)
TK) mutation

TAL AN wih

‘AH, oF

FLTS mutation

is. |

Es.

cs

se)

Can we establish
optimal
sequencing with
targeted
platforms?

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4. Despite Progress in Using Newer Platforms,
More Work Needs to Be Done

First-Line Treatment Regimen Dist:

ution Among

Patients With ND AML, % (N = 5,135)
Real-world evidence 100
from a US claims database!
5,135 patients with ND AML 80
934 patients with R/R AML 60
January 1, 2016, and August 31, 2022 m
Over the entire study period 20
39% of ND patients and 31% &
OLR parents received ne " 2016 2017 2018 2019 2020 2021 2022
No treatment Omerunspectes weatment Other gees therapy
Cit wihoutlargotd agents HET Venstocax based therapy
HA Based tery CIT wi targeted agents

ntinus

frail

1. Huntington SF et al. ASH 2023, Abstract 2428. PeerView.com

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5. Our Goals for Today

Augment your knowledge of predictive and prognostic factors in AML

Increase your knowledge of evidence supporting the use of newer agents
for the management of ND and R/R AML

Equip you with the skills you need to develop personalized treatment
plans relevant for different treatment settings and patient needs

Provide you with guidance on practical care delivery and safety
management considerations in AML

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6. HealthTree Foundation for AML offers resources for patients to
tell their stories and contribute to scientific research

eds HealthTree + HealthTree
®g® Cure Hub’ Research Hub

A patient data hub and companion research hub
that power lifesaving research using complete
real-world data

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7. eds HealthTree
848 Cure Hub”

Patients contribute their data
into HealthTree Cure Hub via
EHR connections and can
add additional data

(eg, PRO, demographics).

They can also answer

investigator surveys and
studies.

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Bm

EHR PRO

sb

A treatments. >.

/ genetics \
1 comorbidities \
diagnosis \
a family history}
Y imaging
\ Se labs 5
y demographics /
\ ;
HealthTree
Cure Hub”

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8. s HealthTree
QT TS Research Hub

Researchers can access the
data through data mining,
chart reviews and synthetic
control arms.

They can also invite patients
to complete surveys/studies.

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9. Frontline Management in AML
Patients With NPM1 Mutations

Gail J. Roboz, MD

William S. Paley Professor of Medicine

Director, Clinical and Translational Leukemia Programs
Weill Cornell Medicine

The New York Presbyterian Hospital

New York, New York

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10. Case: An Older Adult With NPM1-Mutated AML

Additional Findings How would you treat this patient?

+ BM bx shows 75% blasts Let's explore the evidence ...
+ NGS: NPM1, SRSF2, DNMT3A
mutation; FLT3wt
+ Normal renal and hepatic function
+ Normal echocardiogram

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11. Definitions of ELN 2022 Risk Categories!

Favorable

Intermediate

ic Abnormality OS in Patients Aged <60 y

With De Novo AML* (N = 867)?

18:21)(022;922.1RUNX1

UNXAT1

inv(16Xp13.1922) or t(16:16Xp13.1:922/CBFB:MYH11 100
Mutated NPM? without FLTSATD.

bZIP in-frame mutated CEBPA

Mutated NPM? with FLT3.TD 80

Wild-type NPM with FLT3-ITD (without adverse-risk
‘genetic lesions)

(9:11)(p21.3:923.3MLLT3:;KMT2A 60
Cytogenetic and/or molecular abnormalities not classified

as favorable or adverse

1(6;9)(p23.3:994.1))DEK:NUP214 40
Uv:11923.3/KMT2A-rearranged

19:22934.1:q11 2) BCR:ABLI
18:16Xp11.2:p13.3)KATGA:CREBBP

inv(3)(q21.3q26.2) or t(3;3)(q21.3;926.2)/GATA2, 20

OS, %

CEBPAdm

RUNXI-RUNATI/CBFE-MVH11

NPMI=HFLTSATO-
(nad, To mutation i ASALT,
TP89 or FLTITO

TS

WASXL, TPS3, oF FLTINTO

MECOM(EVI1)
1426 2:V)MECOM(EVI1)-rearranged TAO

-5 or del(5q); -7; -17/abn(17p) 0 eerrangemen
Complex karyotype, monosomal karyotype 0 1 2 3 4 5 6 7 8 9 10

Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2,
STAG2, U2AFT, andlor ZRSR2
Mutated TP53

1. Döhner Het a. Blood, 2022:140:1345-1377. 2. Haferach C e al ASH 2016, Abstract 286

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Time, y

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12. AMLSG 09-09: Intensive Chemotherapy
With or Without GO in NPM1-Mutated AML"

Phase 3 randomized, open-label, multicenter trial —>| Age >18 y (stratified for 18-60 y vs >60 y)
+ No EFS or OS benefit for GO Chemo backbone: IDA D1-3, cytarabine
+ GO significantly reduced the risk of relapse D1-7, etoposide D1-3, ATRA D6-21
(mostly in patients <60 years old)
+ GO significantly improved MRD negativity
+ GO improved EFS in patients with NPM1 and DNMT3a mutations
+ The authors concluded that the addition of GO to intensive chemo
should be standard for younger patients with NPM1-mutated AML

(<60 years old)
: re bo
x so z di Standard
8° oe co ue
Standard 5 E =
= bs HE
: Standard La
Time Since Enrolment, mo Time Since Envoliment, mo Time Since Completo Remission or CRI, mo
No ta Caner) No a Camera ot Cao
SE HE) moon zum mm sun "Se IO” un men mon 700) ta "Sens ATO am man aan zum Jen
% mm ani) ison m CESE EA 2m O m mm 00 am aim
1. DöhnerH et al. Lancet Hoomatol 2023;10:0495-0509. PeerView.com

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13. UK NCRI AML19 Study:
FLAG-IDA + GO Improves EFS and OS'

Improves EFS in patient >60 years old
with ND AML and OS in patients with
NPM1 and FLT3 mutations
N = 1,045

EventFree Survival

Patios Wan NP Patients With NPM Mutation

FLAGADA + GO

149 (14%) patients >60 years old
3-year OS for patients with NPM1m:
FLAG-IDA + GO: 86%

DA + GO: 64%

“note DA = daunorubicin D1-3-5, cytarabine D1-10

A+ GO

TERR
Timo in Study, mo

Timo in Study, mo

Overall Survival

Event-Free Survival
Patones With FLTS Mutation

‘Patonts With FLTS Mutation

DZ]

zu 0m 076037451)

Treo air 01802007

Ont 04902007
Fevers AGO "Favre OA

1. Russo Net al. Gin Oncol, 2024:42:1158-1168

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Time in Study, mo

Time in Study, mo

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14. FLAG-IDA + Venetoclax Is an Active Regimen in ND AML

Results of the expanded ND cohort (

ORR 98% (N = 44/45)
CR (CRe + CRh + CRi) 89% (N = 40/45)
MRD-negative responses 93% (N = 37/40)
Twenty-seven (60%) patients transitioned to alloHCT
Event-Free Survival Overall Survival
210 310
3 075 3 075
2 2
£ 050 & 050
3 3
202 2025
= a
5 Group “+ Al patents 5 Group + Anpatens
ao ä 0
0 6 2 6 A % % 0 6 2 8 24 0 %
Kork Time, mo No. at Rak Time, mo
Aa patents Sw tk

1. DiNardo et al. Am J Hematol. 2022:1035-1043, PeerView.com

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15. FLAG-IDA + Venetoclax Continues
to Show Encouraging Activity in ND AML'

Response, n(%) = 68) #5 (ns 33) Pe
ORR 67 (99) 13 (100) 21 (96) 33 (100) risk groups
CRe 65 (96) 13 (100) 20 (91) 32 (97)

CR 56 (82) 13 (100) 19 (86) 24 (73)

CRh 3 (4) o 1(4) 2(6)

CRi 6(6) o 0 6 (18)

MLFS 26) o 14) 1(3)

NR 42) o 1(4) 0

MRD negative 58 (89) 12 (92) 18 (90) 28 (88)

1.Jon Wa otal, ASCO 2024. Abstract 6519.

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16. Venetoclax Combined With Induction
Chemotherapy in Patients With ND AML"

100 100
EJ EJ
El MRD-negatve El
To o Alo-HCT
RO Ro
Pr] MRD-posiive gs
Su 5% No akoHCT
2 À HR:044 (95% C1, 0.27-0.70) 2 À HR: 0.50 (95% CI. 0.320,76)
19 | P= 00043 10 | Poors

0 6 2 8 À %
MRD-Negative Response Rates Between Cohorts

Ven +10 nic en

100 a]

> LE pr 7 Sey AML a Pen TE 10 CE
zo ls note ET mon m
5» “ pa con pots 209 so eaten) m
22 “ monas m 12000) mon =
ao ent nay um sans m
3 x Et amet et mon 00 mon 2
io) HO EN Ba He een i sn wen enero m

CR : EB : fa & ST

o

Al Patents ELNFavontio ELN Htermedato ELN Adverse Favors Ven + Intensive CT 4— —b Favors intensive CT
Cohort

1. Lachowiez € etal Lancet Hoomalo.2022:9:2350-2380 PeerView.com

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17. VIALE-A: Long-Term Follow-Up Continues to Show a
Survival Benefit With Ven + AZA!

24 Survival
EventsPatents, "E mos,
oa 106) Estimate moco PRSC =
Von + AZA IZA SOIN TAT ZIION SOUS
Pr Placebo+AZA — 196/45(05) 169112235) 9674127) Pe. g
4 i
3 5
E
£ H pau
& Ki
©
o Time, mo
+ Censored Placebo + AZA Median Follow-Up Time:
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 43.2 mo (range: <0.1-53.4)
No at Risk Time, mo HR = 0.58 (95% Cl, 0.465-
VEN+AZA 286 220 199 173 153 133 122 113 101 89 78 G7 ST 45 M 18 6 2 0 QUES A
Placebo +AZA 145 100 2 77 69 47 7 3 22 17 12 6 5 5 3 0 0 0 0 E
HR reduction from 0.66

(95% Cl, 0.52-0.85) at
75% OS analysis

1. PratzK etal. Am J Hematol 2024.99:615.624, PeerView.com

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18. VEN + AZA Showed Efficacy Across
Age and Molecular Subgroups’

VEN + AZA n HR (08%
AN Patents 222286 (77.6) 198/145 05.2) (057 (045-070)
Amy
1810.65 8110 (0) 5 (100) 061 (10-195)
650475 791102 (77.5) 49/53 (825) 069 (0480.99)
as amn2c77) 54/58 a) 10.68 048086)
ES 138/7477.) 24187 (968) 050(037-068)
Molecular marker
An 2329 103) 2072 0) 065 (0.35-1.19)
om 21723 013) ana (100) 026 (012068)
one 30140 (75) 18/18 (100) 030(0.16057)
Ion 4001 003) 28728 (10) 031 (019082)
Tess 2828 (94.7) 13114 629) I A 076 (040-145)

= en 1727 63) 47/47 (100) —— |
y Fo y
Favors VEN+AZA Favors Placebo + AZA
1. PratzK etal. Am J Homatol 2024:98:618-624 PeerView.com

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19. Workshop: Discussing Treatment Options for Paul

Paul is a 69-year-old male with ND AML, HTN, and

hyperlipidemia and works full-time as a sales manager

Additional Findings

+ BM bx shows 75% blasts

* NGS: NPM1, SRSF2, DNMT3A
mutation; FLT3wt

Normal renal and hepatic function
Normal echocardiogram

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How would you treat this patient?

Intensive?

7 + 3? FLAG/CLIA?
+Ven? +GO?

HMA + Ven?

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20. Molecular, Clinical and Therapeutic Determinants of
Outcome in NPM1-Mutated AML"

Rocchi PostC2MRDmgale 3-rrelapse rom MAD

SFE

Therapeutic Determinants of Outcome in
d Acute Myeloid Leukemia (AML)

Factors associated with key outcomes on multivariable analysis

peine aer wie
Le 3

Overall Survival, ll Patients Relapse, Al Patient.

Survival Probability

Cumulative incidence of Relapse

41. Othman Jet al. Blood. 2024:143:336-941, PeerV

‚com

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21. “Transplant in AML: Just Follow the NPM1 Guide!”

Easier Said Than Done’.

(Consolidation to negate FLT3i
MRD before allo-HCT |-¥ Allo-HCT [>] maintenance
‘Add BCL2i, menin-? if FLT3-ITO
Frontline alo-HCT
> FLTSI maintenance it
en FLT3:ITD at diagnosis?)
POR inervertion
PCR i i
Fe before frank
rela
a ER (er
molecular LA Monin? [>] FLTS maintenance if
relapse FLT? ) [FLTSATD at diagnosis?)
T
PMI MRD
monitoring a
No NPM1
molecular
relapse
Relapse
with
NEMA wt

1.Röcher € etal. Blood. 2024:143:1881-1882.

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22. QUAZAR: Updated Findings Show Long-Term
OS Benefit With Oral Azacitidine Maintenance’

Median Follow-Up: 55.5 mo

09
>
= os
3
5 ©
2 06
à 05 5y survival estimates:
e OlR2R 26.5%
3 04 Placebo: 20.1%
2 as 816.3% (85% C1. 21-147)
2 34 survival estimates
a & Oral AZA: 37.4%
64 Placebo: 279%
OCensored 4 +95(95%C1,0.9-8.1) |
r
12 24 36 48 60 72 84 96 108
er Time From Randomization, mo
Oral AZA 238 168 116 83 60 40 19 9 5 o
Placebo 234 127 82 s7 33 20 9 3 - -

1. Wei AH et al Am J Homato. 202598:E84-687.

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23. Prognostic Impact of NPM1 and FLT3 Mutations in Patients
With AML in First Remission Treated With Oral Azacitidine!

RS
+ pou a

2 = NeMt-mutatos placebo n= 71) LP =.005_ |p< 001
38° [Pr Jp on
Ea”
53%
332
© o

SA SEE . a + + + + + %

Time From Randomization, mo
[NPUt-mutated, orl AZA: 472 NPMI WT, oral AZA: 19.5
[NPM t-mutated, placebo: 15.9

Median OS, mo

‘Time From Randomization, mo

[NPUt.mutated ral AZA: 232 NPA WT, oral AZA: 7.7
[NPM t-mutated, placebo: 6.9

an u Median RFS, mo

PM WT, placebo: 4
NPMI-Mutated: Oral AZA vs Placebo | Mena 0
45% > 45.6 mo
+37% NPMt-mutated MRO- Oral AZA prolonged
— OS and RFS
estrada MES ss 46.1 mo compared with
=D 10 mo, placebo regardless
FLT3-Mutated: Oral AZA vs Placebo | FLT3-Mutated of NPM1 or FLT3
49% Median OS

+37%

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mutation status at
AML diagnosis

A NN 2620

> 24 mo

FLT3-mutated MRD+ a, à mo

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24. Survival Outcomes With Oral AZA Maintenance in Patients

in Remission by Receipt of Ini

consolidation 22 consolidation
ne 212 48%) n= 68 35%),

1. Wei AH et al, Haematologica, 2023108:2820-2028.

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E

No Consolidation

Medion (95% CI RES, mo
OntacAras 75103)
Paca 3901949)

He = 0.58 05% 01 036099)
Copan des

Time From Randomization, y
mo. 20
4 1 à

No Consolidation
Median (95% cl 08, mo
SARA 233095975)
Prcebo: 109 (83-157)

Look P= 0103

Timo From Randomization,
3 #6 8 4 0
ns 3 2 4

ca

R= OS 68% CL. 035087)

Survival Probability,

ial Chemotherapy!

Any Consolidation
Median (95% CD RFS, mo
MAZA 0207-81)
Preto: 54673)

R= 087 GK cl 05308)

os a P= 0010
02
0
o
Time From Randomization, y
sa
# B os 300

Any Consolidation
Median (95% Ch 08, mo

ALA 247 (17.931)

Puesto 184 12021)

HR = 074 95% GI 058090)

[er

LA
Time From Randomization, y
m 4 ow ot
0 oR 2 # 8 8
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25. Venetoclax-Based Low Intensity Therapy in
Molecular Failure of NPM1-Mutated AML'

Response Rates in All Patients and in Presence of FLT3-TD Mutations

NP AL th All Patients MRD negative
Pros meme CT = MRD reduction
à none cl FLT3ATDm
+ Retrospective multicenter
study FLT3ATD wt
N=70
0 0 6 D 4% © © 7 © % w
MRO Response, %
Reason for treatment
+ Molecular relapse (n = 43) i
bc pensions Whole Cohort OS OS in FLT3ATD Mutated vs WT
(n=27) “
ss 10
Molecular progression (n = 9) FLT3ATD wt
3 08
Bos os
Los 04
Treatment with vonetoclax and FLT34TOm
low-dose CT (AZA, DEC, LOAC) [A 02
o o
D 6s 2 + à + % 0 6 2 6 À » %
Time, mo Time, mo
1. Jimanez-Chllon © et al. Blood Adv, 20248:343-362. PeerView.com

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26. Molecular MRD Is Strongly Prognostic in Patients With
NPM1m AML Receiving Ven-Based Non-Intensive Therapy!

Best MRD Response by Cycle dé EFS
Includes responses attained in previous cycles
100% Best MRD Response by the End of C4 e hy EN EC

E

100% 2 Ga
2 Negative Bigg legative
a 2
3 Eo
Detectable &
Em D 2% Detectable
8 “ „les.
2% om JP<-00
0 6 ? % à
= Time From Diagnosis, mo
0 5 2 6 à
Time From Diagnosis, mo Cumulative Incidence of Relapse
ISLA A Best MRD Response by the End of C4
Patients With BM Biopsy at Each Cycle Na bs 8 100%
SONIA! ce A E P<.001
Patients Included in Cumulative MRD Analysis 3 Detectable
Go 72 76 76 76 76 m £
A
si 84109 Mio EB MRO negative ¿o
reducion ™ reduction ™ reducion 3
ge Negative
Sm
0 6 2 6 à
Time From Diagnosis, mo
1. Othman Jet. Blood. 2023;143:336-341 PeerView.com

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27. An Intertwined Relationship

Maintenance

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28. Workshop: Post-Remission Options for Paul

PR re So, after all of that, what would
you do for this patient once he
+ BM bx shows 75% blasts is in remission?
+ NGS: NPM1, SRSF2, DNMT3A
mutation; FLT3wt
+ Normal renal and hepatic function
+ Normal echocardiogram

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29. a Panel Discussion on Live Follow-Up Question

Think of a fit 69-year-old patient with ND AML, comorbid HTN and
hyperlipidemia but normal cardiac, renal, and hepatic function.
NGS shows NPM1, SRSF2, and DNMT3A mutations, and FLT3wt status.

What treatment plans should now be considered/discussed for
this patient?

+ 7+3, +GO, and then consider post-remission maintenance?
+ Oris venetoclax-AZA the best option?

+ Orvenetoclax and intensive chemotherapy, then consider
post-remission maintenance

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30. Unleashing Potent Care in AML:
Targeting FLT3 Mutations

Naval Daver, MD

Professor
Department of Leukemia, Division of Cancer Medicine e
The University of Texas MD Anderson Cancer Center LA y
Houston, Texas

Director, Leukemia Research Alliance Program | +
[|
|

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31. Case: A Patient With ND AML and a FLT3-ITD Mutation

new diagnosis

of AML; she presents with a PS of 1

What are the 1L options
+ Creatinine 1.4 when a FLT3-ITD

+ Hlo stent 4 years ago mutation is present?
+ 90% blasts

+ NGS shows FLT3-/TD, DNMT3A, and WT1

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32. FLT3 Mutations in AML12

FLT3-WT is a critical signaling
molecule in myeloid development
+ Associated with increased
downstream signaling to promote
survival and proliferation

FLT3 mutations in AML
+ ~25% with FLT3-ITD
+ Associated with poor prognosis
and increased relapse risk
+ ~5% to 10% with FLT3-TKD
+ Unclear effect on prognosis

1. Litzow MR. Blood. 2005.106:3331-3392. 2. Metzeler KH e al. Blood. 2016:128:686-696.

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078 044.120)

wr 0.83 082-110)
NRAS 083 (0744.17)
IPN 0.94 (069-429)
ezn2
one

120 (0.82-1.75)
RAS. 121 (0.824178)
ONMTZA 124 (1.024182)
SRSF2 136 102181)
Asııı 138 (119.208)

174 124243)
RUNX! 199 (159243)
Uaarı 221 (147.339)

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33. Classification of FLT3 Inhibitors:
Summary of Type I vs Type Il

First Generation’ Second Generation’
Lacks Specificity More Specific
for FLT3 and Potent
+ Pure ATP-competitive? Sunitinib Gilteritinib
Type! + Inhibits FLT3-WT, FLT3-ITD, Lestaurtinib Crenolanib
and FLT3-TKD cells Midostaurin

+ Binds to the inactive
conformation

Inhibits FLT3-WT and en

+ Inhibits an sa ei

Type Il FLT3-ITD cells Tandutinib Quizartinib
Ponatinib

+ Relatively inactive against
FLT3-TKD
+ Sings wo he ATP binding ste when te rocoto an he activo conformabon. ITR wih a hydrophobic region Immedatey adjacent to he ATP Ding sto at
‘sly acces wen th capo sin the nave conformation prevent receptor aciaton. Because most TKD (0835) mans favor the ate conformal,

‘ype I inhibtors are usualy ineffective on TKD-positwe cals

1 Adapt rom Lartosa-Garcia Met al. Mol Cancer Ter, 2017:16:991-1001. PeerView.com

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34. FLT3-Mutated AML: FLT3i Improves Survival
in Fit Patients Across the Treatment Spectrum‘

ND, Intensive Chemotherapy + TKI Maintenance After AlloHCT RIR Single Agent TKI vs CT
TKUPlacebo (Sorafenib 2 Studies)
Fi HR = 0665 (98% CL, 0518-0853)
508
3 © Boe
3 E
£ « 24-mo 08, % (95% CI: 5
2 & 90507.) E
8 02 À ur = 0776 05% 1, 0615-0979) ga pre] & 02
NÉE A = 0281 09% 0.008070 3,
ERROR ERE PITT 0 0 w D W 100 EREETITEETTETITITET
Time, mo Time, mo
zo 210 HR = 076 (05% C1, 058.098)
= 9 < ‘sided P = 0177
a gos
Bn Median OS, mo (95% Ci:
© 306 626372)
33 conan é ds
Es Placebo. 504
3 2 | survival Probabitty, mo (85% Ci; $
ER Etre en Sus utzarin (n= 245)
HA HR = 0.48 95% C1, 027-026 E DR
39 er AL ¡28 208 Sanage CT n= 122)
RADA 5 D D a m m À III VER eD2AS2%
Time, mo Time, mo Time, mo
1. tba HP etal.EHA 2022 Abarat $100.2. Stone RM eta N Eng! J Med. 2017;377 454-464. 3. Bucher A ota. J Cin Oncol 2020:38.2099:9002.4.Xuan Y eta. A
Lancet Oncol. 2020.21:1201-1212. 5. Per AE et al, Blood. 2022,139:3366:9375. 6. Cortos JE otal. Lancet Oncol 2019.20:984-397. PeerView.com

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35. Snapshot of Current Guidelines for Capturing
FLT3 Mutations and Treating FLT3-Mutated AML'

NCCN: Testing for FLT3 (ITD and TKD) Mutations
is Recommended at Baseline and at Relapse

Patients + Standard 7+3 (daunorubicin or idarubicin) +

eligible for — FLT3ITD ____. | midostaurin (category 1; included based in
à A or TKD RATIFY)

intensivo, mutations

induction

+ Standard 7+3 (daunorubicin or idarubicin) +
quizartinib (FLT3-ITD only) (category 1;
based on QuANTUM-First)

Patients ineligible for

intensive induction and + Gilteritinib + AZA (category 2B)
FLT3-ITD or > | + AZAor decitabine or sorafenib
TKD mutations (FLT3-ITD only)
1. NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 3.2024. htps:/wunw.ncen.orgprofessionaliphysican_glsipdtlami pdt. PeerView.com
PeerView.com/YGR827

Copyright © 2000-2024, PeerView

36. QuANTUM-First: Addition of Quizartinib
Improves OS vs Placebo in ND FLT3-ITD+ AML"

10

QuANTUM-First enrolled patients
aged 18-75 years with FLT3-ITD AML

Quizartinib HR=
mOS: 31.9 mo

08

.776 (95% Cl, 0.615-0.979)
.0324 (2-sided)

06

04
A mOS: 16.8 mo

OS Probability

Improvement in OS translates to a

a n in the risk of death

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

No. at Risk Time, mo
Quizartinib 268 233 216 195 176 162 153 145 139 126 110 96 83 68 53 36 24 8 4 1 0
Placebo 271 249 211 175 151 131 126 121 117 103 97 81 70 56 39 31 17 8 5 0 0

1. Erba H et al Lancet, 2023:401:1871-1583. PeerView.com

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37. QuANTUM-First: Overall Survival by Age!

OS of Patients <60 Years of Age OS of Patients 260 Years of Age
Quizartnib (n= 161) Placebo (n= 162) uizariib (n=107) Placebo (0 =109)
Events, m0) EX CT) Events, n 04) 70654) 75688)
MOS, mo (95% Ci) NR NE-NE) 230 (130€) mOS, mo (95% Cf) 175 (139.255) 14207205)
Unstratied HR (95% Ct) 0684 (04050549) Unstratied HR (95% Ct) 0.911 (0658-1263)
400; 100
8 © 5 80
2 Quizartinib 3
3 6 Bo
8 2
2 È 40 Quizarinib
go =
7 woe °
So 2 Placebo
o o
0 3 6 9 1215 18 21 24 27 30 39 36 39 42 45 48 51 54 57 60 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time, mo Time, mo
1.Erba H etal. Lancet. 2028:401:1871-1583. PeerView.com

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38. MRD and QuANTUM-First

Schema for FLT3-ITD MRD Assay
MRD

- Key prognostic factor in AML13

- Conventional PCR for FLT3-ITD less
useful due to insensitivity (~1%)?

PCR-NGS is sensitive and specific for

FLT3-ITD MRD (targeting exons 14-15)24

PCR amplification step?

Amplicons analyzed by NGS?
Developed specifically for this trial24 y
LLOQ = 10 if
LLOI x 10% #
Often identifies multiple
ITD sequences

*[ Dent by porter
Din ae hugo

Eon 15 Exon 14 ‘Exon 13
Utra-deep sequencing ofthe region (llumina SBS)

Tengan Meta g/d Med. 2183781189190 2 Love Metal Blood Ady. 20182825831, 3. Der Hal lod. 2122 10:1345-17 m
4. Levis Metal. Blood. 2020,135:758, PeerView.com

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39. In QUANTUM-First, FLT3-ITD MRD Clearance
Was Associated With Improved OS in ND FLT3-ITD+ AML"

100
Median: 0% quizartinib vs 0.0017% placebo ®
er Nominal P (2-sided) = .0006 .
& 10 :
Among patients with CRe ES 1 mii 3
at the end of induction, EN z
the median best FLT3-ITD do e
VAF by the end of e
consolidation was lower with E
quizartinib vs placebo z 29 La
um: n=68 (1%)
Not Cutoff 0
detectable

Quizartinib (n = 172) Placebo (n = 165)

1. Pos A ot al ASH 2023. Abstract 832. PeerView.com

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40. QuANTUM-First: Adding Quizartinib
Was a Tolerable Strategy in ND FLT3-Mutated AML12

+ Overall, combining quizartinib with intensive Grade 23 TEAEs, %
chemotherapy and as continuation Treatment arm Control arm
monotherapy was found to be manageable! 0-2 (n= 268)

+ No new safety signals were reported

| 92.1 89.6

+ 30-day mortality: Q 5.7%, P 3.4%

+ 60-day mortality: Q 7.5%, P 4.9%

+ Grade 3 arf: Q 23%, P 07% Most Common TEAEs (Any Grade), %

Fe 2
ee EM

July 2023: FDA approval of quizartinib with Pyrexia 423 40.7
‘standard chemotherapy induction, and as

‘maintenance monotherapy following o
consolidation, for FLT3-ITD-mutated AML; Diarrea RS 35.1
not indicated as maintenance monotherapy

following alloHCT Neutropenia 104 A

JE Wot a Local 2023401571 68,2. Vea (uz) roc Innata. a
ips vw aocessdata fda govirugsatida_docs PeerView.com

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41. PrECOG 0905: Midostaurin vs Gilteritinib
Induction/Consolidation in FLT3-Mutated AML"

Stratification i
TKD vs ITD FLT3 mutation induction

+ If FLT3.TD mutation: NPM1 mutation status
+ If FLT3.1TD mutation: signal ratio (high vs low)

Consolidation

mg/m in Arm A

o + Cytarabine 3 g/m? every 12h IV d 1,
Prosersening + Daunorubicin 90 mg/m?/d 2 = 35 E a wu a
Screening consent pe
with central o d 8 of each cycle (up to 4 cycles)

testing
+ FLT3 mutation
NPM1 mutation
Signal ratio
Flow cytometry

AmB
Cytarabine 3 gm? every 12h IV d 1,
3, and 5 for 6 doses for up to 4 cycles
Midostaurin 50 mg BID x 14 d
starting d 8 of each cycle (up to
4 cycles)

Daunorubicin

Midostaurin

+ In addition, HOVON 156 (NCT04027309) and the AAML1831 (NCT04293562) trial will provide more
information on the upfront use of gilteritinib combined with chemotherapy

1. tps cinicolials.gouict2/showNCTO3836209. PeerView.com

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42. Is Upfront Therapy With a
Triplet an Option?

43. What Are the Most Urgent Populations in
Need of Improvement?!

Three Subgroups by OS Benefit of Patients Receiving Ven + AZA

+ First, a higher benefit group was identified, with a median OS >24 mo
+ Subsequently, a lower benefit group was determined, with a mOS <6 m
+ Patients fitting neither criteria were categorized as the intermediate benefit group, with a mOS of 12 mo

Median OS,
Events ne ech
10 A + =
2 PSI, No FLT3-TD, KNRAS" Higher Benefit 145 96 26.51 (20.24, 32.69)
3
g 46 Intermediate Benefit 71 57 12.12 (7.26-15.15)
2 os Lower Benefit 63 61 5.52 (2.79-7.59)
3
2 025 + Majority of patients in the Ven + AZA
E Ts ut and FLT3ATO arm are in the higher benefit group:
a or K/NRASM 52% (145/279)
cn ao 50 + The remainder of the patients are
No. at Risk is distributed equally between the
o HS 17 7 a E 2 intermediate and lower benefit groups:
London 63 19 7 3 2 o

25.4% (71/279) and 22.6% (63/279),
respectively

1. Döhner Het al. Blood. 2022:140:1345-1977 PeerView.com

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44. Other FLT3i Triplets: Decitabine, Venetoclax, and Quizartinib

« Decitabine + Ven + quizartinib

Early Data!

Response Rates From the Frontline Cohort

Response," n (%)

demonstrated activity CRe
in heavily pretreated and prior CR
FLT3i-exposed R/R CRi
FLT3-ITD-mutated patients MLFS

+ Inthe frontline setting
— All patients achieved CRc

Day 14 BM blasts <5%?
Best MRD, any time

with no early mortality; Flow cytometry ()
median count recovery of FLT3 PCR (-)
43 to 36 days 30-day mortality
— Median OS not reached 60-day mortality
Bridge to ASCT

Frontl

‘Response assessment by modified IWC criteria (Cheson otal J Cin Oncol. 2003;21:4642-4649). Including cellular or aplastic bone marrow.
1. Yilmaz M eta. ASH 2029. Abstract 158.

PeerView.com/YGR827

e (
14 (100)
11 (79)
3(21)
0(0)
14 (100)

4)

9/12 (75)
12/14 (86)
0(0)
1(7)

4 (19)

PeerView.com

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45. Azacitidine, Venetoclax, and Gilteritinib
Appears Highly Effective in FLT3-Mutated AML‘

Efficacy Outcomes 0 Patients With ND AMI

CRICRi 96%
CR 92%
Median RFS and OS NR
18-mo RFS 71%
18-mo OS 72%

+ 65% of evaluable patients achieved FLT3-ITD MRD <10 within 4 cycles of therapy
+ Median time to ANC>0.5 was 37 days, and to PLT>50K was 25 days in C1

100

#
5 ©
8
N_ ARES 6m RFS 120 RFSIE RES N_m0S_6mo0$ 12m008 18m008
EC EC
6 2 6 À © % & 6 2 6 À © % à
Time, mo. Time, mo
Neat isk Wo at Rsk

MILE 3040) 25(2) 16) 963) 310) 120) 0021 001 MEME 2000 28(1) 1910) 13(10)5(18) 122) 0 0129)
1. Shor et al. J Gin Oncol 2024:42:1499-1508 PeerView.com

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46. Dosing, Duration, and Response Evaluation Timing With
FLT3i Triplets (Dose Optimization Critical and Ongoing)'

Ongoing Prospective Trial Dosing: AZA + Ven + Gilteritinib;
PI: Nick Short; DAC + VEN + Quiz; Pl: Musa Yilmaz

Cycle 1 (HMA + VEN 14 + FLT3i 14) ‘Subsequent Cycles (VEN 7)
Day1 Day7 Day14 Day21 Day28* Day 1 Day7 Day 14 Day 21 Day 28

Day 1-5 Day 1-5
| =

oR EN 17
AZA75 mln?

Start 2nd-gen Day 1-14 Day 1-28
| [EE
WBC <10k

+ 1-14 Day 1-7
Venetciax Ey

interrupting FLT3I and using figrastin to enhance count " .
N: PeerView.com

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47. Workshop: Debating Frontline Options
for FLT3-ITD-Mutated AML

ew diagnosis

of AML; she presents with a PS of 1

Discussion

+ Creatinine 1.4 + What is the prognosis for this patient?
+ H/o stent 4 years ago Is SCT an option?

* 90% blasts + Is adding a FLT3i to 7+3 the best
+ NGS shows FLT3-ITD, DNMT3A, and WT1 * option? If so, which FLT3i?

What has been the experience with
dosing and AE management to date
with quizartinib and 7+3 pre-HCT?
Would you consider a triplet as
upfront therapy?

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48. a Live Follow-Up Question
aa

Reconsider Susan, a 68-year-old woman with a new diagnosis of AML;
she presents with a PS of 1, creatinine 1.4, and h/o of a stent 4 years
ago. NGS shows FLT3-ITD, DNMT3A, and WT1.

What are the upfront treatment strategies to discuss?

+ 7+3, then transplant? Or add a FLT3i to intensive chemo, then transplant?
+ Ora ‘chemo-sparing triplet’ with a FLTI3i + venetoclax + HMA, then transplant?
+ Or should you consider venetoclax + HMA

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49. Case Continued: Susan Achieves a Remission,
But MRD+ Status Is Confirmed

jo)
CoH
What are the options if Susan
* Creatinine 1.4 proceeds to HCT?
+ H/o stent 4 years ago
+ 90% blasts What happens if she declines
+ NGS shows FLT3-ITD, DNMT3A, and WT1 HCT—canitreatment be

continued?

Treatment history

* Induction/consolidation with a FLT3i and
chemotherapy

+ CR1

+ MRD+ by PCR-NGS (FLT3 MRD assay)

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50. FLT3i Are Now a Standard Part of Maintenance
Therapy in AML (Patients Aged 218 Years)!

Patient with intermediate-risk or adverse-risk

Oral azacitidine 300 mg PO daily on days 1-14 of

RG eee each 28-day cycle until progression or
ee ns soeces unacceptable toxicity (category 1, preferred for
age 255
+ Completed no consolidation, some consolidation, we
or a recommended course of consolidation; and Maintenance with HMA until progression or
Hi No allogeneie stam cea ueneriartie Blanned unacceptable toxicity (azacitidine, decitabine)
(category 28)

+ Sorafenib (FLT3-ITD; SORMAIN?)

5 3 - Ñ i

in remission, and history of FLT3-TD Midostaurin (FLTS-ITD/TKD) (category 28)
+ Gilteritinib (FLT3-ITD/TKD) (category 2B)
+ Quizartinib (FLT3-ITD) (category 2B)

Patient with history of FLT3-ITD mutation

+ Previously received quizartinib * Quizartinib (FLT3-ITD)

+ No allogeneic HCT is plann

1.NCCN Cinial Practice Guideines in Oncology. Acute Myeloid Leukemia. Version 3.2024. hs /www.ncen oxpprotessionalsphysiian_os/pdam pt 7

2 Burcher A et al. J Cin Oncol. 2020.38:2993-3002, PeerView.com

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51. BMT-CTN 1506 (MORPHO): Study Design’?

Legal adult by local regulation
AML with a FLT3-ITD mutation

Morphologic first remission with only 1 or 2 inductions
Participant signs consent

Registration ————> Marrow aspirate sample for MRD analysis

Allogeneic transplant within 1 year of CR1
Any con donor, or GVHD prophylaxis allowed

Day +30 to +90 after transplant CT
+ Engraftment (ANC 2500, platelets 220K, transfusion independent) ie
+ Able to take oral medication y

+ No active grades II-IV acute GVHD requiring >0.5 mg/kg prednisone daily

Gilteritinib
ERREUR _ Randomization

— ES
Stratification

24 months + Conditioning regimen intensity (myeloablative vs reduced intensity) 24 months
maintenance | * Time from transplant to randomization (30-60 days vs 61-90 days) maintenance
treatment + Measurable residual disease 210~ (presence vs absence from registration sample) treatment
1. Levis MJ et al. Blood Adv. 2018,2:825-831. 2. Levis Metal. EHA 2023, Abstract 82711. PeerView.com

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52. BMT-CTN 1506 (MORPHO): Main Efficacy Outcomes’

Primary Objective: RFS Key Secondary Objective: OS
HR = 0.679 (0.459-1.005) HR = 0.846 (0.554-1.293)

Gilteritinib
Gilteritinib

Placebo

of Survival

EventsiN Year 2 Rate Year 2 Rato
Giterinib 45478 71.2% Gitertinib 41178 807%
Placebo 58/178 69.9% Placebo 45178 775%

P= 0518 P= 4304
0 12 24 36 48 60 72 0 12 24 36 48 60 72
Time, mo Time, mo

1. Levis Mot al. JCin Oncol. 2024:42:1766-1775.

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53. Measurable Residual Disease (MRD)**

MRD Assay for FLT3-ITD: WT Burden

PCR-NGS Assay
Two-step assay

PCR of juxta-membrane region,
amplicons analyzed by NGS

Detects FLT3-ITD mutation with Ultra-deep

region (Illumina SBS) *

Quantitative/linear down to 1 x 104 ITD identified by
a Diverse reads bioinformatics pipeline and
Qualitative to LLOD at 1 x 10% ve aligned to FLT3 late frequency 1 calculated
Patient-specific “fingerprint” Y genomic sequence 19
S Relevant FLT: y
Frequently detects multiple ITDs cintas E 5) ig
targeted
PA AAA
“get ITD”

1. Levis Meta. EHA 2023. Abstract LB2711.2. Levis Metal. Blood Ady. 20182225 831. ñ
3. Déhner Het al. Blo. 2022:140:145-1377. 4. Levis Metal. Blood. 2020:195:75-78. PeerView.com

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54. MORPHO: Effect of Detectable MRD6 on RFS by Study Arm!

Improvement in RFS With Gilteri e in MRD+ Group

MRD+ MRD-

Placebo
Gilteritinib

Gilteritinib

Placebo

Probability of RFS

EvontsiN Events
Sitertinb 26169 19169
Placebo as 15/87
HR = 0.515 (0.316-0.838) P= 5750
P=.0065

0 12 24 36 48 60 72 36 48 60 72

Time, mo Time, mo

1. Levis Metal. JCin Oncol, 2024:42:1766-1775. PeerView.com

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55. All Levels of Detectable MRD Impact RFS"

Probability of Survival
8 2
2
>
8
$
8

F
2
Ê

Neuro
moe OM
os
tro

+ 10°<MRD6 <10$
+ 10°°<MRD5 <104

+ 104 <MRD4

1. Levis Mot al. ASH 2023. Abstract 973

PeerView.com/YGR827

Probability of Survival

MRD Events/N
NoMRD 14/82
MRD6 5119
MRDS 14132
MRD4 22137

7

Probability of Survival

MRD EventsíN
No MRD 18/85
MRD6 2114
MRDS 831
MRD4 16141

Gilteritinib

Time, mo
a « 2 4 ©
2 1% © 0 0
A Ww 8 + 8
2 à 8 o ©

At each level of MRD:

RFS with gilteritinib >RFS
with placebo

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56. MORPHO: Drug-Related Grade 23 TEAEs'

Gilteritinib, Total,

Adverse Event n (%) n (%)
(n=178) (N =355)

Hematologic

Neutrophil count decreased 64 (36) 23 (13) 87 (24.5)
Platelet count decreased 38 (21.3) 20 (11.3) 58 (16.3)
Anemia 17 (9.6) 14 (7.9) 31 (8.7)
WBC count decreased 18 (10.1) 3 (1.7) 21 (5.9)
Nonhematologic
ALT increased 11 (6.2) 8 (4.5) 19 (5.4)
AST increased 11 (6.2) 6 (3.4) 17 (4.8)
Hypertension 11 (6.2) 6 (3.4) 17 (4.8)
Creatine phosphokinase elevation 14 (7.9) 1 (0.6) 15 (4.2)

1. Levis Mota. J Clin Oncol. 2024:42:1768-1775. PeerView.com

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57. What Are the Practical Take-Home Points
on Maintenance in FLT3-Mutated AML?

+ MRD+ patients benefit from gilteritinib maintenance in the
post-HCT setting

+ Patients should only be considered MRD- if they have been
given the right test

+ In the non-HCT patient, survival benefit has been shown with
the use of maintenance regardless of MRD status in remission

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58. What Would the Role of
Maintenance Be
If Transplant Was Not

Pursued?

59. QuANTUM-First: Overall Survival

in Patients Who Ach

ieved CR by HCT Status!

Patients With CR Who Received AlloHCT in CR1

Quizartinid

Patients With CR NOT Receiving AlloHCT in CR1

08
z
qa
gos
8
u HR = 001 02 eer Placebo
(95% Ci, 0330-1050) (05% Ci, 0387-0954)
o o
NE TE ECTEECEEREE TR THOORHBDAMNTHSDDNE BHAA TO
No at Rsk Timo, mo Pe Time, mo
Qurarin 84 84 83 81 74 72 70 69 67 63 5750 42 M 29.22 14 3 1 0 O — Chizarind 63 60 54 51 48 44 41 37 35 30 25 21 17 15 9 5 3 1 000
Placebo 73 73 68 63 56 52 51 50 48 43 39 37 32 27 2120 12 5 300 Ped 77 76 61 50 42 3331302025 217 14 10 7 4 21000

Patients receiving quizartinib had longer

OS irrespective of alloHCT in CR112

1.Erba H ot al Lancet 2023:401:1571-1583. 2. Schlonck Rot al. EHA 2023. Abstract 5137.

PeerView.com/YGR827

FDA approved as maintenance monotherapy following
consolidation for FLT3-ITD-mutated AML; not indicated

as maintenance monotherapy following alloHCT

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60. In QUAZAR, Oral AZA Prolonged OS and RFS
Regardless of FLT3 Mutation Status at AML Diagnosis!

os RFS
100 100
ELTS mt, AZA =
FLTS matted placebo, ==
© LT ue oral AZA TE Er m rn
eo {fea FLT3 wad pe poco = J

‘Survival Probability, %
8
RFS Probability, %

a a
LT wi ype, placebo (a =197)

0 12 24 36 48 60 72 4 9% 0 12 as 2 6 72 &

Time From Randomization, mo ‘Time From Randomization, mo

Median OS, mo Median RFS, mo
FLT3 mutated, oral AZA 282 FLTS mutated, oral AZA 231
FLT3 mutated, placebo 97 FLT3 mutated, placebo 46
FLT3 wild-type, oral AZA 24.7 FLT3 wild-type, oral AZA 102
FLT3 wild-type, placebo 152 FLT3 wild-type, placebo 49
1.Döhner H ta. Blood, 2022:140:1674-1685. PeerView.com

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61. Case Continued: Susan Achieves a Remission,
But MRD+ Status Is Confirmed

jo)

Cap of AML; she presents with a PS of 1
+ Creatinine 1.4 + In the post-HCT setting, what is the role
+ H/o stent 4 years ago of MRD in guiding next steps?
+ 90% blasts + Does MORPHO support using gilteritinib
+ NGS shows FLT3-ITD, DNMT3A, and WT1 as maintenance after any 1L FLT3i?
Treatment history + For maintenance outside of HCT,
+ Induction/consolidation with a FLT3i and what is the optimal choice?

chemotherapy

+ CRI + What principles inform dosing and safety
+ MRD+ by PCR-NGS management with FLT3i in the

maintenance setting?
PeerV

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62. Unleashing Potent Care in AML:
Targeting [DH Mutations

Eunice S. Wang, MD

Chief, Leukemia/Benign Hematology Service
Professor of Oncology, Dept. of Medicine
Department of Medicine

Roswell Park Comprehensive Cancer Center
Buffalo, New York

Copyrigh

2000-2024, PeerView

63. Case: A Patient Presenting With /DH1-Mutated AML

fe} recently diagnosed
Cap with AML who presents with an ECOG PS of 2
Additional Findings How can we characterize the
+ Comorbid HTN presentation—and what are the
+ Progressive thrombocytopenia next steps?

and neutropenia

+ Intermediate cytogenetics

+ NGS shows /DH1 mutation (R132C);
FLT3wt

+ BM: 30% blasts

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64. What Do /DH Mutations Mean for Patients,
and What Is Needed for Baseline Evaluation?!

Characteristics and Prognostic Impact of DH Mutations in AML: COG, SWOG, ECOG Analysis

DH mutation prevalence increases across the ag Impact of IDH mutation on AML survival outcomes

fe gun Oke e
lee) ui Intermediate-age 309 EFS: IDH + NPM1 <60 years of age

OS: IDH + NPM in pediatric and intermediate-a
mann. 40 se ped e
O»:

AYA 113(17.7)

18-39 Presence of any IDH mutation
ih Oi ibn ve
50 (11.3) IDH132 ys IDH2R40 ys IDH2RI72
es

Pediatric
0-17
1,744 IDH-mutant AML without NPM1 mutation

60 (3.4) © 34% Triple mutant: IDH + NPM1 + FLT3-ITD

Triple mutant: IDH + NPM1 + DNMT3A

Highlights the need for baseline geriatric assessment and rapid and accurate mutational testing
1. Zamegar-Lumiey S et al. Blood Adv. 2023:7:5941-5953. PeerView.com

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65. Case: Debating Upfront Choices
in /DH1/2-Mutated AML

jo)
Cap with AML who presents with an ECOG PS of 2
* Comorbid HTN + What is the best frontline option for
+ Progressive thrombocytopenia this patient with /DH1-mutated AML?
and neutropenia + Could either a Ven or IVO platform be
+ Intermediate cytogenetics considered?
+ NGS shows /DH1 mutation (R132C) + Depending on what is chosen, what
are the implications for subsequent
therapy?

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66. NCCN Guidelines for Patients Aged 218 Years
Who Are Not Candidates for Intensive Therapy!

Options for Patients Presenting With ND AML and IDH Mutations

Azacitidine + venetoclax (category 1)
Preferred
E Ivosidenib + azacitidine (category 1)
a Decitabine + venetoclax Other
Ivosidenib recommended
LDAC + venetoclax (prior exposure to HMA) Useful in certain
Azacitidine or decitabine (contraindication to venetoclax) circumstances
£ Azacitidine + enasidenib Useful in certain
a Enasidenib circumstances

In patients without an /DH1m, azacitidine + venetoclax is a preferred category 1 option

1.NCCN Clinical Practice Guidalnos in Oncology. Acute Myeloid Leukemia. Version 3.2024. aps. nccn orp/rolessionalsphysican_ gsm pa PeerView.com

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67. Practical Considerations With Ivosidenib'

+ Hematologic toxicities are common
— Particularly during the first cycle of therapy

« Monitor azoles and CYP drug-drug interactions

+ Bleeding events were more frequent with IVO and AZA than with placebo and AZA

(41% vs 29%)

Differentiation syndrome (DS) of any grade was 14% with IVO and AZA (no grade 24 events)

and 8% with placebo and AZA (including one grade 4 event)!

+» All cases were managed with glucocorticoids (eg, dex 10 mg BID), diuretics, and
hydroxyurea

Warning symptoms for DS include: unexplained fever, weight gain, respiratory symptoms
(pleural effusions), hypotension, and renal failure?

1. Montesinos P etal. N Eng! J Med. 2022:386:1519-1531. 2. Fathi AT et al. JAMA Oncol. 2018:4:1106-1110. PeerView.com

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68. AGILE: Adding IVO to AZA Substantially Improved OS
in Older Patients With IDH1-Mutated AML"

Median fotowup: 12.4 mo (range, <0.1-28.8) Median folow.up: 18.1 mo (ange, 0.2-34.1)
1.0 y HR for treatment tare, relapse from remission, or death = 0.33 1.0.7 HR or death = 0.44 (95% C1, 0.27-0.73)
(95% Ci, 0.16.09) 09 Ih Onesiced P= 001

‘Tworsided P=.002

08
07
06
05
04
03
02
01
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 0 2 4 6 8 101214 16 18202224 26 28 30 3234 36
No. a Risk Time, mo Mo, at Risk Time, mo
NO+AZA 72 2625201917139 8 5 5 4 2 2 2 0 IO+AZA T2 58 83 42 98 39 29 24 21 19 18 19 7 4 4 2 24

3
2
E

32

ER

a6

Event-Free Survival

Placabo +

Placebo +
= MAREA Se Se I 74 53 38 29 23 21 18:11 9 9 6 5 4 3 3 0 - -

Led to the FDA approval of IVO in combination with AZA for adults 275 years of age with
IDH1-mutated AML with comorbidities that preclude the use of intensive induction chemotherapy

1. Montesinos P eta. N Eng! J Mod. 2022:386:1519-1591. PeerView.com

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69. AGILE: Safety of IVO + AZA vs AZA Therapy!

Any TEAE, n (%)
‘Any hematologic TEAES, n (%)
‘Most common hematologic

TEAES (220%), n (%)
‘Anemia

Febrile neutropenia
Neutropenia
Thrombocytopenia

Most common TEAES (>20%),
n 0%)

Nausea

Vomiting

Diarrhea

Pyrexia

Constipation

Pneumonia

Bleeding, n (%)

Infections, n (%)

IVO + AZA (n =71)

Any Gra
70 (98.6)
55 (77.5)

22(31.0)
20 (28.2)
20 (28.2)
20 (28.2)

30 (423)
29(40.8)
25 (35.2)
24 (33.8)
19.268)
17 (239)

29(408)
20 (28.2)

1. Montesins Pt al, N Engl J Med. 2022:386:1519-1831,

PeerView.com/YGR827

Gradi
66 (98.6)
50 (70.4)

2(28)
0

1(14)
1(14)
0

16 (22.5)

4(56)
15 (21.1)

PBO + AZA (n
Any Grade | Grad

73 (100)
48 (65.8)

21 (28.8)
25(34.2)
12 (16.4)
15 (205)

28 (38.4)
19 (26.0)
26 (35.6)
29 (39.7)
38 (62.1)
23 (815)

21 (28.8)
36 (49.3)

69 (94.5)
47 (64.4)

19(26.0)
25 (34.2)
12 (16.4)
15(20.5)

301)
1(14)
5(68)
2(27)
1(14)

21 (288)

5(68)
22 (30.1)

TEAEs with IVO + AZA vs AZA

Grade 22 DS (14.1% vs 8.2%)
Grade 23 QT prolong (9.9% vs 4.1%)

Infections were less common with
IVO+AZA (28.2%) compared with
PBO+AZA (49.3%)

No deaths related to treatment

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70. AGILE: OS Update Shows Efficacy of IVO + AZA!

After a Median Follow-Up of 28.6 Months

m Vo+ Aza
oe M PBO+AZA
3 #
E 6
fu wen ©
8
02
o
OF 4 © 1O 12 va 16 10 20 22 da 26 20 do 32 d 36 30 do 42 da de UB SO
Timo, mo Timo, mo
1. De Botton Set al. ASCO 2023. Abstract 7012. PeerView.com

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71. AGILE: Improved Remission Rates With IVO + AZA vs AZA!

Response Category Ivosidenib + Azacitidine (n=72) | Placebo + Azacitidine (n = 74)

Best response, n (
Complete remission 34 (47) 11 (15)

Complete remission with
incomplete hematologic or 5(7) 10)
platelet recovery

Partial remission 4(6) 2(3)
Morphologic leukemia-free state 2(3) 0
Stable disease 7 (10) 27 (36)
Progressive disease 2(3) 4(5)
Could not be evaluated 4(1) 2(3)
Not assessed 17 (24) 27 (36)
1. Montesinos P eta. N Eng! J Med. 2022:386:1519-1531. PeerView.com

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72. Evidence With Venetoclax in IDH-Mutated AML

OS Outcomes in /DH1-Mutated and /DH2-Mutated Subgroups

IDH1 IDH2

o do
Eos HR=ox9¢5%c100804) E HR = 0.34 (95% 0.017.009)
3 2 os
Eu ES ES CE RE eN
3 Bo
02 3
&
he
o
SIA
Time, mo ot
os eo mw MO ws
a sta at Time, mo
ve aint OI ‘aa Ets, 09% 60
ohne en nt ent Mare
ne
mem IA sans wozu Tsetse Msn (78
Poren “mean Green. HMS moron mas
1. Pollyea D et al. Gin Cancer Res. 2022:28:2753-2761 PeerView.com

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73. In VIALE-A, VEN + AZA Showed Efficacy in IDH1/2 AML"

VEN + AZA NN (4) Peabo AZA WN) HR (8% 9
Patents 2227280079) 198/145 (052) 051045020)
Ar
10105 e110 (@0) 85000) 061 010:1.30)
=> os 7o1102 75) 42159 025)
as aan His en 088 048090)
21 19174078) sa (66) 050 (037.006)
Molecular marker
furs ETS 022000) 068 (036-119)
om 223613) 1111 (100) 08 0.1206)
‘one 204075) see (100) 020 (016087)
wwe 4218160) 2128100) 031 010082)
es 20128 (04.7) 1914 029) Hol ore 040145)
D DR) zo) m
a 70 y
Favors VENSAZA Favors Placebo + AZA
1.Pratz K etal. Am J Hematol 2024:99:615-624. PeerView.com

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74. Triplet Therapy: IVO + Ven + AZA for IDH1-Mutated AML"

+ High composite CR rates in ND and R/R AML
— ND AML: 92%
— R/R AML: 63%

OS by Dose Level

+ MRD-negative remissions in ND and R/R AML. EN

— ND AML: 60%
— R/R AML: 60%

Ivo + VEN800

ivo+
VEN400

12:m0 05, % (95% Cl
(23-100)

+ Durable responses and prolonged survival across
disease groups

Percent Surviving, %
8

comes it, Pi u m, na” nme AN
ee ae

~~ oe elaine ee SS

noon lly ally aly oh a

1. Lachowiez CA et al. Blood Cancer Discov. 2023:4:276-209. PeerView.com

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75. Workshop: Debating Upfront Choices
in IDH1/2-Mutated AML

o
Cap with AML who presents with an ECOG PS of 2
+ Comorbid HTN + If he had presented with /DH2-
+ Progressive thrombocytopenia mutated AML, would you have faced
and neutropenia a similar choice—a venetoclax or
+ Intermediate cytogenetics enasidenib-based option?

+ NGS shows /DH1 mutation (R132C)

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76. Enasidenib + AZA vs AZA Only for
ND /DH2-Mutated AML"

Maximum Reductions From BL in 2-HG Event-Free Survival (Aug 2020 cutoff)
Concentrations On-Study ENA + AZA vs AZA
- = 089 05% 039.12; Pe 04
j y pom
3 i EFS
i ERA
2-HG En
E
= ENASAZA AZAONY Penn ‘Time From Randomization, mo
Re i ee a we ee ay
Com 67 2 LEAR DAR
eden 00228 usr Overall Survival (Aug 2020 eutof)
a DIA + AA AZA
TO SC per
AZA (n = 33): ORR 36% 3 pe
os Es
Grade 3 febrile neutropenia 13% 34
Differentiation 10% = oz
Pneumonia 4% ae
a Time From Randomization, mo

Hasna 6 ST St 4 M D 7 1 1 8 1 0
1. Dinardo © et al. Lancet Oncol 2021:22:1597. A BA M M A n nn. à ‘0 PeeViéWcom:

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77. Newly Diagnosed /DH2-Mutated AML:
Enasidenib + AZA or Ven + AZA?1

CR+CRh (%) 86.0% 74.0%

Median OS NR (17.6-NE) 22.0 mo
HR = 0.34 (95% CI, 0.17-0.69)

Nn n regimen:
ENA + AZA requires Dx /DH2 mutation
ENA + AZA differentiation syndrome
VEN + AZA mutation status not needed
VEN + AZA myelosuppressive, infections

Probability of No Event

0 5 COR HDA À 2 RSS %
Time, mo

1. Polyea Det al. Cin Can Ros. 2022:28:2753. 2. Dinardo C et al. Lancet Oncol. 2021:22:1597. PeerView.com

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78. Enasidenib + AZA + Ven in ND and R/R /DH2-Mutated AML"

Response ND RIR N E m0S,mo
nen) nz) ENA + AZA + VEN 7 2 NR
CRe 7 (100) 11 (58) ENA + AZA 12 9 60
CR 5(72) 5(26) 100
CRi 2(28) 6(32)
MRD negativity by FCM 777 (100) 2/9 (22)
3 ENA + AZA + VEN
ND RIR 2 50
= (n=7) (n= 19) 5
IDH-DS 1(14) 16) 3
FN grade 23 1014) 5 (26) =
ALT grade 23 o 16) o
AST grade 23 0 16) o 6 12 18 24
Time, mo
Total bilirubin grade 23 2(29) zen
1. Venugopal $ et al. Blood Cancer J. 2022:12. PeerView.com

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79. Case Continued: Owen Receives
a Venetoclax Platform as 1L Therapy

fe} recently diagnosed
Cap with AML who presents with an ECOG PS of 2
Additional Findings What principles and science
+ Comorbid HTN can guide sequential therapy
+ Progressive thrombocytopenia in this setting?

and neutropenia
+ Intermediate cytogenetics
+ NGS shows /DH1 mutation (R132C)

Treatment history

+ Ven + AZA (as per VIALE-A)

+ Achieves rapid remission

+ However, relapse noted after 3 years

+ IDH1m reconfirmed with repeat testing PeerView.com

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80. NCCN Recommended Options for R/R AML
Based on Molecular Features!

Targeted Therapy

Therapy for AML with FLT3-ITD mutation Therapy for AML with /DH1 mutation
+ Gilteritinib (category 1) + Ivosidenib

+ HMAs (azacitidine or decitabine) + sorafenib + Olutasidenib

+ Quizartinib (category 2B)

Therapy for CD33+ AML
Therapy for AML with FLT3-TKD mutation + Gemtuzumab ozogamicin
* Gilteritinib (category 1)

Therapy for AML with /DH2 mutation
+ Enasidenib

1.NCCN Clinical Practice Guidalnos in Oncology. Acute Myeloid Leukemia. Version 3.2024 aps. nc orgprossional/physician_g/péaml pal PeerView.com

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81. Olutasidenib: Potent, Orally Bioavailable,
Brain Penetrant, and Highly Selective /DH1m Inhibitor
Dosing and Safety Experience

+ FDA approved for patients with R/R /DH1-mutated AML
at a dose of 150 mg orally twice daily

ies!

Grade 3 or 4 TEAEs (210%) From Olutasidenib S:

Febrile neutropenia and anemia (n = 31; 20% each)
Thrombocytopenia (n = 25; 16%)

Neutropenia (n = 20; 13%)

Differentiation syndrome and adverse events of special
interest occurred in 22 (14%) patients,

with 14 (9%) grade 23

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1. De Botton $ et al. Blood Adv. 2028:73117-3127

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82. Olutasidenib Induced Deep and Durable
Remissions in Patients With R/R /DH1-Mutated AML'

CR + CRh rate = 35% (51/147)
CR rate = 32% (47/147)

Transfusion Independence

de ORR = 48% (71/147) „m

os E ® Patients with deep
Pat) 5 © remissions achieved high
gor jr rates of transfusion
À 06 po independence
Eos io
Bos ¿o
Bos zx
Ë 02 ia

017 censored a

o

o 3 6 9 12 15 18 A 24 27 DB q CR+CRh Other Non Responders,
Duration of Response, mo Responders

A ES —

+ 16 treated with olutasidenib were able to proceed to HCT, including those who had received prior
HCT, prior intensive chemotherapy and/or were refractory to intensive chemotherapy?

1. De Botton Seta. Blood Adv. 2023,7:3117-3127. 2. De Botton eta ASCO 2024. Abstract 018516 PeerView.com

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83. Survival Probability

Survival Outcomes With Olutasidenib in
R/R IDH1-Mutated AML!

Median OS was 11.6 months in the
overall population

In patients who achieved CR/CRh, the
mOS was not reached and estimated
18-mo survival was 78%

10
09
os
o7
06
os
04
03
02
01
o

°

+ Censored

3

5

3

ra

No.atRisk 153 119 97 83 71

1. De Botton $ et al. Blood Adv. 2028:7:3117-3127

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10

09
Bos
3 07
3 0
Eos
5 04
Los
50
os
o
NEFEFEEEE LE:
Time, mo
ss 41 29 21 1 1m 6 1 oem ss

Omer responders. 20 19
Nonesponders 76 45

st 47
16
26 18

y

46
"

5

«
7

5

a
6
2

CRICRh

Other responders

aa DS ew
Time, mo

5
o

nw wm 7 1 0
210000
000000

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84. Olutasidenib Shows Encouraging

Activity in the Post-Venetoclax R/R Setting!

A A A e GAS
tangos A En u
Monoicombe Tx | | | “4

cut YC" HL coro
Rotary, lapse, or CR: ori

hie
rn
en
pensar
fon
panei
Haltern

+ Ofthe 16 patients who were RAR, 4 (25%) achieved CR
+ One patient (6.3%) achieved CRh and 7 (43.8%) achieved a CRe

+ Median time to CRc was 1.9 mo (range 1-2.8)

+ Median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ mo)

1. Cortes Jota. Leuk Lymphoma. 2024:1-, PeerView.com

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85. Evidence With Ivosidenib and Enasidenib
in the Post-Venetoclax /DH1/2-Mutated AML Setting

Assessment of 53 patients who received FLT3, IDH1 or IDH2 inhibitors after disease
progression on venetoclax-based therapy’
+ ORR was 17.7%

+ 10f 17 patients treated with enasidenib (6%) achieved a CRi
+ No patient treated with midostaurin, sorafenib, or ivosidenib had an objective response

In the subset of patients who received IDH
8 05 inhibitors after venetoclax-based therapy
(n = 22), the median OS was 3.6 mo from

e the initiation of IDH1/2 inhibitors at a

median duration of follow-up of 29.3 mo
o = 3

Time From IDH, mo

4 1

1. Bewersdor JP et al. Leuk Ros. 2022;122:106942 PeerView.com

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86. Evidence With Ivosidenib and Enasidenib
in the Post-Venetoclax /DH1/2-Mutated AML Setting

+ Retrospective study from 4 US medical centers!
+ N = 22 patients with AML and FLT3, IDH1, and/or IDH2 mutations

Post-Venetoclax Therapy for Patients

With IDH1 or IDH2-Mutated AML" Se e ESTES

+ 1 patient with a CR; DOR of 9.3 mo
2 patients treated with ivosidenib + 1 patient with PD

+ 1 patient with CR1; DOR 14.1 mo
5 patients treated with enasidenib + 2patients with PD
+ 1 patient with SD

1 patient treated with enasidenib + HMA + SD

1. Kanna V etal. Leuk Ros. 2023:131:107331. PeerView.com

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87. Principles for Using Newer
Therapeutics in Challenging
R/R Settings Update on
Menin Inhibitors

Amir T. Fathi, MD
Program Director, Center for Leukemia | À |
Massachusetts General Hospital Cancer Center
Associate Professor of Medicine a
Harvard Medical School A 2
Boston, Massachusetts

Copyright © 2000-2024, PeerView

88. Case: A Patient With AML Progressing
After Multiple Lines of Prior Therapy

[A Dana is a 69-year-old woman presenting with R/R AML progres:
Cop on 7+3 and a subsequent venetoclax platform
What i this patients
+ Initial diagnosis with t(9;11) current prognosis?
+ Subsequent confirmation of KMT2Ar
(MLLr) at most recent relapse

+ Other considerations: To date Dana
has been reluctant to consider HCT

Conversely, how would
relapse with NPM1-mutated
AML inform prognostication?

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89. KMT2Ar AML Represents a Challenging Disease Subtype

“KMT2A-rearranged AML is 60-Day Mortality
demonstrably associated with higher 16
early mortality and an increased risk of 14 15
bleeding and coagulopathy, specifically, 212 PE
disseminated intravascular coagulation, w 10
compared with normal-karyotype AML”? 5 8
=6
a 4
2
0 T

+ Extramedullary disease +++

KMT2Ar AML Normal Karyotype
+ Risk of DIC and DAH

1. Nguyen D etal. Cancer, 2023:129:1856-1865. PeerView.com

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90. Lack of Effective Therapy for KMT2Ar AML
Represents an Unmet Medical Need’

KMT2Ar Acute Leukemias?

5%-10%

+ Global incidence: ~7,000
of AML

+ KMT2Ar leukemias are a therapeutic
challenge

+ 5-year OS for adults is <25%

8% of MPAL

g
E
3

2
3

2
2
3

<

KMT2Ar
10% of
pediatric leukemia
70%-80% of
infant leukemia

* Figure courtesy of Ghayas Isa, Mt ñ
1 Donner tol Blood 21 120404-47 2 Fal Bt al, Blood. 201:117:1100-1120. PeerView.com

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91. NPM1-Mutated AML Has Long Been
Recognized as a Dis

'NPM1 mutation is specific for AML, mostly de novo
Usually al leukemic cells carry the NPM? mutation

‘Mutually exclusive with other “AML with recurrent genetic abnormalities”
NPM1 mutation is stable (consistently retained at relapse)

NPM1 mutation usually precedes other associated mutations (eg, FLT3-TD)
Unique GEP signature (| CD34 gene; 1 HOX gene)

Distinct microRNA profile

Clinical, Pathologic, Immunophenotypic, and Cytogenetic Features
‘Common in adult AML (-30% of cases), less frequent in children (6.5%-8.4%)
Higher incidence in women

Close association with normal karyotype (-85% of cases)

~15% of cases carry chromosome aberrations, especially +8, del(9q), +4
‘Wide morphologic spectrum (more often M4 and MS)

Frequent multlineage involvement

Negativity for CD34 (90%-95% of cases)

Good response to induction therapy

Rela nosis (in the absence of FLT3-TD)

1. Flin 8 eta. Blood. 2011:117:1108-112. PeerView.com

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92. NPM 1m Are Associated With a Favorable
Prognosis in ND AML; However ...

In R/R AML? ...

Median OS following salvage
1, 2 or 3 therapies in NPM1m
vs NPM1wt

NPM1m had no impact on risk of
relapse or death
7.8 vs 6.0;
5.3 vs 4.1; and
3.5 vs 3.6 months, respectively

Venetoclax salvage in NPM1-
mutated AML improves
outcomes

t

Median OS, 14.7 vs 5.9 months for
NPM1m vs no NPM1m (P = .02)

What are the options for NPM1m R/R AML in the post-Ven setting?

1.1868 Gt at. Blood Adv. 2023.7959-242.

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93. Workshop: Care Considerations in R/R Settings

[IA Dana is a 69-year-old woman presenting with R/R Al ogres:
Cop on 7+3 and a subsequent venetoclax platform

+ Initial diagnosis with t(9;11)

+ Subsequent confirmation of KMT2Ar at
most recent relapse

+ Other considerations: To date Dana
has been reluctant to consider HCT

What is the clinical
experience to date with
menin inhibitors in R/R

AML, in both NPM1m and

KMT2Ar settings?

PeerView.com/YGR827

+ When should we be testing for
KMT2Ar in AML? What do you tell
patients once this diagnosis is
confirmed?

+ What is the efficacy of standard
(eg, 7+3, Ven-AZA) platforms in
this setting?

+ In contrast, what is the prognosis for
a patient with Ven-exposed,
NPM1-mutated R/R AML?

PeerView.com

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94. Menin Inhibitors: Current Stages of Clinical Development

Menin Inhibitor Phase 1 Phase 2 Regulatory Approval (R/R Monotherapy)
Revumenib (SNDX-5613)
Monotherapy
combination
omo 10-539 (tomen)
Ziftomenib (KO-539) orosIssss0 Ne
Monotherapy re CD / Pi
combination 2 Y am \. à
JINJ-7527661722 = ” cae
Monotherapy a ‘SNDX-5613 (evumen
combina! use ea
DSP-5336 y 5
Monotherapy à Sorzano (SL
BMF-219 à 37
Monotherapy
DS-1594b
Monotherapy

* Chemotypesifered fom patent reviews and applications
1. ps pubcnem ncbinim hh govleompouna/1S40880T4 2. Bai Met al Expert Opin Ther Pat. 2022:32°507-522. 3. ps ciicahals govlstudyINCTO4D6736. en
4. ps cinicalrials govistudyINCTO4988555, 5. Pemer Fetal, Nature. 2023:615:913:919 PeerView.com

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95. KOMET-001: Phase 1/2 Study of Ziftomenib
in R/R NPM1-Mutated AML'

Phase ta Phase 1b Phase 1b Phase 2
Dose Escalation Validation Cohorts Expansion Registration-Enabling
Completed | Completed Completed Ongoing

| © cohort 2: 600 mg ap

mn € | (O cohort1:200 mg ap | Expansion of 600 mg QD 600
mL |
a | EP =

mNPM1, KMT2Ar, other MNPM1 or KMT2Ar mNPMt
Objectives
+ Safety and tolerability | + Safety and tolerability Continue enroliment of Primary endpoint
+ Pharmacokinetics | + Pharmacokinetics phase 1b validation + CR/CRh
+ Early evidence of clinical | + Clinical activity cohort(s) consistent with Seconda 5
| 5 > ry endpoints
activi | FDA's Project Optimus
id | ject Optimu: + Duration of CR/CRh
| + Safety and tolerability + Transfusion independence
| + Pharmacokinetics + CR/CRh MRD negativity
l + Clinical activity + AES
1. Fathi À et al EHA 2023. Abstract LB2713. PeerView.com

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96. KOMET-001 Included Patients
With Prior Venetoclax Treatment and HCT'

Demographics

Age, median (min, max), y

Men, n (%)
ECOG PS 0, n (%)
PS1
PS2
Number of prior therapies, median (min, max)
Prior venetoclax, n %
Prior SCT, n (%)
Comutations, n (%)
FLT3
IDHW2
Comutations with both FLT3 and IDH1/2

A et al. EHA 2023, Abstract LB2713.

PeerView.com/YGR827

600 mg
(N = 20)

70.5
(22, 86)

6 (30)
3 (15)
14 (70)
3(15)

3(1, 10)
13 (65)
4 (20)

6 (30)
8 (40)
4 (20)

Disposition Neon
Patients in follow-up, n (%) 7 (35)
Reason for treatment discontinuation, n (%)
AE (not study drug-related) 5 (25)
Death 165
Disease progression (including clinical) 9(45)
All other reasons 5 (25)
Patients off study, n (%) 13 (65)
Reason for study discontinuation, n (%)
Death 13 (65)

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97. Ziftomenib Was Well Tolerated, With a Safety Profile
Supporting Future Combination Therapy’

A “a mNPM1 7 . mNPM1
220% TEAES, n (%) (N=20) |] 220% TRAES, n (%) (N= 20)
Patients with TEAEs (all grades) 19 (95) Patients with TRAES (all grades) 12 (60)

Diarrhea 9 (45) Nausea 4 (20)
Hypokalemia 8 (40) Differentiation syndrome 4 (20)
Naussa 6 (30) Patients with TRAEs (grade 23) 6 (30)
Anemia 6 (30) WA
Back pain seo No reports of drug-induced QTc prolongation
Epa) ES) 1 report of grade 3 differentiation syndrome,
Patients with TEAEs (grade 23) 17 (85) manageable with mitigation strategy
Anemia 5 (25) Other reports of differentiation syndrome
<
Thrombocytopenia 4 (20) CRE
1. Fathi tal. EHA 2023. Abstract LB2713. PeerView.com

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98. Ziftomenib Showed Encouraging Clinical Activity’

Best Overall Response

Complete remission rate (CR) 7(35) for CRe Up te

CRe rate (CR + CRh + CRI) 8 (40) E Es Platelets ns :
Complete response rate 9(45) ge at is
(CR + CRh + CRI + MLFS) Kin E
oR 705) i i. ai
m;
= Zu :
cn bbe! une D ci ein son où où
MLFS 16) visit

+ Comutations in FLT3 and IDH1/2 did not affect chances of response to single-agent ziftomenib
+ One patient achieved CRi, proceeded to HSCT, and achieved and remains in CR
+ Median time to first response: 51 days

1. Fathi A et a. EHA 2023. Abstract LB2713, PeerView.com

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99. Ziftomenib Monotherapy Induced Durable Responses!

mNPM1 Duration of Ziftomenib and CRe up to 12 mo

+ Median DOR 8.2 mo ! >
(95% CI, 1.0-NE) with a median :
follow-up time of 8.8 mo ‘

;

H

H

7

+ Patient 1 remained on ziftomenib in PA
CR (MRD-) into cycle 36 E
au

+ Patients 9 and 21 proceeded Es

to HSCT 7
> Ongoing in response

- Patient 9 remains in CR on 19 AE Adverse event

= ‘DTH Death
ziftomenib for post-HCT 3 N rar
maintenance 2 Wo Weiher by subject

2 PD _ Disease progression as assessed by investgaor
Patient 21 remains in CR 25) HSCT Stem cell transplant

2 ‘OTH Ober

. 1 2 os 4 6 6 v 6 nm

Duration of Treatment, mo

FDA has granted a Breakthrough Therapy Designation for ziftomenib in patients with R/R
NPM1-mutant AML based on data from KOMET-001

1. Fat A etal. EHA 2023. Abstract 182712. PeerView.com

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100. Revumenib Final Phase 1 Results
Showed Promising Efficacy in R/R AML1:2

a Efficacy Population

(N=60)
‘ORR® 32160 (53) 10
Best response” man Overall median DOR: 9.1 (95% Cl, 2.7-NR)
ER! 1200) | cricrn | 8
Rh sc] 18(30%) | Sos
cr 5@ es
MLES 9115) 3
MRD-negative rate» 18132 (56) e
CRICRh MRO negative 14/18 (78) é
CRETE TS RETEETERTETETTTT.
KMT2Ar (1 16) mNPM1 (n = 14) No. at Risk Tree
LE en ET wEnNNS 66666633310
CRICRh 15 (33) 31)
CR/CRh MRD-negative rate 11/15 (73) 3/3 (100)

Responses were assessed bythe investigators responses and MRO-negatve rates ar shown as 4) * MRO assessed at parcipatng stes by ether mutator
‘tow cytomety or PCR: MRD status percentage based on patients win nonmassing MRD satus out ofl responders z
4. Issa G et al, ASH 2022. Abstract 63.2. Issa G etal. Noturo, 2029:615:920-924. PeerView.com

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101. Phase 1 Safety Summary: Revumenib Demonstrated
a Clinically Manageable Safety Profile’:

Safety Safety
Any-Grade TRAE (25%) Population |} Grade 23 TRAE Population
(N= 68) (N= 68)
Patients with 21 TRAE, n (%) 53(78) Patients with grade 23 TRAE, n (%) 11 (16)
ECG QTc prolonged 36 (53) ECG QTc prolonged 9 (13)
Nausea 18 (27) Diarrhea 2(3)
Vomiting 11 (16) Anemia 23)
Differentiation syndrome 11 (16) estes) 10)
Fatigue 12)
1
Darniea 710) Hypercalcemia 1 (2)
Dysgeusia 5(7) Hypokalemia 1 (2)
Decreased appetite 5(7) Neutropenia 102
No treatment discontinuations for QTc prolongations Thrombocytopenia 12)
orressocated annyihmias: Tumor lysis syndrome 1(2)
1. Issa G et al, ASH 2022. Abstract 63.2. Issa G eta. Nature. 2025:615:920-924. PeerView.com

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102. AUGMENT-101 Phase 2 Pivotal Trials Are Underway
Three Distinct Patient Populations'

AUGMENT-101

RIR
KMT2Ar
(MLLr) or
mNPM1
acute
leukemia

Revumenib 163 mg
Q12H with a strong
CYP3A4 inhibitor

IT

+ Primary objective: CR/CRh*
+ Secondary objectives: durability of CR/CRh, OS, transfusion independence

* Patients takan to HSCT can estat treatment with revumen posttransplant.
BAS.

4. Ados let al. ASH 2029. Abstract

PeerView.com/YGR827

Independent, Pivotal Trials

64 adults AUGMENT-101-2A:
+ up to 20 children KMT2Ar ALL

64 adults AUGMENT-101-2B:
+ up to 20 children KMT2Ar AML

64 adults AUGMENT-101-2C:
+ up to 20 children mNPM1 AML.

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103. AUGMENT-101 Phase 2: Revumenib Induced Clinically
Meaningful Responses In a Pretreated KMT2Ar Population’

+ High rates of overall Efficacy

response (65%) Parameter Population
(n= 57)

« 39% of responders ORR, n (%) 36 (63)
proceeded to HCT, with half CR + CRh rate, n (%) 13 (23)
resuming rev post-HCT 95% Cl 12.7-35.8

P, one-sided .0036
At interim analysis, this CRe, n (%) 25 (44)
pivotal study met its primary 95% Cl 30.7-57.6
endpoint and
the KMT2Ar cohorts were Negative MRD status, n (%)?
stopped early for efficacy CR+CRh 7/10 (70)
CRe 15/22 (68)

Data eo July 24, 2028,

IRD done Icaly ot al patients had MRO status reporte. N

1.Aldoss let al. ASH 2023, Abstract LBAS. PeerView.com

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104. Next Steps With Menin Inhibitors

Ziftomenib Revumenib

KOMET-001 e
En o a BEAT-AML consortium

+ Currently recruiting patients with R/R NPM1- ES PE
mutated AML AZA + VEN + revumenib in ND AML

KOMET-007 (NCT05735184)

+ Currently enrolling patients SAVE in R/R AML

+ Testing ziftomenib in combination with IC and + Showed activity in combination with
nonintensive IC SOC in ND and R/R NPM1- decitabine/cedazuridine and venetoclax'
mutated or KMT2A-rearranged AML

KOMET-008 AUGMENT-102

+ Testing ziftomenib in combination with FLAG-IDA, + Revumenib in combination with chemotherapy in
LDAC, or gilteritinib (for FLT3-mutated AML) in patients with KMT2Ar or mNPM1 acute
NPM1-mutated or KMT2A-rearranged AML leukemias (NCT05326516)

1.1563 GC et a, ASH 2023, Abstract 58. PeerView.com

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105. Dana Prepares for a Clinical Trial With a Menin Inhibitor

[A Dana is a 69-year-old woman presenting with R/R Al ogres:
Cop on 7+3 and a subsequent venetoclax platform

+ Initial diagnosis with t(9;11)

+ Subsequent confirmation of KMT2Ar at
most recent relapse

+ Other considerations: To date Dana
has been reluctant to consider HCT

Next steps

+ Dana is counseled on the potential of
receiving a menin inhibitor as part of a
clinical trial

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For this patient, is a menin inhibitor
trial the best option?

Would you consider a menin
inhibitor if this Ven-exposed patient
presented with an NPM1m?

What is the experience so far with
dosing and safety with ziftomenib
and revumenib?

What is the future for menin
inhibitor combinations?

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106. e Panel Discussion on Live Follow-Up Question

Reassess your knowledge: In your opinion, which of the following best
reflects current evidence with menin inhibitor therapy in R/R AML?

« I'm not familiar with this class of agents and their role in AML
+ Effective in favorable-risk and intermediate-risk R/R AML

+ Effective against KMT2Ar R/R AML

+ Effective against KMT2Ar and NPM1-mutated R/R AML

+ No single-agent activity in KMT2Ar R/R AML, but promising as part of a
combination

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107. Audience Q&A O ;

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