Renovating Frontline Care for Metastatic Melanoma: Guidance on Upgrading to Combination Immunotherapy Standards Across Disease Presentations

Chair, Hussein Tawbi, MD, PhD, discusses melanoma in this CME/MOC/AAPA/IPCE activity titled “Renovating Frontline Care for Metastatic Melanoma: Guidance on Upgrading to Combination Immunotherapy Standards Across Disease Presentations.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3wCMKuI. CME/MOC/AAPA/IPCE credit will be available until August 4, 2025.

1. Renovating Frontline Care for

Metastatic Melanoma
Guidance on Upgrading to Combination
Immunotherapy Standards Across
Disease Presentations

Hussein Tawbi, MD, PhD
Deputy Chair and Professor

Department of Melanoma Medical Oncology
Co-Director, Andrew M. McDougall

Brain Metastasis Clinic & Program

Melanoma Medical Oncology |

Investigational Cancer Therapeutics

The University of Texas MD Anderson Cancer Center
Houston, Texas

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

Copyright © 200

2. Over a Decade of Sustained OS Improvement
During the Immunotherapy Era in Melanoma‘42

— COMBI-dev;: dabrafenib + trametinib (N = 563)?
— CheckMate -067: iplimumab + nivolumab (N = 314)
— CheckMate -067: nivolumab (N = 316)*

— KEYNOTE-006: pembrolizumab (N = 556)?

a — CA184.002: ipilimumab (N = 137)"
Anti-PD-1 + anti-CTLA-4
03
50% sx
eos 5% 50% 40%
ar 43% 42% Anti-PD-1 + ant-CTLA 4

08

Anti-PD-1

04
BRAFVMEKi

Proportion Alive

02

Time Since Randomization, mo

jraly present jra V. Lo Prof LongMlA
«Terra nt ene em at St rat pens sy eo. tro PY aro

{HodlFS ia. NEng Mod 20,0260 71-723.2, Rober C eta Eng Med, 2019:381:020.0%0 A
3. Rober etal. Lancet Oncol. 2019.20-1239-1251. 4. Larkin J tal. N Engl Med. 2019:381:1535-1546. PeerView.com

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3. Combination Immunotherapy Now the Preferred 1L
Option for Metastatic or Unresectable Melanoma’

apy Options (Metastatic or Unresectable Disease)

regimens

Combination checkpoint blockade (preferred)
- Supported bj
= Nivolumab + ipilimumab (category 1) ESPA
- Nivolumab and relatlimab (category 1) + DreamSeq (improves
à OS as initial therapy
PD-1/LAG-3 + Anti-PD-1 monotherapy in BRAFm setting vs
combination - Pembrolizumab (category 1) BRAF/MEKi)

rted by
lave = Nivolumab (category 1)

Other recommended regimens
Combination targeted therapy if BRAF V600 mutation positive
- Dabrafenib + trametinib (category 1)

- Vemurafenib + cobimetinib (category 1)

- Encorafenib + binimetinib (category 1)

Pembrolizumab + low-dose ipilimumab (category 2B)

1. NCGN Cincal Pracice Gudeinesin Oncology Melanoma: Cutaneous. Version 22024. 7
ips iwww.ncen orgiprotessionalsphysican_gls/pdleutaneous melanoma pdf. PeerView.com

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4. Despite Progress Integrating Immunotherapy
in Melanoma Care, More Work Needs to Be Done

First-Line Treatment Choices
for Stage IV Melanoma: 2010 vs 2019, %

100
se 38% of patients still
80 were not receiving
Nationwide cohort study of adult patients 270 frst-fne (Clin. 2019
with cutaneous melanoma (2010 to 2019) E
identified using the US NCDB* 2
+ N= 16,831 patients with stage IV melanoma *

2010 2019
IM 1Limmunotherapy I 1L targeted therapy/CT

munotherapy was associated with substan!

provements in OS

ints with metastatic melanoma, but rates of use remain suboptimal

1 Lamba N etal. JAMA Netw Open, 2022:5.02225450. PeerView.com

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5. In Addition, Disparities in Exposure to Immunotherapy
Have Been Noted in the Metastatic Melanoma Setting

National Cancer Database, N = 9512 Patients With Metastatic Melanoma’

Increasing age and high
comorbidity were among

Increasing age
Increasing Charison-Deyo

0,96 (0,97-0.98)

the factors associated with RT 086 (0.00.02)
lower likelihood of Living in metropolitan areas vs not | 1.06(039-121)
receiving immunotherapy MR 159148178)
Expansion vs nonexpansion states. 1.16 (1.05-1.27)

—_—_—__—_—.
D 0s 10 ts 20
(Odds Ratio (95% Ci)

Similar findings reported at the state level?

+ Example: In Texas, the likelihood of receipt of immunotherapy decreased with older age
(aOR = 0.92), living in high poverty neighborhoods (aOR, 0.52), and having comorbidities
(aOR, 0.48)

A. Moyers JT eta. JAMA Netw Open. 2020:3:02015056. 2. Olateju OA ot al. BMC Cancer. 2023:23:686 PeerView.com

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6. Our Goals for Today

Improve your knowledge of updated guidelines and evidence supporting
the use of immunotherapy for the frontline management of unresectable and
metastatic melanoma

Provide you with guidance on using immunotherapy platforms for the
personalized management of newly diagnosed advanced melanoma

Equip you with the skills you need to address dosing and safety
considerations with immunotherapy regimens in the melanoma setting

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7. Modern Principles Informing
the Frontline Use of
Immunotherapy Combinations

8. PD-1/LAG-3 Combination Therapy
As a New Dual Checkpoint Option in Melanoma

ER E

cr TUMOR

CELL

LAG-3 regulates a checkpoint pathway that limits the
activity of T cells*

Preclinical data suggested combining LAG-3 with PD-1
inhibitors improved activity vs single-agent PD-1

41, Gross JF eta. J Cin Invest 2007:117:3389-3392, 2. Tai H ot al N Engl J Mod. 2022:386 24-54.

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RELATIVITY-047: Phase 2/3 trial?

Key Eligibility Criteria
+ Previously untreated unresectable or
metastatic melanoma
+ ECOG PS 0-1

nera @ 11

Nivolumab 480 mg
+ relatlimab 160 mg

Nivolumab 480 mg

fixed-dose IV Q4W

combination IV Q4W

+ Primary endpoint: PFS by BICR
* Secondary endpoints: OS; ORR by BICR

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9. 3-Year Data From RELATIVITY-047 Confirm
PFS Benefits With NIVO + RELA in Metastatic Melanoma’

10 NIVO + RELA Nivo
(n= 355) (n=359)
PR mPFS, mo (95% Cl) 10.2 (6.5-15.4) 4.6 (3.5-6.5)
x HR (95% Cl) 0.79 (0.86-0.95)
g 12.mo rate (95% CI)
a 0 49 (43.0-53.8)
5 LUE SERS) seme rate (95% CD gam
mo r
E i 301255354) 0667) en
2 27 (224-319) 22118278)
NIVO + RELA
20 NIVO
0
0 3 6 9 12 16 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60
Time, mo
No, at Risk
NVO*RELA 35588] n si 45 » 2
No Mo M NS 00 7 si y » a 1
1.Tonbi Hot al ASCO 2024. Abstract. 9524. PeerView.com

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10. Efficacy Benefits With NIVO + RELA
Were Consistent Across Subgroups ...

PES by BICR ORR by BICR
Unstraited ORR
+ regardless of vor Unstratiied HR nuvo + Diterence
age, BRAF status, so RELAn_NVO.n "Ben j REA D _NVo.n 5% CD
. Oe F0 OR + Tar eet
and baseline LDH1 146: exprossion = 3
oe zu 2% ospsrao) À wa ma scan A
a 7 9 ompAsos) À D2 Ma 7755207)
PO expression +
2% 148 ur or mr 46 re à
am ze 22 OOo) | Ms 5 necems À
200.1 4 4
Mono «es wm omosion 2 me 1 astra à
265 168 163 0.76 (0.590,99) 1 482 El 102 (0.5205) 1
Hier + +
(alone? une) 4 4
Cutaneous ronacal 250 259 08008100 IL en as À
heal 0 42 opa DE as wa tazas IL
oso 2 2% opi Tt Me © oecwona Y
RAF mue stos = q
Mutant ww ones TI #4 nr moss À
via e 20 20 OMG) À MS 05 estosia
Baseline Lon H
SUN 25 21 070606) = 514 259 18261239)
Eu m oros À 97 1208024

VO + RELA = MO NINO + RELA NYO,

1.Tonbi Hot al ASCO 2024, Abstract. 8624. PeerView.com

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11. Sustained Survival Benefits With
NIVO + RELA Compared With NIVO!

NIVO + RELA NIVO
100 (n= 355) (n=359)
MOS, mo (95% CI) 31 (34.0-NR) 341 (252447)
12-mo rate (95% Cl)
77 (72.0-80.8) HR (95% CI) 0.80 (0.66-0.99)
so 22005775) 24 morate (95% GI
62086687 96-mo rate (95% Cl) mor
x 58 (528-631) U Us me ate sx cn
5 60 48 (42.7-53.1
g Mar) MES) WC

NIVO + RELA,
Nvo

0 +
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
No. at Rak
NWOWRELA 255 394 305 207 270 250 241 220 214 206 190 192 172 188 148 122 107 119 I 72 22 2 0
vo 359 330 202 270 254 209 225 219 208 191 104 175 161 140 126 100 00 87 87 ST 15 1 0
1.Tonbi Hot al ASCO 2024, Abstract. 8624. PeerView.com

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12. Melanoma-Specific Survival Improved
With NIVO + RELA Compared With NIVO'

No. at Rise

12mo rato (95% Ci)
8176-050)
77722811)
24-mo rate (95% CH) NIVO + RELA
681629729) 36-mo rate (95% CI) (n= 356)
641982585) G3(57287.) | demo rate (05% CN
51484592) 60(641-65.0)
50 440553) NVO+ RELA

Median MSS, mo (95% Ci) NRNR-NR) 46.7 (54:1-NR)

HR (95% cl 075 (0.60094)
Melanoma deaths,*n(%) 193(38) 166 (46)
N° Gensored pationts. nh) 2226) 193(58)
Nonmelanoma death,n(%) 40 (11) 36 (10)
‘Study arg tech? 4) 2)
Unknown 80) 134)
Omer 23 (8) 2166)

0 3 6 9 1215 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66

Time, mo

IND + RELA 256 394 305 287 270 258 241 228 214 206 196 192 172 150 145 122 117 113 111 72 22 2 0

no

250 200 202 279 254 200 225 213 200 101 184 175 161 140 128 100 90 87 87 67 15 1 0

‘Reasons for death were determined by the investigator. * Death due to toxicty was considered a nonmelanoma death Most common reasons for other included

Sopte Shock. myocardial infarcion, srake, pnoumania, and fospiatory insuticoney,
1. Tawbl Metal ASCO 2024. Abetract. 8624.

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13. What’s Next With PD-1/LAG-3?
Is There a Role for Triplet Therapy?
Response to NIVO + RELA + IPI

BOR per INV (N = 46)
"PR CR

wo BOR per BICR (N = 46)
"PR CR

RELATIVITY-048
tested a triplet

s
es
4373)
combination of

NIVO + RELA + IPI

Patients, %
Patients, %

ORR sp PD ORR sD PD

NIVO 480 mg + RELA 160 mg + IPI 1 mg/kg was active in untreated advanced melanoma!
+ IPI dose of 1 mg/kg Q8 weeks; NIVO + RELA Q4 weeks
+ 59% ORR

+ No new safety signals; grade 23 TRAEs: 39%

1. Ascieto P et a, ASCO 2024, Abstract 9604. PeerView.com
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14. RELATIVITY-048: Encouraging 48-Month PFS
and OS Rates Reported With Triplet Therapy!

NO + RELA + PI
in= 46)
Ea El

MPFS, mo (95% CI) NR GONR)

NIVO + RELA + IPI
Bens 73
MOS, mo (95% CI)

100 NR (NRA)

80 NIVO + RELA + IPI

& 60 een # 60
E ao

Eso ' Tage 8 a0
2 20
o i | o

0 © 3 1218102128 278089 062042484081 8437 D 3 8 9 1219 1021 28270029 363042 0540516487

Time, mo Time, mo

Pen iste

Moe i SAAR URE ET MOL, ARAS ARA 3

1. Ascioo P et al, ASCO 2024. Abstract 9608,

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15. What Options Should Be Considered for
Metastatic, BRAF-Mutated Melanoma?’

NCCN First-Line Therapy Options (Metastatic or Unresectable Disease)

+ Combination checkpoint blockade (preferred)
= Nivolumab + ipilimumab (category 1)
- Nivolumab + relatlimab (category 1)
+ Anti-PD-1 monotherapy
- Pembrolizumab (category 1)
— Nivolumab (category 1)
Other recommended regimens
Combination targeted therapy if BRAF V600 mutation positive
- Dabrafenib + trametinib (category 1)
- Vemurafenib + cobimetinib (category 1)
- Encorafenib + binimetinib (category 1)
Pembrolizumab + low-dose ipilimumab (category 2B)

Immunotherapy is a
preferred option
REGARDLESS of
BRAF mutation status

1. NCCN Cinial Practice Guidelines in Oncology. Melanoma: Cutaneous. Version 22024, a
ips hmww.ncen orgiprotessionalsphysic'an_gls/pdleutaneous_melanoma pe PeerView.com

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16. DREAMseq Was Designed to Answer Questions
Over Optimal 1L Therapy in BRAF-Mutated Disease’

Arm C
Dabrafenib/trametinib,
continuous

Stratification

Era Factors

mutant At disease

+ ECOG PS 0/1 progres
+ LDH (WNL,
high) Arm D
IPI/NIVO induction
followed by NIVO
mainte

metastatic
melanoma

Dabrafenib/trametinib,
continuous

Primary endpoint: 2-year landmark OS (70% vs 50%)
+ 90% power 2-year OS rate of 70% in arm A to C sequence vs 50% in arm B to D,
two-sided type | error rate of 0.05

4. Atkins MB eta. J Gin Oncol 2023:41:186:197. PeerView.com

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17. DREAMseq Showed Superior OS With Frontline
Dual Checkpoint Blockade in BRAF-Mutated Melanoma’

10
09
08
07
08
05
04
03
02

0.1
o
o
Time interval, mo os
No. at Risk
IPI+NIVO + DT 133
OT £IPI+NIVO. 132

4. Atkins MB et a. J Gin Oncol 2023:41:186-197.

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20% difference
in 2-year OS; P=.01

Dabrafenib/trametinib + IPI + NIVO
(Started on dabrafenib/trametinib )
51.5% (41.7-60.4)

30

IPI + NIVO £ dabrafenib/trametinib (Started on IPI + NIVO)
71.8% (62.5-79.1)

40 50 60 70
Time, mo
3036 3642 4248 4854 5460 6008

“2 3 2 15 6 3
35 30 18 15 6 1

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18. SECOMBIT Tested Multiple Immunotherapy-Targeted
Agent Sequences in BRAF-Mutated Melanoma’

Arm A*
First line: Encorafenib + binimetinib

PD: Ipilimumab + nivolumab

Unresectable
stage III/IV, BRAF
V600E/K-mutated
melanoma with no
prior systemic
therapy

Arm B*
First line: Ipilimumab + nivolumab
PD: Encorafenib + binimetinib

Arm C (Sandwich Approach)*
Encorafenib + binimetinib x 8 weeks,

N=251

then ipilimumab + nivolumab
PD: Reinitiation of encorafenib + binimetinib

*Elevated LDH: 41% arm A, 48% arm B, and 36% arm C

1. Ascierto PA eta. Annals of Oncology. 2021:32(5uppl_6)31289-51346. PeerView.com

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19. SECOMBIT: 4-Year Data Confirm Benefits of First-Line
Immunotherapy + Targeted Therapy’

75 ‚Arm B: IP! + NIVO (PO: ENCO + BINI)
e ‘Arm B: PI + NIVO (PO: ENCO + BIN) ‘am €:ENCO
a wh
550 5 nen Pie
2 Arm A: ENCO + BI (PD: IPINIVO) NINO (PD:
arm c:ERCO + Bi 8 we hen y
2 PLE + NIVO (PD: ENCO + BINI) RR
25
“Arm A: ENCO + SN PO + NIVO)
o
0 6 12 18 24 30 36 42 48 54 60 6 12 18 24 30 36 42 48 54 60
iene Time, 110, Time, mo
Am A 69 60 52 43 31 29 24 17 11 4 3 aren eaesnanunn6 3
IS MEE EE
amc 69 67 6 54 47 39 26 24 1 7 4

4-year follow-up data continued to demonstrate meaningful survi
with or without an 8-week course of targeted therapy in BRA!

immunotherapy
utated metastatic melanoma

1. Asciono P ot al. Nat Commun, 202415146.

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20. EBIN: Does Induction With Targeted
Therapy Make a Difference?

2years

Ipilimumab 1 mg/kg
+ nivolumab 3 mg/ Nivolumab 480 mg Q4W IV Investigators choice

Q3W IV x 4 doses

+ Not resectable
or metastatic
melanoma

Progression

+ BRAF V600E/K iat
ion Encorafenib 450 mg + arena mo he
binimetinib 45 mg map SD

N=271 m Q3W IV x 4 doses

Nivolumab 4:
Q4W 1

80 mg MA Encorafenib 450 mg
+ binimetinib 45 mg

12 weeks 4 week

"Strafe by stage/LOH (unresectable stage Ma with LOH SULN vs MIbAMTe with LDH SULN vs ULN <LDH s2ULN vs LOH >2ULN) and center. PeerView.com

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21. EBIN: Although Sequential Therapy
Did Not Improve PFS, Some Subgroups Benefited!

we MO Bos

N
No differences in ES ©
PFS between 23 oo
immunotherapy and SE 2
h N Ë «
targeted induction $3 »
followed by gz 2
immunotherapy eo

Eventem HR (90% Ci
ENCO > BiNTinducion 00/196 DEPOT
Placebo esas Reference

trail log-ankod P = 360

1 Pracebo
H ERED INI incio
+

5 3 6 6

StageiLDH at randomization

; ‘want win ton sun 128
Sequential therapy Amen win COM SUN ae
may benefit patients [ann

te exes
with very high LDH FA m
or liver metastases WM sore

1. Robert G et al. ASCO 2024, Abstract LBAGSOS,

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Evans
ENCO + BIN!

5
Time From Randomization, mo

1027
amas

senos
27132

aus
GE]

2% 7 0 à % ® &

Interaction
Test

HR «CH HR (CI

209 (097-458)
0.74 (043-129)

1.10 (076-158)
049 (026-084)

092 (068-125)

9% 05 10 20 40
ga 05 19 20 «e
|ENCO + BIN Induction Better Control Better

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22. Does the Sequence of Care in BRAF-Mutated Melanoma
Impact the Development of Brain Metastases?

Type of PFS Event ENCO + BIN! Induction Control
Metastasis in LN, skin, or other sof tissue only 10 10

EBIN: N = 34 patients Metastasis in lung and not in visceral area or CNS 9 3

with CNS metastases at Metastasis in visceral area and notin CNS 47 24

progression in the ENCO ‘CNS metastasis EJ 1

+ BINI induction group! Progression without reported new metastases 18 3
Death without progression 2 2
Overall 90 83

Am c: ENCO.
(PO: ENCO + INT)

SECOMBIT: Patients in

arms with first-line FE Fame PIE NIVO
immunotherapy (arms B ¢ NEE. AU
and C) had longer brain zo arme) come ate
MFS than those treated E = so
with first-line targeted HR TSX CN 035 er >
therapy in arm A? mms om |

0 so 8 © À o © m © a © ©

Time From Randomization, mo
1. Robert © etal, ASCO 2024. Abstract LBA9503. 2. Asciorto Pel al. ESMO 2023. Abstract 1089MO. PeerView.com

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23. What Is the Role of Dual
Checkpoint Blockade in Melanoma
With Brain Metastases?

24. Combination Checkpoint Blockade Is Effective
in the Management of Melanoma Brain Mets'

Intracranial PFS: Asymptomatic.

icons AD

Br metatas tested wth combination rivolemab pls

‘plimumal (CheckMate 204} fal results fan apor Label © FRE
Beeren zung =: Do
ee EEG EE (Bo
Eso] eramos
Assessment of intracranial CBR; complete responses, 40
partial responses, or stable disease lasting 26 months 3

o
% o
£ Durable benefits in asymptomatic patients! 03 6 8 1215 10.21 24 2 9 35 36 30 42 A 48 91 SH
3 + CBR of 22.2% (symptomatic) Team Since First Dose, me,
E * GER of 07:42 (ssmplomatio) vq Intracranial PFS: Symptomatic
É E

ry
5 7
3 25
3 2

<
E ES] | sensmene wer
E » +

10] messes Troma from anv)

Mean change: 57.1% ains À {
oT COR HMAMT DHMH M
Time Since First Dose, mo .

A. Tonti Het al N mold Med. 2018:379:722:730, 2, Tawbi HA et a. Lancet Oncol 2021:22:1082-1704. PeerView.com

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25. IPI + NIVO Associated With Robust OS in Patients With
Melanoma and Asymptomatic Brain Mets (ABC Study)!-2

A: IPI + NIVO B: NIVO A: IPI + NIVO B: NIVO C: NIVO
(n=27) (n=35) (n=25) (m1
Total
Intracranial response, n (%) 16 (59) 4021) OS) 17 (49) 16 (64) 14 (88)
CR 8 (30) 3 (18) aS
PR 8 (30) 106) ledian OS, mo = m" |
aS en di (05% CI NR(11.9-NR) 26.1(6.9-NR) 5.1 (1.8-53.0)
PD 8 (30) 14 (74) 7
NE» 1) 16) orc’ sm (2060) 13(646)
Arm A:NIVO 1 moikg + 100
¡PIS mohg, Q3W <4, then
NIVO Borg A so

+ Arm B: NIVO 3 mg/kg Q2W

+ Arm ©: NIVO 3 mg/kg Q2W
(Patients with brain mets who
local therapy had filed, or
had neurological symptoms,
‘or leptomeningeal disease 2
were enrolled in this
nonrandomized cohort)

‘Arm A: IPI+NIVO 519%

OS, %

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

"Median duration ol inrararial response at reached in any am Time, mo Eau
1: Long GV et al. Lancet Oncol, 2018:19:872-681. 2. Long GV etal, ASCO 2021. Abstract 9508. PeerView.com

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26. IPI + NIVO for Asymptomatic
Brain Metastases: Review of 3-Year OS13

NIBIT-M2 (IPI + NIVO)*

ABC (IPI + NIVO)? CheckMate -2043
33% 2-4 BM 29% 2-3 BM 77% 1-2 BM
43% 24 BM 40% 24 BM

33% 23 BM
Median follow-up: 67 mo Median size: 19 mm

Median size: 15 mm
Prior BRAFI/MEKi: 23% Median follow-up: 34.3 mo
‘Median follow-up: 52.8 mo

Arm A: IPI + NIVO

Arm A: IPI +

‘Arm B: NIVO

0 3 6 9 1215 18 24 24 27 90 39 95 29 42 4548 61 4 7 BD

ELZETTITTEITEIZT

ne. Tim Dose, mo

CheckMate -067: IPI + NIVO 3-year OS = 58%

1. Tawbi HA tal Lancot Oncol 2021,22:1692-1704. 2. Long GV et al ASCO 2021. Abstract 9508. 3, Di Giacomo AM otal ESMO 2023. Abstract 1084MO.

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27. What Is the Role of PD-1/LAG-3
in Melanoma With Brain Metastases?

+ Ongoing studies are evaluating NIVO + RELA in the setting of brain metastases (NCT05704647)

+ In RELATIVITY-047, times to development of new CNS lesions and CNS MFS were improved with
NIVO + RELA compared with NIVO"

seme megane
go 0: Tr)
ö HAE TI NIVO + RELA
z ch æ ©
¿es - vo
2% H
I mors Bm
38%] nmomamen H =
Eds] 2808 q tintin Ze
ia nee fame” ea 8
2 Toc {Stott inten 2x a
Bs area A u
Bo Fan y veo
TILCARA ICAA 0 3 6 9 12 15 18 21 24 27 30 39 36 39 42 45 48 51 54 57 60 63
Ho. at Risk Time, mo osa: Time, mo
NO “sarssato2 69 80 66 57 49 46 42 40 37 31 25 23 20 19 14 7 4 3 0 MON yersset02 99 80 69 67 49 45 42 40 37 31 25 23 20 19 14 7 4 5 0

RELA 224149103 78 67 61 56 47 42 39 38 32 32 27 25 20 18 14 10 4 O O RELA 22414910378 67 61 56 47 42 39 30 32 32 27 25 20 18 14 10 4 0 0

An intriguing signal of the CNS activity of PD-1/LAG-3 combinations

1.Tonbi Hot aL ASCO 2024, Abstract. 8624. PeerView.com

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28. BLUEBONNET: Phase 2 Trial of NIVO + RELA in Patients
With Untreated Melanoma Brain Metastases’

Key Eligibility Criteria

+ 21 measurable, unirradiated MBM
(0.5-3.0 cm)

+ Prior SRT in <5 MBM

+ Previous treatment with

Efficacy MRI
to monitor intracranial
response al 12 weeks

BRAFUMEKi permitted
80 mg +

+ No prior checkpoint inhibitor MIO Soma
therapy for advanced disease RELA 160 mg

Qaw
Exclusion Criteria
+ Neurological symptoms; steroids
>10 days; WERT; prior treatment
with checkpoint inhibitors; and
leptomeningeal disease

N=30

Clinically stable
continues. continue

+ Primary endpoint: intracranial ORR by modified RECIST

+ Secondary endpoints: CBR, PFS, OS, 1-y PFS, and ¡ORR by RANO-BM and iRANO

+ Exploratory endpoint: SRS-assisted PFS

+ Hypothesis: NIVO + RELA is safe and will result in higher IC efficacy compared with NIVO alone
+ Stats: 82% power to detect difference between 20% and 40%, BOP2 futility monitoring

à Nota responsa iagingefauaon,ssympomade progression wale alowed 1 conve. .
‘Galas gore NC TS Fe PeerView.com

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29. COMBI-MB: Targeted Therapy in BRAF-Mutated
Metastatic Melanoma and Brain Metastases‘

COMBI-MB: BRAFi/MEKi is active

against melanoma brain metastases
but with a short duration of response!

Intracranial Intracranial

‘ORR DCR
Arm A (n = 78) 58% 78%
Arm B (n = 16) 56% 88%
Arm C (n= 16) 44% 75%
Arm D (n = 17) 59% 22%

* Arm A: BRAFV6O0E, asympiomatic MBM, and
no prior local treatment

‘+ ArmB: BRAFVEODE, asymptomatic MBM, and prior
local treatment

+ Arm ©: BRAFVEOODIKR, asymptomatic MBM, with or
without prior local treatment.

+ ArmD: BRAFVSOODIE/KIR, symptomatic MBM, with or
without prior local treatment

1. Davies MA et al ASCO 2017. Abstract 9506

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Progression-Free, %

Proportion Remai

Frequent and Rapid Intracranial Responses in
Patients With BRAF-Mutated Melanoma Brain
Metastases With BRAFi/MEKi

Lo PFS 95% ch,

ETC]
WIE) 7207148)
ne) 42(17-65)
1817(88) — 552873)

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30. Practical Implications
of PD-1/LAG-3 Combinations

31. Dosing With Combination Immunotherapy: PD-1/CTLA-412

sa After completing 4 doses,
Nivolumab 1 mg/kg administer nivolumab as a single agent
| Ipilimumab 3 mg/kg with every 2 or every 4 week schedule

|

HUE Oe

a ee

Start Week3 Week6 Week9 QW or

1. Yenoy (ptinumad) Presea nlomañon. hp mw accessdata fea. govangsatéa_doesMabel2023/1259778120 pc 7
2. Opaiv (ivlumab) Prescbing Information. Hip: acoassdata fd, govldragsatia_docs/abel 2028/1258540rg1s 1211 pl PeerView.com

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32. n Immunotherapy’

Nuances of Dosing With Combina

RELATIVITY-127 Is Assessing Fixed-

Fixed-dose combination Dose SC NIVO + RELA in Melanoma?

480 mg of 160 mg of
nivolumab relatlimab

In the RCC setting, SC nivolumab
demonstrated noninferior pharmacokinetics
and ORR compared with IV nivolumab,
supporting the use of SC nivolumab to
improve healthcare efficiency?

May 2024: Under FDA review for
all indications*

1. Opdualag (nivolumab and relatimab)Proserbing Information, pas accossdata fda goueruggatida, doceabal20221761234:0001! pat
BASED,

2 hips lic Go YNCTOS625368 3. George Set a J Cin Oncol 2024.42 (up) L
‘hips iw bunesswe.convnews/nome'20280520855208/eNBrist-yers-Squbd-Announces-Updaed Acton Dir by 5 FO0dan-DUD- =
ronda. PeerView.com

‘Adminstraton for-Subcutaneous-Nivolumad-nivlumab-and-hyali

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33. Classically, Immune-Related AE Management Is Based
on Severity and Use of Corticosteroids’?

Clinical notes

+ Continue immunotherapy (or consider a
temporary delay [eg, for diarrhea or hepatitis]) _, In general, grade 1 irAEs are very mild: eg, early rash,
+ Symptomatic therapy occasional loose stools, and slight elevation in LFTs

+ Withhold immunotherapy o _, For grade 2, expect slightly more severe events:

* Corticosteroids if symptoms do not resolve in eg, higher LFTs and more consistent loose stools
1 wk (followed by steroid taper)

+ If toxicity resolves to grade <1, redose

Grade 3/4

+ Discontinue immunotherapy; hospitalization and multidisciplinary evaluation indicated
+ High-dose corticosteroids (followed by taper until toxicity resolves to grade <1)

1, NGON Cinca Practico Guidelines in Oncology. Management of Inmunaherapy Related Toxics 7
Version 2.2024. tps ima .ncon.orgiprotessionalsphysician_gls/pdlimmunothorapy pel. 2. Brahmer JR et al. J Immunother Cancer. 2021:9:0002435. PeerView.com

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34. Nuances of irAE Management
With PD-1/LAG-3 Combinations’

Ni

ces of irAE Management

ith PI

AG-3 Combinations

1. For NIVO + RELA, no dose reduction is recommended
2. In general, withhold for severe (grade 3) irAEs
3. Permanently discontinue for:

Life-threatening grade 4 irAEs

- Recurrent severe grade 3 irAEs that require systemic immunosuppressive treatment

— An inability to reduce corticosteroid dose to <10 mg of prednisone or equivalent per
day within 12 weeks of initiating steroids

1. Opduaing (ovolumab and rolatkmab) Prosenbing Information. Nps ww. accessdata {do govdeugsatida_docslabel2022/761234s0001 pat PeerView.com

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35. Indirect Comparison Suggests That NIVO + RELA May Have
Comparable Efficacy and Lower Toxicity Versus IPI + NIVO!

NIVO + RELA ~22%

PFS, %

grade 3/4 toxicity

No. at Risk
NIVO RELATIVITY.047
NIVO CheckiMato -087

IPI + NIVO ~55%

grade 3/4 toxicity

No, at Risk
NINO RELATIVITY.047
NIVO CheekMate 067

1. Schadondo D et al, ASCO 2024, Abstract 9657,

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PFS per Investigator

w VO RELATNITYGST NIVO Cheat 07
= Evens, 01%) 183
2 Moden. mon) 676102) 570800
3 br) enorm
E
IVO RELATIVITY.47
= TE VO Great 287
2 FE No oa
°
Time From Randomization, mo
ge 14 er 106 95 7 6 4 »% 2 0
28 M 107 9% ë 7 ® 8 0
os
m VO RELATIMTY.047 IVO Checite-067
H ree Hee
E EU >
E Mn MISC) sssG8ts09) RAN
E Et ES
2 H Te pro
a 1 1 NO Chockate 07 RELATIITY.047
E H 4
E H Hl
o - -
oo E SEE NOR wa E © à
Time From Randomization, mo
me 27 9 28 1% 10 we 124 1 & 13 0
Me Mi 20 M2 16 1 1 16 0
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36. Interprofessional Collaboration:
The Role of the Wider Team in Melanoma Care

Pharmacist
Collaborative irAE management

Patient
with metastatic
melanoma

Radiologist

+ Endocrinologist
+ Gl specialist

+ Rheumatologist y nurse

Dermatologist

Example: Gl specialists can be consulted

when managing irAEs such as colitis Surgeon

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37. Aligning Frontline Care
With the Latest Evidence

and Guidelines

38. Case 1: Mary Presents With Unresectable
Metastatic Melanoma and Lung Lesions

©)
Cap

Presentation & Clinical Assessment

Mary is a 62-year-
old patient with a
recent diagnosis + Chest CT demonstrated multiple lung lesions
of stage IV - Largest lung lesion measures 2 cm
unresectable + LDH is elevated
melanoma PS of 4

+ Mutational testing: BRAF wild type

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39. Case 1: What Are the Options for Mary?

(cop Fi Options & Next Steps

Mary isa
62-year-old patient + Combination therapy comprised of dual ICI therapy is the
with a recent current SOC and is appropriate for this patient
diagnosis of stage + Phase 3 evidence supports NIVO + RELA as an effective
IV unresectable and tolerable choice for Mary
+ Although IPI + NIVO could also be used, weigh toxicity
Coes lung considerations when making decisions
;

+ Single-agent PD-1 and lower-dose IPI + NIVO are unlikely
mets, PS of 1) to be as beneficial

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40. Case 1 Variation: How Would Older
Age Change Treatment Decisions?

©
ar

Mary is an
82-year-old
patient with a
recent diagnosis
of stage IV
unresectable
melanoma

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Presentation & Clinical Assessment

Chest CT demonstrated multiple lung lesions
- Largest lung lesion measures 2 cm

LDH is elevated

PS of 2

Mutational testing: BRAF wild type

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41. Case 1 Variation: What Are the Options for Mary?

Ce

Mary is an

82-year-old
patient with a

recent diagnosis
of stage IV
unresectable

melanoma
(elevated LDH and
a PS of 2)

Options & Next Steps
aa

+ Combination therapy with the more tolerable
NIVO + RELA regimen is likely the optimal choice

+ Use of first-line NIVO + RELA also allows for
subsequent re-exposure to combination
immunotherapy (PD-1/CTLA-4) after progression’

1. Tabi Hot al ASCO 2024. Abstract 9524

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42. Case 2: Gerald, a Patient With BRAF-Mutated Melanoma

©
Ce

Geraldis a
50-year-old
patient with a
recent diagnosis
of metastatic
melanoma

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Presentation & Clinical Assessment

Multiple liver metastases
LDH is normal
PS of 1

Mutational testing: BRAF V600 mutation

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43. Case 2: What Are the Options for Gerald?

Le Options & Next Steps

Cap aa

Gerald is a
+ DREAMsegq: Current guidelines clearly support combination
50-year-old therapy with IPI + NIVO as the initial treatment choice for
patient with a this patient!

recent diagnosis
of metastatic

+» Tolerability should not be a major concern given his PS
and fitness

melanoma
A + Ifa higher tumor burden or more symptomatic disease had
(liver Losa been present, starting with a short course of BRAFi/MEKi
BRAFm, PS o 1) followed by immunotherapy could be considered23

1. Atkins MB etal J Gi Oncol. 2028:41:186-197. 2. Ascieo Petal. Not Commun, 2024:15:146.3. Robert C etal, ASCO 2024. Abstract LBAS503. PeerView.com

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44. Case 3: A Patient With Metastatic
Melanoma and Brain Metastases

(©)
Cap

Presentation & Clinical Assessment

Thomas is a
67-year-old + Initially presented with lung mets
patient with + Brain mets subsequently confirmed by imaging
metastatic (asymptomatic)
melanoma and + LDH normal
brain metastases + Comorbid HTN

+ PSof1
+ Mutational testing: BRAF mutant

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45. melanoma and
brain metastases

Case 3: What Are the Options for Thomas?

Cap

Thomas is a
67-year-old
patient with

metastatic

(BRAFm)

ya, Options & Next Steps

24

For this patient, use immunotherapy or BRAFi/MEKi?

+ Evidence from CheckMate -204 and the ABC trial clearly
support the use of IPI + NIVO in this population’?

+ Targeted therapy is associated with more transient responses
in this setting?

+ For highly symptomatic patients requiring steroids before
immunotherapy, reducing the need for steroids with a short
course of RT may be useful

- Underscores the need for multidisciplinary collaboration

1.Tonbi HA ta. Lanoot Oncol 2021:22-1682-1704. 2. Long GV et al. ASCO 2021. Abstract 9508. 3, Daves MA et al ASCO 2017. Abstract 606. PeerView.com

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46. Take-Homes and Conclusion: Efficacy

Checkpoint inhibitors are the best tools for patients with metastatic melanoma with
evidence supporting long-term OS

+ Combination immunotherapy has shown clear OS benefit over targeted therapy in
BRAF-mutated melanoma, as well as consistent PFS and ORR benefit over
monotherapy with some OS benefit

+ Combination therapy with PD-1/CTLA-4 agents offers a higher ORR and remains the
best choice for patients with brain metastases until further data are available

+ There is very little role for monotherapy in the first-line setting, regardless of age,
performance status, and comorbidities, compared with PD-1/LAG-3, which has an
excellent safety profile

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47. Take-Homes and Conclusion: Safety

+ Toxicity (grade 3-4 irAEs) with PD-1/CTLA-4 is consistently shown in ~50-55%
of patients, while in PD-1/LAG-3, toxicity is shown in 22% of patients

+ There is very little role for low-dose IPI + NIVO because toxicity is still higher
(~35%) than PD-1/LAG-3 and it's not clear if efficacy is maintained

+ Choosing between PD-1/CTLA-4 vs PD-1/LAG-3 remains individualized and
dependent on tolerance of irAEs and plans to manage toxicities

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