A Roadmap for Modern RCC Care: Navigating Personalized Treatment Selection and Sequencing

Chair and Presenters, Sumanta Kumar Pal, MD, FASCO, Nizar M. Tannir, MD, FACP, and Tian Zhang, MD, MHS, discuss renal cell carcinoma in this CME/MOC/NCPD/AAPA/IPCE activity titled “A Roadmap for Modern RCC Care: Navigating Personalized Treatment Selection and Sequencing.” 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/3xgpDpY. CME/MOC/NCPD/AAPA/IPCE credit will be available until July 2, 2025.

1. A Roadmap for Modern RCC Care

Navigating Personalized
Treatment Selection and Sequencing

Professor, Department of Medical Oncology & Therapeutics Research
Co-Director, Kidney Cancer Program

City of Hope Comprehensive Cancer Center

Duarte, California

Nizar M. Tannir, MD, FACP Tian Zhang, MD, MHS
Professor, Department (8 Associate Professor, Division of Hematology

of Genitourinary Medical Oncology and Oncology
Ransom Horne, Jr. Endowed Professorship Department of Internal Medicine
for Cancer Research Associate Director for Clinical Research

The University of Texas Harold C. Simmons

MD Anderson Cancer Center Comprehensive Cancer Center

Houston, Texas UT Southwestern Medical Center

Dallas, Texas

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

Sumanta Kumar Pal, MD, FASCO > |

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2. Our Goals for Today

Bolster your knowledge of the latest efficacy and safety data
on approved and emerging treatment options for RCC

Equip you with strategies for personalizing care for patients
and engaging in shared decision-making approaches

Provide you with strategies to anticipate, mitigate, and
manage practical challenges and adverse events associated
with RCC treatments

Copyright © 2000-2024, Peerview

3. Thank You to Our Partner, KCCure kecure

KCCure’s Research Helps Inform Providers of the Patient Voice
The Kidney Cancer Research Alliance (KCCure) provides
answers to questions that patients and caregivers are asking
KCCure conducts its own patient-centered research aimed
at improving the quality of life of all patients with kidney cancer
by better identifying and defining patients’ needs and concerns

know that they may contribute to a patient's decision

Providers should be aware of patient perspectives and
about therapy choice

See results of patient surveys throughout tonight’s presentation ...

Kecure org PeerView.com

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4. Navigating the Choices of First-Line
Therapeutic Regimens in mRCC

Nizar M. Tannir, MD, FACP

Professor, Department of Genitourinary Medical Oncology
Ransom Horne, Jr. Endowed Professorship for Cancer Research
The University of Texas MD Anderson Cancer Center

Houston, Texas

2000-2024, PeerView

5. Timeline of FDA-Approved Regimens for
Metastatic Clear-Cell RCC in the 1L Setting

1992:
High-dose IL-2

2005 2006 2007 2009 2018 2019 2021

Bevacizumab/ Nivolumab + P]Pembrolizumab]| Nivolumab +
IFNa pilimumab + axitinib cabozant
Avelumab + brolizumab)
axitinib + lenvatinib

Dual lO 10 + TKI

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6. CheckMate -214: OS Benefit Maintained Over 8 Years With
Nivolumab Plus Ipilimumab Versus Sunitinib*?

The HR for OS has been stable over 8 years of median follow-up in ITT and

intermediate/pooi

isk patients and has improved over time in favorable-risk patients

nr Intermediate/Poor Risk Favorable Risk
2 sa sos
Pa: dns Team Immun

. ri Be

E AS
ge 23
in NO + Pt No; PI
a CEA

[REXEFFTTETTIETTITT MEELIEELZZELTZELLLITEMELITELZZTLIITIEITIIT)

HR
1. Motzer RU et al. N Engl J Med, 2018:378:1277-1200, 2. Tann NM et al. ASCO GU 2024, Abstract 263,

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7. CheckMate -214: PFS Benefit Maintained Over 8 Years With
Nivolumab Plus Ipilimumab Versus Sunitinib'’2

Median follow-up: 99.1 mí PFS in the ITT Population

a Tresment EventPatente Median PFS (5% C1, mo
E More Me Gen —
a su srasıs 12368182)
» INR 2038 (95% 0,075.09)
xe HR at prima nas = 0.98 821% CL 0701.23)
es zer
en 32 2s
> NIVO + 1PI
* SUN
Time, mo
PFS by IRRC in the IntermediatelPoor Risk Group PFS by IRRC in the Favorable-Risk Group
mo AS mo: Treatment Events/Patients Median PFS (95%.
> more za A erie ” +
© su zu san » SUN nas 289 052428)
” HR=073(95% 1.010) Pr: HR 176054 1, 125248)
Ro Rtn many nas = 082 981% CL 066105) xo gos Hate pinay ays = 210/02 1% CL 120.268)
go 288 4 Eo
bos NIVO + IPL = i #79 ro
I sun “4 { NIVO+IPI
Time, mo Time, mo
4. Motzer Real. Eng! J Med, 2018;378:1277-1290. 2, Tanne NM e al. ASCO GU 2024. Abstract 363 PeerView.com
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8. Improvements in Response Rates and DOR Maintained Over
8 Years With Ipilimumab Plus Nivolumab Versus Sunitinib'-?

ITT Population Intermediate/Poor Risk Favorable Risk
NIVO + IPI SUN NIVO + IPI SUN NIVO + IPI SUN
(n=550) (n=546) (n=425) (n= 422) (n=125) (n=124)
ORR (95% Cl), % 39 (35-44) 33(29-37) 42(38-47) 27 (23-32) 30(22-38) 52 (43-61)
BOR, n (%)
CR 66 (12) 19 (3) 50 (12) 1(3) 16 (13) 8 (6)
PR 151 (27 161 (29 130 (31 105 (25) 21 (17 56 (45)
SD 197 (36) 230 (42) 130 (31) 186 (44) 67 (54) 44 (35)
PD 97 (18) 77 (14) 82 (19) 71 (17) 15 (12) 6(5)
UTD/NR 39 (7) 59 (11) 33 (8) 49 (12) 6 (5) 10 (8)
Ongoing response, % 58 50 59 50 51 50
(n/N) (126/217) (90/180) (1071180) (58116) (19137) (32/64)
Ongoing CR, % (n/N) 80 (53/66) 89 (17/19) 84 (42/50) 91 (10/11) 69(11/16) 88 (7/8)

In the ITT population, mDOR was 76.2 mo with NIVO + IPI and 25.1 mo with SUN
HR = 0.52 (95% Cl, 0.38-0.72)

*RECIST v1.1 response cer Satfed Cox proporional hazards model =
1. Tann NM etal ASCO GU 2024. Abstract 363. PeerView.com

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9. KEYNOTE-426: Sustained Benefit With
Pembrolizumab Plus Axitinib!

Median follow-up: 67.2 mo

Median PFS Median OS

Events, n (95% CI), mo Events, n (%) (95% cl), mo ORR Re TT
PEMBRO*AX! 306 1570136202) PEMBRO+AXI 2700629 472(436548) ,, Population
SUN 311 11:1(89-125) SUN 280(65.3) 40.8 (34.3-47.5)
HR = 0.69 (95% Cl, 0.59-0.81) HR = 0.84 (95% Cl, 0.71-0.99) ©
lore one
7 CS x Den = [60 =
» » 3%
Re ©
ES E »
= » o
” * | PEMBRO +AXI SUN
" A A AA pues; pren
Time, mo Time, mo
1. Rini Bl etal ASCO 2023, Abstract LBA4SO! PeerView.com

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10. CheckMate -9ER: PFS, OS, and ORR Were Maintained With
Nivolumab Plus Cabozantinib at 55-Month Follow-Up???

Median follow-up: 55 mo

PFS per BICR

Median PES (95% Ch, mo
NIVO+CABO 16.4 125-10.)

os

Median OS (95% Cl. mo
NIVO + CABO 465 40.6524)

‘ORR per BICR

so sun 247097) ” sun 360 202428)
so HR 2 0.5 (99% CL. 0.49.70) so HR = 07 (954 Cl, 0.63.95)
70 Hat poro ara 051 Th stp arabes 060
tr) ud sur (sem. 040095)
zo x” us
pa go avo + caso
Es Ss
» x j
2» » H
VO + CABO {
w ho | Ivo + CABO sun
o o Mean men
NEEDED EEITELITEIT)
mera 28 43
Time, mo Time, mo em (022) (47304)
moor 20 152
(@5mcn,mo (8022 (109103)
* Mecian (range) feu fr OS, 888 (8.1.8.1) mo (ITT population, ñ
1. Chouei TK et al. N Engl J Med, 2021;384:820-841. 2. Bouton MT et al, ASCO GU 2024. Abstract 362. PeerView.com

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11. CLEAR: Continued Benefit With
ib at 4 Years!

PFS Final OS Analysis
Medion PFS, mo Median OS, mo
ET] TENTE 7 a7
SUN 926010) sn 543 409NE)
RAT GK CL 038057) N HR 078 95% C1 083098)
Nominal P= 0428

Len PEMBRO

1. Motzer RJ etal J Cin Oncol. 2024:42:1222-1228.

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ORR
w
”
lone one
_ 8 #7
3%
»
o
LEN+PEueRo su
Ge messn

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12. Summary of 1L ICI Combination Regimens
for Intermediate/Poor-Risk mRCC

CheckMate -21412 KEYNOTE-426% CheckMate -9ER* CLEARSS
IPI+ NIVO AXI + PEMBRO CABO + NIVO LEN + PEMBRO

(n= 550 vs n = 546) (n= 432 vs n= 429) (n= 323 vs n= 328) 66 vs n = 357)

2018; 1L for intermediate

FDA approval or Ra 2019; 1L 2021; AL 2021; 1L
Favorable/int/poor, % 23/61/17 32/55/13 29/58/19 31/59/9
Median follow-up, mo 99.4 672 556 498

MOS (ITT), mo 53 vs 38 47 vs 41 47 vs 36 54 vs 54
HR (Cl) 0.72 (0.62-0.83) 0.84 (0.71-0.99) 0.77 (0.63-0.95) 0.79 (0.63-0.99)
mOS (int/poor), mo 47 v526 42 vs 29 44 vs 29 48 vs 34

HR (Cl) 0.69 (0.59-0.81) 0.76 (0.62-0.93) 073 (0.58-0.91) 0.74 (0.57-0.96)
mPFS (ITT), mo 12 vs 12 16 vs 11 16vs8 24vs9
HR (Cl) 0.88 (0.75-1.03) 0.69 (0.59-0.81) 0.58 (0.49-0.70) 0.47 (0.38-0.57)
MPFS (int/poor), mo 12,59 1458 15vs7 2256

HR (Cl) 0.73 (0.61-0.87) 0.68 (0.56-0.82) 0.56 (0.45-0.68) 0.43 (0.34-0.55)
ORR (ITT), % 39 vs 33 61 vs 40 56 vs 28 71 vs 37
CR (TT), % 12vs3 12v84 14vs5 18vs5

PD (ITT), % 18 vs 14 12vs17 Tvs 14 Svs 14
ORR (intipoor), % 42v27 57 vs 35 53 vs 29 72529
CR (intpoor), %. 12183 11vs3 13vs4 s4vs4

Primary endpaits of CheckMate -214 included OS (HR. 74; 95% Cl, 0.62-0.88) and ORR per IRRC (41.9% vs
28.8%; P < 0001) in the intermediate/poorsisk population,

1. Tannir N, et al. ASCO GU 2024. Abstract 363.2. Ri Bl.
4. Bouton MT tal. ASCO GU 2024. Abstract 362.5. Maize

165; 08% Cl, 0.54-0.78), PFS per RRC (H

ASCO 2023. LBAAS01. 3, Rin Bl eta. N Engl J Med. 2019:360:1115-1127. as
al. J Clin Oncol. 2024:42:1222-1228. 6. Grunwald V et al. Eur J Urol 2023:6:437-446, PeerView.com

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13. Summary of 1L ICI Combination Regimens
for Favorable-Risk mRCC

CheckMate -2141 KEYNOTE-4262 CheckMate -SER* CLEARS®
IPI+ NIVO AXI + PEMBRO CABO + NIVO LEN + PEMBRO
(n=550vsn=548) (n=432vs n= 429) (n=323 vs n = 328) (n= 355 vs n = 357)

2018, IL for
FDA approval ET 2019, 1L 2021, 1L 2021, 1L
Favorable/intipoor, % 29/61/17 32/55/13 23/58/19 31/59/9
Median follow-up, mo 99.4 672 556 498
MOS (TT), mo 53 vs 38 47 vs 4 47536 54 vs 54
HR (Cl) 0.72 (0.62-0.83) 0.84 (0.71-0.99) 0.77 (0.63-0.95) 0.79 (0.63-0.99)
MOS (favorable), mo 78 vs 67 60 vs 62 53 vs 59 48 vs 34
HR (Cl) 0.82 (0.60-1.13) 110 (0.79-1.54) 1.10 (0.69-1.75) 0.74 (0.57-0.96)
mPFS (ITT), mo 42vs 12 16 vs 11 16vs8 24vs9
HR (Cl) 0.88 (0.75-1.03) 0.69 (0.59-0.81) 0.58 (0.49-0.70) 0.47 (0.38-0.57)
MPFS (favorable), mo 12 vs 29 21 vs 18 21513 22486
HR (CI 1.76 (1.25-2.48) 0.76 (0.57-1.02) 0.69 (0.48-1.00) 0.43 (0.34-0.55)
ORR (ITT), % vs sunitinib 39 vs 33 61 vs 40 56 vs 28 71 vs 37
CR (ITT), % 12vs3 12vs4 14v5 18vs5
PD (ITT), % 18 vs 14 12 vs 17 Tvs 14 5vs 14
ORR (favorable), % 30 vs 52 69 vs 50 66 vs 44 68 vs 51
CR (favorable), % 13v5 6, 13vs6 16ys8 2185

* Primary endpoints of CheckMate -214 included OS (HR.
28.8%; P < 0001) in the inermediate/poorsk population.
1. Tannir NM, et al. ASCO GU 2024, Abstract 363,2. Rın Bl.
4. Bouton MT et al. ASCO GU 2024. Abstract 362.5. Matze

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85: 08% Cl, 0.540 78) PFS per IRRC (HR = 0.74; 95% CI 0.62-0 88) and ORR per IRC (41.9% vs

ASCO 2023. Abstract LBAASO 3. Rini Bl et al. N Engl J Med. 2019:380:1115-1127.
al. J Cin Oncol 2024:42:1222-1228. 6. Grunwald Veta. Eur J Urol, 2023:6:437-448.

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14. 1L ICI Combination Trials in mRCC:
Safety Overview Summary

CheckMate -21413 KEYNOTE-426*7 CheckMate -9ER®® CLEAR?
IPI+ NIVO AXI + PEMBRO CABO + NIVO LEN + PEMBRO
(n=550vsn=54) (n=432vsn=429) (n=323vsn=328) (n= 355 vs

99.1 4 5

Median follow-up, mo

TRAE, any grade, % 94 vs 98 96 vs 98 98 vs 93 97 vs 92
TRAE, grade 23, % 48 vs 64 (grade 23) 68 vs 64 (grade 23) 68 vs 55 (grade 3-4) — 74 vs 60 (grade 23)
21 (PEMBRO) 10 (NIVO) 24 (LEN)
Discontinuations 23 (IVO + IPI) 20 (AXI) 810 (CABO) 26 (PEMBRO)
due to AES, % 13 (SUN) 7(AXI + PEMBRO) 7(NIVO+CABO) 10 (LEN + PEMBRO)
12 (SUN) 11 (SUN) 11 (SUN)
High dose 29 27 219 15

corticosteroid use, %

1. Tanne NM et a, ASCO GU 2024. Abstract 363.2. Abiges Let al ESMO Open. 2020.5:e001079, 3. Opdio (nvlumab), Preserbing Information.
Nip ru aczessdataf6a govänugsatfda_ docs/abel2024/125S54s1281 pal. 4. Ri Bet al ASCO 2021. Abstract 4500. 5. Pontes T. et al. Lancet Oncol

2020.21-1583-1573. 6. Ina (xiii) Preserbing Information. Nips ln accessdata a govlrugsatsa. socsabel/2022/202524009 130 14CorrectecL pa

7. Keytruda (pembrolizumab) Preserbing Information. nip www accesadata (da gov/drugsatsa_docalabel/2024/125514 16010 pat, 8. Bouron MT et al i

ASCO GU 2024, Abstract 362.9. Choueti TK et al N Engl J Med 2021304 829-841. 10. Motzer R et al. J Cin Oncol 202442:1222-1228, PeerView.com

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15. HRQOL: Summary of 1L Combination Studies?

„21412
Checkmate 21% KEYNOTE-426? CheckMate -9ER* CLEARSS

‚N = Bar) (N = 861) (N = 651) (N = 1,069)
All Risk Groups AllRisk Groups All Risk Groups

Intermediate/
Poor Risk Only

NIVO + AXI +
iy |

FKSI-19 Y
FKSI-DRS
EORTC QLO-C30
FACT-G

CABO LEN+
PEMBRO SUN nv SUN PEMBRO

Y

SUN

EQ-5D-3L

Presentes by Apolo AB et al. ASCO 2021. Abstract 4563,
1. Cella Det al ASCO GU 2022. Abstract 307. 2, Cela D eta. Lancet Oncol 2019:20297-310. 3. Bedke Jet al 2020 EAU Viral Congress. Game-Changing ass
Session 4.4. Cela D et al. Lancet Oncol, 202223:292-303. 5. Motzer R et al Lancet Oncol 2022223.768-780. 6, Motzer Ret al, ASCO 2021. Abstract 4502. PeerView.com

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16. Management of AEs
in IO Plus TKI Therapy!*

+ Two mechanisms of action result in two sets of AE profiles that are not mutually exclusive
+ Itis important to determine which therapy is causing the AE to plan a management strategy
+ Consult irAE management guidelines (eg, ASCO, NCCN, SITC, ESMO)

10 + TKI Combination Toxicities

Overlapping

Pneumonitis Rash Hypertension
Myocarditis Diarrhea Taste changes

Myositis Hepatitis Stomatitis
Adrenal crisis Hypothyroidism Dyspepsia
Hypophysitis Cytopenia HFSR

Determining Which Therapy Is Causing the AE
Hold TKI (shorter half-life than immune checkpoint inhibitor)

1. Wood LS, Omstein MC. JCO Onco Pract. 2020:16(suppl 2): 188-198 2. Schneider EJ et al. J Cin Oncol, 2021:394073-4128. 3. NCCN Cine! Practice Guidelnes
in Oncology À of Immunotherapy Related Toxcises, Version 12024, ps www een or/pretessionals/physician_gl/edtimmunotnerapy pat da
4 Rin Bl etal. Jimmunather Cancer. 2019/7354. 5. Haanen Jet al Ann Oncol, 2022:33 1217-1238. PeerView.com

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17. Phase 3 Next-Generation 1L Trials
in mRCC With lO Combination
as Comparator Arm

18. COSMIC-31312

Cabozantinib Cabozantinib
40 mg orally once daily + 40 mg orally

nivolumab 3 mg/kg IV once daily +
every 3 wk x 4 + nivolumab
ipilimumab 1 mg/kg IV 480 mg IV
Stratification every 3 wk x 4 very 4 wk?
or poor risk SIND score
per IMDC + Region
Measurable
disease per
RECIST v1.1

+ Advanced
RCC with a
clear-cell
component
Intermediate

Placebo orally once daily Placebo
+ nivolumab 3 mg/kg IV orally once daily +
every 3 wk x 4 + nivolumab
ipilimumab
1 mg/kg IV every 3 w

Endpoints
+ Primary: PFS per RECIST 1.1 by BIRC + Tumor assessment every 8 wk (RECIST v1.1)?
+ Key secondary: OS + Treatment until loss of clinical benefit or intolerable toxicity

2 Nivolumab administered ora maximum of 2 years. Tumor assessment (RECIST v1.1) a week 10, nen every weeks forthe rst 50 weeks, then every 12 weeks
teteañer * Patents may be treated beyond progression ere is cnica! benefit inthe opinion of he investgator nee
Y pin govstudyINCTO3GS7219. 2 Choveld TK etal ASCO 2020, Abstract TPSS102. PeerView.com

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19. COSMIC-313!

Median PFS, mo
n Events, n Me cl) = e
CABO +NIVO +IPI 276 116 NR(14.0-NE) CABO + NIVO: 43%
PBO+NIVO+IPI 274 133 113(7.7-182) (CR: 3%)

PBO + NIVO + IPI: 36%

CABO +NIVO + IPL (CR: 3%)
= mDOR: NR for both arms

PBO + NIVO + IPI

Probability of PFS
efRSessssss

1. Choueld TK eta N Engl J Med 2023:388:1767-1788. PeerView.com

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20. PeerView.com/GXM827

Phase 3 PDIGREE Study Design!

Fully Enrolled

N=1,111 Nivolumab 480 mg IV Q28D Nivolumab
480 mg IV Q28D
+ cabozantinib

+ Metastatic PP. Induction 40 mg orally daily
clear cell RCC Stratification

IMDC » Bone Nivolumab

3 mg/kg IV Until PD,
intermediate or . Ho + ipilimumab unacceptable toxicity,
poor risk

\ . 1 mg/kg IV Q21D orCRat1y
A intermediate/

Archival tissue AER

available ES

(biopsy not
required)

Nivolumab

+ Primary endpoint: OS
+ Key secondary endpoints: PFS, 1-y CR rate, ORR by RECIST, toxicity, and correlatives

1. MtpsflniallsgovistudyNCTOS799166. PeerView.com

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21. LITESPARK-012'

Arm A
Key Eligibility Criteria Belzutifan 120 mg PO QD +
Advanced or metastatic clear cell RCC pembrolizumab 400 mg IV Q6W +
No prior systemic therapy lenvatinib 20 mg PO QD
Measurable disease per RECIST v1.1
KPS score 270%

Tumor imaging
AmB at week 12
mulated quavonlimab 25 mg/ OUT]
pembrolizumab 400 mg to week 78 and
lenvatinib 20 mg PO QD then Q12W
thereafter

Stratification Factors

IMDC prognostic scores (0 vs 1-2 vs 3-6)
Geographic region (North America vs
Western Europe vs ROW)

‘Sarcomatoid features (yes vs no)

Arm C
Pembrolizumab 400 mg IV Q6W +
lenvatinib 20 mg PO QD

+ Treatment with pembrolizumab or pembrolizumab/quavonlimab will be limited to 18 infusions (approximately 2 years)
+ Treatment with belzutifan and lenvatinib may continue until treatment discontinuation event

+ Primary endpoints: PFS per RECIST v1.1 by BICR, OS
+ Secondary endpoints: ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, safety, and tolerability

1. ps flia govistudyNCTOA736708. PeerView.com

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22. SWOG 1931/PROBE Trial!

RCC

primary tumor and mets

Start on IO based regimen (any of the 5 FDA
approved regimens are permitted)
10- to 12-wk scan for response assessment
Randomize patient if PR or SD within 10-14 wk
Steps 1 and 2 registration can be done together!

©

CR, PD, or
decrease in PS
Not eligible for
randomization

Nephrectomy followed by

continued systemic
immune therapy

+ Primary endpoint: OS

1. hits:etnicaias govstudyNNCTO4S 10507 PeerView.com

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Thoughts on Long-Term Data

for Key 1L Regimens

Dual lO

Improved OS

Longest follow-up

Durable responses

Potential to stop therapy
(treatment-free survival [TFS])
QOL

Sarcomatoid clear-cell RCC

+ Potential for higher initial
irAE

+ Lower PFS/
response rates

10 + TKI

Improved OS

High ORR, low PD
Longer PFS/earlier
disease control
Lower irAE rate

+ Overlapping toxicity
+ Potential for

chronic TKI toxicity

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24. Maria’s Case:

A 68-Year-Old Patient

Patient Case

+ 68 years old
+ Intermediate/poor risk

When would you offer Maria
an 10 + TKI regimen?

When would you offer Maria
a dual lO regimen?

Panel
Discussion

What if she had sarcomatoid
features?

What if she had received prior
adjuvant 10?

How do AE profiles come into your
shared decision-making discussions?
How would you educate her on
dosing, scheduling, and AEs?

Which team members would be
involved in her education and care?

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25. Treatment-Free Survival

CheckMate -9ER:

Use of immunotherapy can be associated 48-Month Analysis!

with prolonged disease control after
discontinuation of treatment without the

Previous analysis of 1L nivolumab + ipilimumab for
advanced RCC in CheckMate -214 showed TFS was
twice as long vs sunitinib

need for further anticancer therapy;
however, TRAEs may persist after
therapy cessation

Over the 4-year period since initiation of 1L
therapy for advanced RCC, the longer OS achieved
with nivolumab + cabozantinib in CheckMate -9ER
was accompanied by 1.5 times longer mean time
surviving treatment-free before 2L therapy compared
with sunitinib

Describing the quality of survival
time may provide additional insight
for individual decision-making about
initiation of 1L therapy for patients
with advanced RCC

1. Manta C ta. ASCO 2024. Abstract 4507. PeerView.com

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26. Combination Treatments: kecure
Understanding the Patient’s Viewpoint

Results From a Recent Patient Survey Focusing
on the Use of Combination Treatment Regimens*

Dus o ida ac, did your doctor Was the dose Have you evernot taken your oral
dose of your oral reduction helpful? rapy to reduce side effects
therapy (wile on combination)? Kid notmakea (without teling your doctor)?
‘iference 2
%

By encouraging patients

to report any AEs right

away, providers may be
able to suggest AE

management strategies,
including dose
adjustments, that allow
patients to keep receiving
an effective treatment as
long as possible while
maintaining QOL

Askodtora Dose Rnducton — Foñaleved Woried About Reding ca)
spin oni sao mens Le pe

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27. Optimizing Therapy Selection
in Refractory mRCC

Tian Zhang, MD, MHS

Associate Professor, Division of Hematology and Oncology
Department of Internal Medicine

Associate Director for Clinical Research

Harold C. Simmons Comprehensive Cancer Center

UT Southwestern Medical Center

Dallas, Texas

2000-2024, PeerView

28. Patient Priorities and Expectations
of Systemic Therapy in mRCC*
‘Survey of 1,062 patients; 399 had metastatic disease

When Thinking About Therapy for Metastatic Cancer, What
Important Desire or Outcome You Want to See From
+ 69% of patients reported that they did not know their IMDC or
risk status

Least important Most important
Chance of eliminating al evidence lease (CR)
+ 70% of patients defined “long-term” response to therapy as

D CNRS
25 years, and over a quarter of patients (26%) defined long-term | "== Eo CNE
response as 210 years Improved quay of te = =m
‘How would you define long-term response to treatment?
<Smonths <2years y

<10 years

Understanding how patients
Most patients are not familiar with their risk classification and may not realize the
significance of this factor in treatment selection

prioritize treatment selection

and define treatment success
Patients rank complete response as the most important outcome/desire when considering e pe
treatment options; cost is Ihe least important factor for patients in selecting treatment see à O
Patient perceptions of long-term response to therapy may differ from provider perceptions selection process,
1. Battle Det al, ASCO 2023, Abstract 4560, PeerView.com
PeerView.com/GXM827

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29. Therapeutic Selection in Refractory Disease’

1L Treatment Received 2L Treatment Options

10 + 10 combination => VEGFR TKI monotherapy
VEGFR TKI + immunotherapy => Alternative VEGFR TKI

Nivolumab or
MESSI UL delta und alternative VEGFR TKI

Dependent on 1L treatment and timing of resistance
1. Rahme IK ea. J Gin nec, 2022:40:2057 2008, PeerView.com

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30. 2L and Beyond: Advanced RCC Management

Singl
Randomized phase 3 AXIS Nonrandomized phase 2 KEYNOTE-146
Axitinib vs sorafenib Lenvatinib + pembrolizumab
Randomized phase 3 METEOR Nonrandomized phase 1b/2 TiNivo
Cabozantinib vs everolimus Tivozanib + nivolumab

Randomized phase 3 CheckMate -025 Randomized phase 3 TiNivo-2
Nivolumab vs everolimus Tivozanib + nivolumab results

Randomized phase 3 TIVO-3 Randomized phase 3 CONTACT-03
Tivozanib vs sorafenib Cabozantinib + atezolizumab
Nonrandomized phase 2 CaboPoint Phase 3 LITESPARK-011 dl
Cabozantinib Belzutifan + lenvatinib

| Randomized phase 3 LITESPARK-005 Nonrandomized phase 2 LITESPARK-003|
Belzutifan vs everolimus Belzutifan + cabozantinib

-Agent Treatment Combination Treatme!

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31. Phase 2 CaboPoint: Pure 2L Cabozantinib‘?

Key Eligibility Criteria
+ Histologically confirmed, advanced, or metastatic
RCC with a clear cell component
+ Radiographic disease progression following ICI +
ICI therapy or ICI + VEGF-targeted therapy
+ No previous use of cabozantinib or untreated brain
or leptomeningeal metastases

vera (N= 88)

10 + TKI

(ipilimumab + nivolum

Cabozantinib 60 mg/day

+ Primary endpoint: ORR per RECIST v1.1 in cohort A, by independent central review
+ Secondary endpoints: ORR in cohort B by independent central review, ORR for both cohorts by local investigator review,
TTR, DOR, DCR, PFS, OS, change in disease-related symptoms, safety and tolerability
1. Abiges et al. Future Oncol. 2022:18:915-926.2. ABiges Let al. ASCO GU 2023. Abstract 608, PeerView.com

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32. Phase 3 TIVO-3: Tivozanib in RCC1

Tivozanib

+ Long half-life

+ Selective and potent VEGFR TKI that inhibits VEGFR 1, 2, and 3

FDA Approved
March 2021

+ FDA approved for patients with relapsed or refractory advanced RCC following 22 systemic therapies

350 Patients Randomized 1:1
INV PFS favored tivozanib vs
sorafenib (HR = 0.624)

* Data Cutt: May 24, 2021.
1. Beckerman KE etal. Oncolopst, 2024 20:254-262.

PeerView.com/GXM827

+ A clinically relevant

proportion of patients
were alive and
progression free at 3 and

4 after initiating
tivozanib vs sorafenib

- This difference is
sistent across all
evaluated subgroups

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33. Phase 3 TIVO-3: Tivozanib in RCC’

Kaplan-Meier Survival Curve of Conditional OS i
in Patients With 12:mo PFS Serial OS With Extended Follow-Up

== Data Cutoff Mean OS HR

low. o Events, n 2
Date (95% Cl) (95% Cl)

Tivozanib August 2019 17.9(16.7-19.1) 227 0.99 (0.76-1.29)

HR = 0.45,
P=.0221
May2020 20.3(18.8-218) 251 0.97 (0.75-1.24)
January 2021 21.9 (20.2-23.6) 270 0.91 (0.72-1.17)
Sorafenib May 2021 22.8 (20.9-24.6) 280 0.89 (0.70-1.14)

Probability of OS

0 6 12 18 24 30 36 42 48
Time, mo

Long-term follow-up in TIVO-3 suggests that early and consistent

PFS benefit with tivozanib vs sorafenib may be associated with an
improvement in OS HR over time as more events accumulate

1. Beckerman KE et a. Oncologst 2024 20:254-262. PeerView.com

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34. Phase 3 TIVO-3: Tivozanib in RCC1-5

Incidence of VEGFR TKI Class Effect Grade 23 TEAEs
Tivozanib demonstrated

HIN favorable tolerability and,
ared with sorafenib,
ne
Aeiheniereions was associated with fewer
Diarrhea EEE — All-grade and grade
PE la is 23 TEAES
a Dose reduct
Hesesivorniting sai = ose reductions,
kur 1 Sorafenib grade 23, % —— | interruptions, and

discontinuations, despite

a longer time on therapy
Tivozanib was better
tolerated than sorafenib

regardless of age or prior
immune checkpoint inhibitor
treatment

1. Rini tet al Lancet Oncol, 202021:95-104. 2. Pal SK eta ASCO 2020, Absrac £062. 3. Verzoni etal ASCO 2021. Abstract 4548, =
4. Pal SK et al ASCO 2021. Abstract 4567. 5. EscudierB etal, ASCO 2021. Abstract 616553 PeerView.com

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35. What About a Combination Approach?
KEYNOTE-146: Lenvatinib Plus Pembrolizumab'

Patient group

IM Treatment naive (n = 22)

IM Previously treated ICI naive (n = 17)
ICI pretreated (n = 101)

Key Eligibility Criteria
+ MRCC with clear cell component
+ Measurable disease per irRECIST
+ Disease progression after
PD-1/PD-L1 treatment
= 22 doses of anti-PD-1/PD-L1

— Defined by RECIST v1.1;
confirmed 24 wk

| Change From Baseline, %
88868-38888

g/d PO + Patients
mg once

+ Primary endpoint: ORR at wk 24
+ Secondary endpoints: ORR, PFS, OS, safety

1. Lee CH et al Lancet Oncol 2021:22:946-058 PeerView.com

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36. What About a Combination Approach?
Phase 3 CONTACT-0312

Key Eligibility Criteria Atezolizumab os

1,200 mg IV 10
+ Inoperable, locally en

advanced, or metastatic + cabozantinib e

RCC with radiographic 60 mg PO daily &

disease progression during ee

or following immune 2

checkpoint inhibitor ls ATEZO+CABO caso

treatment & nn ATEZO +

Femme #0 GO CABO

8

Clear cell or non-clear cell Cabozantinib MOSER STEHE) NERLNAE)
rea eos esc mm Tea

logy mg PO dai Sree HR GER ON —_ 09070427) Pa 880
KPS >70% Ce a

Time, mo

+ Primary endpoints: IRF-PFS, OS
+ Key secondary endpoints: INV-PFS, ORR, DOR, safety
The addition of the PD-L1 inhibitor, atezolizumab, to cabozantinib did not result in improved clinical
outcomes in patients with RCC who progressed on or after prior immune checkpoint inhibitor treatment
+ mPFS: 10.6 mo vs 10.8 mo; HR = 1.03 (95% Cl, 0.83-1.28)
+ mOS: 25.7 mo vs NE; HR = 0.94 (95% CI, 0.70-1.27)

Median flow-up: 15.2 months a
1. Pal SK tal Lancet 2023:02:185-195. PeerView.com

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37. PeerView.com/GXM827

What About a Combination Approach?
Phase 1/2 TiNivo: Tivozanib Plus Nivolumab!

Median follow-up of 19.0 mo

so
x Previously treated
J Treatment Previously
É
Lao > All Patients
BOR),* n (%) Ni Treated
«| mers: nr Treatment naive O) a (en EEE
FS: 18.9 mi
5] ERS: 189 mp CR 1(4) 1(8) 0
5 5 ©, © > %
% Time, mo PR 13 (62) 5 (42) 8 (62)
Fl sp 10 (40) 5 (42) 5 (38)
el PD 14) 16) 0
¿o ORR (CR + PR) 14.66) 6 (60) 8 (62)
ze ea DCR(CR+PR+SD) 24 (96) 11082) 13 (100)
O 0 Previously treated ¡EI ooo cc—coo——
400! !
120

westgator-assessed response One patent had progressive disease as their est response dueto appearance of new lesions in her frst scan an is nat included
the reduction presented; therefore, tis graph is representative of 4 patents, not 25. a
Y Albiges Let a Ann Oncol 2021:32:97-102, PeerView.com

Copyright © 2000-2024, PeerView

38. Phase 3 TiNivo-2: Tivozanib Plus Nivolumab in RCC‘?

Enrollment completed

Key Eligibility Criteria Combination therapy (n = 163)
Histologically/cytologically Tivozanib 0.89 mg PO QD for 21 d on/7 d off +
confirmed recurrent or mRCC k nivolumab 480 mg IV Q4W
ECOG PS 0-1
1-2 prior lines of therapy,
including an immunotherapy Monotherapy (n = 163)

Stratified by IMDC risk score and Tivozanib 1.34 mg PO QD for 21 d on/7 d off
prior lines of therapy

4-wk treatment cycles
(2+ cycles required for assessment)

Primary endpoint: PFS
Secondary endpoints: OS, ORR, DOR, safety
Exploratory endpoint: HRQOL

1. tps cinicatiis govtucyNNCTO4967203.2 Chovein TK tal. ASCO GU 2022. Abstract TPS405 PeerView.com

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39. Modern Mode of Action:
HIF-2a Inhibition in RCC'

bou + The HIF pathway is central to the pathophysiology of
clear cell RCC and von Hippel-Lindau (VHL) disease
+ Belzutifan, is a first-in-class oral HIF-2a inhibitor that
blocks heterodimerization with HIF-18 and
downstream oncogenic pathways
— Approved in the United States for certain VHL
disease-associated RCC, pNET, and CNS-HB
— Approved in the United States for advanced
RCC following a PD-1 or PD-L1 inhibitor
and a VEGF-TKI

E pass |

1 donasehE et al New Engl Mel 2021:385:2038-2046. 2. Choue TK tal, Nat Med. 2021:27:802-805, 3. hips fé govldrugsiresoures-infrmation- en
approves cup és approvesbelzuian-advanced senalcel<arcnoma PeerView.com

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40. Evolution to Belzutifan’*

20 mg QD (n=6)
40 mg QD (n= 6)

400 —
— 80 mg QD (n =6)

120 mg QD Part 1 (n = 6)
120 mg QD Part 18 (n= 47)
120 mg QD (n= 53)
160 mg QD (n = 6)
240 mg QD (n = 7)
120 mg BID (n= 5)

&

H No, SBDD te

u
A mb
UTSW Lead PT2385
(Phase 1)

Mean (SD) Belzutifan
Concentration, ng/mL.
g

° y 3 = ” 2 24

1. Wehn PM et al J ed Chem, 2018:61:9691-8721, 2. Xu R et al. J Med Chem. 2019.82 6876-6893. 3. Choue TK e a. Nat Med, 2021:27:202-80. PeerView.com

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41. Modern Mode of Action:

HIF-2a Inhibition With Belzutifan in RCC?

Phase 3 Study: LITESPARK-005

Key Eligibility Criteria
Unresectable, locally
advanced, or metastatic

clear cell REC
Previously received <3 prior [11
systemic regimens

+ Primary endpoints: PFS, OS

w

HR: 0.74

FDA Approved
December 2023

HR: 0.88

(95% Cl: 0.73-1.07)

PE

y

”

5

az
Time, mo

E

1. tips lciicatials govistudy/NCTO4195750. 2. Abiges Let al. ESMO 2023. Abstract LBABS. 3. tps da govidrugs/rescurces information approved»

duos hée-approres Baltar edvencec renal cab corcnoma.

PeerView.com/GXM827

sauna

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42. Phase 2 LITESPARK-003: Belzutifan + Cabozanti

PERTE EAN

What About a Combination Approach?
Belzutifan Plus TKI"

Updated Analysis From Cohort 2°
Duration of Treatment and BOR

ORR: 31%

v CR

APR

= SD

© PD

x Death

> Treatment ongoing

0

5

10 145 20 25 30 35
Time, mo

Phase 3 LITESPARK-0114

Belzutifan
Key Eligibility Criteria 120 mg/d orally
+ Unresectable, locally + lenvatinib
advanced, or d orally
metastatic clear cell

RCC.

Previously received

$2 prior systemic Cabozantinib
regimens 60 mg/d orally

+ Primary endpoints: PFS, OS

"Data cuoft February 1, 2022 (median folow-up of 24.8 mo}; beizuifan 120 mgld PO + cabozantnib 60 mp PO.

1. htps:esnicaials gov/suäyNCTO3634540. 2. MeDermotD et al. ESMO 2022. Abstract 1453P.
3. Chouein TK etal Lancet Oncol 2028;24:553-562 4. hpsicincalias gowstudyNCTO4SE623,

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43. Key Takeaways: Refractory Setting

+ As more treatments are available in earlier mRCC settings, treatment selection in
refractory disease has become more challenging

+ 1L treatment and timing of progression are important considerations for
subsequent treatment choice

« Tivozanib is the only TKI developed in the post-immunotherapy era
+ Belzutifan presents a new MOA targeting HIF-2a in this setting

+ Lenvatinib + pembrolizumab has efficacy as an IO/TKI combination in the
refractory setting
+ Ongoing trials will provide further data for treatment sequencing
— TiNivo-2
— PDIGREE

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44. Case Modifications

Patient Case

Maria, a 68-year-old patient with mRCC

and lung metastases

+ Started on initial therapy with an lO +
TKI, and salvaged with second TKI

+ Experienced progression in the liver...

nel
Discussion

Which factors should you consider when
developing Maria’s treatment plan?

How do AE profiles come into your shared

+ Symptomatic and rapid tumor kinetics decision-making discussions?
— Two sets of scans 6 weeks apart How would you educate her on dosing,
> Liver lesion has grown from scheduling, and AEs?
2to6cm How does genomic profiling come

> Lung metastases have into play?
increased from 1 to 4 cm

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45. Contemporary Challenges
and Ongoing Innovations

Co-Director, Kidney Cancer Program
City of Hope Comprehensive Cancer Center
Duarte, California

Sumanta Kumar Pal, MD, FASCO 3 |
Professor, Department of Medical Oncology & Therapeutics Research |

Copyright © 2000-2024, PeerView

46. How Can We Improve the Patient Experience?

IV infusions can be associated
with treatment burdens (eg,
long administration times, risk
for complications)

SC approaches will have an
impact not only for the patient
but also for the healthcare
professional, as it will affect the
organization of care

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47. Potential for Improving Daily Management:
Subcutaneous 10

Downloadable

Phase 3 Studies Assessing SC 10
Across Tumor Types

12 January 2024:
IMscin0OT'* 7 Approved in the EU for
SC atezolizumab in NSCLC il Indications?

CheckMate -67T*5 May 2024: Under FDA

aa 5 Review for Al
SC nivolumab in RCC puerta

CREST’
Cohort B: SC sasanlimab in NMIBC

RELATIVITY-1278
nivolumab + relatlimab in metastatic
melanoma

1. Buratto Metal. Ann Oncol, 2023:34:899-702. 2. htpselnicalials govistudy/NCTO3735121. 3 hips /Mrstwordpharma comvstoy/5818870,
4. tps letnicaliials govistudyINCTO4810078. 5. George S et a. ASCO GU 2024. Abstract LBA360,

$ hits vw businessnie.comnews/home20240520053206/en/Brsto- Myers Squbb-Announces-Updated-Acton-Date-by-he-U.S -Food-and-Orug-Administation- 7) , „17:

{for Subcutaneous Nivlumab nivelumab-and hyaluronidase, 7. hps/enicatials govistudyINCTO4 165317. 8. Ios cuca govietudyiNCTOS625900. eerView.com

7 Copyright © 2000-2024, PeerView

48. Phase 3 CheckMate -67T: Subcutaneous Nivolumab in
Patients With Advanced/Metastatic RCC’

Key Eligibility Criteria
+ Advanced RCC/mRCC with

Arm À
NIVO sc

clear cell component A 5 5 MN Treatment up to
progressed during or after SEEN 1,200 mg + rHuPH20 Qaw > years until
receiving <2 prior systemic + Weight (<80 kg disease
regimens vs 280 kg) progression or
+ 1O naive + IMDC (favorable Arm B unacceptable
+ KPS 270 ye intermediate NIVO IV toxicity
+ IMDC of favorable,
intermediate, or poor risk
allowed
+ Primary endpoints: time-averaged serum concentration over 28 days (Cavgd28),
trough serum concentration at steady state (Cminss)
+ Key secondary endpoint: ORR by BICR
Pr PeerView.com

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49. CheckMate -67T: Nivolumab SC Provides Clinical
Equipoise to Standard IV Dosing!

NIVO SC NIVO IV
1,200 mg + rHuPH20 Q4W 3 mg/kg Q2W
(n = 247) (n = 245)
Number of doses received 8.6 METE

4

30.9
Patients with 21 dose delayed, n (%) 89 (36.0) 134 (54.7)
Patients with 21 infusion/injection interrupted, n (%) 1(0.4) 10 (4.1)

Average administration time with nivolumab SC was <5 minutes

1. George S et al, ASCO GU 2024. LBA 260, PeerView.com

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50. CheckMate -67T: Nivolumab SC Provides
Clinical Equipoise to Standard IV Dosing!

NIVO SC + rHuPH20 (n = 248)

60 (24.2)
19.0-30.0

‘ORR, n (%)
95% CI

Relative risk (95% CI)

Median TTR, months (range)

Median PFS, months (95% Cl)
HR, 95% Cl

1.33 (0.94-1.87)
3.70 1.7-11.1)
7.23 (5.13-7.49)
1.06 (0.84-1.34)

NIVO IV (n = 247)

45 (18.2)
136-236

3.68 (1.6-11.3)
5.65 (5.29-7.39)

CheckMate -67T: Safety and PROS?

+ The safety profile of NIVO SC was consistent with
NIVO IV

+ Toxicity was manageable with immune-modulating
medications

+ No bother by treatment side effects

Relative risk ratio of ORR is strated Mantel-Haenszel estimate,
1: George § etal, ASCO GU 2024. LBA 360, 2. Bourin MT etal ASCO 2024. Abstract 4532. 3. George Set a. ASCO 2024, Abstract 4525,

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CheckMate -67T: HRQOL*

+ Previous analysis of 1L nivolumab + ipilimumab for
HRQOL was maintained while on treatment with
NIVO, regardless of the mode of administration
(SC or IV)

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51. Implications for SC Checkpoint Inhibition

Panel
Discussion

+ When might you use nivolumab SC in RCC?
— 1L dual lO (ipilimumab + nivolumab)?

— 1L10 + TKI (cabozantinib + nivolumab)?

— Refractory monotherapy?

+ In which other GU cancers outside of RCC might
you consider it?

+ What does the care team need to keep in mind?

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52. Multi-Targeted Inhibitor:
Zanzalintinib'*

TAM Kinase (AXL, MER) Inhibition

EGFR2, MET, AXL, and N

ofile

+ Increases numbers of circulating and VEGFR2 Inhibition Sur
tumor-infiltrating CD8+ T cells Decreases number! fe (16-22 hours)

+ Promotes macrophage phenotype function of regulatory once-daily oral dosing
transition from M2 (immunosuppressive) T cells and MDSCs
to M1 (immune stimulating)

+ Blocks MET-induced tumor expression of PD-L1
+ Blocks mobilization of immunosuppressive neutrophils

STELLAR-001: Phase 1 zanzalintinib alone
or in combination with atezolizumab or
avelumab in solid tumors

+ STELLAR-002: Phase 1 zanzalintinib in
‘combination with nivolumab or nivolumab +

AXL Inhibition ipilimumab in solid tumors
Increases tumor MHC + STELLAR-009: Phase 1b/2 zanzalintinib +
class | expression HIF2a inhibitor (ABS21)
1. Hau Jetal Eur J Cancer 2020:138(supp 2) Abstract 33PD. 2. Sharma MR tal. Ann Oncol. 2022:3(supl 7) Asta 4818

3! Ghaue TK et al. J Cin Oncol 202240(supp 16) Abstract TPS4600, 4. Hsu Jet al Mol Concer Ther, 2023122:179-191 PeerView.com

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53. STELLAR-001: Clear Cell RCC Expansion Cohort

Single-Agent Dose-Escalation Cohorts
Inoperable, locally advanced, metastatic, or
recurrent solid tumor treated with
zanzalintinib 10-140 mg QD
(n= 49)

Recommended dose
zanzalintinib 100 mg

Clear Cell RCC Expansion Cohort
+ Advanced, metastatic, or recurrent RCC with a clear
cell histology (sarcomatoid features permitted)
+ Measurable disease per RECIST v1.1
+ ECOG PS 0-1
Received 1-3 prior systemic anticancer therapies
(n= 32)

Safety Population
(N= 81)

+ Primary endpoints: ORR and
PFS rate at 6 mo per RECIST
--+ V1.1 by investigator
+ Secondary endpoint: safety
+ Exploratory endpoints: PFS and
DOR per RECIST v1.1 by
investigator, OS

* Treatment unstack of cnica! beneft or unacceptable tonicity treatment post progresion atowed there was cnical eneft pr the investigator. en
1.Sharma Met al Ann Oncol. 2022.337 suppl) Abstract 481P. 2. Pal SK tal. IKCS 2023, PeerView.com

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54. STELLAR-001 Baseline Characteristics:
Clear Cell RCC Cohort12

Clear Cell RCC Cohort Clear Cell RCC Cohort
Characteristics, n (%)

Characteristics, n (%)

(N= 32) (N= 32)

‘Age, median (range), y 64 (39-79) ‘Number of prior therapy 203)
Male 23 (72) lines, median (range) is
ECOG PS

o 16 (50)

1 16 (50)
IMDC risk

Favorable 4(13

eng Fa Prior VEGFR TKI 26 (81)

Por. 26) Cabozantinib, 17 (53
Sarcomatoid component 5 (16) Axio 8 (25)
Sites of metastasis Sunitinib 8 (25)
Pazopanib 6 (19)

Lung 20 (63) Best response to last

Lymph node 19 (59) ‘systemic anti-cancer
therapy
Number of metastatic sites? PR 3(9)

1 3(9) sD 16 (50)

2 8 (25) PD 11 (34)
EERE Ee FE mu

Data ct Joe 1,023 * Tota number tnt ge and ont se at basin, Peeeviewoon

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55. STELLAR-001: Best Response to Zanzalintinib!

Clear Cell RCC Cohort (N = 32)

6
ES ORR DCR:
; ” 38% (12 PR)

Io

I.

Eo

A æ.

à

E

Sn

Im

0

fe RUN RU PU UFR

WPR #SD =PD

Prior Prior
Cabozantinibb VEGFR TKIe
Yes No Cabo Included Cabo Excluded
m
a
=| ia 35
» 57 63
ze pcr DER DER pcr
ge 94% 86% 92% 100%
gol 71 a
» 29
2 38
: 14 8
Cabo Cabo AnyPrior _Non-Cabo
exposed Malve VEGFRTKI VEGFRTKI
(iy new ten

Three of the four cabozantinib-exposed patients

who responded to zanzalintinib had discontinued
prior cabozantinib due to disease progression

(Data cute June 10, 2023. OCR is defined as proportion of patients with a best overall response of confined CRIPR or any single best response of SD,

* Cabo exposure was unknown for 1 patient © These subgroups are not mutual exclusive.

1. Pal Sket al IKCS 2023,

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56. STELLAR-001: Zanzalintinib Biomarker Analysis
in Clear Cell RCC'

Circulating plasma biomarkers and immune cell prover peony
populations in blood were assessed at baseline +.
and on study

+ IHC for AXL, c-Met, phosphorylated Met, and
VEGFR2 was performed on archival tissue

Associations between response to zanzalintinib
and biomarker levels were investigated by
comparing zanzalintinib responders (CR/PR) and
nonresponders (SD/PD)

Zanzalintinib in patients with advanced clear cell
RCC led to modulation of plasma biomarkers
associated with angiogenesis and peripheral
immune cell subsets consistent with its expected
mechanism of action pa

nei m=19
1 Pal SK etal ASCO 2024, Abstract 4545 PeerView.com

CRPR sorD
n=10.n=10

Na
P= 0378

Pom.

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57. Phase 1b STELLAR-002 Study Design’.

Cohort 1 Cohort 2 Cohort 6
1L Clear Cell RCC 2L Clear Cell RCC 1L Non-Clear Cell RCC

+ Non-clear cell RCC
(sarcomatoid features allowed)"
~Papillary, unclassified, or
translocation-associated
histologies
+ No prior systemic therapy

+ Clear cell RCC (sarcomatoid
features allowed)

+ Progressed on 1 prior systemic
ICI-based combination therapy?

+ Clear cell RCC (sarcomatoid
features allowed)

+ No prior systemic therapy?

Primary Objectives

+ Dose escalation: safety and RDs of combination therapies

+ Expansion: ORR per RECIST v1.1 by investigator; safety (AEs/SAES/AESIs)
*Dose-escalaton stage vil determine the recommended doses for he expansion stage. > Combination therapy consisting ofa PO-1/PO-L1 inhibitor + VEGFR TKI ora
PD-1 + CTLA inhibitor Prior ret, including VEGFR TKI, PD-1, and CTLA inhibitors, ae at alowed. « Chromophobe, renal medulary carcinoma, and pure

collec duct non-lea call RCC are excluded m
Y tp cinicatils govstucyNNCTOS176483. 2. Motzer RJ et a. KCRS 2023, Abstract TIP 63 PeerView.com

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58. Non-Clear Cell RCC’

+ Comprises ~25% of all RCC subtypes

+ Commonly impacts younger patients and often metastatic at presentation

+ Typically has a worse prognosis in the metastatic setting compared with clear cell RCC

+ Includes a wide range of histological subtypes, the majority of which are papillary,
chromophobe, renal medullary carcinoma, translocation RCC, collecting duct Traditionally, clinical
carcinoma, and unclassified RCC trials have either

excluded or only
included small

numbers of patier

with non-clear cell
RCC

rious therapeutic
modalities and
combinations are
under investigation,
often based

wa Lex :
ee [race | ver | wer aed therapcutic studies
ee > ar cell RCC
Treue lor vec atom] euros | wer E A | TPR | uam
AA
{-2aumpst Pa Cn Gonos Cancer 2Z:09-18 PeerView.com

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59. Phase 3 STELLAR-304:
Non-Clear Cell RCC13

Currently Enrolling

Key Eligibility Criteria

Histologically confirmed non—clear cell RCC that is

unresectable, advanced, or metastatic

+ Papillary, unclassified, and translocation-
associated non-clear cell RCC histologic Zanzalintinib + nivolumab
subtypes, with or without sarcomatoid features

+ Measurable disease per RECIST v1.1 by

investigator Sunitinib

KPS 270%

Archival tumor tissue available

Aged 218 years + Dual primary endpoii

Adequate organ and marrow function RECIST v1.1 by BICR

+ Secondary endpoint: OS

+ Other endpoints: safety, including incidence

and severity of AEs

ts: PFS and ORR per

1. ps encata govistudy/NCTOSST8S73. 2. Pal SK etal ESMO 2023. Abstract 1912TIP. 3. Pal SK eta, ASCO 2024, Abstract TPSAS11 PeerView.com

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60. What About Combination Therapy
in Non-Clear Cell RCC?

Cabozantinib + Nivolumab?

Cabozantinib + Atezolizumab*

Phase 2 FORTUNE

mer
mer >
Trial Underway’

IF

Bevacizumab + Atezolizumab*

Best Change From Baseline, %
Bees hoBs
‘Best Change From Bastin, %

Maximum Tumor Shinkago,%
bebeeovsas

E
it
E

ë

Patents

“ component.
4 Par SK tal ln Ono, 2021393725 5736 2 leper Na Ev Url 20245002 221029021402 3 McGregor BA ta J Ci Oncol 2020 36-70 m
4 Ages Let al Lancet Oncol. 2023:24881-801. 5, Nguyen CB etal. ASCO 2024. Abstract TPS46 PeerView.com

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61. The Gut Microbiome May Predict Outcome

With Immune Checkpoint Inhibitors’
CBM588, a live bacterial product containing Clostridium butyricum

Nivolumab + Ipilimumab + CBM588

" Median, mo,
Alma PAN 127

Improved PFS:
vs 29 mo (HR = 15)
ed: 20% to 58

i | é e SWOG Proposal: A Definitive Study Assessing CBM588

Pis: Barata/Vaishampayan

MRCC with measurable 10-based therapy
metastatic disease + CBM588
ECOG PS 0-1

No prior systemic therapy

for metastatic disease

No history of autoimmune ads

+ placebo

disease

Improved PFS:
5.8 mo (HR
PR increa:

1. Dizman N et al. Nat Med. 2022°28:704-712. 2. Ebrahim Het a ASCO 2023, Abstract LBA104. 3, Dizman N et al ASCO 2024, Abstract 4550. PeerView.com

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62. Modulating the Microbiome: Diet!-*

eee AN
win Camu-camu
Ported ena Sd ect A Mae
‘Common Names.

1. ips: mskee orpleancar-careintegratve-medicine/nerbsleamu-camu. 2. Messaoudene M et al. Cancer Discov. 2022:12:1070-1087
3. Pang SA et al. Curr Oncol. 2023;30:7882-78S0. 4. hips:/www.cinicalials gowstudy/NCTOSO49576.

PeerView.com/GXM827

PI: Barragán-Carrillo

Nivolumab + Ipilimumab + Camu Camu

Nivolumab + ipitimumab

+ mRCC with measurable
metastatic disease

+ Clear cell andlor
‘sarcomatoid component

+ ECOG PS 041

+ No prior systemic therapy for
metastatic disease

+ No active autoimmune
disease or receiving high-
dose steroids

Nivolumab + iplimumab

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63. If Not IO, Then What?
Consider RCC-Specific Phase 1 Studies

Promising target for patients with RCC,
as it is expressed in up to 80% of RCC cells!

CAR-T Cell Therapy [ apc therapy | Therapy

Monn 12

Mm

Noveltinker 1
x
a

<<<
a RCC and NPC =

RCC, NPC, and NHL

Subjects

SK et al. SITC 2022, Abstract 368. 3, Jonasch E etal KCRS23, Abstract $2. PeerView.com

1. Ruf Metal. Cin Cancer Res. 2015:21:889-898, 2.
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64. If Not Checkpoint Inhibitors, Then What?
Consider RCC-Specific Phase 1 Studies...

Promising target for patients with RCC
with differential expression in
normal kidney tissue and RCC

ENPP3 Differential Expression RXF-393 Xenograft Tumor Model in NSG Mice with PBMC Effector Cells

Eng aan

ENPP3 Gene Expression, TPM: log;

1. Pal Sk etalSITC 2022 PeerView.com

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65. If Not Checkpoint Inhibitors, Then What?
Consider RCC-Specific Phase 1 Studies.

Novel HIF-2a inhibitor

Best Percentage Change From BL in Tumor Size, Duration of Exposure of DFF332
as per RECIST

: = nin (x)= 3540075)

3

8

¿

mPR ms TS

Study Day. d

‘At cutoff, treatment was ongoing in 11 patients (27.5%), with
median (range) duration of exposure of 17.9 (1.0-75.6) weeks

The disease control rate was 52.5% with best response of PR
In 2 patients (5%) and SD In 19 patients (47.5)

1.PalSK etal ASCO 2024, Abstract 4513, PeerView.com

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66. Audience Q&A O ,

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