On Target: Integrating Trop-2-Directed Therapeutics for Urothelial Carcinoma With Precision

Chair, Petros Grivas, MD, PhD discusses bladder cancer in this CME/NCPD/AAPA/IPCE activity titled “On Target: Integrating Trop-2-Directed Therapeutics for Urothelial Carcinoma With Precision.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/AAPA/IPCE information, and to apply for credit, please visit us at https://bit.ly/3VzSjE9. CME/NCPD/AAPA/IPCE credit will be available until June 25, 2025.

1. On Target

Integrating Trop-2-Directed Therapeutics
for Advanced Urothelial Carcinoma

With Precision

Petros Grivas, MD, PhD
Professor, Department of Medicine, Division of Hematology Oncology
Clinical Director, Genitourinary Cancers Program

University of Washington

Professor, Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, Washington

Copyright © 2000-2024, Peerview

2. Our Goals for Today

Augment your understanding of the current rationale and
evidence for the treatment of urothelial cancer with ADCs
targeting Trop-2

Equip you with the expertise required to apply Trop-2-targeting

ADC protocols for individualized treatment strategies

Provide you with guidance on how to support team-based
management of the unique suite of adverse events associated
with Trop-2-targeting ADC therapies

100-2024, PeerView

3. Test Your Knowledge and Earn Credit as You Go!

Answer

ve Baseline Review A" Answer the Each correct
question the supporting 5 ‘
for each module evidence question again answer counts
to evaluate and get expert to demonstrate towards your
your knowledge insights within à en ou pastes!
and skills the module ave learner completion

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4. Addressing Unmet Needs
for Treating mUC

Petros Grivas, MD, PhD

Professor, Department of Medicine, Division of Hematology Oncology
Clinical Director, Genitourinary Cancers Program

University of Washington

Professor, Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, Washington

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

2000-2024, PeerView

5. Shortcomings in the Real-World
Management of Advanced UC

One-quarter to one-half of patients do not
receive any treatment for their disease"

Patients are not

achieving the

-immuni reatment
Post-immunotherapy treatments pe

often include chemotherapy or a
different PD-1/L1 inhibitor, rather

which modern
than a novel agent therapy is
capables?

Switching from one PD-1/L1 inhibitor
to another PD-1/L1 inhibitor occurs in
approximately 20% of patients despite
very limited data on this strategy!

Less than half of patients who progress
on 1L therapy receive 2L therapy

Less than one-third of patients
who discontinue PD-1/L1 inhibitor
therapy receive subsequent
therapy in the 2L or 3L*

Several socioeconomic, demographic,
racial/ethnicity, and gender factors have
been associated with the use of less
cancer-directed treatments?

1. Morgans AK. European Society of Medical Oncology Congress 2021 (ESMO 2021). Abstract 704P. 2. Bien Metal. ESMO 2021. Abstract 701P.

3. Hopp Z et a. J Manag Care Spec Pharm. 2021:27:240-255. 4. Morgans AK etal. J Cin Oncol. 2021:39{supl 6:14.
5. Hasan S ot al. J Clin Oncol 2021:39(suppl 6): 403.6. Boig A et al. Curr Oncol. 2021:28:3812-3824. 7. Simeone JC et a. Cancer Epidemiol 2019:50-121-12.

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6. Shortcomings in the Real-World
Management of Advanced UC

OBJECTIVE 2 a
To elucidate the reataword weatment 4,218 791
patterns, healthcare resource tization en ges

(HRU), and economic burden among
Medicare beneficiaries with la/mUC after
progression on PD-L1 inhibitor therapies.

Cohort

Patents aged 265 years dagnosed with amUC
(2015-2017) who inated and subsoquenty
conta PO-1LY or therapy

(index = dsconbnued dato) using Medcar
Footer Senco Research entitle Fes

o “O

28,063 4,652
Dares’ Pay a
LUC Gagnon

1. Morgans AK etal, Url Oncol-Somin Or 2021:733:01-733.010.

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OF 791 PATIENTS, POST-PD-4/L1 INHIBITOR

‘THERAPY DISCONTINUATION
Treatment Patterns: Bee
Pre= ve Post Progression
Per. Person PerMonth}.

on

CONCLUSION
Amer of patents wo discontinued PD-1L1 Into nera ecos no
further cancer-directed therapy. Although the cost of systemic therapy was.
higher in the pre-index period, this was offset by other medical costs that
¡were higher in the postindex period

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7. Supporting Effective Communication Among gue
Multidisciplinary Healthcare Teams >

Encouragement for
patients to report AES
early and not wait until

next appointment

Clear education for
patients regarding
‘expected AEs

Maintain connections
between clinical

departments (eg, primary

care, urology, oncology)

Training for nurses
to recognize and support
accurate triage

Established point of contact
to guide and navigate
patients between points of
care

Established subspecialty referrals
(eg, dermatology, ophthalmology
gastroenterology, endocrinology)

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8. BCAN Is an Excellent Resource for
Professionals, Patients, and Caregivers

BCAN provides educational

resources to help patients feel We give bladder cancer patients
and caregivers the resources and
more prepared Support they need to.cópe With

the disease:

+ https://clinicaltrials.bcan.org/
+ Bladder Cancer Support Line:
833-ASK-4-BCA

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9. Trop-2 as an Ideal Target for
Bladder Cancer Therapy

Petros Grivas, MD, PhD

Professor, Department of Medicine, Division of Hematology Oncology
Clinical Director, Genitourinary Cancers Program

University of Washington

Professor, Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, Washington

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

Copyright © 2000-2024, PeerView

10. TROP Expression Log2 (SEM)

Trop-2 mRNA Expression Across Cancer Types!

o een ro som .
sccm ps
de 4 Stain obese

» |

oe | $

5 = o.
| il asi 8 23 Trop-2 mRNA is highly

og

expressed across

multiple types of
cancer in the TCGA

1. Chou Jot al. Eur Uro! Oncol. 2022:82888-8311(21)00215.7

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¿ AS 4,5
a
WN

WON SSS SS database, with high

expression in
urothelial carcinomas

Z

N,

y SS A SS

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11. Trop-2 is Highly Expressed Across
Molecular Subtypes of UC!

+ Trop-2 is highly expressed
across basal, luminal, and
stroma-rich subtypes, but
depleted in the
neuroendocrine subtype

- Cells resistant to
enfortumab vedotin, a
Nectin-4—targeting ADC,
may remain sensitive to
sacituzumab govitecan

). Representative immunohistochemistry staining for TROP2 in
the Ba/Sq (A), LumNS (8), LumP (C), LumU (0), NE-like (E), and Stroma-rich (F) bladder cancer subtypes using a bladder cancer tissue
microarray (TMA). The subtypes were previously determined as described in Seiler et al, 2017.2 Scale bar denotes 100 ym.

1. Chou Jet a. Eur Urol Oncol. 2022:82588-8311(21)00215.7. 2. Soler Rot al. Eur Urol, 2017.72:544-564, PeerView.com

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12. ADC Mechanism of Action!

‘Antibody engagement leads

to payload-independent antitumor activity Membrane-permeable payloads enter

via several mechanisms: cells, regardless of target
expression and can also kill these cel
(bystander effect)

jated stimulation of immune cell
ruption of receptor dimerization

[ Fc region of the mAb component of ADCs can orchestrate ADCC

1. Drago JZ tal. Nat Rev Gin Oncol. 2021:18:327-344. PeerView.com

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13. ADCs Targeting TROP2'

Sacituzumab Govitecan

DAR= ET

Hydrolysable
pH-sensitive linker
for SN.

x
Y

Exroceluiar

Humanizod

i epidermal growth
ant-TROPZ 1961 mab ePermal

domain

opta

1. Pari G et al, Cancer Treat Rev. 2023:118:102572.

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Datopotamab Deruxtecan

‘Totrapeptide-based
‘loavable linker
for DXS

NA:
es,

10x more potent
than SN.38)

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14. Sacituzumab Govitecan Is a First-in-Class N
Trop-2-Directed ADC A

a aida (Trop is an epithelial cell surface antigen highiy |

AE | expressed in many solid tumors including invasive
expressed in many bladder cancer!

a0) Distinct from other ADCs:26

SN-38 + High drug-to-antibody ratio
payload: mo

+ Internalization and enzymatic cleavage by tumor cell not
required for SN-38 (active metabolite of irinotecan)
liberation from antibody

FDA-approved for the following:

Treatment of patients with metastatic triple-negative breast

cancer who received 22 prior systemic therapies (21 in

Hydrolyzable metastatic setting); metastatic HR-positive/HER2-negative

linker for SN-38: breast cancer who received endocrine-based therapy and
high drug-to 22 prior systemic therapies in metastatic setting”

arios rato + Treatment of patients with locally advanced or metastatic

UC who have previously received platinum-containing
NN chemotherapy and a PD-1/L1 inhibitor

+ This nations based on FDA accelerated

approval
1. Avelin C ot al. Oneotarge. 2017;8:58642-52653 2. Goldenberg DM etal. Expert Opin Bil Ther. 202020:871-885. 3. Nagayama A tal. Ther Adv Med Oncol

2020.12:1-12, 4. Cardio TM et al. Bloconjugato Chom. 2018:26:919-031. 5. Goldenberg DM etal. Oncotarget.2015:6 22406-224512.

6. Govindan SV etal. Mol Cancer Ther. 2013:12:968-978, 7. rodely (sactuzumab gowtecan-aiy) Proserbing Information, PeerView.
tps. accessdata da govldrugsatda. docslabe/2023/761 11560351 at. ‚com

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15. Trop-2-Targeted Approaches
for Advanced UC

Petros Grivas, MD, PhD

Professor, Department of Medicine, Division of Hematology Oncology
Clinical Director, Genitourinary Cancers Program

University of Washington

Professor, Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, Washington

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

Copyright © 2000-2024, Peerview

16. TROPHY-U-01: Sacituzumab Govitecan in Pretreated
Metastatic Urothelial Carcinoma‘#

Cohort 4 (113 patients)
Patients with mUC who progress
after prior PT- and CPI-based therapies

Cohort 2 (38 patients)
Patients with mUC who progressed
‘after CPI in cispatin-inoigible pts.

‘Cohort 3 (41 patients)
CPl-nalve patients with mUC who progress
after prior PT-based chemotherapy

Cohort 4 (up to 57

or mUC who completed
without progression

1. ips cicalias govc2IshowNCTO3547073.2. Loot Y

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SG 10 mg/kg
Day 1 and day 8, every 21 days

D}

$6 10 mgkg
Day 1 and day 8, every 21 days

SG 10 mgikg
Day 1 and day 8, every 21 days +
pombro 200 mg day 1 every 21 days

Induction: Cis + SG (6 cycles)
Maintenance: (1) SG + avelumab
(2) SG + zimberelimab (zim)

Arms
(1) SG + zim; (2) avolumab; (3) zim

——a_ —
Cohort 6 (up to 226 patients) À * +zim+ J
ES” {Beato m rm naar

(4) carbo + gem + avelumab maintenance

2021
Accelerated FDA approval
for patients with locally
advanced or mUC who

previously received
platinum-containing
chemotherapy and
PD-1/PD-L1 inhibitor

rts

for enrollment

al. Ann Oncol. 2020:31(supl 4}1142-61215. 3. Potyiak DP e al. J Clin Oncol 2024 accepted
4. Grvas P et al. J Cin Oncol 2024:42:1415-1425. 5. Loot Y eta. Ann Oncol, 2024:35:392:401. 6. Ramamurty Cet a. J Cin Oncol 2023:41.16_supal, TPS4611,
7. Powes T eta. J Cin Oncol 2023:41 6, suppl TPS598, 8. Duran et al J Clin Oncol 2023:41.6_ suppl. TPSSE2.

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17. TROPHY-U-01 Cohort 1: Sacituzumab Govitecan in Platinum-
and Immune Checkpoint Inhibitor-Refractory Setting!

m u
i = ORR, % 28

1 : mDOR, mo 82
ÓN mPFS, mo 54

| mOS, mo 109

i

T Discontinued without event

A: ee
fr le PD or death
pe

1.LoriotY etal Ann Onco. 2024; 35:32. PeerView.com

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18. Phase 3 TROPiCS-04'

Key Eligibility Criteria

+ Locally advanced sc emia’

unresectable or mUC cituzumab govitecan treatment until Primary Endpoint?
+ Upper/lower tract tumors 0 mg/kc loss of clinical + os
+ Mixed histologic types 2 Miete Secondary Endpoints
ee es A toxicity + PFS byPI
& assessment using
Ani PO 1PO-LI OR . Gam Bore and
Ces + Paclitaxel @ gir
Py ER assessment using
OR RECIST 1.1

Vinflunine

Platinum in neo/adj + EORTC QLQ C30

setting if progression score and EuroQOL
within 12 months and EQ-5D-5L QOL
subsequent CPI score

+ Primary endpoint of OS inthe ITT population was not met. En

1. Grivas eta. J Clin Oncol2021:39. 2. tps www businesswire.comvnews/home/202405905 16266/enGlead-Provides-Update-on- Phase-3-TROPICS-O4-Study. PeerView.com

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19. TROPHY-U-01 Cohort 2: Sacituzumab Govitecan for
Cisplatin-Ineligible Patients’?

Cohort 2
Endpoint (N=38)
ORR, % 32
MDOR, mo 72
mPFS, mo 56
MOS, mo 13.5
= Best Overall Response
2 mr (= 12) = =
SO(n= 13) - =
1. m "_ =
5 ME NE(0=4) = > I Discontinued witout event
= m > Ongoing response
- > Onset of response
= m
= = Po or dest
= 1
i = m
= m
a
* Mean flow: 93 months 5
“up: 93 mont PeerView.com

1. Petyiak DP et al. ASCO GU 2023. Abstract 520.

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20. TROPHY-U-01 Cohort 3: CPI-Naive Patients!

muc Treatment continued

* Platinum-refractory SG + pembrolizumab until progression or
unmanageable toxicity

+ CPl-naive

Primary endpoint: ORR (central review)
Secondary endpoints included: PFS, CBR, DOR, safety
Median follow-up: 14.8 mo

1.Givas Peta. J Gin Oncol. 2024.42:1415-1425. PeerView.com

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21. TROPHY-U-01 Trial Cohort 3: Primary Endpoint Was Met

Endpoint
ORR, %
CR, %
PR, %
mDOR, mo
mPFS, mo

mOS, mo

Cohort 3
(N = 41)

41
20
22

5.3
12.7

1. Givas Peta. J Cin Oncol. 2024:42:1415-1425,

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Target Lesions
MXN:

Percent Change From Baseline-

Bost Percent Change From Baseline

8

ME PR(n=9)
m0
Mm S0(n=9)
EPO (n= 10)
CT) Patient

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22. EA8231: Proposed Phase 3 Trial?

Key Eligibility Criteria
Metastatic or LA
unresectable UC
ECOG PS 0-2

Anti-PD-L1 therapy
required; prior
platinum-based chemo
Tx & EV allowed

‘$2 lines of systemic
therapy for advanced
UC setting in FGFR2/3
(unknown ($3 lines of
therapy for FGFR2/3
mutation/fusion)
Measurable disease
per RECIST 1.1

CrCl 2 30 mL/min

+ Side coutesy of Dr Potros Gras.

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a

sG +
pembrolizumab

Stratification Factors

Bellmunt score (0-1 vs 2-3)

Prior exposure to enfortumab vedotin

Prior exposure to platinum (cisplatin or carboplatin)-based

chemotherapy

Primary vs acquired resistance to anti PD-L1 therapy
Primary resistance: PD within 6 mo from starting anti PD-L1
‘Acquired resistance: PD after 6 mo from starting anti PD-L1

Primary Endpoint
+ OS

Secondary Endpoints
+ PFS

ORR

CBR (CR/PR/SD)
QOL/PRO
Safety/toxicity

Correlative Biomarkers
+ NGS: DNA/RNA tumor
Trop-2 IHC

PD-L1 IHC

TMB, MSI status
CtDNA in blood/urine

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23. Understanding Dosing and
Safety Considerations of
Trop-2-Directed ADCs

Petros Grivas, MD, PhD

Professor, Department of Medicine, Division of Hematology Oncology
Clinical Director, Genitourinary Cancers Program

University of Washington

Professor, Clinical Research Division

Fred Hutchinson Cancer Center

Seattle, Washington

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

© 2000-2024, PeerView

24. Safety Considerations

+ ADCs have a unique set of AEs to consider compared with
other agent classes
+ Common AEs
— Sacituzumab govitecan: Diarrhea & neutropenia
— Datopotamab deruxtecan: ILD, stomatitis, ocular
toxicities
« A multi/inter-disciplinary approach to management and the
use of prophylaxis can help mitigate AEs

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25. Safety Considerations During ADC Infusion’ $

+ Monoclonal antibodies may result in infusion-related
reactions (IRRs)

- Grade 3-4 reactions are rare, but do occur

- Hypersensitivity reactions observed with 24 hours of
administration of SG, ranging from mild to
any anaphylaxis
> Premedicate with an antipyretic and H1 & H2
blockers prior to each infusion
> Medication to treat such reactions and
emergency equipment, should be available for
immediate use
Monitor patients during the infusion and for at least 30
min after completion of infusion

1. Trodety sacituzumab goviecan-hay)Prescrbing Information. ps ww accessdata1da.govidrugsatida docslabel2023/611 15903504 pat PeerView.com

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26. Using Approved ADCs in the Clinic: a
Tactics for Safety Management‘?

Sacituzumab Govitecan

Neutropenia

Key Grade 23 TRAEs Recommend G-CSF as primary prophylaxis
From TROPHY-U-01 Cohort 1

Neutropenia (35%)
Leukopenia (18%)

Anemia (14%)
Diarrhea (10%) Educate patients very well; rule out other causes

Dose reduction/delay as needed

Educate & monitor patients very well; urgent care if needed

Diarrhea

Febrile neutropenia (10%) Hydration with electrolytes, monitor labs closely

Anti-diarrheal medications/best supportive care

1.Lorit Y etal. Ann Oncol. 2024; 35:392.2.Trodelvy (sactuzumab govitecan-haly) Prescribing Information. a A
Hits accesedata.Ida.govidrugeatida_ doce/abel2023/7611 1580950 pal PeerView.com

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27. Patient Interaction

Petros Grivas, MD, PhD
Professor, Department of Medicine, Division of Hematology Oncology

Clinical Director, Genitourinary Cancers Program
University of Washington

Professor, Clinical Research Division

Paul Weaver Fred Hutchinson Cancer Center
Patient Actor Seattle, Washington

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

Copyright © 2000-2024, Peerview

28. Calvin: 67-Year-Old Patient With mUC

Retired math teacher
Married with 5 grandchildren

Enjoys gardening and being
active

Lung and lymph node

metastases
Grade 2 neuropathy in
hands and feet Initial therapy managed by
(trouble tying shoes, local oncologist
buttoning shirt) Urothelial cancer has

+ History of T2DM progressed
(HbA1C 9%) Reached out to tertiary

+ Prior treatment: center to guide discussion
gem/cis; maintenance for future therapy options
avelumab

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29. 3 Months Later...