Familiar Tools, New Uses? Assessing Novel Combination Approaches in the First-Line Management of Advanced Urothelial Carcinoma

Andrea Necchi, MD, Shilpa Gupta, MD, and Begoña Pérez-Valderrama, MD, discuss urothelial carcinoma in this CE activity titled "Familiar Tools, New Uses? Assessing Novel Combination Approaches in the First-Line Management of Advanced Urothelial Carcinoma." For the full presentation, please visit us at www.peervoice.com/YQM870.

1. PeerVoice

Familiar Tools, New Uses? Assessing Novel Combination Approaches in
the First-Line Management of Advanced Urothelial Carcinoma

Learning Objectives

Recall safety and efficacy data evaluating the combination of an antibody-drug
conjugate (ADC) plus an immune checkpoint inhibitor (ICI) for the first-line
management of locally advanced/metastatic urothelial carcinoma (la/mUC)
Apply recently updated guideline recommendations regarding first-line
management of patients with la/mUC

Recognise adverse events associated with the combination of an ADC and ICI for
the management of la/mUC

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Part 1 of 2: Reviewing the Rationale: Current Needs and Available Evidence
for First-Line Combination Therapy in Advanced Bladder Cancer

y

Andrea Necchi, MD Shilpa Gupta, MD Begoña Pérez-Valderrama, MD
Associate Professor Clinical Professor Head of Genitourinary Tumors Unit,
Vita-Salute San Raffaele University Cleveland Clinic Lerner College of Medicine at Medical Oncology Department
Director of GU Medical Oncology Case Comprehensive Cancer Center University Hospital Virgen del Rocío
IRCCS San Raffaele Hospital Director, Genitourinary Oncology Seville, Spain
Milan, Italy Cleveland Clinic Taussig Cancer Institute

Cleveland, Ohio, USA

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Disclosures

‘Andrea Necchi, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for AstraZeneca; Bristol Myers Squibb Company; Catalym GmbH; F. Hoffmann-La Roche Ltd; Gilead Sciences, Inc;

? | Johnson & Johnson; Merck KGaA; Merck Sharp & Dohme Corp; Pfizer Inc; and Seagen Inc.

Grant/Research Support from Bristol Myers Squibb Company; Gilead Sciences, Inc. Incyte: and Merck Sharp & Dohme Corp.
Advisory Board for AstraZeneca; Bristol Myers Squibb Company; Catalym GmbH; F. Hoffmann-La Roche Ltd; Gilead Sciences, Inc.;
Johnson & Johnson; Merck KGaA; Merck Sharp & Dohme Corp; Pfizer Inc; and Seagen Inc.

Shilpa Gupta, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Astellas Pharma Inc. Bayer AG; Bristol Myers Squibb Company; Foundation Medicine, Inc;
Inc, Sanofi; and Seattle Genetics, Inc.

Grant/Research Support from Acrivon Therapeutics; Bristol Myers Squibb Company; F. Hoffmann-La Roche Ltd; Merck KGaA;
Novartis AG; Pfizer Inc.; QED Therapeutics, Inc. Seattle Genetics, Inc; and Tyra Biosciences, Inc.

Speakers Bureau participant with Bristol Myers Squibb Company; Gilead Sciences, Inc; and Seattle Genetics, Inc.

Stock Shareholder in BioNTech SE and Nektar Therapeutics.

Advisory Board for Astellas Pharma Inc; Bayer AG; Bristol Myers Squibb Company; Foundation Medicine, Inc; Gilead Sciences, Inc;
Pfizer Inc.; Sanofi; and Seattle Genetics, Inc.

Speaker or participant in accredited CME/CPD for PeerView, Inc.

lead Sciences, Inc; Pfizer

Begoña Pérez-Valderrama, MD, has a financial interest/relationship or af in the form of:
Advisory Board for Astellas Pharma Inc Bristol Myers Squibb Company; Merck KGaA; and Merck Sharp & Dohme Corp.

Other Financial or Material Support from travel accomodations provided by Bristol Myers Squibb Company and Merck KGaA.
Speaker or participant in accredited CME/CPD for Astellas Pharma Inc; Bristol Myers Squibb Company; Merck KGaA; and Merck
Sharp & Dohme Corp.

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Approved First-Line Options for la/mUC

y y y
Pt-ChT ineligible
and

eligible eligible

PD-LI-positive

| Cisplatin- | | Carboplatin- |

Atezolizumab or
pembrolizumab

CisGem boGem

Maintenance
avelumab

Diagram does not include the most recent FDA-approved or EMA-approved therapeutic options.

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JAVELIN Bladder 100: Long-Term Efficacy Outcomes

os

0S, %

Avelumab + BSC

so PFS

PFS, %

159% — Avelumab + BSC

O 4 8 DB 20 24 28 32 36 40 44 48 52 56 60
Time, mo

BSC alone
o H
0 4 8 2 % 20 24 28 32 36 40 44 48 52 56 60
Time, mo

Avelumab + BSC BSC Alone Avelumab + BSC. ‘BSC Alone
(n= 350) (n=350) (n = 350) (n = 350)

Events, n (%)

215 (614) 237 (67.7)
OS. median (95% Cl) mo 238(19.9-288) 150(135-182)
Stratified HR (95% Cl) 076 (063-091)
2-sided P

0036

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Events, n (%6) 268 (766) 287 (820)
PFS, median (95% Cl),mo 55(42-72) 21(19-3.0)
Stratified HR (95% Cl) 0.54 (0.46-0.64)
2-sided P <0001

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First-Line la/mUC: Efficacy Outcomes With Pembro or Atezo

Drug and

Control Arm sur

RR, %
(95% Cl)

Median PFS, mo
(95% Cl)

Median OS, mo
(95% Cl)

Pembrolizumab | 1: er no | 47(38-57) NR 18.5 (122-285)
| ee | ILinPD-Li-positive | 160 32% NR ER en
| Atezolizumab | E De 32 | 2804-47) | 41(23-18) 123 (6.0-NE)
| Atezolizumab | ILinPD-Li-positive | 88 NA NA eos)

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Defining Platinum Eligibility Criteria for la/mUC

Recommended Cri

Survey Results for European-Based

for Pt El y Oncologists / Urologists (N = 503)
eria for Pt
Eligibility reed
ECOG PS 3 Age, years =
= er 33.2
CrCl, ml/min <30 22 406
Ee OSES 23 453
PN grade 22
he CrCl, ml/min = =
NYHA HF class m :
PN grade a pas
CrCl, ml/min «30 23 41.7
(ECOG PS 2) 1 245
Deed GE MEL SS i 58.4
CrCl, ml/min <40 227
(ECOG PS 2) <30 322
CrCl, ml/min, for <40 223
Cis ineligibility «50 34.4

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EV-302: Efficacy Outcomes

os
Risk of death was reduced by 53%
in patients who received EV + P

PFS
Risk of progression or death was reduced by 55%
in patients who received EV + P
29
©

Ev+P

PFS,%

Ev+P

Chemo 20

OS, %
08385883888

Chemo

024689011 % 5 20222426 28 3032 343638 0246800 M 1 20 22 24 26 28 30 32 34

Time, mo Time, mo
RS) A AENA
Events, n (%) 133 (30.1) 226 (50.9) Events, n(%) 223 (50.5) 307 (69.1)

HR (95% CI) 0.47 (0.38-0.58) HR (95% CI) 0.45 (0.38-0.54)
PE — Sue —_
OS, median (95% Cl), mo 315 (25.4-NR) 16.1(13.9-18.3) PFS, median, (95% Cl), mo 125 (10.4-16.6) 63(6.2-6.5)

Enfortumab vedotin plus pembrolizumab: FDA-approved (2023) as a first-line treatment
for all patients with laUC or mUC, regardless of cisplatin eligibility or PD-L1 status

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CheckMate-901: Efficacy Outcomes

0S, %

Events, n (%)
HR (95% Cl)
P

OS, median (95% Cl), mo

os PFS
% a
E >
o RO
so gs
» sa E? Nivolumab
2 2 + Gom-cis
» Gem-Ci » Gem-Cis
AREA NPEPETER DS
Time, mo Time, mo
Gom-Gis (n= 304)
172(56.5) 193 (63.4) Events, n (%) 211(69.4) 191 (62.8)
0.78 (0.63-0.96) HR (95% CI) 072 (0.59-0.88)
02 P -001
217 (18.6-26.4) 18.9 (147-224) PFS, median (95% Cl), mo 7.9 (76-95) 7.6 (61-7.8)

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Abbreviations and References

Approved First-Line Options for la/mUC

Abbreviation(s): ChT: chemotherapy; Carbo/Gem: carboplatin/gemcitabine; CisGem: cisplatin/gemcitabine;
la/mUC: locally advanced/metastatic urothelial carcinoma; Pt: platinum.
Reference(s): Adapted from Powles T et al; ESMO Guidelines Committee. Ann Oncol. 2022;33:244-258.

JAVELIN Bladder 100: Long-Term Efficacy Outcomes
Reference(s): Powles T et al. J Clin Oncol. 2023;41:3486-3492.

First-Line la/mUC: Efficacy Outcomes With Pembro or Atezo

Abbreviation(s): 1L: first-line; atezo: atezolizumab; NA: not available; NE: not estimable/evaluable; NR: not reached;
pembro: pembrolizumab.

Reference(s): 1. Balar AV et al. Lancet Oncol. 2017,18:1483-1492.

2. Powles T et al. Lancet Oncol. 2021;22:931-945.

3. Balar AV et al. Lancet. 2017;389:67-76.

4. Galsky MD et al. Lancet. 2020;395:1547-1557.

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Abbreviations and References (Cont'd)

Defining Platinum Eligibility Criteria for la/mUC

Abbreviation(s): CrCl: creatinine clearance; HF: heart failure; NYHA: New York Heart Association;
PN: peripheral neuropathy; PS: performance status.
Reference(s): Gupta S et al. Abstract 696. J Clin Oncol. 2024:42(suppl 4): Abstract 696.

EV-302: Efficacy Outcomes

Abbreviation(s): EV + P: enfortumab vedotin plus pembrolizumab.
Reference(s): Powles T et al. Ann Oncol. 2023:34(suppl 2): Abstract LBAG.

CheckMate-901: Efficacy Outcomes
Abbreviation(s): GemCik

gemcitabine/cisplatin.
ijden MS et al; CheckMate 901 Trial Investigators. N Engl J Med. 2023;389:1778-1789.

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Part 2 of 2: Lessons Learned From the USA: Prac

al Considerations

in the Use of ADC-ICI Combinations in Advanced Bladder Cancer

Andrea Necchi, MD
Associate Professor

Vita-Salute San Raffaele University
Director of GU Medical Oncology
IRCCS San Raffaele Hospital

Milan, Italy

Shilpa Gupta, MD
Clinical Professor

Cleveland Clinic Lerner College of Medicine at
Case Comprehensive Cancer Center
Director, Genitourinary Oncology

Cleveland Clinic Taussig Cancer Institute
Cleveland, Ohio, USA

Begoña Pérez-Valderrama, MD
Head of Genitourinary Tumors Unit,
Medical Oncology Department
University Hospital Virgen del Rocio

Seville, Spain

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Disclosures

‘Andrea Necchi, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for AstraZeneca; Bristol Myers Squibb Company; Catalym GmbH; F. Hoffmann-La Roche Ltd; Gilead Sciences, Inc;

? | Johnson & Johnson; Merck KGaA; Merck Sharp & Dohme Corp; Pfizer Inc; and Seagen Inc.

Grant/Research Support from Bristol Myers Squibb Company; Gilead Sciences, Inc. Incyte: and Merck Sharp & Dohme Corp.
Advisory Board for AstraZeneca; Bristol Myers Squibb Company; Catalym GmbH; F. Hoffmann-La Roche Ltd; Gilead Sciences, Inc.;
Johnson & Johnson; Merck KGaA; Merck Sharp & Dohme Corp; Pfizer Inc; and Seagen Inc.

Shilpa Gupta, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Astellas Pharma Inc. Bayer AG; Bristol Myers Squibb Company; Foundation Medicine, Inc;
Inc, Sanofi; and Seattle Genetics, Inc.

Grant/Research Support from Acrivon Therapeutics; Bristol Myers Squibb Company; F. Hoffmann-La Roche Ltd; Merck KGaA;
Novartis AG; Pfizer Inc.; QED Therapeutics, Inc. Seattle Genetics, Inc; and Tyra Biosciences, Inc.

Speakers Bureau participant with Bristol Myers Squibb Company; Gilead Sciences, Inc; and Seattle Genetics, Inc.

Stock Shareholder in BioNTech SE and Nektar Therapeutics.

Advisory Board for Astellas Pharma Inc; Bayer AG; Bristol Myers Squibb Company; Foundation Medicine, Inc; Gilead Sciences, Inc;
Pfizer Inc.; Sanofi; and Seattle Genetics, Inc.

Speaker or participant in accredited CME/CPD for PeerView, Inc.

lead Sciences, Inc; Pfizer

Begoña Pérez-Valderrama, MD, has a financial interest/relationship or af in the form of:
Advisory Board for Astellas Pharma Inc Bristol Myers Squibb Company; Merck KGaA; and Merck Sharp & Dohme Corp.

Other Financial or Material Support from travel accomodations provided by Bristol Myers Squibb Company and Merck KGaA.
Speaker or participant in accredited CME/CPD for Astellas Pharma Inc; Bristol Myers Squibb Company; Merck KGaA; and Merck
Sharp & Dohme Corp.

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First-Line Approved and Emerging Options for la/mUC

Avelumab Avelumab
Pembrolizumab!

"Date of initial approval by EMA: indication was updated in 2018. “Approved by the FDA in May 2016; licence withdrawn by company in Nov 2022.

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EV + Pembro: New Recommended SoC for First-Line la/mUC

Treatment-i anced or metastatic UC (stage IV)
tatic UC V when EV + P unavailable or contraindicated

Cisplatin- Cisplatin- or
ible only carboplatin-eligible
+
= A Disease Disease No disease
Disesse progression progression progression progression

Pembrolizumab Maintenance
Atezolizumab avelumab

+ EV4P is preferred over platinum-based ChT irrespective of platinum eligibility

+ Nivolumeb-cisplatin-gemcitabine or platinum-based ChT and maintenance
avelumab are alternatives if EV+P is not possible

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EV-302: TRAEs With EV + Pembro

Overall

Peripheral sensory neuropathy
Pruritus

Alopaecia
Maculopapular rash
Fatigue

Diarrhoea
Decreased appetite
Nausea

Anaemia
Neutropaenia

‘Thrombocytopaenia

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970

EV+P(n=440)

ChT (n =433)
950

Grades 1/2 23
EV+P =
cht =

360

388

Incidence, %

Serious TRAEs
+ EV +P: 122, 27.7%
+ Chemotherapy: 85, 19.6%

Grade 23 TRAEs
+ EV +P: 56%
+ Chemotherapy: 70%

TRAES Leading to Death
(per investigator)
+ EV+P(4,0.9%)
— Asthaenia
- Diarrhoea
- Immune-mediated lung
disease
= Multiple organ dysfunction
syndrome
+ Chemotherapy (4, 0.9%)
Febrile neutropaenia
Myocardial infarction
Neutropaenic sepsis
Sepsis

1

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AEs of Clinical Interest With EV + Pembro

Median Times to Onset of Select AEs in Patients With
la/mUC Treated With EV + P

Hypergiycaemia 20

conri on 1035) O:

2

rr

¡Grade 23 skin reactions Y _
' L7 mo.
(range: 0110172)

ero

¡Grade 22 peripheral
neuropathy

Pneumonitis
(range: 0.3 td 26)
6mo
y $ (range: 0.3 to 25)
Median Time Since Start of Treatment (mo) >

An AE may occur at any point in time; data reflect patients with UC who received
at least one dose of EV + P from EV-302 and EV-103 (N = 564.

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Sequenci

g Treatment Options in la/mUC

Disease progression

Treatment-naive
when EV + P una

isplatin-
eligible only

Nivolumab:
GemCis

Gemcitabir

or carboplatin

e + cisplatin

Disease
progression

Disease

progression

No disease
progression

Atezolizumab

Erdafitinib
Enfortumab ved
Sacituzumab govite
Vinfluni

Pembrolizumab

tin
an
or taxane

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progression

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Abbreviations and References

First-Line Approved and Emerging Options for la/mUC
Abbreviation(s): GemCis: gemcitabine/cisplatin; la/mUC: locally advanced/metastatic urothelial carcinoma.

EV + Pembro: New Recommended SoC for First-Line la/mUC

Abbreviation(s): ChT: chemotherapy; EV + P/pembro: enfortumab vedotin plus pembrolizumab.
Reference(s): Powles T et al; ESMO Guidelines Committee. Ann Oncol. 2024;35:485-490.

EV-302: TRAEs With EV + Pembro

Abbreviation(s): TRAE: treatment-related adverse event.

Reference(s): Powles T et al. Ann Oncol. 2023;34 (suppl 2): Abstract LBAS.
AEs of Cl al Interest With EV + Pembro

Reference(s): Brower B et al. Front Oncol. 2024;14:1326715.

Sequencing Treatment Options in la/mUC
Reference(s): Powles T et al; ESMO Guidelines Committee. Ann Oncol. 2024;35:485-490.

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