Immunotherapy In Bladder Cancerd2qrtshcpf0x30.cloudfront.net/nodes/188/AUA Slides FINAL...

Agenda

Agenda Item Speaker

8:00-8:15 AM Welcome/Introductions/Pretest Dr. Kamat, Chair

8:15-8:25 AM Immunotherapy in Bladder Cancer: Basic Concepts Dr. Dreicer

8:25-9:05 AM Clinical Experience with Immunotherapy in Bladder Cancer

8:25-8:40 AM ICI in Advanced/Met Disease and Lessons Learned Dr. Bellmunt

8:40-8:50 AM Predictive Biomarkers for Checkpoint Blockade Therapy Dr. Dinney

8:50-9:05 AM Roundtable Discussion Dr. Dreicer (Moderator)

9:05-9:50 AM Practical Aspects of Immune Checkpoint Inhibitors

9:05-9:15 AM Safety Profile of ICIs: Early Recognition & Management Dr. Dreicer

9:15-9:25 AM Ways Urologists Can Adopt ICI into Clinical Practice: Med Onc Perspective Dr. Bellmunt

9:25-9:35 AM Ways Urologists Can Adopt ICI into Clinical Practice: Urologist’s Perspective Dr. Dinney

9:35-9:50 AM Roundtable Discussion Dr. Kamat (Moderator)

9:50-10:00 AM Concluding Remarks/Posttest Dr. Kamat, Chair

1. Describe the basic concepts of cancer immunotherapy, including immune checkpoint blockade, and rationale for its use in bladder cancer.

2. Appraise safety and efficacy of current and emerging cancer immunotherapy, including immune checkpoint inhibitors, in patients with locally advanced or metastatic bladder cancer.

3. Evaluate the role for biomarkers in locally advanced or metastatic bladder cancer when immune checkpoint inhibitors are used.

4. Identify practical strategies to prevent, anticipate, and manage immune-related adverse events in patients with locally advanced or metastatic bladder cancer in your urology practice.

Learning Objectives

Faculty

Faculty Disclosures

Joaquim Bellmunt, MD, PhD - has disclosed that he is a consultant for AstraZeneca, Genentech, and Merck and receives grant/research support from Novartis and Sanofi.

Colin P.N. Dinney, MD - has disclosed that he receives financial or material support from FKD Therapies.

Robert Dreicer, MD, MS, MACP, FASCO - has disclosed that he is a consultant for Asana, Astellas, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Medivation, Roche, and Sanofi-Genzyme. He also receives grant/research support from Asana, Genentech, and Merck.

Ashish M. Kamat, MD, MBBS, FACS - has disclosed that he is a consultant for Abbott Molecular, Cepheid, Heat Biologics, Merck, Oncogenics, Photocure, Spectrum Pharmaceuticals, Telesta Therapeutics, and Theralase. He also receives grant/research support from FKD Therapies, Heat Biologics, Merck, and Photocure.

Agenda

Agenda Item Speaker













Robert Dreicer, MD, MS, MACP, FASCOHead, Medical Oncology Section

Deputy Director, University of Virginia Cancer Center

Co-Director Paul Mellon Urologic Oncology Center

Professor of Medicine and Urology

University of Virginia School of Medicine

Immunotherapy in Bladder Cancer

• Renal Cancer

– HD IL2 – FDA-approved

– Interferon alfa

• Prostate Cancer

– Sipuleucel T – first and only FDA-approved cancer vaccine

• Bladder Cancer

– BCG

– Avelumab, Atezolizumab, Durvalumab, Nivolumab: FDA-approved in advanced urothelial cancer and in cisplatin-ineligible cases (atezolizumab)

Immunomodulatory Therapeutics in GU Cancers

U.S. Food and Drug Administration

Funt SA, Rosenberg JE. Nat Rev Clin Oncol. 2017; Kamat AM, et al. Lancet. 2016.

Bladder Cancer Therapeutic Landscape

T2-T4: Muscle-Invasive Bladder

Cancer (MIBC)

Radical cystectomy; <25% get adjuvant/

neoadjuvant (Gem/Cis)

First-Line Metastatic

Gem/Cis or MVAC are SOC in US; Gem/Carbo or Atezolizumab for

Cis-ineligible (50%)

Second-Line Metastatic

Avelumab, Atezolizumab,Durvalumab, Nivolumab

ORR 15%-19.6%mOS: 7.9-11.4 mo

Taxanes, gemcitabine,pemetrexed,

vinflunine (EU)ORR: 10%

mOS: 7-9 mo

10%-15%

10%-15%

70%-80%Ta/T1/Tis: Non‒Muscle-Invasive Bladder

Cancer (NMIBC)

TURBT/intravesical BCG

Normal Urothelium

Non–Muscle-Invasive Bladder Cancer: Bacillus Calmette-Guérin (BCG)

Initial response rates of approximately 70%

Functions via activation of immune system and induction of inflammatory response

Mechanism of action not completely understood

• BCG attaches to urothelial cells, followed by internalization

• Cells then upregulate MHC-II molecules and secrete cytokines, resulting in recruitment of immune cells, including lymphocytes, to tumor environment

BCG: gold standard in treatment of high-risk NMIBC

Kamat AM, et al. Lancet. 2016.

• Tumors must evolve mechanisms to locally evade and or disable the immune system.

• The goal of T-cell checkpoint blockade is to prohibit access of tumor cells to the “off switch” of the T-cell, restoring and maintaining tumor-specific immunity.

Why do tumors evade the immune response?

Mellman I, et al. Nature. 2011.

T-Cell Activation Represents a Balance of Activating and Inhibitory Factors

CD28

OX40

GITR

CD137

CD27

HVEM LAG-3

VISTA

BTLA

TIM-3

PD-1

CTLA-4

Agonistic antibodies

Blocking antibodies

T-cell stimulation

Activating Receptors

Inhibitory Receptors

Hayden EC. Nature. 2012.

Anti-PD-1/PD-L1: Unleash Cytotoxic CD8+ T-cells

PD-L1 binds PD-1, inhibiting T-cell response

A separate therapyuses antibodiesthat bind PD-L1on the tumour cell

PD-L1

Antibodies block inhibitory signal to PD-1

T-cell receptor recognizes tumour cell

Cancer Genome Atlas Research Network. Nature. 2014.

Expression Patterns Define Subsets of Bladder Cancer

mut/amp/fusionPapillary/squamous

Missing data

mRNA/miRNA/protein

Integrated Analysis of mRNA, miRNA and Protein Data

-2 0 2

Bladder Cancer Molecular Taxonomy: Summary from a Consensus Meeting


TCGA Cluster II corresponds to the MDACC p53-like subtype

Powles T, et al. Nature. 2014.

PD-L1 Expression in Metastatic Bladder Cancer

IHC Score(N = 205)

Tumor-Infiltrating Immune Cells, n (%)

Tumor Cells, n (%)

IHC 3 18 (9) 14 (7)

IHC 2 37 (18) 8 (4)

IHC 1 89 (43) 37 (18)

IHC 0 61 (30) 146 (71)

PD-L1 Positivity in UBC Tumors by IHC

Tumor Response With Atezolizumab Anti-PD-L1 Therapy in Metastatic Bladder Cancer

aPatients with CRs who had ≤100% reduction of target lesions due to lymph node target lesions; all lymph nodes returned to normal size per RECIST v1.1.

Max

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100

90

80

70

60

50

40

30

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-10

-20

-30

-40

-50

-60

-70

-80

-90

-100

IHC (IC) 0IHC (IC) 1IHC (IC) 2IHC (IC) 3IHC (IC) Unknown

a

a

Powles T, et al. Nature. 2014.

• Non-muscle invasive disease– Building upon BCG– Beyond BCG

• Locally advanced disease– Neoadjuvant/adjuvant

• Metastatic disease– Four agents approved– Phase III trial demonstrating survival compared to chemotherapy

• Combinatorial strategies – Extending the benefit to more patients

Immunotherapeutics in Bladder Cancer

Agenda

Agenda Item Speaker




8:25-8:40 AM ICIs in Advanced/Metastatic Disease and Lessons Learned Dr. Bellmunt









Joaquim Bellmunt, MD PhDAssociate Professor of Medicine

Harvard Medical School

Dana-Farber Cancer Institute

Immune Checkpoint Inhibitors (ICIs)in Advanced/Metastatic Disease and

Lessons Learned from Other Malignancies

Overview of APPROVED Checkpoint Inhibitors in THE US, EU, and JAPAN*

US EU Japan

PD-1 PD-L1 CTLA-4 Combination

Nivolumab1-3 Pembrolizumab4-6 Atezolizumab7 Durvalumab11 Avelumab8 Ipilimumab9,10 Nivolumab + ipilimumab1,2

Manufacturer BMS Merck Roche/Genentech AstraZeneca EMD Serono BMS BMS

Line 1L+ 2L+ 3L+ 1L+ 2L+ 3L+ 1L+** 2L+ 2L+ 1L+ 2L+ 1L+ 1L+

mMelanoma

mNSCLC

aRCC

cHL

mSCCHN

mUC

mMCC

Treatment schedule

q2w q3w q3w q2w q2w q3w X4Nivo then ipiq3w X4, then

nivo q2w

Atezolizumab, avelumab, durvalumab, and tremelimumab are not currently approved in Europe (status as of 05/10/2017).

*As of May 10, 2017. Please refer to product labeling for approved indications for each tumor type. **For cisplatin-ineligible patients only

1L, first line; 2L, second line; 3L, third line; aRCC, advanced renal cell carcinoma; cHL, classical Hodgkin lymphoma; CTLA-4, cytotoxic T-lymphocyte antigen-4; DTC, differentiated thyroid cancer; EU, European Union; ipi, ipilimumab; IV, intravenous; mMCC, metastatic Merkel cell carcinoma; mMelanoma, metastatic melanoma; mNSCLC, metastatic non-small cell lung cancer; mRCC, metastatic renal cell carcinoma; mSCCHN, metastatic squamous cell carcinoma of the head and neck; mUC, metastatic urothelial carcinoma; nivo, nivolumab; PD-1, programmed death receptor-1; PD-L1, programmed death ligand 1; PO, orally; q2w, every 2 weeks; q3w, every 3 weeks.1Nivolumab U.S. Prescribing Information. 2Nivolumab EU Prescribing Information. 3Ono Pharmaceuticals, Japan [Press Release]. 4Pembrolizumab U.S. Prescribing Information. 5Pembrolizumab EU Prescribing Information. 6Merck, Japan [Press Release]. 7Atezolizumab U.S. Prescribing Information. 8Avelumab U.S. Prescribing Information. 9Ipilimumab U.S. Prescribing Information. 10Ipilimumab EU Prescribing Information. 11Durvalumab U.S. Prescribing Information

Pembrolizumab Updated Results and Biomarker Analysis from KEYNOTE-012

Overall Response Rate = 28% (8/33)

64% experienced a decrease in target lesions

–30% decrease

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Median OS (N = 29) 12.7 months (95% CI 5.7-NR)12m OS = 52.9%

Analysis cutoff date: March 23, 2015.

Plimack ER, et al. Lancet Oncol. 2017.

IMvigor210, CheckMate 275, STUDY 1108 and JAVELIN: Recent Investigational and Registrational Trials in Pretreated mUC*

Patient number

Study Arms

Key Inclusion Criteria

Primary Endpoints

PD-L1 expressionPD-L1+PD-L1-NE/unknown

*No head-to-head studies have been conducted and direct comparisons cannot be made between these studies. †265 patients were evaluated for efficacy. ‡191 locally advanced/mUC patients enrolled and received treatment; 103 patients were eligible for efficacy analysis..§241 mUC patients were evaluated for safety and 153 mUC patients were evaluated for efficacy.BOR, best overall response; ECOG, Eastern Cooperative Oncology Group performance score; IC, immune cell; NE, not evaluable; ORR, objective response rate; PD-L1, programmed death ligand 1; TC, tumor cell

1Loriot Y, et al. Poster presentation at ESMO 2016. 783P; 2Sharma P, et al. Lancet Oncol. 2017; 3Powles T, et al. Poster presentation at 2017 ASCO GU. 286. 4Patel M, et al. Poster presentation at 2017 ASCO GU. 330.

CheckMate 2752

NivolumabPhase 2

270†

Nivolumab 3 mg/kg IV q2w

• ≥1 Platinum-containing or ≤12 months of neoadjuvant/adjuvant treatment

• Tumor tissue for PD-L1 testing• ECOG PS 0-1

• ORR

1% cut-off on TC• 46%• 54%

Study 11083

DurvalumabPhase 1/2

191‡

Durvalumab10 mg/kg IV q2w

• Histologically confirmed solid tumors

Locally advanced or mUC cohort:• Had progressed, on were

ineligible for, or refused any number of prior therapies

• ECOG PS 0-1

• Safety• ORR

25% cut-off on TC or IC• 51.3%• 41.4%• 7.3%

IMvigor 2101

Atezolizumab Phase 2

310 (Cohort 2)

Atezolizumab 1200 mg IV q3w

Cohort 2:• ≥1 Platinum-containing or ≤12

months of neoadjuvant/adjuvant treatment

• Tumor tissue for PD-L1 testing• ECOG PS 0-1

• ORR

IC1/2/3 (1% cut-off on IC)• 67%• 33%

JAVELIN solid tumor4

AvelumabPhase 1

241§

Avelumab 10 mg/kg IV q2w

• Solid tumors

mUC cohort:• Had progressed on post-

platinum treatment or cisplatin-ineligible

• Unselected for PD-L1• ECOG PS 0-1

• BOR• Safety

5% cut-off on TC• 33.6%• 48.5%• 17.8%

Phase 1 Evaluation of Pembrolizumab, Avelumab, Atezolizumab and Durvalumab in Advanced UC Shows Robust Activity

PembrolizumabPlimack 2017 AtezolizumabPowles 2014

AvelumabApolo 2016 DurvalumabMassard 2016

Phase II Studies with PD1/PD-L1 INHIBITORSin Second Line and Beyond (Platinum Treated)

Rosenberg JE, et al. Lancet. 2016.

Outcome, %All

N=265

Confirmed ORR by BIRCa 19.6

95% CI 15.0–24.9

Median PFS in months (95% CI) 2.00 (1.87–2.63)

Median OS in months (95% CI) 8.74 (6.05–NR)

PD-L1 <1%n=143

PD-L1 ≥1%n=122

PD-L1<5%n=184

PD-L1 ≥5%n=81

16.1 23.8 15.8 28.4

10.5–23.1 16.5–32.3 10.8–21.8 18.9–39.5

1.87 (1.77–2.04)

3.55 (1.94–3.71)

5.95 (4.30–8.08)

11.30 (8.74–NR)

In 52 responders • Time to response: 1.9 months (1.6–5.9)• Duration of response: NR (7.4-NR)• Ongoing responders at time of response: 40/52 (77%)

Safety: no new safety profile compare to prior reports

aBIRC, blinded independent review committee

Phase II CheckMate 275 studyAntitumor Activity of Nivolumab

Sharma P, et al. Lancet Oncol. 2017.

Phase I/II Studies with PD1/PD-L1 InhibitorsFirst-Line

“Unfit” Patients

Balar AV, et al. Lancet. 2017.

Agent and Indication(s) Dosing Guideline

Avelumab (PD-L1–blocking antibody)• Locally advanced or metastatic urothelial carcinoma (mUC) with disease progression during or

following platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks.Premedicate for the first 4 infusions and subsequently as needed.

Atezolizumab (PD-L1–blocking antibody)• Locally advanced or metastatic urothelial carcinoma (mUC) with disease progression during or

following platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

• Locally advanced or mUC who are not eligible for cisplatin chemotherapy (initial treatment)

1200 mg IV every 3weeks; treat until disease progression or unacceptable toxicity. Infuse over 1 hr for initial infusion; if tolerated, subsequent infusions may be given over 30 mins.

Durvalumab (PD-L1–blocking antibody)

• Patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

10 mg/kg as an intravenous infusion over 60 minutes every 2 weeks.

Nivolumab (PD-1–blocking antibody)• Patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease

progression during or following platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

240 mg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

FDA-Approved Immune Checkpoint Inhibitors for Urothelial Carcinoma

FDA Prescribing Information.

Objective Response (by PD-L1 Subgroups)

N = 100

CPS <1%†

N = 33CPS ≥1% to <10%

N = 33CPS ≥10%

N = 30

n % (95% CI) n % (95% CI) n % (95% CI)

ORR ( 24%) 6 18% (7-36%) 5 15% (5-32%) 11 37% (20-56%)

Complete response 1 3% (0.1-16%) 0 – 4 13% (4-31%)

Partial response 5 15% (5-32%) 5 15% (5-32%) 7 23% (10-42%)

Stable disease 3 9% (2-24%) 5 15% (5-32%) 7 23% (10-42%)

Data cutoff date: June 1, 2016

†Excluding those with CPS unknown

• The PD-L1 high expression cut point was determined to be CPS ≥10% (PD-L1 positive tumor, immune cells) and enriched for response; this cut point will be validated in the remaining patients in the cohort (n = 274 additional patients)

• Median time to response: 2.0 months (range, 1.9-4.8) • Median duration of response : Not reached (range, 1.4+ to 9.8+ months)• Duration of response rate ≥6 months: 83%

*CPS = combined positive score for PD-L1–positive cells (tumor, immune cells)

KEYNOTE-052: Pembrolizumab1st-Line Therapy for Cisplatin-Ineligible

Balar, et al. Ann Oncol. 2016.

KEYNOTE-045 Study Design (NCT02256436)1

SECOND LINE Phase III

IMvigor211 Study Design (NCT02302807)2

Estimated timelines Estimated completion: Sept 2016 (Early termination)

Pembrolizumab

SOC:Paclitaxel,

Docetaxel or Vinflunine

Secondary end points

•ORR•Safety

Primary end points•OS•PFS

• Urothelial cancer

• Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen.

• No more than 2 prior lines of systemic chemotherapy.

RandomizationN = 542 patients

1Bellmunt J, et al. N Engl J Med. 2017; 2Clinicaltrials.gov.

Estimated timelines Estimated completion: Nov 2017

Atezolizumab

SOC:Docetaxel,

Paclitaxel or Vinflunine

Secondary end points

•ORR•PFS•DOR•Safety

Primary end points

•OS • Urothelial cancer

• Progression or recurrence of urothelial cancer following a first-line platinum-containing regimen.

RandomizationN = 932 patients

Bellmunt J, et al. N Engl J Med. 2017.

43.9%30.7%

KEYNOTE-045 Study (NCT02256436) Overall Survival: Total

Median (95% CI)10.3 mo (8.0-11.8) 7.4 mo (6.1-8.3)

270 226 194 169 147 131 87 54 27 13 4 0 0

272 232 171 138 109 89 55 27 14 3 0 0 0

No. at risk

Events, n HR (95% CI) P

Pembro 155 0.73 (0.59-0.91) 0.0022

Chemo 179


Confirmed Objective Response Rate

Assessed per RECIST v1.1 by blinded, independent central review.Data cutoff date: Sep 7, 2016.

No alpha allocated to the comparison of ORR in the CPS ≥10% population.

0

5

10

15

20

25

30

35

40

OR

R, %

(9

5%

CI) 21.1%

11.4%

Δ9.6%P = 0.0011

PR

CR

Total Population

0

5

10

15

20

25

30

35

40

OR

R, %

(9

5%

CI)

21.6%

6.7%

CPS ≥10% Population

7.0%

14.1%3.3%

8.1%

6.8%

14.9%

2.2%4.4%

Pembrolizumab(N = 270)

Chemotherapy(N = 272)

Pembrolizumab(N = 74)

Chemotherapy(N = 90)

0

5

10

15

20

25

30

Inci

de

nce

, %

Data cutoff date: Sep 7, 2016.

Pembrolizumab

1-2 3-5Grade


Treatment-Related AEs with Incidence ≥10%

0

5

10

15

20

25

30

Inci

de

nce

, %Treatment-Related AEs with Incidence ≥10%

Pembrolizumab

1-2 3-5Grade


Chemotherapy

Alopecia occurred in 37.6% of patients in the chemotherapy arm.Data cutoff date: Sep 7, 2016.

• The primary efficacy endpoint, overall survival, was to be tested in a successive fashion in study populations defined by PD-L1 expression.

• The first population tested was people with the highest levels of PD-L1 expression (IC2/3), followed by those with any level of PD-L1 expression (IC1/2/3), and followed by the overall study population (Intention-To-Treat; ITT).

• Statistical significance needed to be achieved in the IC2/3 population in order to evaluate the IC1/2/3 population for statistical significance, and similarly achieved in the IC1/2/3 population in order to evaluate the overall study population for statistical significance.

• Exciting times in the treatment of urothelial carcinoma

• Immunotherapy is a well tolerated and active treatment for our patients

• Many open questions remain with regards to understanding predicting factors

• Several other novel immunotherapies are in clinical development

– Checkpoint inhibitors

– Combinations

– Antibody drug conjugates

– Targeted agents

Immunotherapy in UC - Conclusions

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Colin P.N. Dinney, MDDepartment of Urology

MD Anderson Cancer Center

Predictive Biomarkers for Checkpoint Blockade Therapy

• Tumors with high PD-L1 expression will be more susceptible to checkpoint blockade.

• Phase I trials with nivolumab (anti PD-1) and atezolizumab revealed 18-25% response rates.

• Nivolumab: 36% (9/25) with >5% tumor cell PD-L1 expression responded compared with 0/17 with neg. expression (Mouse anti human PDL-1 (clone 5H1)1

• Atezolizumab: highest response was in tumors with >10% TIL staining (Rabbit anti-human PD-L1 (clone SP142)2

• Different antibodies, different target tissue

Hypothesis

1Topalian SL, et al. N Engl J Med. 2012; 2Herbst RS, et al. Nature. 2014.

• Powles, et al. Nature. 2014. Phase I Atezolizumab

• Rosenberg, et al. Lancet. 2016. Phase II Atezolizumab

• Balar, et al. Lancet. 2017. Phase II Atezolizumab

• Massard, et al. J Clin Oncol. 2016. Phase I Durvalumab

• Sharma, et al. Lancet Oncol. 2016. Phase I/II Nivolumab

• Sharma, et al. Lancet Oncol. 2017. Phase I/II Nivolumab

• Plimack, et al. Lancet Oncol. 2017. Phase I Pembrolizumab

• Bellmunt, et al. N Engl J Med. 2017. Phase III Pembrolizumab

PD-L1 Expression as a Predictor of Checkpoint Blockade Sensitivity in UC

5/8 studies reported positive association with PD-L1 staining

Summary of the Results

Study AgentCompanion IHC

AntibodyThreshold for

PositivityTarget Cells

Assay Associated w/ Response?

Powles T, et al. Nature. 2014. Atezolizumab “Proprietary” 5% TILs Yes

Rosenberg JE, et al. Lancet. 2016. Atezolizumab SP142 5% TILs Yes

Balar AV, et al. Lancet. 2017. (platinum ineligible)

Atezolizumab SP142 5% TILs No

Massard C, et al. J Clin Oncol. 2017. Durvalumab SP263 25%TILs &

TCsYes

Sharma P, et al. Lancet Oncol. 2016. Nivolumab Dako 28-8 1% TCs No

Sharma P, et al. Lancet Oncol. 2017. Nivolumab Dako 28-8 1% TCs Yes

Plimack ER, et al. Lancet Oncol. 2017.

Pembrolizumab 22C3 1%TILs &

TCsTILs only

Bellmunt J, et al. N Engl J Med. 2017. (chemo vs immuno 2nd line)

Pembrolizumab 22C3 10%TILs &

TCsNo

Can PD-L1-negative Cells become PD-L1-positive?Adaptive Regulation of PD-L1 Expression

MPDL3280A

PD-L1CD8

Baseline

PD-L1CD8

On-Tx

Powderly, ASCO 2013.

Anti-PD-L1

T cells and tumor cells expressing PD-L1

Question: Instead of focusing so much attention on a single marker such as PD-L1, should we consider additional biomarkers such as T-cell subsets and tumor burden?

CD8 T-cells PD-L1 CD8 T-cells PD-L1

• PD-L1 expression associated with worse overall mortality after cystectomy for organ-confined disease (HR: 3.2).1

• No association with PD-L1 expression and post-cystectomy survival.2

• No association of PD-L1 TC staining with outcomes, but positive association of PD-L1 IC staining with improved survival in M1 patients.3

PD-L1 Expression As A Prognostic Biomarker In Bladder Cancer? The Jury is Still Out

1Boorjian SA, et al. Clin Cancer Res. 2008; 2Faraj SF, et al. Urology. 2015; 3Bellmunt J, et al. Ann Oncol. 2015.

• What cells are important? Tumor cells vs ICs?

• What is the appropriate threshold for positive staining?

• Which assays are more reliable? – “Blueprint project” – industry sponsored comparison of four companion

assays• SP142 is outlier with consistently lower scoring

• More inter-observer variability with IC with intraclass correlation coefficients 0.2 c/w 0.8 for TC

• 37% of patients had assay-dependent classification (one or more of 4 assays would reclassify response).

Why No Consistent Performance?

Hirsch FR, et al. J Thorac Oncol. 2017.

• PD-L1 “positivity” inconsistently enriches for clinical benefit

• For bladder cancer, there is currently no requirement for PD-L1 testing prior to checkpoint blockade therapy

• IHC is unreliable for measuring PD-L1 expression

• Mutational burden correlates with response

• Need to look beyond a single static biomarker

Bottom Line

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1. What is the “sense” of the urologic community to the emergence of checkpoint inhibitor therapy in advanced disease and how may it help drive clinical trials in both non-muscle invasive and locally advanced disease?

2. Given the different PD-L1 assays and the results of trials to date, is there a role for routine PD-L1 testing in urothelial cancer?

3. What is the future for chemotherapy in bladder cancer?

4. Can you envision a role for cytoreductive surgery in metastatic urothelial cancer in the context of immunotherapy?

Roundtable Discussion 1

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Robert Dreicer, MD, MS, MACP, FASCO

Safety Profile of Checkpoint Inhibitors: Early Recognition & Management Strategies

• Major side effects of immunotherapy are related to development of “autoimmunity”

• Immune-related adverse events, also known as “immune-mediated adverse events” (irAEs, imAEs), may occur in any organ system

• Certain events may be life threatening or fatal

• Prompt recognition of potentially severe irAEs improves outcomes

• Combining checkpoint inhibitors with agents such at CTLA4 inhibitors significantly increases irAEs

Toxicity of Immune Checkpoint Blockade

Teply BA and Lipson EJ. Oncology. 2014.

Immune-Related Adverse Events

GastrointestinalColitis/diarrhea

NeuromuscularPeripheral sensory

neuropathy

RespiratoryPneumonitis

HepaticAutoimmune hepatitis

ALT/AST increases

RenalNephritis

Renal failure

SkinMaculopapular rash

Pruritus

EndocrineHypophysitis

ThyroiditisType 1 diabetes

Avelumab Atezolizumab Durvalumab Nivolumab

Adverse Event, (%) All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4 All Grades Grades 3-4

Gen - Fatigue 41 7 52 6 39 6 46 7

Gen – Peripheral edema 17 0.4 18 1 15 2 13 0.4

Gen - Pyrexia 16 1 21 1 14 1 17 0.4

GI - Constipation 18 1 21 0.3 21 1 16 0.4

GI - Nausea 24 1 25 2 16 2 22 0.7

GI - Vomiting 14 1 17 1 - - 12 1.9

GI – Abdominal pain 19 2 17 4 14 3 13 1.5

GI – Diarrhea/colitis 18 2 18 1 13 1 17 2.6

Resp - Cough 14 0 14 0.3 10 0 18 0

Resp - Dyspnea 17 2 16 4 13 2 14 3.3

Skin - Rash 15 0.4 15 0.3 11 1 16 1.5

GU - UTI 21 5 22 9 15 4 17 7

GU - Hematuria - - 14 3 - - - -

Musculoskeletal pain 25 3 15 2 24 4 30 2.6

Reduced appetite 21 2 26 1 19 1 22 2.2

U.S. FDA Prescribing Information

Checkpoint Inhibitor Adverse Events(occurring in ≥10% of those with urothelial cancer that has progressed on platinum-containing regimen)

Adverse event Severity Dose modification

Colitis

Grade 2 diarrhea or colitis Withhold dose

Grade 3 diarrhea or colitisWithhold dose when administered as single agent

Grade 4 diarrhea or colitis Permanently discontinue

PneumonitisGrade 2 Withhold dose

Grade 3 or 4 Permanently discontinue

HepatitisAST or ALT >3 and up to 5x ULN or T bili >1.5 and up to 3x ULN Withhold dose

AST or ALT >5x ULN or T bili >3x ULN Permanently discontinue

NephritisSerum creatinine >1.5 and up to 6x ULN Withhold dose

Serum creatinine more than 6x ULN Permanently discontinue

Nivolumab Prescribing Information.

Nivolumab: Management of Selected AEs

Nivolumab Prescribing Information.

Nivolumab: Management of Selected AEs

Adverse event Severity Dose modification

Skin

Grade 3 rash or suspected Stevens-Johnson syndrome (SJS) or TEN

Withhold dose

Grade 4 rash or confirmed SJS or TEN Permanently discontinue

Other

Grade 3 AE1st occurrenceRecurrence of same grade 3 AE

Withhold dosePermanently discontinue

Life threatening or grade 4 AE Permanently discontinue

Requirement for prednisone or equivalent 10 mg daily for >12 weeks

Permanently discontinue

Persistent grade 2 or 3 AEs lasting12 weeks or longer

Permanently discontinue

• Anti-TNFα chimeric mAb (infliximab) → binds circulating TNFα

• Indications include ankylosing spondylitis, Crohn’s, psoriasis/psoriatic arthritis, rheumatoid arthritis, ulcerative colitis

• Dosing – Standard (rheumatologic conditions): 5 mg/kg IV at 0, 2, and 6 weeks,

then every 8 weeks maintenance– For irAEs, 5 mg/kg IV x 1 or 2 doses often sufficient to control

symptoms

Management Beyond Steroids

Naidoo J, et al. Ann Oncol. 2016; Infliximab Prescribing Information.

• No reliable means to predict who or when patients will develop irAEs

– History of autoimmunity exclusionary in clinical trials

– irAE may reflect nascent autoimmunity unmasked by checkpoint blockade

• Early diagnosis and aggressive systemic corticosteroids are key to prevent life-threatening consequences

• Biologics (TNFα antagonists) are highly effective in management of irAEs refractory to high-dose steroids or steroid-taper refractory

– Potential use as first-line treatment

Immune-Related Adverse Events

• Immune checkpoint inhibitor therapy is NOT chemotherapy

– Patient education, close follow-up MANDATORY

• Education of our colleagues (i.e. Hospital Medicine, Family Medicine, ER, and Internal Medicine docs) is critical

– Colitis

• Combination IO therapies have potential to improve outcomes, but with a potential price in toxicity

• Implications for an older patient population

Immune-Related Adverse Events: Caveats

Agenda

Agenda Item Speaker













Joaquim Bellmunt, MD

Ways Urologists Can Adopt ICI into Clinical Practice: Medical Oncologist’s Perspective

20161989 1993 1997 2001 2005 2009 2013

MVAC (Ph II)1

Paclitaxel (Ph II)2

Docetaxel (Ph II)4

Gemcitabine + Cisplatin (Ph III)5

HD-MVAC (Ph III)6

Gemcitabine + Paclitaxel (Ph II)7

Vinflunine (Ph III)9

Gemcitabine + Carboplatin / MCaVi (Ph III)11

Gemcitabine + Cisplatin + Paclitaxel (Ph III)12

Gemcitabine authorisation in UK

(Oct 26, '95)3Gemcitabine

EMA harmonisation (Sep 23, '08)8

Vinflunine EMA approval (Sep 21, '09)10

1Sternberg CN, et al. Cancer. 1989; 2Roth BJ, et al. J Clin Oncol. 1994; 3Eli Lilly. SmPC Gemzar® 01-Jul-2014 (www.medicined.org.uk); 4McCaffrey JA, et al. J Clin Oncol. 1997; 5Von der Maase H, et al. J Clin Oncol. 2000; 6Sternberg CN, et al. J Clin Oncol. 2001; 7Meluch AA, et al. J Clin Oncol. 2001; 8EMA. EMEA/CHMP/512295/2008; 24.09.2018 (www.ema.europa.eu); 9Bellmunt J, et al. J Clin Oncol. 2009; 10EMA. EMEA/H/C/000983; 2012 (www.ema.europa.eu); 11De Santis M, et al. J Clin Oncol. 2009; 12Bellmunt J, et al. J Clin Oncol. 2012.

Pu

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Evolution of Systemic Therapy for Urothelial Cancer

2016 20171989 1993 1997 2001 2005 2009 2013

MVAC (Ph II)1

Paclitaxel (Ph II)2

Docetaxel (Ph II)4

Gemcitabine + Cisplatin (Ph III)5

HD-MVAC (Ph III)6

Gemcitabine + Paclitaxel (Ph II)7

Vinflunine (Ph III)9

Gemcitabine + Carboplatin / MCaVi (Ph III)11

Gemcitabine + Cisplatin + Paclitaxel (Ph III)12

Gemcitabine authorisation in UK

(Oct 26, '95)3Gemcitabine

EMA harmonisation (Sep 23, '08)8

Vinflunine EMA approval (Sep 21, '09)10

1Sternberg CN, et al. Cancer. 1989; 2Roth BJ, et al. J Clin Oncol. 1994; 3Eli Lilly. SmPC Gemzar® 01-Jul-2014 (www.medicined.org.uk); 4McCaffrey JA, et al. J Clin Oncol. 1997; 5Von der Maase H, et al. J Clin Oncol. 2000; 6Sternberg CN, et al. J Clin Oncol. 2001; 7Meluch AA, et al. J Clin Oncol. 2001; 8EMA. EMEA/CHMP/512295/2008; 24.09.2018 (www.ema.europa.eu); 9Bellmunt J, et al. J Clin Oncol. 2009; 10EMA. EMEA/H/C/000983; 2012 (www.ema.europa.eu); 11De Santis M, et al. J Clin Oncol. 2009; 12Bellmunt J, et al. J Clin Oncol. 2012; 13Rosenberg JE, et al. Lancet. 2016; 14Massard C et al. ASCO 2016: abstract #4502 and oral presentation; 15AstraZeneca. Press Release 17.02.2016 (access: www.astrazeneca.com); 16FDA. Press Release 18.05.2016 (access: www.fda.gov); 17Apolo AB, et al. J Clin Oncol. 2016; 18Galsky MD, et al. ESMO 2016: abstract #LBA31_PR; 19Balar A, et al. Ann Oncol. 2016.

Pu

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Nivolumab (Ph II)18

Pembrolizumab (Ph I/II)19

Durvalumab FDA breakthrough

designation (Feb 17, '16)15

Atezolizumab FDA approval

(May 18, '16)16

Atezolizumab (Ph II)13

Durvalumab (Ph I/II)14

Avelumab (Ph I)17

NivolumabFDA approval(Feb 2, 2017)

AtezolizumabFDA approval

1st line cis-inelig(Apr 16, 2017)

DurvalumabFDA approval(May 1, 2017)

AvelumabFDA approval(May 9, 2017)

PembroFDA approval (?June 2017?)

• Durability of responses

• Continued response or disease stabilization even off therapy

– Suggests induction of a tumour specific memory response

• Unconventional or delayed immune-mediated responses

• Overall tolerability as a monotherapy (good partner compound)

• Non-cumulative toxicities

Rationale to Use Anti-PD-1/L1 Further in GU: Distinct Features of PD-1/L1 Blockade

Motzer RJ, et al. J Clin Oncol. 2014; Amin A, et al. J Clin Oncol.2014; Topalian SL, et al. J Clin Oncol. 2014; Drake CG, et al. J Clin Oncol. 2013.

Safety Profile of IO Therapy in Patients With Advanced Bladder Cancer Differs from Systemic Chemotherapy1

Rash Pneumonitis Dyspnea

Colitis

Increased Aspartate Aminotransferase

Increased Alanine Aminotransferase

Adverse event monitoring and early identification of immune-mediated

adverse events is crucial to safe use of IO therapy2

Immune-related adverse reactions related to T-cell modulation may affect

various organ systems

Endocrinopathy(eg, thyroid dysfunction)

1Rosenberg JE, et al. Lancet. 2016; 2Helissey C, et al. J Geriatr Oncol. 2016.

• Effective management of severe irAEsbased on

– Early recognition: assess patients for signs/symptoms of enterocolitis, dermatitis, neuropathy, endocrinopathy, or hepatotoxicity at baseline and before each dose

– Frequent monitoring

– Use of corticosteroids (and/or other immunosuppressive therapies) combined with either delaying or discontinuing ipilimumab

• Experience from sites utilizing the following recommendations suggest that it minimizes morbidity and hospitalizations

Global Management of irAEs

• Screen patients for adverse events: Weekly call to pts for first 16 weeks

– Review checklist to assess key symptoms

– Reinforce importance of reporting any new or worsening symptom

• Monitor outpatients with ongoing AEs: minimum biweekly call

• For patients admitted to an outside hospital for AEs

– Frequent contact with admitting physician and subspecialist

– Provide guidance on detection and management of irAEs

NMIBC BCG refractory

MIBC Neoadjuvant:Cisplatin-eligible

MIBC Neoadjuvant:Cisplatin-ineligible

MIBC Adjuvant: Cisplatin-eligible

MIBC Adjuvant: Cisplatin refractor and cisplatin-ineligible

Metastatic Cisplatin-eligible Front-line

Metastatic Cisplatin-ineligible Front-line

Metastatic Maintenance after front-line

2nd line and beyond

Disease States Model For Immunotherapy

• Genomic inducers of response

– Somatic/germline profiling

– Neoantigen discovery

• Pathologic score to predict response

Adapted from Bellmunt J, et al. Cancer Treat Rev. 2017.

Where Do We Go from Here? Select Ongoing Trials in Bladder Cancer

Non-Muscle Invasive

KEYNOTE-057 (Ph 2): • Pembrolizumab in BCG

unresponsive NMIBC

NCT02792192 (Ph 1/2):• Atezolizumab ± BCG in high

risk NMIBC

Muscle Invasive

CheckMate 274 (Ph 3): • Nivolumab vs placebo

postsurgery MIBC

IMvigor 010 (Ph 3):• Atezolizumab vs observation

postsurgery PD-L1+ MIBC

DANUBE (Ph 3):• Durvalumab ± Tremelimumab

vs chemo Tx-naïve, unresectable, urothelial carcinoma

KEYNOTE-052 (Ph 2):• Pembrolizumab Tx-naïve,

cisplatin ineligible, locally advanced mUC

KEYNOTE-361 (Ph 3):• Pembrolizumab ± chemo vs

chemo in Tx-naïve advanced or mUC

IMvigor 130 (Ph 3):• Atezolizumab gem-cis vs gem-

cis in untreated advanced or mUC

Pretreated Metastatic

CheckMate 275 (Ph 2):• Nivolumab for locally

advanced or mUC after Pt failure

IMvigor 211 (Ph 3):• Atezolizumab vs chemo in

locally adv or mUC, after Pt failure

KEYNOTE-045 (Ph 3):• Pembrolizumab vs chemo in

locally adv or mUC, after Pt failure

JAVELIN Bladder 100 (Ph 3):• Avelumab as maintenance vs BSC for locally advanced mUC

Bellmunt J, et al. Cancer Treat Rev. 2017

Treatment NaïveMetastatic

The Future: Combinatorial Strategies

PD-1 Blockade

Immune Inhibitory Molecules

+

CTLA-4 AbLAG-3TIM3

Immune Stimulating Molecules

IL-2TLR agonistsCD-137 AbAnti-OX40

Targeted Therapies

VEGF TKIsmTOR inhibitorsVEGF AbHDAC inhibitors

Vaccines IMA901Dendritic cells

Chemotherapy

RadiationVanneman M and Dranoff G. Nat Rev Cancer. 2012.

Gemcitabine5-FU

MIBC, muscle-invasive bladder cancer1Amin MB, et al. Eur Urol. 2013; 2Hansel DE, et al. Eur Urol. 2013; 3Milowsky MI, et al. J Clin Oncol. 2016; 4Montironi R, et al. Arch Pathol Lab Med. 2016; 5NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer V.2.2016.

Optimal Management of Advanced Bladder Cancer Requires a Multidisciplinary Approach1-5

Multidisciplinary Team

Medical Oncologist

OncologyNurse

Radiation Oncologist

Urologist

Pharmacist

• “Providing the best management for patients with bladder neoplasia relies on close cooperation and teamwork among urologists, oncologists, radiologists, and pathologists”

– 2nd International Consultation on Bladder Cancer1

• “Multidisciplinary input via tumor board discussions and/or directed consultations is critical to the optimal management of patients with MIBC and MBC”

– ASCO Clinical Practice Guideline Endorsement3

• Toxicity is mostly low grade and can be treated with supportive treatment.

• A concerted effort to educate the whole multidisciplinary team needs to take place and development of accessible algorithms to ensure minimized risk with toxicity.

• The key to successful management of checkpoint antibody toxicities is early diagnosis, high suspicion, excellent patient-provider communication, and rapid and aggressive use of corticosteroids and other immune suppressants for irAEs.

Conclusions

• The majority of both nivolumab and ipilimumab related AEs to date have been reversible and manageable by delaying study drug ±administration of corticosteroids; other immunosuppressants may also be needed.

• The following categories of AEs, requiring greater vigilance and early intervention: pulmonary, hepatic, renal, GI, endocrine, neurological, skin.

Conclusions

Agenda

Agenda Item Speaker













Colin P.N. Dinney, MD

Ways Urologists Can Adopt ICI into Clinical Practice: Urologist’s Perspective

• Unprecedented activity in the 2nd line metastatic setting

• Approved as 1st line therapy for platinum-ineligible metastatic disease

• Neoadjuvant and adjuvant trials ongoing

• Patient selection remains a challenge

Question: How do you identify platinum-eligible patients for chemotherapy or immunotherapy?

Immunotherapy for Locally Advanced and Metastatic UC

Immune Infiltration in MIBC

Cluster II Cluster IVCluster II Cluster IV

Basal TCGA Cluster IV tumors are enriched with lymphocytes

Choi adapted from TCGA

Bladder Cancer Molecular Taxonomy: Summary from a Consensus Meeting


TCGA Cluster II corresponds to the MDACC p53-like subtype

Subtype Specific Response to Chemotherapy

McConkey, et al. Eur Urol. 2016.

MDACC Discovery (P=0.018)

Choi, et al. Cancer Cell. 2014.

Lessons Learned from the IMvigor 210 Trial: Atezolizumab

• Basal tumors had the highest prevalence of immune infiltration.• Response was higher in the Luminal Cluster II (MDACC p53-like which is chemoresistant)• Non-overlapping sensitivity to chemo- and immunotherapy.

Rosenberg JE, et al. Lancet. 2016.

Ways Urologists Can Adopt ICI into Clinical PracticeWhat about NMIBC?

• Who should design and lead these trials?

• Which disease states?

• Which agents should be evaluated in this space?

• Does toxicity commensurate with disease lethality?

• Could checkpoint blockade inhibitors cause a delay or change in operative plan?

• How do you select the appropriate patients?

Questions for Checkpoint Blockade Inhibitor Therapy for NMIBC

• Single arm trials in BCG-unresponsive population

• BCG-failure group not a current approval strategy

• What about the BCG-intolerant patient?

• Randomized trials vs. BCG necessary for approval in the BCG-naïve population

• Does the progression rate and lethality of LG NMIBC justify extension to this indication?

• Anything short of a CR will be a treatment failure

Trial Design Considerations for Checkpoint Blockade in NMIBC

• Is it safe?

• Are checkpoint blockade biomarkers expressed by BCG naïve and unresponsive NMIBC?

• Does this matter?

• How effective are these agents?

• We don’t have much information yet

• Answers to some of these questions on the way

What Do We Know about Checkpoint Blockade Inhibitors in NMIBC So Far?

Immune-Mediated Adverse Events (imAEs)

• Pneumonitis

• Colitis

• Hypophysitis

• Dermatitis

• Hepatitis

Checkpoint biomarkers are expressed at relatively low levels

in untreated NMIBCs.

Checkpoint Blockade Biomarker Expressionin BCG Naive NMIBC

PD-L1 Expression Following BCG

Inman et al, Cancer 2007Inman BA, et al. Cancer. 2007.

UC demonstrating absence of PD-L1 staining (20x) UC demonstrating marked membranous PD-L1 staining (20x)

PD-L1+ BCG granuloma in recurrent UC (2.5x) PD-L1+ BCG granuloma in recurrent UC (40x)

PD-L1 Expression by Bladder Cancer

Bellmunt J, et al. Ann Oncol. 2015.

PD-L1 expression did not correlate with BCG exposure

Surveillance for 18 months

BCG unresponsive Ta/T1/Tis (TURBT)

MP

DL3

28

0A

cystocytol

MP

DL3

28

0A

MP

DL3

28

0A

MP

DL3

28

0A

cystobiopsy cytol

MP

DL3

28

0A

MP

DL3

28

0A

Phase II Trial of Atezolizumab (PD-L1) in BCG-Unresponsive NMIBC

MP

DL3

28

0A

MPDL3280Amaintenance

q3wks for 9 cyclesM

PD

L32

80

A

RFS @ 18months

q3 weeksCR @

21 weeks*(=6 months post TURBT)

q3 weeks9 weeks*

•Registration within 6 weeks of TURBT•Start therapy within 5 days of registration

* time is relative to first dose of MPDL3280A

Clinicaltrials.gov: NCT02844816.

Pembrolizumab (PD-1) for BCG-Unresponsive NMIBC

Patients with BCG-unresponsive

HR NMIBC

CystoscopyMonth 3

(q3m)

CystoscopyMonth 6 Cystoscopy

Month 24

Imaging Month 6

(q6m)

Imaging Month 24

Primary Endpoint: CR/DFSUp to 2 year of treatment with 1 year of post-treatment follow-up

Pembrolizumab 200 mg IV solution for infusion

… …Pembrolizumab (q3w)

Clinicaltrials.gov: NCT02625961.

BCG Unresponsive

NMIBCN=15

Month0 3 6 9 12 15 18 21 24

Legend

PD-1 or PD-L1 antibodyQ 2 weeks

rAd-IFN/Syn3 day 0 and day 1 Month 3

Primary End Point: Safety as per NCI CTCAE version 4.0

Secondary End Points:1. Rate of recurrent or progressive cancer at 24 months 2. Rate of patients able to tolerate ≥2 doses of rAd-IFN/Syn33. Tolerance as per AUASS

Correlative Studies: Urinary/blood: cytokines, DNA, mRNA, miRNA Q28 days x 6 Tissue biopsy at study entry and on progression: TIL characteristics IHC/Flow, cytokines, DNA, mRNA, miRNA

Combination Therapy Will be the KeySUO CTC rAd-Interferon (IFN)/Syn3 + Nivolumab

Proposed SUO CTC

• Decision should be data driven

• Early efficacy and tolerability will be available from ongoing trials

• Toxicity profile in the metastatic setting suggests that these agents can be delivered by urologists

• Comfort with delivering systemic therapy depends on training and support

• Cost/reimbursement and loss of technical fees will play a factor

• Availability of BCG

Checkpoint Blockade vs Intravesical Therapy?

• Role in locally advanced disease

• Patient selection is the key

• NMIBC is in a wait-and-see period

• Results from ongoing trials eagerly anticipated

• Support clinical trials and get smarter

Summary

Do you want to give up NMIBC as well?

Agenda

Agenda Item Speaker













1. Are there any differences in the safety profile of the various PD-L1 and PD-1 inhibitors or can they be considered one “class”?

2. What are the challenges in imAE identification and management, especially for those not accustomed to administering chemotherapy?

3. What are the most challenging imAEs to treat and why? Which potential imAEs are most likely to guide your patient selection? Given urologists’ knowledge of UC patients, which of the presented imAEs could present particular challenges?

4. What practical points would you make to a busy urological practice looking to incorporate IO agents into their practice—say for MIBC/NMIBC?

Roundtable Discussion 2

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