METASTATIC UROTHELIAL CARCINOMA Systemic second-line …

METASTATIC UROTHELIAL CARCINOMA

Systemic second-line therapy: The platinum-refractory setting

Alfonso Gómez de Liaño Lista, MD

Medical Oncology Department

Complejo Hospitalario Universitario Insular-Materno Infantil

Las Palmas de Gran Canaria, Spain

Ignacio Durán, MD, PhD

Medical Oncology Department,

Hospital Universitario Marqués de Valdecilla, IDIVAL

Santander, Spain

LEARNING OBJECTIVES

To become familiar with the current state-of-the-art in platinum-refractory metastatic urothelial carcinoma therapeutics

To specifically review the role of chemotherapy and immune checkpoint inhibitors in this setting

To understand the evolving scenario with the development of many novel promising drugs

OUTLINE

Introduction

General overview

Chemotherapy in second-line

Maintenance studies (early second-line)

Immuno-oncology: Checkpoint inhibition

Targeted therapy

◆ FGFR inhibitors

◆ Antibody Drug Conjugates

A glimpse into the future

Conclusions

THE SECOND-LINE SETTING:

AN UNMET NEED

First-line platinum-based chemotherapy has remained the standard of care for >30 years1,2

All patients virtually progress to first-line chemotherapy despite an initial response

Until recently, second-line options have remained scarce3,4

1. Sternberg CN, et al. J Urol 1985;133:403–7; 2. von der Maase H, et al. J Clin Oncol 2005;23:4602–8; 3. Bellmunt J, et al. J Clin Oncol 2009;2:4454–61; 4. McCaffrey JA, et al. J Clin Oncol 1997;15:1853–7

THE SECOND-LINE SETTING:

A GENERAL OVERVIEW

The “old” era1,2 Randomised era and early

targeted-therapy approaches3-6

Immuno-oncology (IO)

irruption7 The near future8,9

◆ No randomised data until 2006

◆ Vinflunine: First agent to

demonstrate in a randomised

controlled trial (RCT) OS

advantage (against best

supportive care)

◆ Failure of targeted therapies in

biomarker unselected

population

◆ Maintenance concept after first-

line response (early second-line

treatment)

◆ PD-1 and PDL-1 inhibitors

leading to encouraging results

(long-term durable responses)

in a subset of patients

◆ Development and “success” of

Phase 3 RCT – from hype to

cautiousness

◆ Molecular understanding leads

to novel targeted therapies in

biomarker selected patients

◆ Fibroblast Growth Factor

Receptor 3 (FGFR3) inhibitors

◆ Antibody drug conjugates

◆ IO-targeted treatment combos

◆ Hypothetical scenario: second-

line setting after front-line IO

◆ Mostly single-agent cytotoxic

chemotherapy

◆ Taxanes introduction

◆ Non-randomised data

◆ Small size trials

◆ Heterogenic population

◆ Limited efficacy

1. McCaffrey JA, et al. J Clin Oncol 1997;15:1853–7; 2. Papamichael D, et al. Br J Cancer 1997;75:606–7; 3. Fechner G, et al. Int J Clin Pract 2006;60:27–3; 4. Bellmunt J, et al. J Clin Oncol 2009:27;4454–61;

5. Ghosh M, et al. Curr Opin Oncol 2014;26:305–20; 6. Garcia-Donas J, et al. Lancet Oncol 2017;18:672–81; 7. Powles T, et al. Clin Genitourin Cancer 2018;16(2):117–29; 8. Loriot Y, et al. N Engl J Med 2019 (In press);

9. Petrylak DP, et al. Oral presentation at ASCO 2019.

SECOND-LINE:

NON-RANDOMISED CHEMOTHERAPY TRIALS

Gomez De Liaño A, Duran I. Ther Adv Urol 2018;10(12):455–80. Reproduced under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/.

Accessed Sept 2019)

Difficult setting (ill defined, mixed

populations, prognostic factors)

Multiple undersized single-agent

studies with scarce success (N less

than 50 in most of them)

ORR ranging from 0–28%

OS around 7–8 months

Few small combination studies with

poor outcomes in general

Author [Year] Chemotherapy Phase n ORR (%)PFS/TTP* (months)

OS/CSS**(months)

Single-agent chemotherapy

McCaffrey [1997] Docetaxel (3 weekly) 2 30 13.3 4 9

Kim [2016] Docetaxel (weekly) 2 31 6 1.4 8.3

Papamichael [1997] Paclitaxel (3 weekly) 2 14 7 NR NR

Vaughn [2002] Paclitaxel (weekly) 2 31 10 2.2 7.2

Joly [2009] Paclitaxel (weekly) 2 55 9 3 7

Ko [2013] Nab-Paclitaxel 2 48 28 6 9.8

Hoffman-Censits [2014] Cabazitaxel 2 14 0 NR NR

Arranz [2015] Cabazitaxel 2 71 5 2.1 4.3

Culine [2006] Vinflunine 2 51 18 3 6.6

Vaughn [2009] Vinflunine 2 175 15 2.8 8.2

Lorusso [1998] Gemcitabine 2 35 23 3.8* 5

Gebbia [1999] Gemcitabine 2 24 29 NR 13

Albers [2002] Gemcitabine 2 30 11 4.9* 8.7**

Akaza [2007] Gemcitabine 2 46 25 3.1 12.6

Sweeney [2006] Pemetrexed 2 47 28 2.9* 9.6

Galsky [2007] Pemetrexed 2 13 8 NR NR

Winquist [2005] Oxaliplatin 2 20 5 1.4* 6.9

Dreicer [2007] Ixabepilone 2 45 12 2.7 8

Chemotherapy combinations

Krege [2001] Docetaxel-Ifosfamide 2 22 25 NR 4

Sweeney [1999] Paclitaxel-Ifosfamide 2 13 15 NR 8

Sternberg [2001] Paclitaxel-Gemc 2 41 60 6.4 14.4

Bellmunt [2018] Docetaxel+ B-701 1b 19 16 3.2 6.9

CSS, cancer-specific survival; NR, not reported; ORR, overall response rate;

OS, overall survival; PFS, progression-free survival; TTP, time to progression.

*TTP reported when PFS data is not available.

**CSS reported when OS not available.

http://www.creativecommons.org/licenses/by-nc/4.0/

VINFLUNINE PHASE 3 TRIAL

Second-line

T4bN0M0 or TxN2-3 or M1

Progression after first-line platinum

treatment

Stratify:

- Centre

- Refractory vs. non-refractory

VINFLUNINE + BSC

(PS0: 320 mg/m2 q3w; PS 0 with previous

pelvic irradiation and PS1: 280 mg/m2)

BSC with treatment upon progression

permitted

R

N=370 n=253

n=117

Primary endpoint: OS

Secondary endpoints: ORR, PFS, DCR, QoL, CB

Bellmunt J, et al. J Clin Oncol 2009;27(27):4454–61.

HB <10: 86%

Liver metastases: 29%

VINFLUNINE PHASE 3 TRIAL:

PATIENT CHARACTERISTICS

Bellmunt J, et al. J Clin Oncol 2009;27(27):4454–61.

Patient demographics and clinical characteristicsVFL + BSC (n=253) BSC (n=117)

No. of patients % No. of patients %

All treated patients* 248 98.0 117 100

Eligible population† 249 98.4 108 92.3

Age, years

<65

≥65

135

118

53.4

46.6

60

57

51.3

48.7

ECOG PS

0

1

72

181

28.5

71.5

45

72

38.5

61.5

Creatinine clearance in the treated population, mL/min

<60

40–60

<40

Missing

134

104

10

0

54.0

41.9

4.0

0

69

41

4

3

59.0

35.0

3.4

2.6

No. organs involved

1

2

≥3

62

87

104

24.5

34.4

41.4

31

39

47

26.5

33.3

40.2

Visceral involvement 187 73.9 87 74.4

Patients experiencing relapse or progression within

6 months after the prior chemotherapy‡ 82.4 86.1

Prior pelvic/abdominal irradiation 22.5 22.2

Prior therapy with platinum-based regimen

Cisplatin and no other platinum

Carboplatin and no other platinum

Other platinum combination

164

75

14

64.8

29.6

5.6

85

23

9

72.6

19.7

7.7

VFL, vinflunine; BSC, best supportive care; ECOG PS,

Eastern Cooperative Oncology Group performance status.

*Used for safety analysis.†Excludes patients presenting at baseline with ≥1 of four

significant protocol deviations (>1 previous chemotherapy

regimen, no locally advanced or metastatic histologically

proven transitional cell carcinoma of urothelial tract at study

entry, no progression after first-line platinum-containing

chemotherapy for advanced disease, and patients having

received a neoadjuvant or adjuvant chemotherapy).‡Percentages based on 250 patients in BSC + VFL arm and

108 patients in BSC arm.

VINFLUNINE: OVERALL SURVIVAL RESULTS

Bellmunt J, et al. J Clin Oncol 27(27), 2009: 4454–61. Reprinted with permission. © (2009) American Society of Clinical Oncology. All rights reserved

Bellmunt J, et al. Ann Oncol 2013;24(6):1466–72.

VINFLUNINE: SECONDARY ENDPOINTS

ORR (%, p) DCR (%, p) PFS (months, p) DoR (months)

Vinflunine 8.6p=0.0063

41.1p=0.0024

3.0p=0.0012

7.4

BSC 0 24.8 1.5 NA

VFL BSC

Fatigue/asthenia 19.3 17.9

Nausea 2.4 0.9

Vomiting 2.8 0

Mucositis 1.6 0

Constipation 16.1 0.9

Myalgia 3.2 0

Sens. neuropathy 1.2 0

SAFETY PROFILE: Most common Grade 3/4 events (%)

VFL BSC

Anaemia 19.1 8.1

Neutropenia 50 0.9

Febrile neutropenia 6 0

Thrombocytopenia 5.7 0.9

Bellmunt J, et al. J Clin Oncol 2009;27(27):4454–61

RANGE (NCT02426125) TRIAL DESIGN

*Docetaxel 60 mg/m2 in East Asia. #Docetaxel was limited to 6 cycles; up to 4 additional cycles could be given after sponsor approval.De Wit R, et al. Presented at 2019 Genitourinary Cancers Symposium. Reproduced with permission from Dr R. De Wit

Key inclusion criteria:

Locally advanced, unresectable or

metastatic UC

Progression ≤14 mo after platinum regimen

Prior immune checkpoint inhibitor allowed

ECOG PS 0 or 1

Ramucirumab 10 mg/kg +

docetaxel 75 mg/m2 (RAM+DOC) IV*#

Day 1 of a 21-day cycle, N=263

Placebo 10 mg/kg +

docetaxel 75 mg/m2 (P+DOC) IV*#

Day 1 of a 21-day cycle, N=267

R

1:1

Disease

progression

or other

withdrawal

criteria met

Primary endpoint:

PFS (investigator assessment)

Secondary endpoints:

OS, ORR, DCR, DOR, safety, PRO, PK and

immunogenicity

Stratification factors:

◆ Geography (North America vs. East Asia vs. Europe/other)

◆ ECOG PS (0 vs. 1)

◆ Visceral metastasis (Yes vs. No), defined as liver, lung or bone

RANGE PRIMARY AND SECONDARY EFFICACY

OUTCOMES

De Wit R, et al. Presented at 2019 Genitourinary Cancers Symposium. Reproduced with permission from Dr Ronald De Wit

1. Reprinted from The Lancet, 390(10109):, Petrylak DP, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy

(RANGE): a randomised, double-blind, phase 3 trial, 2266–77. Copyright 2017, with permission from Elsevier;

2. Petrylak DP, et al. Ann Oncol 2018;29(suppl_8):viii303-viii331. Presented at ESMO 2018. By permission of Dr DP Petrylak.

Progression-free survival1 Overall survival2 Best overall response1

Median PFS (months)

Ramucirumab + docetaxel (n=216) 4.07

PBO + docetaxel (n=221) 2.76

Prognostic factors

Cabazitaxel

(n=35)

Vinflunine

(n=35)

0 n (%) 13 (37) 13 (37)

1 n (%) 22 (63) 22 (63)

Age (median) 64 66

Gender, male n (%) 28 (80) 28 (80)

Race, caucasian n (%) 34 (97) 35 (100)

Previous surgery n (%) 26 (74) 33 (94)

Prior chemotherapy

Carbo-gemcitabine n (%) 6 (17) 14 (40)

Cisplatin-gemcitabine 28 (80) 20 (57)

Other n (%) 9 (26) 6 (17)

Cabazitaxel Vinflunine p HR

ORR (%) 13 30 0.26

OS (mo) 5.5 7.6 0.342 1.4004

PFS (mo) 1.9 2.9 0.0391 2.0360

Bellmunt J, et al. Ann Oncol 2017;28(7):1517–22

A RANDOMISED PHASE 2/3 STUDY OF CABAZITAXEL

VS. VINFLUNINE

In metastatic or locally advanced transitional cell

carcinoma of the urothelium (SECAVIN)

Primary endpoints:

◆ Phase 2 → ORR

◆ Phase 3 → OS

Randomised Phase 2/3

Population: locally advanced/metastatic UC who have failed

a first-line platinum-based chemotherapy

Stratification factors: PS 0-1, Hb <10 g/dL, liver metastases

Hypothesis: Cabazitaxel has sufficient activity (≥15% ORR)

to test in a Phase 3 trial against vinflunine

N=70

Eligible

patients

Cabazitaxel 25 mg/m2 every 21 days

Vinflunine 250–320 mg/m2 every 21 days

R

1:1

SECOND-LINE CHEMOTHERAPY:

THE RANDOMISED DATA

†Significant in eligible population, not in ITT

*Time to progression (TTP) is reported when PFS is not available

**Cancer specific survival (CSS) is reported when OS is not available

Adapted from Gomez De Liaño A, Duran I. Ther Adv Urol 2018;10(12):455–80.

Author [Year] Experimental arm Control arm Phase n ORR (%) PFS/TTP* (months)OS/CSS**

(months)

Ch

emo

ther

apy

(CT

) al

on

e Fechner [2006] Gem-Paclitaxel q2w cont Gem-Paclitaxel q3w x6 2 30 39 vs. 50 6 vs. 11 (NS) 9 vs. 13 (NS)

Albers [2010] Gem-Paclitaxel q3w cont Gem-Paclitaxel q3w x6 3 10241.5 vs. 37.5

(NS)3.1 vs. 4 (NS) 8 vs. 7.8 (NS)

Bellmunt [2009, 2013] Vinflunine BSC 3 370 8.6 vs. 0 3 vs. 1.56.9 vs. 4.3†

(HR 0.78)

Bellmunt [2017] Cabazitaxel Vinflunine 2 70 13 vs. 30 (NS) 1.9 vs. 2.9 5.5 vs. 7.6 (NS)

Sridhar [2018] Nab-Paclitaxel Paclitaxel 2 160 22 vs. 25 3.35 vs. 3.02 (NS)7.46 vs. 8.77

(NS)

CT

+ t

arg

eted

th

erap

y

Choueiri [2012] Docetaxel-Vandetanib Docetaxel 2 142 7 vs. 11 2.56 vs. 1.58 (NS)5.85 vs. 7.03

(NS)

Petrylak [2017] Docetaxel-Ramucirumab Docetaxel 3 530 24.5 vs. 14 4.07 vs. 2.76 9.4 vs. 7.85 (NS)

Choueiri [2017] Docetaxel-Apatorsen Docetaxel 2 99 16 vs. 11 (NS) 1.8 vs. 1.6 (NS) 6.4 vs. 5.9 (NS)

EARLY SECOND-LINE CHEMOTHERAPY:

THE MAINTENANCE CONCEPT

MAJA trial

Design: Randomised, open-label,

Phase 2 trial

Population: mUC patients who

have not progressed during first-line

Gem-Cisplatin (4–6 cycles)

PFS 6.5 mo (95% CI 2.0, 11.1)

PFS 4.2 mo (95% CI 2.1, 6.3)

HR 0.59; 95% CI 0.37, 0.96; p=0.031G3/4 events of interest %

Neutropenia 18%

Febrile neutropenia 2%

Ashtenia 16%

Constipation 14%

Abdominal pain 5%

Patients

characteristics

Vinflunine

(n=45)

BSC

(n=43)

ECOG 0 21 (47%) 23 (53%)

Age (median) 63.7 65.0

Gender, male 37 (82%) 40 (93%)

Primary site, bladder 36 (80%) 37 (86%)

Pure TCC histology 38 (84%) 37 (86%)

Prognostic factors

0

1

2

3

20 (44%)

19 (42%)

6 (13%)

0

17 (40%)

20 (47%)

5 (12%)

1 (2%)

Liver metastasis 5 (11%) 13 (30%)

GemCis response

CR

PR

SD

7 (16%)

28 (63%)

10 (22%)

7 (16%)

23 (54%)

13 (30%)

Reprinted from The Lancet, 18(5), Garcia-Donas J, et al. Maintenance therapy with vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after

first-line chemotherapy (MAJA; SOGUG 2011/02): a multicentre, randomised, controlled, open-label, phase 2 trial, 672-681a Copyright 2017, with permission from Elsevier.

n=43

Gem/platinum

chemotherapy

Vinflunine

Best SC

Disease

control

n=45

Primary endpoint: PFS

SECOND-LINE CHEMOTHERAPY: CONCLUSIONS

Vinflunine is the only cytotoxic agent to prove OS improvement in platinum refractory patients1

Docetaxel–ramucirumab increases PFS but not OS against docetaxel

Single-agent chemotherapy tested (mainly taxanes) has shown limited efficacy, ORR ranges 0–28% and data from

single-arm trials → should not be standard of care

Vinflunine has superior outcomes than cabazitaxel

Nabpaclitaxel is not superior to paclitaxel

Maintenance chemotherapy may have a role in mUC but needs to be proven (and may be hard in the current era)

1. Not in the intention-to-treat population, only in the per-protocol analysis.

IMMUNE CHECKPOINT INHIBITION AS SECOND-LINE TREATMENT

IMMUNO-THERAPY: SINGLE-ARM DATA

Atezolizumab1 Pembrolizumab2 Nivolumab3 Avelumab4,5 Durvalumab6

Phase Phase 2 Phase 1 Phase 2 Phase 1b Phase 1/2

Patients, N 310 33 265249

(161 post-plat)

191

(182 post-plat)

Dosing 1200 mg q3w 10 mg/kg/q2w 3 mg/kg/q3w 10 mg/kg q2w 10 mg/kg q2w

ORR, % 15 26 19.6 17 17.8

Duration of

response

84% after median f-u of

11.7 mo. Median NRMedian 10 months

77% after median f-u of

7 mo. Median NR

64% at data cut,

median NR

76.5% at data cut,

median NR

OS, months 7.9 13 8.7 7.7 18.2

PFS, months 2.1 2.0 2.0 1.5 1.5

G3/4 TRAEs, % 16 15 (G3) 18 10.8 (G3-5) 6.8

f-u, follow-up; TRAEs, treatment-related adverse events1. Rosenberg JE, et al. Lancet 2016; 2. Plimack E, et al. Lancet Oncol 2017; 3. Sharma P, et al. Lancet Oncol 2017; 4. Patel MR, et al. Lancet Oncol 2018;

5. Apolo AB, et al. J Clin Oncol 2017; 6. Powles T, et al. JAMA Oncol 2017

KEYNOTE-045 STUDY DESIGN (NCT02256436)

aIn total ITT population and in patients with combined positive score ≥10%.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26

Key eligibility criteria:

Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra

Transitional cell predominant

PD after 1–2 lines of platinum-based chemotherapy or recurrence <12 months after perioperative platinum-based therapy

ECOG performance status 0–2

Provision of tumour sample for biomarker assessment

Pembrolizumab 200 mg IV q3w

Paclitaxel 175 mg/m2 q3w

OR

Docetaxel 75 mg/m2 q3w

OR

Vinflunine 320 mg/m2 q3w

R

1:1

N=542

n=270

n=272

◆ Dual primary endpoints: OS and PFS

◆ Key secondary endpoints: ORR, DOR, safety

◆ Response: RECIST v1.1 by blinded, independent central review

◆ Both unselected and biomarker-selected patients

Stratification factors:

◆ ECOG performance status (0/1 vs. 2)

◆ Hemoglobin level (<10 vs. ≥10 g/dL)

◆ Liver metastases (Yes vs. No)

◆ Time from last chemotherapy dose (<3 vs. ≥3 months)

BASELINE CHARACTERISTICS

aMissing for 5 patients in pembrolizumab arm and 4 patients in chemotherapy arm. bMissing for 7 patients in pembrolizumab arm and 4 patients in chemotherapy arm.cRisk factors include Bellmunt risk factors of ECOG performance-status score >0, Hb concentration <10 g/dL, and presence of liver metastases, plus a time since completion or

discontinuation of previous therapy <3 months.

Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26

n (%)

Pembro

(n=270)

Chemo

(n=272)

Age, median

(range), y67 (29-88) 65 (26-84)

Men 200 (74.1) 202 (74.3)

Upper tract

disease38 (14.1) 37 (13.6)

Lower tract

disease232 (85.9) 235 (86.4)

ECOG PSa

0

1

2

120 (44.4)

142 (52.6)

3 (1.1)

106 (39.0

158 (58.1)

4 (1.5)

Visceral disease 241 (89.3) 235 (86.4)

Disease in lymph

node only28 (10.4) 37 (13.6)

n (%)

Pembro

(n=270)

Chemo

(n=272)

Liver metastases 91 (33.7) 95 (34.9)

Hemoglobin <10

g/dLb 43 (15.9) 44 (16.2)

Time since completion of most recent prior therapy

≥3 months 167 (61.9) 168 (61.8)

<3 months 103 (38.1) 104 (38.2)

Setting of most recent prior therapy

Neoadjuvant 19 (7.0) 22 (8.1)

Adjuvant 12 (4.4) 3 (11.4)

First line 184 (68.1) 158 (58.1)

Second line 55 (20.4) 59 (21.7)

Third line 0 2 (0.7)

n (%)

Pembro

(n=270)

Chemo

(n=272)

Risk factorsc

0

1

2

3–4

54 (20.0)

96 (35.6)

66 (24.4)

45 (16.7)

45 (16.5)

97 (35.7)

80 (29.4)

45 (16.5)

Prior platinum therapy

Cisplatin

Carboplatin

Othera

199 (73.7)

70 (25.9)

1 (0.4)

214 (78.7)

56 (20.6)

2 (0.7)

Smoking statusb

Never

Former

Current

104 (38.5)

136 (50.4)

29 (10.7)

83 (30.5)

148 (54.4)

38 (14.0)

PD-L1 CPS ≥10% 74 (27.4) 90 (33.1)

OVERALL SURVIVAL

At 24 months, 60% of chemotherapy arm patients had

received an IO agent (including pembro at crossover)

Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.

A: Based on Cox regression model with treatment as a covariate stratified by ECOG performance status (0/1 vs 2). Liver metastases (yes vs no), hemoglobin (<10 vs >10 gr/dL) and time from completion of chemotherapy (<3

vs. > or = 3months)

B: One-sided P value based on stratified log-rank test

Events, n HR (95% CI)a p-valueb

Pembro 155 0.73

(0.59, 0.91)0.0022

Chemo 179

14.1 months of follow-up1

Events, n HR (95% CI)a p-valueb

Pembro 199 0.70

(0.57, 0.85)0.00017

Chemo 218

27.7 months of follow-up

OVERALL SURVIVAL: SUBGROUPS

aIncludes Bellmunt risk factors of ECOG performance status >0, haemoglobin level <10 g/dL, and liver metastases (J Clin Oncol. 2010;27:1850–5) and time from prior chemotherapy

<3 months (Eur Urol 2013;63:717-723). bN is shown for the chemotherapy arm only. All comparisons were to all patients in the pembrolizumab arm.

Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.

PROGRESSION-FREE SURVIVAL

Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.

OBJECTIVE RESPONSE BY PD-L1 STATUS

Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.

CPS ≥10 CPS <10

TREATMENT-RELATED AEs OCCURRING IN ≥10% OF

PATIENTS*

*Of patients in either treatment arm. 7.5% febrile neutropenia in the chemotherapy arm. Data cut-off date: October 26, 2017.Bellmunt J, et al. N Engl J Med 2017;376(11):1015–26. Updated results presented at ASCO GU 2018. Reproduced with permission from Dr J Bellmunt.

Pembrolizumab Chemotherapy

IMMVIGOR 211: TRIAL DESIGN

Powles T, et al. Lancet 2018;391(10122):748–57

Atezolizumab vs. chemotherapy in platinum refractory PD-L1 positive disease

n=464

Key eligibility criteria

• Urothelial carcinoma of the renal pelvis,

ureter, bladder, or urethra

• Transitional cell predominant

• PD after 1–2 lines of platinum-based

chemo or recurrence within 12 months of

perioperative platinum-based therapy

• ECOG PS 0-1

• Provision of tumour sample for biomarker

assessment

Atezolizumab

1200 mg IV q3w

Paclitaxel 175 mg/m2 q3w

OR

Docetaxel 75 mg/m2 q3w

OR

Vinflunine 320 mg/m2 q3w

R(1:1)

N=931

n=467

Key endpoints:

Primary: OS in PD-L1 +ve population

Hierarchical analysis: OS in ITT population

WHY CHOOSING THE BIOMARKER AS THE

PRIMARY ENDPOINT?

Summary of Phase 1 and 2 atezolizumab data

◆ PD-L1 positive was defined as ≥5 % of immune cells with SP142Ab

Phase 1 Study PCD4989g Phase 2 Study IMvigor210 (Cohort 2)

◆ The biomarker positive patients did better than historical chemotherapy controls

◆ The biomarker negative patients had similar outcomes to historical chemotherapy controls

Powles T, et al. Presented at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care. Reproduced with permission from Dr T. Powles.

IMMVIGOR 211: PATIENTS CHARACTERISTICS

Baseline characteristics

ITT population

Atezolizumab

(n=467)

Chemotherapy

(n=464)

Age, median (range) 67 (33–88) years 67 (31–84) years

Gender, male 76% 78%

ECOG 0 | 1 47% | 53% 45% | 55%

Smoker: current | past | never 13% | 57% | 30% 13% | 61% | 26%

Hemoglobin ≤10 g/dL 14% 16%

Bellmunt Risk factors 0 | 1 | 2 | 3 31% | 46% | 18% | 5% 30% | 45% | 21% | 4%

Primary site:

Lower tract bladder | urethra 69% | 2% 73% | 2%

Upper tract (renal pelvis| ureter | other) 14% | 13% | 2% 11% | 13% | 2%

Metastatic disease 91% 93%

Metastatic sites:

Only lymph nodes| visceral | liver 12% | 77% | 30% 14% | 77% | 28%

Prior cystectomy 43% 43%

Previous chemotherapy <3 mo 34% 35%

No. of previous lines (metastatic setting): 0 | 1 | 2 | ≥3 28% | 53% | 17% | 2% 26% | 56% | 16% | 2%

PD-L1 score: IC2/3 | IC1 | IC0 25% | 43% | 32% 25% | 41% | 33%


ATEZOLIZUMAB VS. CHEMOTHERAPY IN BIOMARKER-

POSITIVE PLATINUM REFRACTORY UBC

HR, hazard ratio.Reprinted from The Lancet, 391(10122) Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3

randomised controlled trial, 748-757, Copyright 2018, with permission from Elsevier.

The biomarker was prognostic and not predictive (SP142 >5% in IC)

OS ANALYSIS: ITT POPULATION (N=931)

Reprinted from The Lancet, 391(10122) Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3

randomised controlled trial, 748-757, Copyright (2018, with permission from Elsevier.

Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo)

IMVIGOR 211: PFS, ORR, DOR


IC2/3 population ITT population

Atezolizumab group

(n=116)

Chemotherapy group

(n=118)

Atezolizumab group

(n=467)

Chemotherapy group

(n=464)

Progression-free survival

Patients with event, n (%) 93 (80) 105 (89) 407 (87) 410 (88)

Median, months (95% CI) 2.4 (2.1, 4.2) 4.2 (3.7, 5.0) 2.1 (2.1, 2.2) 4.0 (3.4, 4.2)

Objective response

Evaluable patients, n 113 116 462 461

Patients with response, n (%; 95% CI) 26 (23.0; 15.6, 31.9) 25 (21.6; 14.5, 30.2) 62 (13.4; 10.5, 16.9) 62 (13.4; 10.5, 16.9)

Best overall response, n (%)

Complete response 8 (7) 8 (7) 16 (3) 16 (3)

Partial response 18 (16) 17 (15) 46 (10) 46 (10)

Stable disease 23 (20) 37 (32) 92 (20) 162 (35)

Progressive disease 47 (42) 30 (26) 240 (52) 150 (32)

Missing or unevaluable 17 (15) 24 (21) 68 (15) 87 (19)

Duration of response

Patients with event, n/N (%) 10/26 (38) 20/25 (80) 23/62 (37) 49/62 (79)

Median, months (95% CI) 15.9 (10.4, NE) 8.3 (5.6, 13.2) 21.7 (13.0, 21.7) 7.4 (6.1, 10.3)

IMVIGOR 211: DURATION OF RESPONSE

21.7 months

7.4 months

Reprinted from The Lancet, 391,(10122) Powles T, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3

randomised controlled trial, 748–57, Copyright 2018, with permission from Elsevier.

Duration of response*

*Duration of response determined by Investigator using RECIST v1.1; defined as time from first occurrence of complete response or partial response, whichever came first, to first

documented progression of disease or death, whichever occurred first.

ATEZOLIZUMAB: TOXICITY PROFILE

Atezolizumab Chemotherapy

All grades

Grades 3-4

Nausea

Constipation

Alopecia

Fatigue

Anaemia

Decreased appetite

Asthenia

Diarrhoea

Neutropenia

Vomiting

Peripheral neuropathy

Myalgia

Mucosal inflammation

Neutrophil count decreased

Febrile neutropenia

Pruritus

Proportion of patients

Adapted from Powles T, et al. Lancet. 2018;391(10122):748–57

ATEZOLIZUMAB REAL-WORLD DATA:

SAUL PHASE 3B TRIAL

Between 30 Nov 2016 and 16 March 2018, 1004 patients

were enrolled (997 treated) from sites in 32 countries

worldwide

Sternberg C, et al. Eur Urol 2019;76(1):73-81; Merseburger AS, et al. Presented at EAU 2019. Reproduced with permission from Dr AS Merseburger.

bIC2/3 = expression on ≥5% of tumour-infiltrating immune cells; denominator = 928 patients with known PD-L1 status. cOther non-urothelial/mixed in 6 patients (1%). dOther in 24 (2%).

Adverse events

aDefined as the SAUL ITT population MINUS populations excluded from IMvigor211

Sternberg C, et al. Eur Urol 2019;76(1):73-81; figures reproduced under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License (CC BY NC ND). https://creativecommons.org/licenses/by-nc-

nd/4.0/. Accessed Sep 2019; Merseburger AS, et al. Presented at EAU 2019. Reproduced with permission from Dr AS Merseburger.

OVERALL SURVIVAL ANALYSIS IN THE DIFFERENT POPULATIONS

IN SAUL STUDY

https://creativecommons.org/licenses/by-nc-nd/4.0/

IMMUNE CHECKPOINT INHIBITORS IN PLATINUM

REFRACTORY PATIENTS – SUMMARY

IO agents have superseded chemotherapy in the second-line setting as the preferred option, based on duration of

response and safety

Nevertheless, there is a lack of predictive biomarkers to help us selecting those patients [15–25%] most likely to

benefit from CPI

Pembrolizumab has the highest level of evidence in a randomised setting. Atezolizumab seems a reasonable option

based on Phase 3 and 3b results. The SAUL trial demonstrates that the efficacy of atezolizumab is consistent with

previous pivotal anti-PD-L1/PD-1 mUC trials

Other ICI agents (avelumab, durvalumab, and nivolumab) seem to achieve similar benefit, although randomised data

are lacking

TARGETED THERAPY: FROM FAILURE TO SUCCESS?

High somatic mutation frequencies in bladder cancer

Multiple failed attempts (mainly single-arm trials) in unselected populations over the last decade

Main agents tested: VEGF-targeted therapy (TKIs, mABs), EGFR/HER2 inhibitors, mTOR inhibitors

Randomised trials are scarce and have failed (LAMB trial) or demonstrated little benefit (RANGE trial)

Better understanding of mUC molecular behaviour has led to the design of novel trials, testing targeted therapies in

biomarker-selected patients

TARGETED THERAPY: BACKGROUND IN A SNAPSHOT

*Low predicted likelihood of response based on preliminary data. **Low response rate.Reprinted from Cell, 171(3), Robertson AG, et al. Comprehensive Molecular Characterisation of Muscle-Invasive Bladder Cancer, 540–56.e25. Copyright 2017, with permission from Elsevier.

Reprinted by permission from Springer Nature: Nature, Mutational heterogeneity in cancer and

the search for new cancer-associated genes, Lawrence MS, et al. Copyright 2013

Eligibility criteria for randomisation

1. Metastatic or advanced UBC

2. HER1 or 2 positive transitional cell

histology

3. Clinical benefit with first-line

chemotherapy

4. Normal ejection fractionCommonest reason for

screen failure: n=214

1. Disease progression (24%)

2. Biomarker –ve (20%)

3. Low LVEF (19%)

4. Patient choice (9%)

Endpoints

Primary: PFS

Secondary: OS / adverse events

Exploratory: Subset analysis

Stratification: Chemotherapy

response and PS

EGFR/HER2 INHIBITION: LAMB TRIAL

R=232

Lapatinib 1500 mg OD

Placebo

Chemotherapy

Screening phase

HER1/2 testing

(N=446)

Powles T, et al. J Clin Oncol 2017;35(1):48–55

LAMB TRIAL

0

10

20

30

40

T0 T1 T2 T3 T4

%

% of T Stage ExpressionHER1 +ve

HER2 +ve

HER1 Whole Pop. Trial Pop. HER2 Whole Pop. Trial Pop.

0 15% 6% 0 23% 14%

1+ 15% 12% 1+ 31% 30%

2+ 38% 44% 2+ 34% 40%

3+ 32% 38% 3+ 12% 16%

% of HER expression

Randomly assigned (n=232), n (%) Total, n (%)

Lapatinib Placebo

116 116 445

HER status

HER1 positive 53 (45.7) 49 (42.2) 175 (39.2)

HER2 positive 21 (18.1) 21 (18.1) 60 (13.5)

Both positive 42 (36.2) 46 (39.7) 145 (32.5)

HER negative 0 (0.0) 0 (0.0) 66 (14.8)

Powles T, et al. J Clin Oncol 2017;35(1):48–55

HR 1.1

(95% CI: 0.8, 1.4); p=0.62

Median PFS

Lapatinib 4.6 months (95% CI: 2.8, 5.4)

Placebo 5.1 months (95% CI: 3.0, 5.8)

Response rate

Lapatinib 14%

Placebo 8%

p=0.14

LAMB TRIAL

Randomised population: PFS for lapatinib vs. placebo (primary endpoint)

Powles T, et al. J Clin Oncol 35(1), 2017: 48–55. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

FGFR3 INHIBITORS: LESSONS LEARNED IN MUC

“Old” trials tested these agents in unselected population

The Cancer Genome Atlas Research Network. Nature 2014;507:315–22. Reproduced under the Creative Commons CC-BY-NC-SA license. https://creativecommons.org/licenses/by-nc-nd/4.0/. Accessed Sept 2019;

Milowsky MI, et al. Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur J Cancer 2014;50(18):3145–52.

Clinical response FGFR3MUT (n=12) FGFR3WT (n=31)

Investigator review, n (%)

CR

PR

SD

PD

UNK

ORR (CR+PR)

DCRa

95% CI for ORR

95% CI for DCR

0

0

5 (42)

5 (42)

2 (17)

0

3 (25)

(0.0, 26.5)

(5.5, 57.2)

0

1 (3)

10 (32)

12 (39)

8 (26)

1 (3)

8 (26)

(0.1 ,16.7)

(11.9, 44.6)

Central radiology review, n (%)

CR

PR

SD

PD

UNK

ORR (CR+PR)

DCRa

95% CI for ORR

95% CI for DCR

0

1 (8)

3 (25)

6 (50)

2 (17)

1 (8)

2 (17)

(0.2, 38.5)

(2.1, 48.4)

0

0

12 (39)

9 (29)

10 (32)

0

9 (29)

(0.0, 11.2)

(14.2, 48.0)

Best overall tumour response by FGFR3 mutation status,

as determined by investigator and central radiology review

FGFR3 alterations in mUC ≈20% and ≈35% in UTUC

A: Defined as the proportion of patients with best overall response of CR or PR, or a response of SD lasting P16 weeks

after the start of dovitinib treatment.

https://creativecommons.org/licenses/by-nc-nd/4.0/

PHASE 2 BLC2001: ERDAFITINIB IN PATIENTS WITH

MUC AND FGFR3 ALTERATIONS

Siefker-Radtke A, et al. J Clin Oncol 36, 2018 (suppl; abstr 4503). Presented at ASCO 2018 Annual Meeting. Reproduced with permission from Dr A Siefker-Radtke.

ERDAFITINIB ACTIVITY

Siefker-Radtke A, et al. J Clin Oncol 36, 2018 (suppl; abstr 4503). Presented at ASCO 2018 Annual Meeting; Updated at ASCO 2019 by SH Park et al. J Clin Oncol 37, 2019 (suppl; abstr 4543). Presented at ASCO 2019

Annual Meeting. Reproduced with permission from Dr A Siefker-Radtke.

REGULATORY APPROVAL

FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma

On April 12, 2019, the Food and Drug Administration granted accelerated approval to erdafitinib (BALVERSA,

Janssen Pharmaceutical Companies) for patients with locally advanced or metastatic urothelial carcinoma, with

susceptible FGFR3 or FGFR2 genetic alterations, that has progressed during or following platinum-containing

chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

Patients should be selected for therapy based on an FDA-approved companion diagnostic for erdafitinib.

Today, the FDA also approved the therascreen® FGFR RGQ RT-PCR Kit, developed by QIAGEN, for use as a

companion diagnostic for this therapeutic indication.

Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma. Accessed Sept 2019

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma

ERDAFITINIB: TOXICITY

Majority of events were Grade 1/2

Serious TRAEs in 9 patients (9%)

Only 7 patients discontinued because of AEs of special interest

CSR rarely led to discontinuation (n=3), no retinal vein or artery occlusion

Treatment-related Adverse Events (TRAEs) TRAEs of special interest


BGJ398 (INFIGRATINIB) IN MUC WITH

FGFR3 MUTATIONS

Most common AEs:

◆ Hyperphosphatemia (46%)

◆ ↑ creatinine (42%)

◆ Constipation (37%)

◆ Anaemia (36%)

◆ ↓ appetite

Most common G3/4 AEs:

◆ ↑ Lipase (10%)

◆ Fatigue (7.5%)

◆ Anaemia (7.5%)

◆ Hypophosphatemia (7.5%)

◆ Palmar-plantar

erythrodysthesia (7.5%)◆ Median PFS: 3.75 months

◆ Median OS 7.75 months

◆ Median DoR: 5.06 months

67 patients with mUC and FGFR3 mutations

ORR: 25.4%

SD: 38.8%

Reprinted from Cancer Discovery, Copyright 2018, 8(7), Pal SK, et al. Author, Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1–3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with

FGFR3 Alterations, with permission from AACR.

Baseline patient and disease characteristics

Variable, n (%)Participants

(N=67)

Age group <65 years≥65 years

29 (43.3)38 (56.7)

Sex MaleFemale

46 (68.7)21 (31.3)

WHO performance status

012Missing

20 (29.9)36 (53.7)10 (14.9)

1 (1.5)

Bellmunt criteriaa Risk group 0Risk group 1Risk group 2Risk group 3

12 (17.9)27 (40.3)25 (37.3)

3 (4.5)

Visceral disease LungLiver

41 (61.2)25 (37.3)

Lymph node metastases

YesNoMissing

19 (28.4)46 (68.7)

2 (3)

Bony metastases YesNoMissing

25 (37.3)40 (59.7)

2 (3)

Prior immunotherapy at last medication 11 (16.4)

FGFR3 status Not mutatedMutatedb

Exon 7 R248CExon 7 S249CExon 10 Y375CExon 15 K625E/QOtherb

067 (100)11 (16.4)38 (56.7)

3 (4.5)0

15 (22.4)

INFIGRATINIB: SUBGROUP OF UPPER TRACT (UTUC)

Patients with UTUC vs. different molecular profile and better outcomes than bladder carcinoma patients

Dizman N, et al. J Clin Oncol 37, 2019:(suppl; abstr 4510). Presented at ASCO 2019.

Reproduced with permission from Dr N Dizman

Progression-free survival

Overall survival

ORR 24%

SD 49%

PD 27%

Analysis in 51 patients with FGFR1-3 mRNA overexpression

Joerger M, et al. J Clin Oncol 36, 2018:(suppl; abstr 4513). Presented at ASCO 2019. Reproduced with permission from Dr M Joerger.

ROGARATINIB IN PATIENTS WITH ADVANCED

UROTHELIAL CARCINOMAS

Pre-screened for tumour FGFR mRNA expression and effects of mutations in FGFR signalling pathway

◆ In line with TCGA research, 133 UC

tumours treated with rogaratinib showed

that samples with high FGFR3 mRNA

levels expressed los PD-L1 mRNA levels

◆ 10 patients had prior IO treatment (6 anti-

PD-L1 treatment)

◆ 9/10 (90%) showed PD as best response

to IO therapy, 1 had SD for 9 months

TEAEs observed in >20% patients with UC (n=51) by

Common Terminology Criteria for AEs grade

The Cancer

Genome

Atlas (n=408)

Rogaratinib

trial (n=133)

Necchi A, et al. J Clin Oncol 37, 2019 (suppl 7S; abstr 409). Presented at ASCO GU 2019.

Reproduced with permission from Dr A Necchi.

FIERCE 22: PRELIMINARY ANALYSIS OF VOFATAMAB +

PEMBROLIZUMAB


FGFR3 INHIBITORS: SELECTED ONGOING TRIALS

Trial Phase N (estimated) Investigational arm Comparative arm Target population

NORSE 1/2 102 Erdafitinib + JNJ-63723283 (anti-PD1) Erdafitinib Platinum refractory

FIERCE-22 1/2 74 Vofatamab + Pembrolizumab None Platinum refractory

FORT-2 1/2 190 Rogaratinib + Atezolizumab PBO + Rogaratinib First-line unfit

Fight-2015 2 372 Pemigatinib + Pembrolizumab Pemigatinib First-line unfit

Selected ICI+FGFR3i combination trials

THOR: Ongoing Phase 3 Study (N=630) of erdafitinib compared with chemotherapy or pembrolizumab

FORT-1: Phase 2/3 trial of rogaratinib compared with chemotherapy (NCT03410693)

• FGRR1 or 3 positive

tumours determined by

mRNA expression

• mUC with prior platinum

treatment

• ≤2 prior lines

Arm 1: Rogaratinib

Arm 2: Comparator

Taxane (docetaxel or

paclitaxel) or vinflunine

R(1:1)

Primary outcome

measure: OS

N=400Molecular

screening of

patients with

advanced UC

for FGFR

alterations

Erdafitinib

Chemotherapy

R(1:1)Prior

treatment with

PD-(L)1

inhibitor?

YES

Erdafitinib

Pembrolizumab

R(1:1)

NO

TARGETED THERAPY AND FGFR3 INHIBITORS –

CONCLUSIONS

Erdafitinib, vofatamab, infigratinib, and rogaratinib show encouraging activity in FGFR3-altered tumours

Preliminary data suggests tumours with FGFR alterations are less likely to respond to ICIs

Multiple FGFR3 inhibitors are currently being tested, either as single-agent or combined with ICIs, in randomised trials

FGRF3 inhibitors are safe, but need to be aware about MAPK class effect toxicity (CSR, hyperphosphatemia, …)

mUC is a heterogeneous disease. Targeted agents should be designed along with a biomarker, unlikely to be effective

in unselected population

ANTIBODY DRUG CONJUGATES (ADCs) IN MUC

New generation of cancer therapeutics: monoclonal antibodies (mAbs) connected by a specified linkage to

antitumour cytotoxic molecules

ADC binds to tumour target cell surface antigens (B)

leading to triggering of a specific receptor-mediated

internalisation (C). The internalised ADCs are

decomposed, releasing their cytotoxic payloads inside

the tumour cell, either through its linkage/linker

sensitivity to protease, acidic, reductive agents or by

lysosomal process, leading to cell death (D)

Targeted Ag Payload Linkage

Enfortumab Vedotin1,2 Nectin-4 Monomethyl Auristatin E (MMAE) Protease cleavable linker

Tisotumab Vedotin3 Tissue factor (thromboplastin) MMAE Protease cleavable linker

ASG-15ME4 SLITRK6 MMAE Protease cleavable linker

Sacituzumab Govitecan5 Trop-2 SN-38 Hydrolysable cleavable linker

RC-486 Her-2 MMAE Cathepsin cleavable linker

ADCs with data on mUC

Image: Nejadmoghaddam MR, et al. Avicenna J Med Biotechnol 2019;11(1):3–23. Reproduced under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/. Accessed Sept 2019).

1. Rosenberg JE, et al. J Clin Oncol 2018;36(15_suppl): Abstract TPS4590. Presented at ASCO 2018; 2. Petrylak D, et al. J Clin Oncol 2019;37(18_suppl); Abstract LBA4505. Presented at ASCO 2019;

3. de Bono JS, et al. Lancet Oncol 2019;20(3):383–93; 4. Petrylak D, et al. Ann Oncol 2016;27(6):266–95. Abstract 780PD. Presented at ESMO 2016; 5. Tagawa S, et al. J Clin Oncol 2019;37(7_suppl): Abstract 354. Presented at ASCO

GU 2019; 6. Sheng X, et al. J Clin Oncol 2019;37(15_suppl): Abstract 4509. Presented at ASCO 2019.

https://creativecommons.org/licenses/by/4.0/

Grade 5 TRAEs: diabetic ketoacidosis, multiple organ dysfunction syndrome, respiratory failure, urinary tract obstruction

EV-101 PHASE 1 STUDY: DESIGN, POPULATION

AND SAFETY

Rosenberg JE, et al. J Clin Oncol 2018;36(15_suppl): Abstract TPS4590. Presented at ASCO 2018. Reproduced with permission from Dr JE Rosenberg.

Part A (closed to accrual)

Dose-escalation/-expansion adaptive trial design

utilising a Continual Reassessment Method to

determine RP2D

◆ Cohort 1: 0.5 mg/kg


◆ Cohort 3: 1 mg/kg


Nectin-4 expressing tumours, including mUC

Part B (enrolling)*

Dose expansion: 3 cohorts

◆ Cohort 1: mUC with severe renal insufficiency

(0.75 mg/kg escalating to 1.25 mg/kg)

◆ Cohort 2: NSCLC (1.25 mg/kg)

◆ Cohort 3: Ovarian cancer (1.25 mg/kg)

RP2D

1.25 mg/kg

Part C (closed to accrual)

Dose expansion: 1 cohort

◆ CPI-treated mUC patients (1.25 mg/kg)

*Only Cohort 1 is a actively recruiting

Petrylak DP, et al. J Clin Oncol 2017;35:106.

Progression-free Survival

Overall Survival

ORR: 41%

ENFORTUMAB-VEDOTIN PHASE 1 STUDY: ACTIVITY

Rosenberg JE, et al. J Clin Oncol 2018;36(15_suppl): Abstract TPS4590. Presented at ASCO 2018. Reproduced with permission from Dr JE Rosenberg.

ENFORTUMAB-VEDOTIN PHASE 2 TRIAL

Patient profile: post-platinum and post-ICI treated

Treatment: E-V 1.25 mg/kg D1, 8 and 15, q28 days

Objectives: ORR (primary), DOR, PFS, OS, safety

Radiological response

◆ ORR: 44%

◆ Liver M1: 38%

◆ ICI-non responders: 41%

◆ PD-L1 negative (CPS <10): 47%

Median DOR: 7.6 months

AEs of special interest

◆ Peripheral neuropathy: any grade 50%; ≥G3 3%

◆ Rash: any grade 48%; ≥G3 12%

◆ Hyperglycemia: any grade 11%; ≥G3 6%

Toxicity leading to discontinuation: 12%

Survival

◆ Median PFS: 5.8 mo

◆ Median OS: 11.7 mo

Petrylak D, et al. J Clin Oncol 2019;37(18_suppl); Abstract LBA4505. Presented at ASCO 2019. Reproduced with permission from Dr D Petrylak.

SACITUZUMAB GOVITECAN (IMMU-132): PHASE 1/2 TRIAL

Phase 1/2 open-label, single-arm, multicenter, basket trial

Sacituzumab govitecan 10 mg/kg on Days 1 and 8, every 21 days

Endpoints: ORR, DoR, PFS, OS

◆ 11% of patients discontinued due to drug-related AEs

◆ No treatment-related deaths

Tagawa S, et al. J Clin Oncol 2019;37(7_suppl): Abstract 354. Presented at ASCO GU 2019. Reproduced with permission from Dr S.Tagawa.

SACITUZUMAB GOVITECAN (IMMU-132): PHASE 1/2 TRIAL

• Median PFS: 7.3 months

(95% CI: 5.0, 10.7)

• Median OS: 16.3 months

(95% CI: 9.0, 31)

Tagawa S, et al. J Clin Oncol 2019;37(7_suppl): Abstract 354. Presented at ASCO GU 2019. Reproduced with permission from Dr S.Tagawa..

• 50% of responses were ≥12 months

• 3 patients still on treatment with

response ongoing at data cut-off (17+,

19+ and 29+ months

TISOTUMAB VEDOTIN IN PATIENTS WITH ADVANCED

OR METASTATIC SOLID TUMOURS: PHASE 1/2 TRIAL

N=174 (bladder cancer: 17)

Reprinted from Lancet Oncol, 20(3), De Bono JS, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial, 383-393. Copyright 2019, with

permission from Elsevier.

All patients

(N=147)

Bladder cancer

(n=15)

Cervical cancer

(n=34)

Endometrial

cancer (n=14)

Oesophageal

cancer (n=15)

NSCLC

(n=15)

Ovarian cancer

(n=36)

Prostate cancer

(n=18)*

Objective response

n (%) 23 (15.6%) 4 (26.7%) 9 (26.5%) 1 (7.1%) 2 (13.3%) 2 (13.3%) 5 (13.9%) 0

95% CI 10.2, 22.5 7.8, 55.1 12.9, 44.4 0.2, 33.9 1.7, 40.5 1.7, 40.5 4.7, 29.5 0, 0.2

Duration of response

INTERIM ANALYSIS OF A PHASE 1 DOSE ESCALATION

TRIAL OF AGS15E IN PATIENTS WITH MUC

**Evaluable subjects are defined as subjects who received ≥1 dose of drug and ≥1 post-baseline assessment.Petrylak D, et al. Ann Oncol 2016;27(6):266–95. Abstract 780PD. Presented at ESMO 2016. Reproduced with permission from Dr D Petrylak.

Best overall response for evaluable patients

Max

imum

cha

nge

from

bas

elin

e (%

)

RC-48: ADC TARGETING HER-2 IN BIOMARKER-

SELECTED PATIENTS

Most common toxicities:

◆ All grades: Hypoesthesia (55.8%), alopecia (55.8%), leukopenia (55.8%), neutropenia (41.9%)

◆ Grade 3/4: hypoesthesia (16.3%), neutropenia (14.0%)

◆ SAEs: intestinal obstruction (4.7%) and incomplete intestinal obstruction (4.7%)

Sheng X, et al. J Clin Oncol 2019;37(15_suppl): Abstract 4509. Presented at ASCO 2019.. Reproduced with permission from Prof X. Sheng.

SURVIVAL:

◆Median PFS: 6.9 months

◆12 m OS rate: 59.6%

ANTIBODY DRUG CONJUGATES – CONCLUSIONS

ADCs show promising activity in heavily pretreated patients, with a favourable comparison to historical controls

Unlike ICIs, ADCs may maintain a high efficacy level in poor prognostic groups, such as patients with hepatic

metastases

ADCs have the potential to become an additional treatment option in the armamentarium of available therapies for UC

Development of surrogate markers of response is critical

Larger trials testing these agents are ongoing, both as single agent or in combinational strategies.* A Phase 3 trial is

comparing enfortumab-vedotin with vinflunine/taxanes in the third-line setting (post-platinum, post-ICI)

*NCT03474107, NCT03219333, NCT03547973, NCT03288545

A STEP-AHEAD INTO THE PRECISE FUTURE?

THE BISCAY TRIAL

Diagnostic sample

analysed

Module A: Durvalumab + AZD4547 OR

AZD4547

Module C: Durvalumab + AZD1775

Module B: Durvalumab + Olaparib

Module D: Durvalumab alone

FGFR

inhibitor

WEE1

inhibitor

PARP

inhibitor

PD-L1

Treatment option MOA

FGFR3 mutations/

fusions

CDKN2A /RB1 del

CCNE1 ampl

MYC ampl

ATM trunc mut/del

BRCA2 trunc

mut/del

ERCC2 mut

Biomarkers

considered

Module B2: Durvalumab + Tremelimumab + Olaparib

Module C2: Durvalumab + Tremelimumab + AZD1775

Module E*: Durvalumab+ Vistusertib mTOR inhRICTOR amplif,

TSC1 / TSC2 mut

Module F: Durvalumab+ AZD9150 STAT3 inh

None

Second-/third-line

metastatic

urothelial cancer

*:cohort unselected, but RICTOR, TSC1 and TSC2 directed to this cohort

SECOND-LINE THERAPY FOR METASTATIC

UROTHELIAL CARCINOMA

The race against bladder cancer

Taxanes / gemcitabine Vinflunine

IO agents? Immuno combos

? Targeted therapy

? ADCs

Taxanes / gemcitabine Taxanes / gemcitabine

CONCLUSIONS

The therapeutic scenario in post-platinum mUC patients has evolved rapidly within the last 5 years with multiple

additions

Checkpoint inhibitors have superseded chemotherapy, with impressive results in a subset of patients (15–20),

although the lack of predictive biomarkers might limit the success of this treatment option

FGFR inhibitors have shown remarkable activity in a biomarker-selected population and erdafitinib has been recently

added to the treatment armamentarium in this setting (FDA approval)

The Antibody Drug Conjugates represent an attractive alternative to all patients (they do not require biomarker

selection) and their preliminary activity appears very promising

Biomarker driven studies are ongoing and hopefully will soon refine mUC treatment

THANK YOU!

Documents

METASTATIC UROTHELIAL CARCINOMA Systemic second-line …