NOVÉ MOŽNOSTI LÉČBY NÁDORŮ MOČOVÉHO

MĚCHÝŘE

A JEJICH ZAŘAZENÍ DO ALGORITMU LÉČBY

Jindřich Fínek

LF UK a FN Plzeň

1

KARCINOM MOČOVÉHO MĚCHÝŘE –

INCIDENCE A MORTALITA

2

KARCINOM MOČOVÉHO MĚCHÝŘE –

ZASTOUPENÍ DLE STÁDIÍ

3

MODRÁ KNIHA – PREDIKTIVNÍ ODHADY

CELKOVÉ INCIDENCE A PREVALENCE 2017

4

MODRÁ KNIHA - ODHADY POČTU PACIENTŮ NOVĚ

LÉČENÝCH PROTINÁDOROVOU TERAPIÍ 2017

5

METASTAZUJÍCÍ KARCINOM MOČOVÉHO MĚCHÝŘE (MUBC) –

LÉČEBNÉ MOŽNOSTI A PROGNÓZA

1st-Line Metastatic1-10

• Carboplatin-based

(~50% of

patients)2,6,9,10

≥2nd-Line

Metastatic11-15

• Vinflunine

• Taxane-based CT

• M-VAC

Cisplatin:

ORR: ~28–56%

mOS: ~8–15 mo

ORR: ~9–30%

mOS: ~5–11 mo

• Cisplatin-based

(~50% of patients)1-8

Cisplatin:

ORR: ~36–72%

mOS: ~13–16 mo

5-ti leté přežití pacientů s mUBC:

~15%16

KARCINOM MOČOVÉHO MĚCHÝŘE – PROČ

IMUNOTERAPIE?

Mutation Frequencies Observed in Cancers1

1000

100

10

1

0.1

0.01

N= 22 20 52 134 26 23 81 227 91 57 121 13 63 214 11 394 219 20 49 181 231 76 88 35 335 179 121

So

mati

c M

uta

tio

n F

req

uen

cy (/

Mb

)

AD, adenocarcinoma; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; PD-1, programmed death-1; RCC, renal cell carcinoma; SQ, squamous.1. Lawrence MS et al. Nature. 2013;499(7457):214-218.

KEY APPROVALS FOR I-O TREATMENT IN GU TUMORS

• Checkpoint inhibitors, discovered in the 1990s, have had a major impact on the treatment of GU cancer

types, particularly over the past few years

RCC

APPROVALS BY CANCER TYPE

Bladder Cancer

Nivolumab1

Nivolumab2

Atezolizumab3

2015

*Indicated for all solid tumor types which are unresectable or metastatic, MSI-H or dMMR that have progressed following prior treatment and who have no satisfactory alternative treatment options. dMMR, mismatch repair deficient; GU, genitourinary; I-O, immuno-oncology; MSI-H, microsatellite instability high; RCC, renal cell carcinoma.Bristol-Myers Squibb receives FDA approval for Opdivo (nivolumab), the only treatment to deliver significant overall survival in advanced renal cell carcinoma vs. a standard of care, in patients who have received prior anti-angiogenic therapy [press release]. November 23, 2015. Accessed October 3, 2017. 2. European commission approves Bristol-Myers Squibb’s Opdivo® (nivolumab) for previously treated advanced renal cell carcinoma [press release]. April 6, 2016. Accessed October 3, 2017. 3. Roche. FDA grants Roche’s cancer immunotherapy Tecentriq (atezolizumab) accelerated approval for people with a specific type of advanced bladder cancer [press release]. May 19, 2016. Accessed September 12, 2017. 4. Bristol-Myers Squibb. Bristol-Myers Squibb receives FDA approval for Opdivo (nivolumab) in previously treated locally advanced or metastatic urothelial carcinoma, a type of bladder cancer [press release]. February 2, 2017. Accessed September 12, 2017. 5. AstraZeneca UK Limited. AstraZeneca’s Imfinzi (durvalumab) receives US FDA accelerated approval for previously treated patients with advanced bladder cancer [press release]. May 1, 2017. Accessed September 12, 2017. 6. Pfizer. FDA grants BAVENCIO® (avelumab) approval for a common type of advanced bladder cancer [press release]. May 9, 2017. Accessed September 12, 2017. 7. Merck and Co., Inc. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer [press release]. May 18, 2017. Accessed September 12, 2017. 8. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient cancer [press release]. May 23, 2017. Accessed October 10, 2017. 9. Bristol-Myers Squibb. European Commission approves Bristol-Myers Squibb’s Opdivo (nivolumab) for previously treated locally advanced unresectable or metastatic urothelial carcinoma in adults after failure of prior platinum-containing therapy [press release]. June 2, 2017. Accessed September 12, 2017. 10. Merck and Co., Inc. European Commision approves Merck’s KEYTRUDA® (pembrolizumab) for the treatment of certain patients with locally advanced or metastatic urothelial carcinoma, a type of bladder cancer [press release]. September 5, 2017. Accessed September 12, 2017. 11. Roche. Roche receives EU approval for TECENTRIQ® (atezolizumab) in a specific type of metastatic lung and two types of metastatic bladder cancer [press release]. September 22, 2017. Accessed September 25, 2017.

2016

Nivolumab4

2017

Durvalumab5, Avelumab6, Pembrolizumab7

Pembrolizumab10,Atezolizumab11

Nivolumab9

MSI-H/dMMR Tumors*

Pembrolizumab8

8

CHECKMATE 275: KLINICKÁ STUDIE

FÁZE 2

Léčba do progrese nebo

neakceptovatelné toxicity

• Metastazující nebo lokálně

pokročilý uroteliální

karcinom

• Progrese onemocnění na

předchozím režimu na

základě platiny

• Vzorky vhodné pro

hodnocení PD-L1*

N=270

* Patients were required to have an evaluable tumor tissue sample for PD-L1 expression testing at screening, but were not excluded based on PD-L1 status. † RECIST v1.1.BIRC, blinded independent review committee; CNS, central nervous system; CTLA-4, cytotoxic T-lymphocyte antigen-4; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; q2w, every 2 weeks; QoL, quality of life; tx, treatment.Galsky M et al. Oral presentation at ESMO 2016. LBA31_PR.

Nivolumab

3 mg/kg IV

q2w (N=270)

• Primární cíl: ORR† (BIRC) u všech

pacientů a pacientů s PD-L1 expresí

≥1% a ≥5%

• Sekundární cíle: PFS, OS,

bezpečnost, QoL, biomarkery

Léčba po progresi povolena pouze

za dodržení podmínek

definovaných protokolem studie

CHECKMATE 275 – LÉČEBNÁ ODPOVĚĎ (ORR) DLE

HLADINY EXPRESE PD-L1

Outcome, %All

N=265†

PD-L1 <1%

n=143

PD-L1 ≥1%

n=122

PD-L1 ≥5%

n=81

Confirmed ORR by BIRC* 19.6 16.1 23.8 28.4

95% CI 15.0–24.9 10.5–23.1 16.5–32.3 18.9–39.5

Best overall response

Complete response 2.3 <1 4.1 4.9

Partial response 17.4 15.4 19.7 23.5

Stable disease 22.6 17.5 28.7 28.4

Progressive disease 39.2 46.9 30.3 25.9

Unable to determine 18.5 19.6 17.2 17.3

Data reported as of October 2016. Median follow-up was 7 months (minimum of 6 months).* By RECIST v1.1. † 265 of 270 patients were evaluated for efficacy, as 5 patients had insufficient followBIRC, blinded independent review committee; CI, confidence interval; ORR, objective response rate; PD-L1, programmed death ligand 1.Galsky M et al. Oral presentation at ESMO 2016. LBA31_PR.

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Měsíce

Prav

děp

od

ob

no

st P

FS

0 3 6 9 12

No. at Risk

All treated patients 265 110 48 17 0

All treated patients

PD-L1 <1%

143 49 21 9 0PD-L1 <1%

122 61 27 8 0PD-L1 ≥1%

PD-L1 ≥1%

CheckMate 275 - mPFSMedián PFS, měsíce (95% CI)*

Všichni pacienti 2,00 (1.87–2.63)

PD-L1 <1% 1,87 (1.77–2.04)

PD-L1 ≥1% 3,55 (1.94–3.71)

Data reported as of October 2016.* Similar results were seen using the 5% PD-L1 tumor expression cutoff.CI, confidence interval; PD-L1, programmed death ligand 1; PFS, progression-free survival.Galsky M et al. Oral presentation at ESMO 2016. LBA31_PR.

All treated patients

No. at RiskAll treated patients

PD-L1 <1%

PD-L1 ≥1%

PD-L1 ≥1%

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15

Prav

děp

od

ob

no

st O

S

Měsíce

PD-L1 <1%

265 198 148 63 5 0143 101 69 26 2 0

122 97 79 37 3 0

CheckMate 275 - mOSMedián OS, měsíce (95% CI)*

Všichni pacienti 8,74 (6,05–NR)

PD-L1 <1% 5,95 (4,30–8,08)

PD-L1 ≥1% 11,30 (8,74–NR)

Data reported as of October 2016.* Similar results were seen using the 5% PD-L1 tumor expression cutoff.CI, confidence interval; NR, not reached; OS, overall survival; PD-L1, programmed death ligand 1.Galsky M et al. Oral presentation at ESMO 2016. LBA31_PR.

• EORTC QLQ-C30, a validated QoL instrument commonly used in oncology studies, assesses QoL using 5 function scales, 8 symptom scales, a global QoL scale, and a finance scale1

• A clinically meaningful change in QoL score may be regarded as 10 points1

• Quality of life was maintained throughout 41 weeks of nivolumab treatment2

• Similar results were observed for general health status using the EQ5D assessment tool2

CheckMate 275 – Kvalita života (QoL)

EORTC QLQ-C30 Global Health Status Score2*

Me

an C

han

ge F

rom

Bas

elin

e(9

5%

CI)

15

20

25

10

5

0

-5

-10

-15

-20

-25

Week 9n=138

Week 17n=95

Week 25n=73

Week 33n=52

Week 41n=23

Worse

Better

6.54.88.35.6

3.2

Data reported as of October 2016.* Completion rates for all treated patients met or exceeded 75% at all QoL assessments through the first 49 weeks of on-treatment visits.CI, confidence interval; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer Patients Version 3.0; EQ5D, EuroQoL Five Dimensions Questionnaire; QoL, quality of life.1. Khan I et al. Health Qual Life Outcomes. 2015;13:180-192. 2. Galsky M et al. Oral presentation at ESMO 2016. LBA31_PR.

Adapted from Galsky et al, 2016, ESMO.

VINFLUNINE + BSC VERSUS BSC: RANDOMIZED PHASE 3

STUDY OF PATIENTS WITH mUC WHO PROGRESSED

AFTER 1L

Efficacy in the ITT Population

Vinflunine +

BSC (n=253)BSC (n=117)

ORR, %

(95% CI)

8.6

(5.0–13.7)0

CR, % 0 0

mDOR, mos 7.4 --

mPFS, mos 3 1.5

mOS, mos (95% CI)* 6.9 (5.7–8.0) 4.3 (3.8–5.4)

HR: 0.78; 95% CI, 0.61–0.99; P=0.0403

* The eligible population excludes 13 patients who presented at least one major protocol violation at baseline.

2L, second line; BSC, best supportive care; CR, complete response; DOR, duration of response; HR, hazard ratio; m, median; mos, months; mUC, metastatic urothelial carcinoma; ORR, objective response; OS, overall survival; PFS, progression-free survival; VFL, vinflunine.

Bellmunt J et al. J Clin Oncol. 2009;27(27):4454-4461.

2L+ mUC

OS in the Eligible Population*

Time (months)

1.0

0.8

0.6

0.0

0.2

0.4

2510 3530200 155

VFL + BSC

BSC

Ove

rall

su

rviv

al (p

rob

ab

ilit

y)

Adapted from Bellmunt et al, 2009.

Most Common Treatment-Related Adverse Events and Hematologic Abnormalities

Vinflunine + BSC (n=248)

BSC (n=117)

Adverse event, %All-

GradeGrade

3-4All-

Grade Grade

3-4

Anemia 93 19 61 8

Neutropenia 77 50 3 <1

Thrombocytopenia 51 6 16 <1

Fatigue/asthenia 50 19 61 18

Constipation 48 16 25 <1

Nausea 39 2 21 <1

Stomatitis/ mucositis

29 2 2 0

Alopecia 29 0 2 0

Vomiting 29 3 15 0

Infusion/injection site

27 <1 0 0

Chemotherapy

14

KEYNOTE-045: PEMBROLIZUMAB VS CT IN

RECURRENT OR PROGRESSIVE mUC

Randomized, phase 3 trial of pembrolizumab versus chemotherapy in patients with previously

treated recurrent or progressive metastatic urothelial carcinoma1,2

• Urothelial carcinoma of the renal pelvis, ureter, bladder,

or urethra

• Disease progression after 1–2 lines of platinum-based

therapy or recurrence within 12 months of perioperative

platinum-based therapy

• ECOG PS 0–2

• Transitional cell predominant

• Provision of tumor sample for biomarker assessment

R

Pembrolizumab 200 mg (IV)

q3w for 2 years

PTX, DTX, or VFL (175, 75, or 320 mg/m2, respectively, IV) q3w

N=542

Primary Outcome Measures: OS and PFS (in total and PD-L1

CPS ≥10% population)

Secondary Outcome Measures: ORR and DOR (in total and

PD-L1 CPS ≥10% population) and safety in total population

2L, second line; 3L, third line; CPS, combined positive score; CT, chemotherapy; DOR, duration of response; DTX, docetaxel; ECOG PS, Eastern Cooperative Oncology Group performance status; I-O, immuno-oncology; IV, intravenous; mUC, metastatic urothelial carcinoma; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival; PTX, paclitaxel; q3w, every 3 weeks; R, randomized; VFL, vinflunine.

1. Bellmunt J et al. N Engl J Med. 2017;376:1015-1026. 2. Clinicaltrials.gov. NCT02256436. Accessed October 3, 2017.

2L–3L mUCI-O monotherapy

15

KEYNOTE-045: OVERALL SURVIVAL AND ORR*

Adapted from Bellmunt et al, 2016.Adapted from Bellmunt et al, 2017.

Outcomes in All Pts Pembro Chemo

mOS, mos (95% CI)* 10.3 (8.0–11.8) 7.4 (6.1–8.3)

ORR, % (95% CI)* 21.1 (16.4–26.5) 11.4 (7.9–15.8)

CR, % 7.0 3.3

PR, % 14.1 8.1

mDOR, mos (range) NR (1.6–15.6) 4.3 (1.4–15.4)

Outcomes in CPS ≥10% Pembro Chemo

mOS, mos (95% CI)* 8.0 (5.0–12.3) 5.2 (4.0–7.4)

ORR, % (95% CI)* 21.6 (12.9–32.7) 6.7 (2.5–13.9)

CR, % 6.8 2.2

PR, % 14.9 4.4

mDOR, mos (range) -- --

Overall Survival: CPS ≥10%2†Overall Survival: Total1

0

10

20

30

40

50

60

70

80

90

100

0 4 6 8 20 24

Ov

era

ll S

urv

ival, (

%)

Time (months)No. at Risk

Pembro 7490

2 10 12 14 16 18 22

51 42 35 0 060 31 18 12 7 3 051 36 28 0 076 24 16 8 4 1 0

0

10

20

30

40

50

60

70

80

90

100

0 4 6 8 20 24

Ov

era

ll S

urv

ival, (

%)

Time (months)No. at Risk

270272

2 10 12 14 16 18 22

194 169 147 4 0226 131 87 54 27 13 0171 138 109 0 0232 89 55 27 14 3 0

Pembro

Chemo Chemo

Pembro

Chemo

Pembro

Chemo

HR (95% CI): 0.73 (0.59–0.91), P=0.002 HR (95% CI): 0.57 (0.37–0.88), P=0.00483

*Confirmed ORR and OS were assessed per RECIST v1.1 by blinded, independent central review. Data cutoff date: September 7, 2016.†CPS is the percentage of PD-L1–positive tumor cells and tumor-infiltrating immune cells relative to the total number of tumor cells.

2L, second line; 3L, third line; chemo, chemotherapy; CI, confidence interval; CPS, combined positive score; CR, complete response; HR, hazard ratio; I-O, immuno-oncology; mDOR, median duration of response; mOS, median overall survival; mos, months; mUC, metastatic urothelial carcinoma; NR, not reached; ORR, objective response rate; OS, overall survival; pembro, pembrolizumab; PR, partial response; Pts, patients; RECIST, Response Evaluation Criteria In Solid tumors.

1. Bellmunt J et al. N Engl J Med. 2017;376:1015-1026. 2. Bellmunt J et al. Oral presentation at SITC 2016.

2L–3L mUCI-O monotherapy

16

KEYNOTE-045: QUALITY OF LIFE

Kaplan-Meier Estimates of Time to Deterioration in the

EORTC QLQ-C30 Global Health Status/QoL Score

* Data are shown as mean ± standard error. The range of possible scores for the global health status/QoL score is 0 to 100.

2L, second line; 3L, third line; chemo, chemotherapy; CI, confidence interval; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer core 30 Quality of Life Questionnaire version 3; HR, hazard ratio; mos, months; mUC, metastatic urothelial carcinoma; pembro, pembrolizumab; QoL, quality of life.

Vaughn DJ et al. Poster presentation at ASCO GU 2017. 282.

EORTC QLQ-C30 Global Health Status/QoL

Score by Visit*

Time (weeks)

No. completed EORTC QLQ-C30

70

60

58

52

500

Glo

ba

l H

ealt

h S

tatu

s/Q

oL

Sc

ore

Events

(n)

Median

(mos)HR (95% CI)

Pembrolizumab 137 3.50.70 (0.55–0.90)

P=0.002

Chemotherapy 133 2.2 –

54

56

62

64

66

68

3 6 9 15 21 27

260 238 215 200 157 126 105

243 220 199 176 118 73 46

Pembrolizumab

Chemotherapy

Time (months)

No. at risk

100

50

40

10

00

Wit

ho

ut

De

teri

ora

tio

n, %

20

30

60

70

80

90

2 4 6 8 14 1610 12

243 101 34 12 2 0 02 1

260 144 77 55 39 3 027 6

Time to deterioration in the global health status/QoL

score was prolonged with pembrolizumab vs chemo

Global health status/QoL score was better with pembrolizumab

starting at Week 3 and maintained through Week 27

I-O monotherapy

Pembro

Chemo

Pembro

Chemo

2L–3L mUC

Adapted from Vaughn et al, 2017.

17

Adapted from Vaughn et al, 2017.

IMvigor 210: ATEZOLIZUMAB IN LOCALLY ADVANCED

OR mUC

• Multicenter, single-arm, phase 2 trial of atezolizumab in patients with locally advanced or metastatic urothelial carcinoma

• Locally advanced or metastatic urothelial carcinoma

(including renal pelvis, ureters, urinary bladder, or

urethra)

• Disease progression during or following at least

1 Pt-containing regimen (cohort 2)

• ECOG PS 0–1

Atezolizumab 1200 mg IV q3w

N=310

Primary Outcome Measure: ORR (CR or PR)*

Secondary Outcome Measures: DOR,*† PD,*†

PFS,*† OS, PK, ATA

*As assessed by the Independent Review Facility (IRF) and investigator using RECIST v1.1. †Using modified RECIST.

2L, second line; ATA, anti-therapeutic antibodies; CR, complete response; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; I-O, immuno-oncology; IV, intravenous; mUC, metastatic urothelial carcinoma; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PK, pharmacokinetics; PR, partial response; Pt, platinum; q3w, every 3 weeks; RECIST, Response Evaluation Criteria In Solid tumors.

Clinicaltrials.gov. NCT02108652. Accessed October 3, 2017.

I-O monotherapy 2L+ mUC

18

IMvigor 210: COHORT 2 OVERALL SURVIVAL & ORR

• Longer OS observed in patients with higher PD-L1 IC status

• 32 of 49 responding patients had ongoing responses at data cutoff*

Outcomes in All Patients1* Atezolizumab

mOS, months (95% CI) 7.9 (6.7–9.3)

ORR, % (95% CI) 16 (12–20)

CR, % 6

mDOR, months (range) NR

Outcomes by PD-L11*† PD-L1 ≥5%*†

PD-L1 <5%*†

PD-L1 ≥1%*†

PD-L1 <1%*†

mOS, months (95% CI)11.9

(9.0–NE)

6.7

(5.4–8.0)NA NA

ORR, % (95% CI) 28 (19–38) NA 19 (14–25) 9 (4–16)

CR, % 14 NA 8 2

0

20

40

60

80

100

Ov

era

ll S

urv

ival (%

)

0 4 8 12 16 20 24

310 203 146 110 91 70 2All patients:

No. at Risk

265 176 126 99 79 23

All treated

Overall Survival in All Patients1*

Time (months)

Atezolizumab

Overall Survival by PD-L1 Expression2‡

No. at risk

30

10

20

40

50

60

70

80

90

100

Ov

era

ll S

urv

ival (%

)

0 2 64 8 10 12 14 160

Time (months)PD-L1 ≥5%

PD-L1 ≥1% but <5%

PD-L1 <1%

100107103

928984

746860

675849

584740

503232

231014

211

Censored

PD-L1 ≥5%

Atezolizumab

PD-L1 ≥1% but <5%PD-L1 <1%

*Data cutoff: March 14, 2016. †PD-L1 expression on IC: IC2/3 (≥5%), IC0/IC1 (< 5%), ICO1/2/3 (≥1%), ICO (<1%). ‡Data cutoff: September 14, 2015.

CI, confidence interval; CR, complete response; IC, tumor-infiltrating immune cells; mDOR, median duration of response; mOS, median OS; NA, not available; NE, not

estimable; NR, not reached; OS, overall survival; ORR, objective response rate; PD-L1, programmed death ligand 1; PR, partial response.

1. Loriot Y et al. Poster presentation at ESMO 2016. Abstract 783P. 2. Rosenberg et al. Lancet. 2016;387:1909-1920.

I-O monotherapy 2L+ mUC

19

Adapted from Rosenberg et al, 2016.

Adapted from Loriot et al, 2016.

IMvigor 210: COHORT 2 TREATMENT

BEYOND PROGRESSION

• 33% (45 of 137) of all patients TBP experienced a reduction in the sum of target lesion tumor diameters from their

measurements at time of PD

• 5 patients experienced objective responses following their continued use of atezolizumab

• TRAEs were evaluated in 137 patients who were TBP with atezolizumab; any Grade TRAEs were reported in 53% of

patients, and Grade 3–4 TRAEs in 9% of patients†

No. of Patients at Risk

Atezolizumab 137 126 104 84 68 48 42 35 25 14 5 0 0

Other systemic therapy 19 16 14 11 7 4 2 1 1 0 0 0 0

No systemic therapy 64 18 5 1 1 1 0 0 0 0 0 0 0

Adapted from Necchi et al, 2017.

Po

st-

Pro

gre

ssio

n O

vera

ll S

urv

ival, %

100

80

60

40

20

00 4 8 12 16 20 24

Time (months)

Post-PD OS by Post-PD Treatment Status

Censored

*RECIST v1.1 (IRF- assessed) and imRECIST (investigator-assessed). †TRAEs reported during post-progression.

2L, second line; CR, complete response; IRF, independent review facility; IV, intravenously; mUC, metastatic urothelial cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; q3w, every 3 weeks; RECIST, Response Evaluation Criteria In Solid tumors; TBP, treated beyond progression; TRAE, treatment-related adverse events.

Necchi A et al. Poster presentation at ESMO 2017. 852PD.

No systemic therapy

Other systemic therapy

Atezolizumab

I-O monotherapy 2L+ mUC

20

IMvigor 211: PHASE 3 TRIAL OF ATEZOLIZUMAB VERSUS

CHEMOTHERAPY IN PLATINUM-TREATED ADVANCED

UROTHELIAL CARCINOMA1,2

Atezolizumab*

1200 mg q3w

Until

disease

progression

Key Inclusion Criteria• mUC with progression during or

following platinum-based chemotherapy (≤2 prior lines of therapy)

• Measurable disease (RECIST v1.1)

• ECOG PS 0 or 1

• Sample for PD-L1 testing

• TCC histology primary component

R

1:1 Chemotherapy*(investigator’s choice)

Vinflunine q3wDocetaxel q3wPaclitaxel q3w

Primary Outcome Measure: OS

Secondary Outcome Measures: ORR, PFS,

DOR‡, safety, ATAs, pharmacokinetics, QoL

N=931

PD-L1 <5% is defined as IC0/1 and PD-L1 ≥5% is defined as IC2/3.

*No crossover permitted. †Defined by time from prior chemotherapy <3 mo, ECOG performance status >0 and hemoglobin <10 g/dL. ‡Confirmed response was not required

for secondary efficacy endpoints. This analysis reports exploratory confirmed responses.

2L, second line; 3L, third line; ATA, antitherapeutic antibodies; DOR, duration of response; ECOG, Eastern Oncology Cooperative Group; IC, immune cell; I-O, immuno-

oncology; mUC, metastatic urothelial carcinoma; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand 1; PFS, progression-free survival;

PS, performance status; q3w, every 3 weeks; R, randomized; QoL, quality of life; RECIST, Response Criteria In Solid Tumors; TCC, transitional cell carcinoma.

1. Powles T et al. Oral presentation at EAS-AACR-SIC 2017. 2. Clinicaltrials.gov NCT02302807. Accessed October 17, 2017.

2L–3L mUCI-O monotherapy

21

Stratification Factors:

• Number of risk factors† (0 vs 1/2/3)

• Liver metastases (yes vs no)

• PD-L1 status (<5% vs ≥5%)

• Chemotherapy (vinflunine vs taxanes)

Until loss

of clinical

benefit

Atezolizumab

Chemo

22

IMvigor 211: OVERALL SURVIVAL AND ORR*

Overall Survival: ITT Population

0

20

40

60

80

100

0 4 6 8 20 24

Ov

era

ll S

urv

ival, (

%)

Time (months)

467464

2 10 12 14 16 18 22

327 280 245 34 1405 201 177 138 90 59 13330 268 219 17 1397 175 140 99 60 42 7

HR = 0.85 (95% CI: 0.73–0.99); P = 0.038

Overall Survival: PD-L1 ≥5% Population†

0 4 6 8 20 24

60

80

100

40

20

Ov

era

ll S

urv

ival, (

%)

Time (months)

116118

2 10 12 14 16 18 22

85 77 71 11 0100 58 51 39 27 19 691 82 71 9 161 47 32 24 15 5

No. at Risk

Atezolizumab

Chemo

No. at Risk

Atezolizumab

Chemo

HR = 0.87 (95% CI: 0.63–1.21), P = 0.410

Atezolizumab

Chemo

100

Powles T, et al. EAS 2017, IMvigor211.

Data cutoff date: March 13, 2017. Median follow-up duration in ITT population: 17.3 months (range: 0–24.5)

* Confirmed ORR was assessed by RECIST v1.1 as an exploratory endpoint. †IC2/3 is defined as PD-L1 ≥ 5% on tumor-infiltrating immune cells. IC3 defined as PD-L1 ≥ 10% on ICs;

IC2 defined as PD-L1 ≥ 5% and < 10% on ICs.

2L, second line; 3L, third line; Atezo, atezolizumab; CI, confidence interval; Chemo, chemotherapy; CR, complete response; DCR, disease control rate; HR, hazard ratio. IC, immune

cell; ITT, intent-to-treat; mDOR, median duration of response, mOS, median overall survival; mUC, metastatic urothelial carcinoma; ORR, objective response rate;PD-L1, programmed

death ligand-1; RECIST, Response Evaluation Criteria in Solid Tumors.

Powles T, et al. EAS 2017, IMvigor211.

2L–3L mUC

Outcomes in ITT Atezo Chemo

mOS, mos (95% CI) 8.6 (7.8–9.6) 8.0 (7.2–8.6)

ORR, % (95% CI) 13 (11–17) 13 (11–17)

CR, % 3 3

mDOR, mos (range) 21.7 (13.0–21.7) 7.4 (6.1–10.3)

PD-L1 ≥5% Population† Atezo Chemo

mOS, mos (95% CI) 11.1 (8.6–15.5) 10.6 (8.4–12.2)

ORR, % (95% CI) 23 (16–32) 22 (15–30)

CR, % 7 7

mDOR, mos (range) -- --

Adapted from Powles et al, 2017.Adapted from Powles et al, 2017.

I-O monotherapy

22

Study design

Median follow-up (range)

ORR, % (95% CI)

CRPR

mOS (95% CI)

mPFS (95% CI)

Evaluation of PD-L1

ORR by PD-L1

Study 11081

DurvalumabPhase 1/2

N=191†

Durvalumab 10 mg/kg IV q2w for 1 year Phase 1/2, single-arm mUC cohort

1’ EP: Safety (AEs/SAEs), ORR by BICR

5.78 months (0.4 to 25.9)

17.8 (12.7–24.0)

3.7%14.1%

18.2 months (8.1–NE)‡

1.5 months (1.4–1.9)

% of PD-L1–expressing TCs or ICs

• PD-L1 ≥25%: 27.6%• PD-L1 <25%: 5.1%

Javelin Solid Tumor2

AvelumabPhase 1

N=242

Avelumab 10 mg/kg IV q2w

Phase 1, single-arm mUC cohorts

1’ EP: ORR by IERC, ORR by BICR

19.6 months (12.0 to 30.4 )

16.1 (11.7–21.4)

5.0%

11.2%

7.7 months (6.2-10.3)

1.5 months (1.4–2.7)

% of PD-L1–expressing TCs

• PD-L1 ≥5%: 23.8%• PD-L1 <5%: 11.5%

SUMMARY OF SELECT RECENT INVESTIGATIONAL AND

REGISTRATIONAL TRIALS IN PRETREATED mUC* (1 OF 2)

Durvalumab and avelumab are currently not approved in Europe for the treatment of urothelial carcinoma (status as of 10 October 2017).

*No head-to-head studies have been conducted and direct comparisons cannot be made between these studies.†As-treated population included 9 1L patients in Study 1108. ‡OS data were considered immature at data cutoff.

1’, primary; AE, adverse event; BICR, blinded independent review committee; CI, confidence interval; CR, complete response; EP, endpoint; IC, immune cell; IERC, independent endpoint review committee; IV, intravenously; I-O, immuno-oncology; NA, not available; NE, not evaluable; mOS, median overall survival; mPFS, median progression-free survival; mUC, metastatic urothelial carcinoma; q2w, every 2 weeks; ORR, objective response rate; PD-L1, programmed death ligand 1; PR, partial response; SAE, serious adverse event; TC, tumor cell.

1. Hahn NM et al. Poster presentation at ASCO 2017. 4525. 2. Apolo AB et al. Poster presentation at.ESMO.2017.856P.

I-O monotherapy 2L+ mUC

23

MVAC VS GEM-CIS IN 1L CISPLATIN-ELIGIBLE AND GEM-CARBO

VS M-CAVI IN 1L CISPLATIN-INELIGIBLE mUC PATIENTS

1L mUCChemotherapy

Phase 3 study of classic MVAC vs Gem-cis

(n=405)1,2

Phase 2/3 study of Gem-carbo vs

M-CAVI in cisplatin-unfit patients (n=238)3

ORR (%)Classic MVAC: 46

Gem-cis: 49

Gem-carbo: 41

M-CAVI: 30

Median PFS (months)Classic MVAC: 8.3

Gem-cis: 7.7

Gem-carbo: 5.8

M-CAVI: 4.2

Median OS (months)Classic MVAC: 15.2

Gem-cis: 14.0

Gem-carbo: 9.3

M-CAVI: 8.1

Top 3 Grade 3/4 AEs (%)

Classic MVAC: Neutropenia (82.3), Alopecia (55.2),

Mucositis (21.9)

Gem-cis: Neutropenia (71.1),

Thrombocytopenia (57.0), Anemia (27.0)

Gem-carbo*†: Neutropenia (52.5),

Thrombocytopenia (48.3), Leucopenia (44.9)

M-CAVI*†: Neutropenia (63.5), Leucopenia (46.6),

Thrombocytopenia (19.4)

*Common Toxicity Criteria v2.0. †Adverse events reported in 118 patients for each arm.Gem-carbo, Gencitabine + Carboplatin; Gem-cis, Gemcitabine + Cisplatin; M-CAVI, Methotrexate + carboplatin + vinblastine; MVAC, Methotrexate + vinblastine + adriamycin + cisplatin. 1. von der Maase H et al. J Clin Oncol. 2000;18:3068-3077. 2. von der Maase H, et al. J Clin Oncol. 2005;23:4602-8 . 3. De Santis M et al. J Clin Oncol. 2012;30:191-199.

Time (years)

Ov

era

ll s

urv

ival (p

rob

ab

ilit

y)

80

60

20

0

40

631 5420 7

100

Time (months)

Ov

era

ll s

urv

ival (p

rob

ab

ilit

y)

80

60

20

0

40

723612 846048240

100

Gem-cis MVAC

mOS (months)2 14.0 15.2

HR=1.09 (log rank p=0.66)

M-CAVI

(n=119)

Gem-carbo

(n=119)

mOS (months)2 8.1 9.3

HR=0.94 (log rank p=0.64)

24

Adapted from von der Maase et al, 2005. Adapted from De Santis et al, 2012.

IMvigor 210: PHASE 2 TRIAL OF ATEZOLIZUMAB IN

LOCALLY ADVANCED OR METASTATIC UROTHELIAL

CARCINOMA (COHORT 1: 1L CPT-INELIGIBLE)

Outcome Atezolizumab

N=119

Confirmed ORR, % (n) (95% CI)23 (27)

(16‒31)

IC0 21 (8)

IC1 21 (10)

IC2/3 28 (9)

IC1/2/3 24 (19)

Complete response, % (n) 9 (11)

IC0 8 (3)

IC1 8 (4)

IC2/3 13 (4)

IC1/2/3 10 (8)

mDOR all patients, months

(95% CI)NE (14.1–NE)

mOS all patients, months

(95% CI)15.9 (10.4–NE)

Atezolizumab

N=119

5 most frequent any-grade TRAEs (%)

Overall (66)• Fatigue (30)• Diarrhea (12)• Pruritus (11)• Decreased appetite (9)• Hypothyroidism (7)

5 most frequent Grade 3–4 TRAEs (%)

Overall (16)• Fatigue (3)• ALT increased (3)• AST increased (3)• Diarrhea (2)• Blood bilirubin increased (2)• Hypophosphatemia (2)• Renal failure (2)

Efficacy Summary Treatment-Related AEs

• 1 death was attributed to a TRAE (sepsis)

1L, first line; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CPT, cisplatin; IC, immune cell; I-O, immuno-oncology; mDOR, median duration of response; mOS, median overall survival; mUC, metastatic urothelial carcinoma; NE, not estimable; ORR, objective response rate; TRAE, treatment-related adverse event.

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

1L mUCI-O monotherapy

25

KEYNOTE-052: A PHASE 2 TRIAL OF PEMBROLIZUMAB IN

1L CISPLATIN-INELIGIBLE ADVANCED OR mUC

OutcomeAll

N=370

CPS ≥10%

n=80

CPS

≥1 to <10%

n=139

CPS

<1%

n=46

Confirmed ORR,* % (n)

95% CI

24 (89)

20–29

39 (31)

28–50

20 (28)

14–28

11 (5)

4–24

Best overall response,

% (n)

Complete response 5 (17) 10 (8) 1 (1) 0 (0)

Partial response 19 (72) 29 (23) 19 (27) 11 (5)

Stable disease 23 (84) 30 (24) 26 (36) 17 (8)

Progressive disease 42 (156) 25 (20) 42 (59) 57 (26)

Non-evaluable† 3 (10) 0 (0) 3 (4) 4 (2)

No assessment‡ 8 (31) 6 (5) 9 (12) 11 (5)

Median time to

response, months

95% CI

2

2.0–2.1-- -- --

Median duration of

response, months

95% CI

NR

9–NR-- -- --

Pembrolizumab

N=370

5 most frequent any-grade TRAEs (%)

Any (62)• Fatigue (17)• Pruritus (15)• Rash (10)• Decreased appetite (10)• Diarrhea (8)

4 most frequent Grade 3–5 TRAEs (%)

Any (16)• Fatigue (2)• Colitis (<2)• Asthenia (<2)• Decreased appetite (<2)

• 1 patient’s death was attributed to a TRAE (myositis)

Efficacy Summary Treatment-related AEs

Data cutoff date: September 1, 2016. Median follow-up was 5 months (IQR: 3.0–8.6).

CPS is the number of PD-L1–positive cells (tumor cells, macrophages, lymphocytes) over total tumor cells, expressed as a percentage.

*By central review per RECIST v1.1. †Patient had post-baseline imaging, but images were not of sufficient quality to determine response. ‡Patient had no post-baseline imaging.

1L, first line; AE, adverse event; CI, confidence interval; CPS, combined positive score; I-O, immuno-oncology; mUC, metastatic urothelial carcinoma; NR, not reached; ORR, objective response rate; PD-L1, programmed death ligand 1; RECIST, Response Evaluation Criteria In Solid tumors; TRAE, treatment-related AE.

Balar AV et al. Lancet Oncol. 2017;pii: S1470-2045(17)30616-2.

1L mUCI-O monotherapy

26

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