Immunotherapy in Urothelial Carcinoma- A New Era · The data regarding adjuvant chemotherapy is limited (trials were small, terminated early, ... Avelumab Anti-PD-L1 Q2Weeks accelerated

Immunotherapy in Urothelial Carcinoma- A New Era

Dr. Eli Rosenbaum

8.3.2018

TNM Staging SystemMuscle-invasive Urothelial Cancer

Tx paradigm in non metastatic muscle invasive disease

surgery or chemoradiation

Two large randomized trials and a meta-analysis support the administration of

cisplatin based neoadjuvant chemotherapy (DD MVAC, GC) for T2-4 disease

The data regarding adjuvant chemotherapy is limited (trials were small,

terminated early, used old protocols). However, a metaanalyses suggests a

survival benefit for T3-4 / N+ disease

For cisplatin non fit patients (Galsky, JCO 2011; ECOG PS ≥ 2, GFR <60, neuropathy/hearing loss grade

≥2, CHG NYHA grade ≥ 3), may consider a carboplatin based regimen; Benefit not shown

Slide 5

Presented By Alison Birtle at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Slide 17

Presented By Alison Birtle at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Urothelial Carcinoma

Treatment of Metastatic Disease

Gemcitabine & Cisplatinversus MVAC

MVAC

Gem/Cis

Proportion

surviving

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0

Pats at risk

202

203

6

161

167

12

124

120

18

54

52

24

18

18

30

4

1

36

0

0

months

MVAC

Gem/Cis

GC M-VAC

Neut. Sepsis 1% 12% < .001

Admissions F-N 9 49

G- or GMCSF 6% 21%

Mucositis Gr 3/4 1% 22% < .001

Toxic Death 1% 3%

CR + PR 50% 46%

CR 12% 12%

EORTC 30986: Gemcitabine/Carboplatin (GC) and Methotrexate/Carboplatin/Vinblastine (M-CAVI) in Cisplatin-

Unfit Patients

mOS ~9 months

De Santis et al. JCO 2012

Standards in Advanced UC

mOSORRRegimenSetting

12-15 months40-50%MVAC1

Gemcitabine + Cisplatin2

PGC3

CisplatinEligible1st

Line

7-9 months36-56%Gemcitabine + Carboplatin4-6

CisplatinIneligible

5-8 months~10%Single agent

chemotherapy7-92nd Line

1. Loehrer et al., JCO 19922. Von der Maase et al., JCO 2000 3. Bellmunt et al. JCO 20124. De Santis et al., JCO 2012 5. Linardou et al., Urology 2004 6. Nogué-Aliguer et al., Cancer 20037. Bellmunt et al., NEJM 20178. Bellmunt et al., JCO 20099. Petrylak et al., JCO 2015

Treatment after platinum failure

• Advanced UC is uniformly fatal after failure of platinum chemotherapy– Responses are transient– High toxicity– Frail patients

• No global consensus for treatment following platinum-based chemotherapy exists– Taxanes are typically used in

the US – Vinflunine (not approved in

the US) is often used in Europe

mOSVinflunine + BSC: 6.9 moBSC: 4.6 mo

2L Regimena ORR mPFS mOS

Paclitaxel (n = 31) 10% 2.2 mo 7.2 mo

Docetaxel (n = 30) 13% — 9.0 mo

Vinflunine (n = 51) 18% 3.0 mo 6.6 mo

Vinflunine (n = 253) 9% 3.0 mo 6.9 mo

Metastatic UBC: New Drug Approvals

1995-2012

Bellmunt J, et al. Ann Oncol. 2013;24:1466-1472.

UBC

RCC

Prostate

Slide credit: clinicaloptions.com

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

Yr

14

12

10

8

6

4

2

0

Nu

mb

er

of

Dru

gs

Ap

pro

ved

by F

DA

http://www.clinicaloptions.com/oncology

2017

Pembrolizumab

Nivolumab

Avelumab

Immunotherapy in Bladder Cancer

Cystoscopy showing

bladder tumor

TURBT Pathology: High Grade TCC extensively invading the muscle layer

TURBT

Proposed Model of BCG Therapy in Bladder Cancer

T cells

NeutrophilsMonocytes

Bladder urothelium

BCG Tumor cells

1. Attachment and invasion of the urothelium

4. Cytolysis of bladder tumor cells by CD8+ T cells

3. Attraction and activation of T cells2. Attraction of innate immune cells and release of cytokines/chemokines

BCG Versus Mitomycin-C(SWOG 8795)

Time To Recurrence

Perc

ent

Recurr

ence

363024181260

100

90

80

70

60

50

40

30

20

10

0

BCG

MMC

190

187

44

64

Not

Reached

20

At Risk FailMedian

in Months

Lamm DL

Urol Oncol

1:119-126, 1995

High Somatic Mutation Frequencies

Observed in Bladder Cancer[1]

▪ High mutational complexity rates similar to tobacco/environmental carcinogen exposure[2-4]

▪ Similar rates observed between pts exposed to tobacco or other environmental carcinogens[3]

▪ Potential for many neoantigens to be seen as foreign by host immune system[4]

1. Bellmunt J, et al. Ann Oncol. 2013;24:1466-1472.

2. Cancer Genome Atlas Research Network. Nature. 2014;507:315-322.

3. Lawrence MS, et al. Nature. 2013;499:214-218.

4. Kandoth C, et al. Nature. 2013;502:333-339. Slide credit: clinicaloptions.com

http://www.clinicaloptions.com/oncology

New US FDA approved treatments for UC (2016-2017)

Agent Mechanism Schedule Post

Platinum

Frontline

Cis-

ineligibleAtezolizumab Anti-PD-L1 Q3Weeks accelerated* accelerated

Nivolumab Anti-PD-1 Q2Weeks accelerated -

Durvalumab Anti-PD-L1 Q2Weeks accelerated -

Avelumab Anti-PD-L1 Q2Weeks accelerated -

Pembrolizumab Anti-PD-1 Q3Weeks Level 1 accelerated

*

Phase 1 evaluation of PD-L1 inhibitors shows robust

activity in refractory disease

IC0IC1

IC2IC3

Atezolizumab: PD-L1

Avelumab: PD-L1

Durvalumab: PD-L1

**

*

*******

****

**

**

*

PD-L1 <1% PD-L1 indeterminate/not

evaluable/missing

–100

–75

–50

–25

0

25

50

75

100

Be

st

Re

du

cti

on

Fro

m B

as

eli

ne

in T

arg

et

Le

sio

n (

%)

PD-L1 ≥1%

Nivolumab: PD1

Pembrolizumab: PD1

PD1 inhibitors in bladder cancer

Avelumab: PD-L1 Durvalumab: PD-L1

Atezolizumab: PD-L1Nivolumab: PD1Pembrolizumab: PD1

Anti PD-1/Pd-L1 Abs Show Promising Antitumor Activity

ORR= 21.1%CR= 9.3%

ORR= 17.8%CR= 3.7%

ORR= 17.4%CR= 6.2%

ORR= 19.6%CR= 2.0%

ORR= 16.0%CR= 6.0%

Change in sum of longest diameters over time (IRF-assessed per RECIST v1.1)

Rosenberg J, et. al, Lancet 2016;387:1909–20

EfficacyStable disease

EfficacyAtezolizumab demonstrates clinical benefit beyond progression

Robert Dreicer et. al, Abstract 4515, ASCO 2016

In patients treated beyond PD:• 19% had SLD reductions ≥30% in

target lesions• 28% had disease stabilization (-

30% to +20% SLD change)• 12-mo OS was 50% in all

patients treated beyond progression

Atezolizumab in patients with metastatic urothelial carcinoma (mUC): A 2-year clinical update from a phase Ia study

Post Platinum Phase III Trials

Median Follow Up- 27.7 months

Key Eligibility Criteriaa

• mUC with progression during or

following platinum-based chemotherapy

– ≤ 2 prior lines of therapy

• Measurable disease per RECIST v1.1

• ECOG PS 0-1

• Evaluable sample for PD-L1 testing

• TCC histology as primary component

(N = 931)

▪ Primary endpoint

– OS, tested hierarchically

in pre-specified populations

41 Powles T, et al. EAS 2017, IMvigor211.

DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research

and Treatment of Cancer; PRO, patient-reported outcome; q3w, every three weeks; RECIST, Response Evaluation

Criteria In Solid Tumors; TCC, transitional cell carcinoma. a ClinicalTrials.gov, NCT02302807. b Defined by time from prior

chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dL. c Confirmed response was not required

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

IMvigor211 Study Design

41

Atezolizumab 1200 mg q3w

R

1:1

No crossover permitted

per protocol

Survival

follow-up

Loss of

clinical benefit

RECIST v1.1

progression

Stratification Factors

• No. of risk factorsb (0 vs. 1/2/3)

• Liver metastases (yes vs. no)

• PD-L1 status (0/1 vs. 2/3)

• Chemotherapy (vinflunine vs. taxanes)

▪ Additional endpoints

– Efficacy: RECIST v1.1 ORR, PFS and DORc

– Safety

– PROs: EORTC QLQ-C30

Chemotherapy

(investigator’s choice)

• Vinflunine q3w

• Docetaxel q3w

• Paclitaxel q3w

Key Eligibility Criteriaa

• mUC with progression during or

following platinum-based chemotherapy

– ≤ 2 prior lines of therapy

• Measurable disease per RECIST v1.1

• ECOG PS 0-1

• Evaluable sample for PD-L1 testing

• TCC histology as primary component

(N = 931)

▪ Primary endpoint

– OS, tested hierarchically

in pre-specified populations


DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research

and Treatment of Cancer; PRO, patient-reported outcome; q3w, every three weeks; RECIST, Response Evaluation

Criteria In Solid Tumors; TCC, transitional cell carcinoma. a ClinicalTrials.gov, NCT02302807. b Defined by time from prior

chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dL. c Confirmed response was not required

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

IMvigor211 Study Design

42

Atezolizumab 1200 mg q3w

R

1:1

No crossover permitted

per protocol

Survival

follow-up

Loss of

clinical benefit

RECIST v1.1

progression

Stratification Factors

• No. of risk factorsb (0 vs. 1/2/3)

• Liver metastases (yes vs. no)

• PD-L1 status (0/1 vs. 2/3)

• Chemotherapy (vinflunine vs. taxanes)

▪ Additional endpoints

– Efficacy: RECIST v1.1 ORR, PFS and DORc

– Safety

– PROs: EORTC QLQ-C30

Chemotherapy

(investigator’s choice)

• Vinflunine q3w

• Docetaxel q3w

• Paclitaxel q3w

Key secondary endpoints:

ORR, then PFS

Primary endpoint:

OS

OS: IC2/3

OS: IC1/2/3

OS: ITT

PFS: IC2/3

PFS: IC1/2/3

PFS: ITT

ORR: IC2/3

ORR: IC1/2/3

ORR: ITT

2-sided = 0.05

43 Powles T, et al. EAS 2017, IMvigor211.HR, hazard ratio.

OS Analysis: IC2/3 Population

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

P = 0.41

Events/

Patient

sMedian OS

(95% CI)

12-mo OS

Rate(95% CI)

Atezolizumab 72/116 11.1 mo (8.6, 15.5) 46% (37, 56)

Chemotherap

y

88/11810.6 mo (8.4, 12.2) 41% (32, 50)

No. at Risk

Atezolizumab 116 100 85 77 71 58 51 39 27 19 11 6 0

Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Overa

ll S

urv

ival

100

Months

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


OS Analysis: ITT Population

Events/

Patient

sMedian OS

(95% CI)

12-mo OS

Rate(95% CI)

Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44)

Chemotherap

y

350/4648.0 mo (7.2, 8.6) 32% (28, 37)

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Overa

ll S

urv

ival

100

Months

80

60

0

10 12 14 16 18 202 4 6 80 2422

20

40

Overa

ll S

urv

ival

100

Months

HR = 0.85 (95% CI: 0.73, 0.99)

P = 0.038

No. at Risk

Atezolizumab 467 405 327 280 245 201 177 138 90 59 34 13 1

Chemotherapy 464 397 330 268 219 175 140 99 60 42 17 7 1

OS by PD-L1 IC Status

Unstratified HRs are displayed. Reprinted in part from The Lancet, Powles T, et al. 2017 Dec 18. [Epub], © 2017, with permission requested from Elsevier.

46Presented by: Powles T, IMvigor211.

• In our study design, we

hypothesized that efficacy

was associated with

PD-L1 status

• Unexpectedly, PD-L1

overexpression resulted in

favorable outcomes in

both arms

• Subsequent biomarker

analyses focused on the

ITT population

10.6 mo 11.1 mo 8.2 mo7.3 mo

MonthsMonths

HR = 0.81 (95% CI: 0.59, 1.10) HR = 0.84 (95% CI: 0.71, 1.00)

OS by TMB and PD-L1 Status

47

Unstratified HRs are displayed. Reprinted in part from The Lancet, Powles T, et al. 2017 Dec 18. [Epub], © 2017, with permission requested from Elsevier.

• Improved OS benefit was observed in patients with high TMB as well as high PD-L1 IC scores

Presented by: Powles T, IMvigor211.

HR = 0.81 (95% CI: 0.59, 1.10)HR = 0.68 (95% CI: 0.51, 0.90) HR = 0.50 (95% CI: 0.29, 0.86)

48 Powles T, et al. EAS 2017, IMvigor211.NE, not estimable. Unstratified hazard ratios are plotted. Dashed line refers to HR for ITT population.

OS in Clinical and Treatment Subgroups

1.0

Atezolizumab better Chemotherapy better

SubgroupPD-L1 status IC2/3

IC1/2/3

ITT

Tobacco use history Current

Previous

Never

ECOG PS 0

1

Primary tumor site Bladder

Urethra

Renal pelvis

Ureter

Liver metastases Yes

No

Lymph node–only metastases Yes

No

Chemotherapy stratification Taxane

Vinflunine

Atezolizumab mOS

Chemotherapy

mOS11.1 mo 10.6 mo

8.9 mo 8.2 mo

8.6 mo 8.0 mo

9.2 mo 6.7 mo

8.4 mo 8.2 mo

10.4 mo 8.1 mo

12.0 mo 10.1 mo

6.1 mo 6.4 mo

8.9 mo 7.7 mo

NE 12.5 mo

5.9 mo 8.5 mo

8.9 mo 8.1 mo

4.0 mo 5.2 mo

10.1 mo 9.7 mo

17.4 mo 12.2 mo

8.1 mo 7.2 mo

8.3 mo 7.5 mo

9.2 mo 8.3 mo

12 14

Months

Confirmed ORRa

IC2/3 IC1/2/3 ITT

Atezo (n = 113)

Chemo (n = 116)

Atezo (n = 312)

Chemo (n = 306)

Atezo (n = 462)

Chemo (n = 461)

Responders, n (%) 26 (23%) 25 (22%) 44 (14%) 45 (15%) 62 (13%) 62 (13%) 95% CI, % 16, 32 15, 30 10, 19 11, 19 11, 17 11, 17

CR, n (%) 8 (7%) 8 (7%) 11 (4%) 13 (4%) 16 (3%) 16 (3%)

▪ Objective response was

similar between arms

▪ Responses to

atezolizumab were durable

regardless of PD-L1 status

– 63% of patients in the

atezolizumab arm and

21% in the chemotherapy

arm had ongoing responses

at data cutoff

49 Powles T, et al. EAS 2017, IMvigor211.•mDOR, median DOR. a Confirmed RECIST v1.1 responses were assessed as an exploratory endpoint.

Response by PD-L1 Subgroup

DOR in ITT Population

No. at Risk

Atezolizumab 62 61 56 50 42 35 23 14 9 5 2 0

Chemotherapy 62 62 59 40 28 23 16 8 5 4 0 0

Events/

Patients mDOR (95% CI)Atezolizumab 23/62 21.7 mo (13.0, 21.7)

Chemotherap

y

49/627.4 mo (6.1, 10.3)

80

60

0

10 12 14 16 18 202 4 6 80 22

20

40

Ob

jective

Re

sp

on

se

100

Months

▪ The safety profile for atezolizumab was consistent with Phase I-II data1,2

50 Powles T, et al. EAS 2017, IMvigor211.1. Powles Nature 2014. 2. Rosenberg Lancet 2016.

Treatment-Related AEs

Treatment-Related AEs in ≥ 10% (All Grade) or ≥ 4% (Grades 3-4) for Either Arm

ChemotherapyAtezolizumab

Proportion of Patients (%)

30% 30%10%10% 0%40% 40%20%20%

■■ All Grade

■■ Grade 3-4

First Line Immunotherapy

Frontline Therapy for UC: Cis-Ineligible

54

Results: mOS (primary end-point) of 15.9m

NE, not estimable. Patients at risk of an event are displayed at indicated time points below plot.

Censored values are indicated with a plus (+) symbol.

Landmark Analysis of OS by PD-L1

Balar, et al. Lancet 2017

Presented by O’Donnell et al., ASCO 2017

Presented by de Wit et al., #LBA37, ESMO 2017

Presented by O’Donnell et al., ASCO 2017

KN-052: ORR by Age and ECOG PS

Combinations in Immunotherapy of UC

Study Design & Patient Population

PLATINUM/GEM +

PLACEBO

Key Eligibility N= 1200• Platinum-eligible• ECOG PS 0-2• TCC histology• Locally Adv/Metastatic

Stratification Factors :• PD-L1 IHC Status0 vs 1 vs. 2/3 • Investigator chemo

choice• Bajorin risk factor

R

1:1:1 ATEZOLIZUMAB

PLATINUM/GEM +

ATEZOLIZUMAB A

B

C

Primary endpoints: PFS and OS as Co-primary for Arm A, OS testing for Arm B only.

Design Details:

• N = 1200 (no minimum required for any IHC IC subgroup)

• Secondary endpoints: (mod)ORR, Safety, PRO as part of totality of evidence (HRQoL, Physical

function, symptoms measured with EORTC QLQ-C30), Euro QoL 5 Dimensions 5-Level (EQ-5D-5L)

• Cross-over not allowed

KEYNOTE 361- 1st Line Therapy in mUC

Presented by Powles et al., ASCO 2017

Immune checkpoint blockade comes to bladder

cancer

Drake CG. Nat Rev Immunol. 2010;10(8):580-593.

PD-L1

PD1

CTLA4

Modified from Drake, Nat Rev Immunol 2010

P Sharma: SITC 2016

Ipilimumab + Nivolumab:CheckMate 032

P Sharma: SITC 2016

Ipilimumab + Nivolumab:Antitumor Activity

P Sharma: SITC 2016

Ipilimumab + Nivolumab: Tumor Change

from Baseline in Target Lesion

P Sharma: SITC 2016

Ipilimumab + Nivolumab: AdverseEvents

DANUBE Trial Design

69

aStage IV T4b, any N; or any T, N2-N3; or M1. bCisplatin +

gemcitabine or carboplatin + gemcitabine, depending on cisplatin

eligibility. IV = intravenous; PD-L1 = programmed cell death-ligand 1;

q4w = every 4 weeks.

Phase III, randomized, open-label,

multicenter, global study1,2

1. Powles T, et al. Poster presented at ASCO Annual Meeting;

June 3-7 2016; Chicago, IL; Poster TPS4574.

2. Study NCT02516241. ClinicalTrials.gov website. Accessed

October 30, 2017.

Arm 1:

Durvalumab IV 1500 mg q4w +

Tremelimumab IV 75 mg q4w

Arm 2:

Durvalumab IV 1500 mg q4w

Arm 3:

Standard of Careb

Randomizat

ion

1:1:1

Patients with

Unresectable Stage

IVa Urothelial

Carcinoma as 1st

Line Therapy

Estimated

enrollment =

1005 patients

IDO1 Enzyme and Epacadostat

Presented By David Smith at 2017 ASCO Annual Meeting

Best Objective Response by RECIST v1.1 Epacadostat Plus Pembrolizumab Phase 1/2 Advanced Urothelial Carcinoma


Percentage Change From Baseline in Target Lesions Epacadostat Plus Pembrolizumab Phase 1/2 Advanced Urothelial Carcinoma by Number of Prior Lines of Treatment


PD-1 Blockade Based Combinations in mRCC: Are they Additive or Synergistic?

Presented By David McDermott at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Thank You!

Documents

Immunotherapy in Urothelial Carcinoma- A New Era · The data regarding adjuvant chemotherapy is limited (trials were small, terminated early, ... Avelumab Anti-PD-L1 Q2Weeks accelerated