bladder cancer: in which scenario is immunotherapy the ... · atezolizumab 1200 mg iv q3w until pd...

Bladder Cancer: In Which Scenario is Immunotherapy The Standard?

Eric Jonasch, M.D.

GU Medical Oncology

UT MD Anderson Cancer Center

Non-muscle invasive

Muscle invasive Metastatic

Disease States And Therapeutic Opportunities in Bladder Cancer

Immunotherapy in Bladder Carcinoma- Not A New Idea

BCG

IFN

AtezolizumabAvelumab

DurvalumabNivolumab

Pembrolizumab

Frontline Cisplatin Eligible

Frontline Cisplatin Ineligible

Second LineIO Refractory

Second LineCisplatin Refractory

CiplatinEligible

CiplatinIneligible

Metastatic Disease- Categories

Key Questions

• In which disease setting should we use immunotherapy?

• Is there a preferred agent in each setting?

• Does PD-L1 staining matter?

Current Status of Immune Checkpoint Inhibitors

for Patients With Urothelial Carcinoma

AgentUS FDA Status

Patient Population Comments

Atezolizumab

ApprovedMay 18 2016

and April 17, 2017

Pts with PD during or following platinum chemotherapy or within 12 mos of (neo)adjuvant

platinum chemotherapy or

Pts with locally advanced/metastatic disease who are ineligible for cisplatin-containing therapy

Restriction to PD-L1 positive in frontline

setting June 20, 2018

NivolumabApproved

Feb 2 2017

Pts with PD during or following platinum chemotherapy or within 12 mos of (neo)adjuvant

platinum chemotherapy

DurvalumabApproved

May 1, 2017Pts with PD after progression on or after 1 previous

platinum chemotherapy

PembrolizumabApproved

May 18, 2017

First-line: pts who are ineligible for cisplatin-containing therapy

orSecond-line: Pts with PD during or following platinum

chemotherapy

Restriction to PD-L1 positive in frontline

setting June 20, 2018

AvelumabApproved

May 9, 2017

Pts with PD during or following platinum chemotherapy or within 12 mos of (neo)adjuvant

platinum chemotherapy

Study Phase/line# subjects

ORR (%) ORR Based onPD-L1 status

PD-L1IHC Ab

IC Cut Point TC Cut Point

Tissue

Atezolizumab(prior platinum)ImVigor 210

Phase IIN = 310 ptsSingle arm

15 26% IC 2/3 (11% CR), 18% IC 1/2/3(6% CR), 10% IC 1 (2%), 8% IC0 (2%)

VENTANA SP142 IC 0 -0%IC 1 <5%IC2/3 ≥5%

None ARCHIVED

Atezolizumab(cis-ineligible)Front lineIMVigor 210

Phase IIN = 123 ptsSingle arm

23 28% IC 2/3 (13%)24% IC 1/2/3 (10% CR) 21% IC 1 (8.3% CR), 21% IC 0 (7.7% CR)

VENTANA SP142 IC 0 -0%IC 1 <5%IC2/3 ≥5%

None ARCHIVED

Nivolumab(prior platinum)Checkmate 275

Phase IIN =270 ptsSingle arm

19.6 28% ORR PD-L1 positive16% ORR PD-L1 negative

DAKO 28-8

None TC<1%TC≥1%TC>5%

ARCHIVED

Durvalumab(prior platinum)

Phase II191 ptsSingle arm

17 27.6% ORR PL-L1+ (98 pts)5.1% ORR PD-L1- (79 pts)

VENTANA SP263

Combined score IC or TC IC<25% IC ≥25%+

TC<25% -TC ≥25%+

ARCHIVED OR FRESH

Avelumab(prior platinum)

Phase Ib249 pts

17 64% TC ≥ 5% (7/13, 4 CR) 4.2% TC <5% (1/24 if TC PD-L1 <5%

DAKO 73-10

None TC<5% -TC≥5%+

ARCHIVED OR FRESH

PembrolizumabvsChemo(prior platinum)Keynote 045

Phase IIIN = 542 pts270 pembro (74PD-L +)272 chemo(90 PD-L+)

21 (IO)

11 (chemo)

PD-L1+ pembro 22% (CR 7%)PD-L1 + chemo 7% (CR 2%)

DAKO 22C3

CombinedIC<10% -IC≥10%+

CombinedTC<10% -TC≥10%+

ARCHIVED

Pembrolizumab(cis ineligible)Front lineKeynote 052

Phase IIN = 374Single arm

24 38% combined PD-L ≥ 10% (42 of 110)27% combined PD-L ≥ 1% (75 of 282)11% combined PD-L <1% (5 of 26)

DAKO 22C3

CombinedIC<1% -IC ≥1%+

CombinedTC<1% -TC≥1%+

FRESH

Study Phase/line# subjects

ORR (%) ORR Based onPD-L1 status

PD-L1IHC Ab

IC Cut Point TC Cut Point

Tissue

Atezolizumab(prior platinum)ImVigor 210

Phase IIN = 310 ptsSingle arm

15 26% IC 2/3 (11% CR), 18% IC 1/2/3(6% CR), 10% IC 1 (2%), 8% IC0 (2%)

VENTANA SP142 IC 0 -0%IC 1 <5%IC2/3 ≥5%

None ARCHIVED

Atezolizumab(cis-ineligible)Front lineIMVigor 210

Phase IIN = 123 ptsSingle arm

23 28% IC 2/3 (13%)24% IC 1/2/3 (10% CR) 21% IC 1 (8.3% CR), 21% IC 0 (7.7% CR)

VENTANA SP142 IC 0 -0%IC 1 <5%IC2/3 ≥5%

None ARCHIVED

Nivolumab(prior platinum)Checkmate 275

Phase IIN =270 ptsSingle arm

19.6 28% ORR PD-L1 positive16% ORR PD-L1 negative

DAKO 28-8

None TC<1%TC≥1%TC>5%

ARCHIVED

Durvalumab(prior platinum)

Phase II191 ptsSingle arm

17 27.6% ORR PL-L1+ (98 pts)5.1% ORR PD-L1- (79 pts)

VENTANA SP263

Combined score IC or TC IC<25% IC ≥25%+

TC<25% -TC ≥25%+

ARCHIVED OR FRESH

Avelumab(prior platinum)

Phase Ib249 pts

17 64% TC ≥ 5% (7/13, 4 CR) 4.2% TC <5% (1/24 if TC PD-L1 <5%

DAKO 73-10

None TC<5% -TC≥5%+

ARCHIVED OR FRESH

PembrolizumabvsChemo(prior platinum)Keynote 045

Phase IIIN = 542 pts270 pembro (74PD-L +)272 chemo(90 PD-L+)

21 (IO)

11 (chemo)

PD-L1+ pembro 22% (CR 7%)PD-L1 + chemo 7% (CR 2%)

DAKO 22C3

CombinedIC<10% -IC≥10%+

CombinedTC<10% -TC≥10%+

ARCHIVED

Pembrolizumab(cis ineligible)Front lineKeynote 052

Phase IIN = 374Single arm

24 38% combined PD-L ≥ 10% (42 of 110)27% combined PD-L ≥ 1% (75 of 282)11% combined PD-L <1% (5 of 26)

DAKO 22C3

CombinedIC<1% -IC ≥1%+

CombinedTC<1% -TC≥1%+

FRESH

Second Line, Platinum Refractory Patients

KEYNOTE-045: Study Design

• Randomized phase III trial

Pembrolizumab200 mg Q3W

(N = 270)

Investigators Choice:Paclitaxel 175 mg/m2 Q3W orDocetaxel 75 mg/m2 Q3W orVinflunine 320 mg/m2 Q3W

(N = 272)

Treated up to 24 mos or

until CR, PD,

unacceptable AE, or

investigator decision*

Treated until PD,

unacceptable AE, or pt

withdrawal of consent

*Select pts allowed to continue treatment beyond initial radiographic progression.

▪ Primary endpoints: OS; PFS in overall, PD-L1 CPS ≥ 10% populations

▪ Secondary endpoints: ORR; DoR in overall, PD-L1 CPS ≥ 10% populations; safety

metastatic or locally advanced

UC after recurrence or

progression following

platinum-based

chemotherapy

ECOG PS ≤ 2; evaluable tumor tissue

for PD-L1 testing

(N = 542)

Bellmunt et al NEJM March 2017

KEYNOTE-045: Baseline Characteristics

Bellmunt et al NEJM March 2017

KEYNOTE-045: Overall Survival

Bellmunt et al NEJM March 2017

10.3 vs 7.4 mos

Keynote-045: Forest Plot

Bellmunt et al NEJM March 2017

Keynote-045: Forest Plot

Bellmunt et al NEJM March 2017

KEYNOTE-045: OS in Pts With PD-L1 CPS ≥ 10%

Bellmunt J, et al. SITC 2016. Abstract 02. Slide credit: clinicaloptions.com

Data cutoff: September 7, 2016.

Events, nMedian OS,

Mos (95% CI)HR

(95% CI) P Value

Pembrolizumab 44 8.0 (5.0-12.3)0.57

(0.37-0.88).0048

Chemotherapy 60 5.2 (4.0-7.4)

0 2 4 6 8 10 12 14 16 18 20 22 24

0

10

20

30

40

50

60

70

80

90

100

Mos

OS

(%

)

74 60 51 42 35 31 18 12 7 3 0 0 0

90 76 51 36 28 24 16 8 4 1 0 0 0

39.8%

26.9%

Pts at Risk, n

Pembrolizumab

Chemotherapy

Checkmate-275: Study Design

• A multicenter, single arm phase II trial

Nivolumab3 mg/kg Q2W

(N = 270)

Sharma P, et al. Lancet Oncol. 2017 Jan 25. [ Epub ahead of print].

Treated PD and

clinical deterioration,

unacceptable AE, or

protocol-defined

decision*

*Pts allowed to continue treatment beyond initial radiographic progression if well tolerated and clinical benefit was noted.

▪ Primary endpoints: ORR in all pts, ORR in pts with PD-L1 ≥ 5% or ≥ 1%

▪ Secondary endpoints: PFS, OS, TTR, DoR, safety, QoL

Slide credit: clinicaloptions.com

Pts with measurable metastatic

or locally advanced urothelial

carcinoma after recurrence or

progression following ≥ 1

platinum-based chemotherapy;

ECOG PS 0 or 1; evaluable

tumor tissue for biomarker

testing

(N = 270)

Checkmate-275: Baseline

Characteristics

Sharma P, et al. Lancet Oncol. 2017 Jan 25.

Checkmate 275: Efficacy

Sharma P, et al. Lancet Oncol. 2017 Jan 25.

Outcome in this study was associated with PD-L1 status

ORR by PD-L1

status

▪< 1%

▪≥ 1%

▪≥ 5%

16.1

23.8

28.4

Front Line, Platinum Ineligible Patients

IMvigor 210: Atezolizumab for Advanced Urothelial

Cancer

▪ Single-arm phase II study with 2 cohorts[1]

Pts with inoperable advanced or

metastatic UC, evaluable tumor

tissue for PD-L1 testing, CrCl ≥ 30

mL/min, ECOG PS 0/1; for Cohort 2,

any number of prior therapies

allowed

(N = 429)

Cohort 1[2]

Previously untreated,cisplatin ineligible

(n = 119)

Cohort 2[3,4]

Prior platinumtreatment(n = 310)

Atezolizumab1200 mg IV Q3W

until PD

Atezolizumab1200 mg IV Q3W

until loss of benefit

1. ClinicalTrials.gov. NCT02108652. 2. Bellmunt J, et al. ESMO 2016. Abstract 782PD.

3. Rosenberg JE, et al. Lancet. 2016;387:1909-1920. 4. Loriot Y, et al. ESMO 2016. Abstract

783PD.

▪ Coprimary endpoints: confirmed ORR by RECIST v1.1 (per central review), ORR by immune-modified RECIST (per investigator)

▪ Secondary endpoints: DoR, PFS, OS, safety

▪ Exploratory endpoints: biomarkers

Slide credit: clinicaloptions.com

Balar et al, Lancet 2017

IMvigor 210: Atezolizumab for Advanced Urothelial

Cancer

▪ Single-arm phase II study with 2 cohorts[1]

Pts with inoperable advanced or

metastatic UC, evaluable tumor

tissue for PD-L1 testing, CrCl ≥ 30

mL/min, ECOG PS 0/1; for Cohort 2,

any number of prior therapies

allowed

(N = 429)

Cohort 1[2]

Previously untreated,cisplatin ineligible

(n = 119)

Cohort 2[3,4]

Prior platinumtreatment(n = 310)

Atezolizumab1200 mg IV Q3W

until PD

Atezolizumab1200 mg IV Q3W

until loss of benefit

1. ClinicalTrials.gov. NCT02108652. 2. Bellmunt J, et al. ESMO 2016. Abstract 782PD.

3. Rosenberg JE, et al. Lancet. 2016;387:1909-1920. 4. Loriot Y, et al. ESMO 2016. Abstract

783PD.

▪ Coprimary endpoints: confirmed ORR by RECIST v1.1 (per central review), ORR by immune-modified RECIST (per investigator)

▪ Secondary endpoints: DoR, PFS, OS, safety

▪ Exploratory endpoints: biomarkers

Slide credit: clinicaloptions.com

Balar et al, Lancet 2017

APPROVED MAY 2016

IMvigor 210: Baseline Characteristics for Frontline Patients

Balar et al, Lancet 2017

IMvigor 210: Baseline Characteristics for Frontline Patients

Balar et al, Lancet 2017

IMVigor 210: Overall Survival (Frontline)

Balar et al, Lancet 2017

IMVigor 210: Response By PD-L1 Status

Balar et al, Lancet 2017

Balar A, et al. ESMO 2016. Abstract LBA32_PR. Slide credit: clinicaloptions.com

KEYNOTE-052: First-line Pembrolizumab for

Cisplatin-Ineligible Advanced Urothelial Cancer

• Open-label, multicenter phase II study: Current preplanned interim analysis on first 100

pts to evaluate ORR, determine PD-L1–high expression cutoff

▪ Primary endpoint: ORR in all pts, ORR in PD-L1–positive pts

▪ Secondary endpoints: DoR, PFS, OS, ORR in all pts, in PD-L1–positive pts, and in PD-L1–high expressing pts; safety/tolerability; establish PD-L1 high expression cutoff

Cisplatin-ineligible* pts with

advanced UC without prior

chemotherapy for metastatic

disease; ECOG PS ≤ 2; evaluable

tumor tissue for PD-L1 testing

(Planned N = 350)

Pembrolizumab200 mg Q3W

Treated up to 24 mos

or until CR, PD,

unacceptable AE, or

investigator

decision†

ORR assessed per RECIST v1.1 by blinded independent clinical review. No alpha for ORR comparison in PD-L1 CPS ≥ 10% population.

Data cutoff: September 7, 2016.

KEYNOTE-052: Pembrolizumab Efficacy

Outcome (N = 100) n % (95% CI)

ORR* (CR + PR)

▪ CR

▪ PR

24

6

18

24 (16-34)

6 (2-13)

18 (11-27)

SD 15 15 (9-24)

PD 48 48 (38-58)

Not evaluable† 3 3 (1-9)

No assessment‡ 10 10 (5-18)

Balar A, et al. ESMO 2016. Abstract LBA32_PR. Slide credit: clinicaloptions.com

*Confirmed ORR per RECIST v1.1 by central review.†n = 3 pts achieved SD within 6 wks of treatment start, then discontinued.‡n = 10 pts withdrew from study due to PD or AE.Data cutoff: June, 2016.

KEYNOTE-052: Response to Pembrolizumab by PD-L1

Expression

Balar A, et al. ESMO 2016. Abstract LBA32_PR. Slide credit: clinicaloptions.com

*Confirmed ORR per RECIST v1.1 by central review.†Excluding those with CPS unknown.Data cutoff: June, 2016.

Response

PD-L1 CPS < 1%†

(n = 33)

PD-L1 CPS

≥ 1% to < 10%

(n = 33)

PD-L1 CPS ≥ 10%

(n = 30)

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

ORR*

▪CR

▪PR

6

1

5

18 (7-36)

3 (0.1-16.0)

15 (5-32)

5

0

5

15 (5-32)

--

15 (5-32)

11

4

7

37 (20-56)

13 (4-31)

23 (10-42)

SD 3 9 (2-24) 5 15 (5-32) 7 23 (10-42)

What About Frontline, Cisplatin Eligible Patients?

KEYNOTE 361

MetastasesNo Prior Tx

990 pts

Cisplatin or Carbo/Gem

Pembrolizumab +Cisplatin or Carbo/Gem

Pembrolizumab

MetastasesNo Prior Tx

1200pts

Gemcitabine + Carboplatin/Cisplatin

Atezolizumab+

Gemcitabine + Carboplatin/Cisplatin

Atezolizumab

IMVIGOR 130

KEYNOTE 361

MetastasesNo Prior Tx

990 pts

Cisplatin or Carbo/Gem

Pembrolizumab +Cisplatin or Carbo/Gem

Pembrolizumab

MetastasesNo Prior Tx

1200 pts

Gemcitabine + Carboplatin/Cisplatin

Atezolizumab+

Gemcitabine + Carboplatin/Cisplatin

Atezolizumab

IMVIGOR 130

KEYNOTE 361

MetastasesNo Prior Tx

990 pts

Cisplatin or Carbo/Gem

Pembrolizumab +Cisplatin or Carbo/Gem

Pembrolizumab

MetastasesNo Prior Tx

1200 pts

Gemcitabine + Carboplatin/Cisplatin

Atezolizumab+

Gemcitabine + Carboplatin/Cisplatin

Atezolizumab

IMVIGOR 130Only recruiting PD-L1 positive

ptsOnly recruiting PD-L1 positive

pts

Neoadjuvant Therapy in Nonmetastatic Bladder Cancer

The Next IO Frontier?

Summary

Checkpoint antibodies should be considered in patients with advanced urothelial cancer if:

1. Previously untreated, PD-L1 positive, and cisplatin ineligible

2. Platinum refractory

Work is currently ongoing to define role in neadjuvant and adjuvant settings.

Summary

Is there a preferred agent:

1. In the frontline setting?

Pembrolizumab data slightly stronger, but both pembrolizumab and atezolizumab show good results.

2. In the second line setting?

Hard to distinguish clinically– may come down to practical matters, including frequency of administration

Acknowlegements

• Rose Joyce, NCCN

• Arlene Siefker-Radtke, Matthew Campbell (MD Anderson Cancer Center)

Thank You