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