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SESSION 4
Systemic chemotherapy is NOT the standard of care in
metastatic urothelial cancer
Aristotle Bamias
National & Kapodistrian University of Athens
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DISCLOSURE OF INTEREST
Honoraria, Advisory, research funding
Pfizer, Roche, Novartis, BMS, AZ, Ipsen, MSD
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WHAT MAKES A THERAPEUTIC OPTION “STANDARD”?
Efficacy
Tolerability
Optimization-patients’ selection
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OUTLINE
Efficacy
Tolerability
Optimization-patients’ selection
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Durable (?) Responses With Cisplatin-Based CT in UC
Slide credit: clinicaloptions.com
Cisplatin Eligible Cisplatin Ineligible
Gemcitabine + Cisplatin[1,2]
ORR: 49%
CR: 12%
Median OS: 14.0 mos
Dose Dense MVAC[3]
ORR: 72%
CR: 25%
Median OS: 15.1 mos
Gemcitabine + Carboplatin[4]
ORR: 36%
CR: 3%
Median OS: 9.3 mos
1. von der Maase H, et al. J Clin Oncol. 2005;23:4602-4608. 2. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077.
3. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54. 4. De Santis M, et al. J Clin Oncol. 2012;30:191-199.
Pro
po
rtio
n S
urv
ivin
g 1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84
Mos
Patients at Risk, n
203
202
118
125
50
62
36
40
30
34
23
29
7
9
0
1GC
MVAC
GC: median 14.0 mos (12.3-15.5 mos)
MVAC: median 15.2 mos (13.2-17.3 mos)
HR: 1.09 (0.88-1.34)
Log-rank P = .44, Walds P = .66
GC
MVAC
100
80
60
40
20
00 2 4 6 8 10 12
YrsPatients at Risk, nN
129
134
32
45
15
29
11
23
4
8
2
0
Median
5 yrs, %
(95% CI)
M-VAC
HD M-VAC
O
112
101
M-VAC
HD M-VAC
HD M-VAC
15.1 mos
21.8
(14.5-21.9)
M-VAC
14.9 mos
13.5
(7.4-19.6)
Log-rank P = .042
HR: 0.76 (95% CI: 0.58- 0.99)
100
80
60
40
20
00 1 2 3 4 5 6
Yrs
Patients at Risk, nN
119
119
37
44
13
15
7
5
3
2
1
2
M-CAVI
GC
O
108
110
Su
rviv
al
(%)
7
Log-rank test P = .64
M-CAVI
GC
1
1
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First-line Therapy for Metastatic UC: Response
Slide credit: clinicaloptions.com
DD MVAC[1]
Cisplatin Eligible Cisplatin Ineligible
1. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54. 2. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077.
3. De Santis M, et al. J Clin Oncol. 2012;30:191-199. 4. Vuky J, et al. ASCO 2018. Abstract 4524.
5. Balar AV, et al. ASCO 2018. Abstract 4523.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
PR
CR
Atezolizumab[5]Pembrolizumab[4]Gemcitabine +
Cisplatin[2]
Gemcitabine +
Carboplatin[3]
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ATEZO VS. CHEMO
DoR
Atezolizumab
Chemotherapy
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AND THE WINNER IS……..
ImVigor130 CheckMate901
Nivolumab 1 mg/kg + Chemotherapy
Q3W X 6 cycles
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Frontline Checkpoint Inhibition in Cisplatin Ineligible UC:
Updates from Single-Arm Trials
Pembrolizumab (n = 370)
KEYNOTE-52[1]
Atezolizumab (n = 119)
IMvigor 210 Cohort 1[2]
Median follow up, mos 11.5 29
ORR, % 29 24
Median OS, mos 11.5 16.3
12 month OS, % 48 58
Pembrolizumab OS Atezolizumab OS100
80
60
40
20
00 4 8 12 16 20 24
MosPatients at Risk, n
370
28 32
283 223 173 147 86 38 11 11
OS
(%
)
100
80
60
40
20
00 4 8 12 16 20 24
MosPatients at Risk, n
370
28 32
283 223 173 147 86 38 11 11
OS
(%
)
36
1-yr OS: 58% (95% CI: 49-67)
2-yr OS: 41% (95% CI: 32-50)
Median OS: 16.3 mo (95% CI: 10.4-24.5)
1. Vuky J, et al. ASCO 2018. Abstract 4524. 2. Balar AV, et al. ASCO 2018. Abstract 4523.
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Carbo/Gem1 MCAVI1 VFL/Gem2* VFL/Carbo2* Pembro3 Atezolizumab4
n 89 89 34 35 374 119
PS 2 44% 45% 0% 0% 42% 20%
Visceral 46% 55% 53% 46% 85% 66%
RR 38% 20% 44% 28% 24% 23%
CR 3% 3% 6% 11% 6% 9%
mOS 9.3 8.1 14 12.8 11.5 16.3 mos
INELIGIBLE-FOR-CISPLATIN ADVANCED UROTHELIAL CANCER PATIENTS
1. De Santis et al. J Clin Oncol 2009; 2 De Santis et al Ann Oncol 2016; 3. Balar et al. lancet Oncol 2017; 4. Balar et al. Lancet 2017
14.3-15.1
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FDA-Approved Checkpoint Inhibitors for 1st-line UC
1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017.
3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018.
5. Pembrolizumab [package insert]. June 2018.
Slide credit: clinicaloptions.com
Agent Target Schedule FDA Approval Type by Setting
Post-Platinum Frontline Cisplatin Ineligible
Atezolizumab[1] PD-L1 Q3W Accelerated Accelerated
Avelumab[2] PD-L1 Q2W Accelerated --
Durvalumab[3] PD-L1 Q2W Accelerated --
Nivolumab[4] PD-1 Q4W Accelerated --
Pembrolizumab[5] PD-1 Q3W Level 1 Accelerated
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Overall survival: Total
Median (95% CI)
Events HR (95% CI) p
Pembro 155 0.73 (0.59-0.91) 0.0022
Chemo 179
Bellmunt et al. New Engl J Med 2017
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OS Analysis in ITT Population
Reprinted from The Lancet, Powles T,
et al. 2017 Dec 18. [Epub], © 2017,
with permission from Elsevier
OS: IC2/3
OS: IC1/2/3
OS: ITT
Events/
PatientsMedian OS
(95% CI)
12-mo OS Rate(95% CI)
Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44)
Chemotherapy 350/464 8.0 mo (7.2, 8.6) 32% (28, 37)
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Post-Platinum UC
OS at 12 Mos
Slide credit: clinicaloptions.com
CT: ~
26%
Atezolizumab[1]
OS
(%
, 9
5%
CI)
39.2 54.3 46.6 40.3 43.90
10
20
30
40
50
60
70
Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]
1. Powles T, et al. Lancet. 2017 2. Patel M, et al. Lancet Oncol 2018 3. Powles T, et al. JAMA Oncol 2017 4. Sharma P, et al. Lancet Oncol. 2017 5. Bellmunt J, et al. N Engl J Med. 2017
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FDA-Approved Checkpoint Inhibitors for relapsed
mUC
1. Atezolizumab [package insert]. July 2018. 2. Avelumab [package insert]. October 2017.
3. Durvalumab [package insert]. February 2018. 4. Nivolumab [package insert]. July 2018.
5. Pembrolizumab [package insert]. June 2018.
Slide credit: clinicaloptions.com
Agent Target Schedule FDA Approval Type by Setting
Post-Platinum Frontline Cisplatin Ineligible
Atezolizumab[1] PD-L1 Q3W Accelerated Accelerated
Avelumab[2] PD-L1 Q2W Accelerated --
Durvalumab[3] PD-L1 Q2W Accelerated --
Nivolumab[4] PD-1 Q4W Accelerated --
Pembrolizumab[5] PD-1 Q3W Level 1
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OUTLINE
Efficacy
Tolerability
Optimization-patients’ selection
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PEMBRO VS. CHEMO
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ATEZO VS. CHEMOAtezolizumab Chemotherapy
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OUTLINE
Efficacy
Tolerability
Optimization-patients’ selection
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Phase I Data: Assays for Measurement of PD-L1 Expression in Advanced Urothelial Cancer
1. Petrylak DP, et al. J Clin Oncol. 2015;33(suppl): Abstract 4501. 2. Sharma P, et al. J Clin Oncol. 2016;34(suppl): Abstract 4501. 3. Plimack ER, et al. J Clin Oncol. 2015;33(suppl): Abstract 4502. 4. Massard C, et al. J Clin
Oncol. 2016;34(suppl): Abstract 4502. 5. Apolo AB, et al. J Clin Oncol. 2016;34(suppl): Abstract 4514.
Atezolizumab1 Nivolumab2 Pembrolizumab3 Durvalumab4 Avelumab5
Detection antibody SP142 28-8 22C3 SP263 73-10
IHC platform Ventana Dako Dako Ventana Dako
Cell types scored for urothelial cancer
IC TC TC IC and TC IC and TC
Cut-off definitions for
urothelial cancer
PD-L1+ (IHC 2/3) as ≥5% of ICs PD-L1+
PD-L1+ ≥1% TC expression
PD-L1+ ≥1% TC stainingPD-L1+ as ≥25% of ICs and TCs with membrane
PD-L1 staining
PD-L1+ as ≥5% TC staining or ≥10% IC
staining
Estimated PD-L1 prevalence
in urothelial cancer trials
PD-L1+ ORR(phase I trials)
~37%2 ~62%3 ~65%4 ~36%5~32%1
0
50
100
OR
R (
%)
DX+1 DX+2 DX+3 DX+4 DX+5
50.0 24.0 29.0 46.0 53.8
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FDA and EMA warn of decreased survival with first-line atezolizumab or pembrolizumab in
cisplatin-ineligible patients with low PD-L1, as assessed by an appropriate companion
diagnostic test
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Checkpoint inhibition in the context of the cancer immunity cycle
Trafficking
Antigen presentation
Infiltration
Antigen release
DC maturation
Migration to lymph node
IL-12
Costimulation
T cell activation & proliferation
Elimination
Peptide
MHC-I
T cell with specific TCR
Recognition
Antigen release
T cell activation & proliferation
Infiltration
Elimination
ImmuneCheckpoints
CTLA-4
PD-L1
PD-L1
PD-1
One has to determine the interruption point
Combination therapy
Cancer immunophenotypes
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IMvigor210: TCGA Subtype in mUC
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Response by TCGA Molecular Subtype
1. Balar AV et al. Lancet 2017; 389:67-76. 2. Rosenberg JE, et al. Lancet. 2016;387(10031):1909-1920.
Atezolizumab 2nd-line2Atezolizumab 1st-line1
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Response by TCGA Molecular Subtype
1.Sharma P, et al. Lancet Oncol. 2017;18(3):312-322.
Nivolumab 2nd-line1
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BLC2001: Antitumor Activity
� Tumor shrinkage observed in 76% of evaluable patients receiving erdafitinib 8 mg QD
� Reponses were durable
Siefker-Radtke AO, et al. ASCO 2018. Abstract 4503. Slide credit: clinicaloptions.com
Response,*† n (%) Patients (N = 99)
ORR
� CR
� PR
40 (40.4)
3 (3.0)
37 (37.4)
SD 39 (39.4)
PD 18 (18.2)
Median TTR, mos 1.4
Median DoR, mos 5.6
Response, %
Patient Subgroups
CT Naive
(n = 12)
PD/Relapse After CT
(n = 87)
Visceral Mets
(n = 78)
No Visceral Mets
(n = 21)
Prior IO
(n = 22)
ORR to erdafitinib 41.7 40.2 38.5 47.6 59.0
ORR to prior IO -- -- -- -- 5
*Investigator-assessed response confirmed with second scan ≥ 6 wks
after first observation of response. †Response unknown, n = 2.
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3 cancer immunophenotypes
Trafficking
Antigen presentation
Infiltration
Antigen release
DC maturation
Migration to lymph node
IL-12
Costimulation
T cell activation & proliferation
Elimination
Peptide
MHC-I
T cell with specific TCR
Recognition
Antigen release
T cell activation & proliferation
Infiltration
Elimination
IMMUNE EXCLUDED
INFLAMED
IMMUNE DESERT
Combinationwith chemo?
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� Immunotherapy is the new standard in metastatic urothelial cancer
� If chemotherapy remains a standard, it will be with immunotherapy
CONCLUSIONS