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BLADDER CANCERSystemic treatment
Carlos Vallejos, MD.Medical Oncologist.
Founding Director – Oncosalud AUNA.
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Bladder Cancer: Spectrum of Disease
Metastatic: ~ 5%NMIBC: 70%
CIS, Ta, T1
MIBC: 30%T2-T4
The Past
Humphrey PA, Eur Urol. 2016 Jul;70(1):106-119. 2. Matulay J, Version 1. F1000Res. 2018; 7: F1000 Faculty Rev-1137. 3. American Cancer Society; Mungan, Urology 2000; 55: 876-880
Localized: ~ 95%
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FIRST-LINE SYSTEMIC TREATMENT FOR METASTATIC UROTHELIAL CARCINOMA OF THE BLADDER
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Standard MVAC1989
Cisplatin FDA approved
20181997 2000 2003 2006 2009 2012 2015
Docetaxel1997
GC 2000
Accelerated MVAC 2001
Paclitaxel2002
Vinflunine2009
Gemcitabine EMA approved
2008
Vinflunine
EMA approved
2009
Pu
blic
atio
nA
gen
cy A
ctio
n 1974
1978
Doxorubicin
FDA approved
Atezolizumab
FDA approved
2016
Evolution of Systemic Therapy for UrothelialCarcinoma
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Identifying Patients Who Are Cisplatin-Ineligeble
Chemotherapy ineligible? : Poorly controled type 2 diabetes, vascular or coronary disease, high risk of myelosuppression
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Cisplatin-Eligible
Gemcitabine Cisplatin
ORR: 49%CR: 12% mOS: 14 mo
1. von der Maase H, et al. J Clin Oncol. 2000;18:3068-3077. 2. Sternberg CN, et al.
Eur J Cancer. 2006;42:50-54. 3. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.
ddMVAC
ORR: 72%CR: 25% mOS: 15.1 mo
CarboplatinGemcitabine
ORR: 36%CR: 3%mOS: 9.3 mo
Cisplatin-Ineligible
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Durable Responses With Cisplatin-Based CT in UC
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
MosPatients at Risk, n
203202
118125
5062
3640
3034
2329
79
01
GCMVAC
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
GCMVAC
100
80
60
40
20
00 2 4 6 8 10 12
YrsPatients at Risk, nN
129134
3245
1529
1123
48
20
Median5 yrs, %(95% CI)
M-VACHD M-VAC
O112101
M-VACHD M-VAC
HD M-VAC15.1 mos
21.8 (14.5-21.9)
M-VAC14.9 mos
13.5 (7.4-19.6)
Log-rank P = .042HR: 0.76 (95% CI: 0.58- 0.99)
100
80
60
40
20
00 1 2 3 4 5 6
YrsPatients at Risk, nN
119119
3744
1315
75
32
12
M-CAVIGC
O108110
Surv
ival
(%
)
7
Log-rank test P = .64
M-CAVIGC
11
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Cisplatin but Not Carboplatin Can Yield Durable and Complete Responses in the Frontline
1. De Santis M, et al. J Clin Oncol. 2012;30:191-199. 2. Sternberg CN, et al. Eur J Cancer. 2006;42:50-54.
mOS: 9.3 mos
OS
(%
)
100
80
60
40
20
00 1 2 3 4 5 6 7
Yrs
MCAVI
Gem/carbo
Log-rank test P = .64
Patients at Risk, n
MCAVI (n = 119)
Gem/carbo (n = 119)
37
44
13
15
7
5
3
2
1
2
1
1
mOS: 15.1 mos
OS
(%
)
100
80
60
40
20
00 2 4 6 8 10 12
Yrs
32
45
15
29
11
23
4
8
2
0
DD MVACHR: 0.76
P = .042
mOS, mos
DD MVAC
15.1
MVAC
14.9
Patients at Risk, n
MVAC (n = 129)
DD MVAC (n = 134)
Gemcitabine/Carboplatin[1] DD MVAC (Cisplatin)[2]
MVAC
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Cisplatin FDA approved
Standard MVAC1989
20181997 2000 2003 2006 2009 2012 2015
Docetaxel1997
GC 2000
Accelerated MVAC 2001
Paclitaxel2002
Vinflunine2009
Gemcitabine EMA approved
2008
Vinflunine
EMA approved
2009
Pu
blic
atio
nA
gen
cy A
ctio
n
2018Feb Mar Apr May
Nivolumab 2nd lineFeb
2017
Atezolizumab 1st-line cis ineligible
Apr 2017Durvalumab 2nd line
May 2017
Avelumab 2nd lineMay 2017
Pembrolizumab 1st-line cis ineligible May 2017
Pembrolizumab 2nd line May 2017
1974
1978
Doxorubicin
FDA approved
AtezolizumabFDA approved
2016
Evolution of Systemic Therapy for Urothelial Carcinoma
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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
28 32
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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Decreased Survival in Patients With Low Levels of PD-L1 Using ICI Monotherapy
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PEMBROLIZUMAB:Clone: 22C3Combined positive score ≥10
the ratio of PD-L1–expressing tumor-infiltrating immune cells relative to the total number of tumor cells
ATEZOLIZUMAB:Clone: SP142staining on tumor-infiltrating immune cells covering at least ≥ 5%
PD-L1 Status Required in the Frontline Setting for Cisplatin Ineligible UC.
IHC PD-L1
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• Cisplatin Is Highly Active In This Space.
• Cisplatin-eligible Patients Should Get Cisplatin.
• Cisplatin-ineligible Patients Should Get Gemcitabine –Carboplatin Unless They Are PD-L1 Positive.
• Patients Inegligible For Any Chemotherapy Can Be Considered For Checkpoint Inhibitor Therapy Regardless Of PD-L1 Status
What We Know About First-line Treatment In Metastatic Bladder Cancer?
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SECOND-LINE (POST-PLATINUM) SYSTEMIC TREATMENT FOR METASTATIC UROTHELIAL CARCINOMA OF THE BLADDER
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FDA-Approved Checkpoint Inhibitors for 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.
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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KEYNOTE-045: Study Design• International, randomized, open-label phase III study
• Primary endpoints: OS, PFS
• Secondary endpoints: ORR, DoR, safety
Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.
Adult patients with predominantly transitional cell UC of the renal pelvis, ureter, bladder, or urethra; PD after
1-2 lines of platinum-based CT or recurrence < 12 mos after
perioperative platinum-based CT; ECOG PS 0-2
(N = 542)
Treatment continued for 2 yrs or until PD,
unacceptable toxicity, or withdrawal of consent
Pembrolizumab 200 mg IV Q3W
(n = 270)
Paclitaxel 175 mg/m2 IV Q3W or Docetaxel 75 mg/m2 IV Q3W orVinflunine 320 mg/m2 IV Q3W
(n = 272)
Stratified by ECOG PS (0/1 vs 2), Hg (< 10 vs ≥ 10 g/dL), liver
mets (yes vs no), and time since last CT (< vs ≥ 3 mos)
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Pembrolizumab
Chemotherapy
KEYNOTE-045: OS
270 194 147 116 98 67 23
272 171 109 73 58 35 13
44.4%30.3% 33.2%
19.7%
Median OS, Mos (95% CI)10.3 (8.0-12.3)
7.4 (6.3-8.3)
0 4 8 12 16 20 24 28 320
20
40
60
80O
S (%
)
Mos
100
Patients at Risk, n
de Wit R, et al. ESMO 2017. Abstract LBA37_PR.
Data cutoff: May 19, 2017
HR: 0.70 (0.57-0.86; P = .0003)
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Pembrolizumab
Chemotherapy
Median PFS, Mos (95% CI)2.1 (2.0-2.2)3.3 (2.4-3.5)
KEYNOTE-045: PFS
270 86 61 44 39 24 6
272 93 39 19 12 7 2
PFS
(%
)
MosPatients at Risk, n
17.8%9.3% 15.3%
4.8%
0 4
60
80
8 12 16 20 24 280
20
40
100
de Wit R, et al. ESMO 2017. Abstract LBA37_PR.
Data cutoff: May 19, 2017
HR: 0.96 (0.79-1.16; P = .32)
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Phase II Studies of Immune Checkpoint Inhibitors Leading to Accelerated Approval
Nivolumab[1]
Durvalumab[3]Avelumab[2]
OS
(%
)
100
80
60
40
20
00 3 6 9 12 15
Pts at Risk, n
(number censored)
All treated pts 265 (0) 198 (3) 148 (4) 63 (71) 5 (125) 0 (130)
All treated pts (n = 265)
Median OS: 8.74 mos
(95% CI: 6.05 to not reached)
100
80
60
40
20
0
OS
(%
)
0 3 6 9 12 151 2 4 5 7 8 1011 1413 161718
Mos Since Treatment Initiation
Pts at Risk, n 44 43 40 31 30 28 25 25 25 23 22 21 19 17 14 10 6 2 0
Median OS: 13.7 mos
(95% CI: 8.5 to NE)
Pro
ba
bil
ity o
f O
S
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27
Mos From First Dose
PD-L1 HighPD-L1
Low/NegativeTotal
Median OS, mos (95% CI)
20.0 (11.6-NE)
8.1 (3.1-NE)
18.2 (8.1-NE)
12-mo OS rate, % (95% CI)
63 (49-74) 41 (21-60) 55 (44-65)
Total (n = 191)
PD-L1 low/negative (n = 79)
PD-L1 high (n = 98)
1. Sharma P, et al. Lancet Oncol. 2017;18:312-322. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124. 3. Powles T, et al.
JAMA Oncol. 2017 Sep 14;3(9):e172411.
Overall population (n = 44)
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Post-Platinum Urothelial Carcinoma: ORR
CT: ~ 10%
1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124. 3. Powles T, et al. JAMA Oncol. 2017;3:e172411. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322.5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.
Atezolizumab[1]
OR
R (
%, 9
5%
CI)
Data from separate studies. Not head-to-head comparisons.
13.4 18.2 17.8 19.6 21.1
0
10
20
30
40
50
60
70
Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]
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Post-Platinum Urothelial Carcinoma: OS at 12 Mos
1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124. 3. O’Donnell P, et al. AACR 2018. Abstract CT031. 4. Sharma P, et al. AACR 2018. Abstract CT178. 5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.
CT: ~ 26%
Atezolizumab[1]
OS
(%, 9
5%
CI)
Data from separate studies. Not head-to-head comparisons.
39.2 54.3 46.6 40.3 43.9
0
10
20
30
40
50
60
70
Pembrolizumab[5]Nivolumab[4]Durvalumab[3]Avelumab[2]
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FIRST LINE(MANDATORY PD-L1 TESTING)
SECOND LINE(NO PD-L1 TESTING)
SETTING
REGIMEN
Cisplatin-eligible
Cisplatin-based CT
Cisplatin-ineligible
(PD-L1 high)
PD-1/PD-L1 blockadeCarboplatin-
based CT
Cisplatin-ineligible (PD-L1
low)CT-ineligible
Evolving Treatment in Advance Urothelial Carcinoma
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Post-Platinum Urothelial Carcinoma: Safety
1. Powles T, et al. Lancet. 2018;391:748-757. 2. Apolo AB, et al. J Clin Oncol. 2017;35:2117-2124.3. Powles T, et al. JAMA Oncol. 2017;3:e172411. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322. 5. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.
Agent Phase Median F/U, Mos
Patients, n
Treatment-Related AEs, %
Any Grade 3/4 Death None
Atezolizumab[1] III 17.3 459 70 20 < 1 30
Avelumab[2] Ib 16.5 44 66 7 0 34
Durvalumab[3] I/II 5.78 191 61 7 1 39
Nivolumab[4] II 7.0 270 64 18 1 36
Pembrolizumab[5] III 14.1 266 61 15* 2 39
*Reported as grade 3-5.
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Immune-Related Toxicities
Organ System Reported Toxicities
Integumentary Hives, eczema, vitiligo, pemphigus, lichenoid reactions
Gastrointestinal Enterocolitis, pancreatitis, gastritis, celiac disease
Hepatic Autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis
Renal Interstitial nephritis, nephrotic syndrome, autoimmune nephropathy
Pulmonary Pneumonitis, interstitial lung disease, pleuritis
Cardiac Myocarditis, pericarditis, cardiomyopathy
Endocrine Hypo/hyperthyroidism, hypophysitis, adrenal insufficiency
NeurologicEncephalitis, Guillain-Barre syndrome, myasthenia gravis, mononeuritis, autoimmune
inner ear disease
HematologicHemolytic anemia, immune thrombocytopenic purpura, thrombotic thrombocytopenic
purpura, hemophilia, Evans syndrome
Rheumatologic Polyarthritis, systemic lupus erythematosus, antiphospholipid syndrome5th
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Select Any-Grade, Treatment-Related AEs Over Time
Weber JS, et al. J Clin Oncol. 2017;35:785-792.
SkinGIEndocrineHepaticPulmonaryRenal
Patients at Risk, nStill in studyStill receiving treatmentTotal with new eventStill in study with new event, %
45329823953
2811723412
1387643
26115
19
10300
9000
160
No
. of
Pati
ents
140
120
100
80
60
40
20
0
Wks Since Initiation of Nivolumab≤ 16 ≤ 32 ≤ 48 ≤ 64 ≤ 80 ≤ 96
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Most Immune-Related AEs Are Reversible With Immunosuppression/Steroids
Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.
Wks
86420
Toxi
city
Gra
de
Rash, pruritusLiver toxicityDiarrhea, colitisHypophysitis
10 18 14
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PERIOPERATIVE SYSTEMIC THERAPY IN BLADDER CANCER
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Bladder Cancer: Spectrum of Disease
MedicalOncology
Localized: ~ 95% Metastatic: ~ 5%
NMIBC: 70%CIS, Ta, T1
MIBC: 30%T2-T4
Urology
The Past
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Bladder Cancer: Spectrum of Disease
MedicalOncology
Localized: ~ 95%
NMIBC: 70%CIS, Ta, T1
MIBC: 30%T2-T4
Urology
The Present
Metastatic: ~ 5%
RadiationOncology5t
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EORTC 30994: Immediate vs Deferred Adjuvant CT
• Improved PFS with immediate vs deferred adjuvant CT
Sternberg CN, et al. Lancet Oncol. 2015;16:76-86.
HR: 0.54 (95% CI: 0.40-0.73)P < .0001
Yrs Since Randomization
PFS
(%
)
DeferredImmediate
100
90
80
70
60
50
40
30
20
10
00 2 4 6 8 10 12
Patients at Risk, nDeferredImmediate
143141
5171
4557
3140
1821
435t
h ES
O-ES
MO
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Am
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EORTC 30994: No Impact in Overall Survival
• No difference in OS between arms
Sternberg CN, et al. Lancet Oncol. 2015;16:76-86.
HR: 0.78 (adjusted 95% CI: 0.56-1.08)P = .13
Yrs Since Randomization
OS
(%)
DeferredImmediate
100
90
80
70
60
50
40
30
20
10
00 2 4 6 8 10 12
Number at riskDeferredImmediate
143141
8395
6770
4244
2125
435t
h ES
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Am
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Clini
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Meta-analysis of Cisplatin-Based Adjuvant CT vs Surgery
Leow JJ, et al. Eur Urol. 2014;66:42-54.
OSStudy ID % WeightES (95 % CI)
9.838.61
12.3714.2210.576.35
61.95
11.0911.09
14.8312.1329.96
100
0.65 (0.34-1.25)0.74 (0.36-1.53)0.82 (0.48-1.39)0.75 (0.48-1.18)0.57 (0.31-1.05)1.11 (0.45-2.73)0.74 (0.58-0.94)
1.02 (0.57-1.83)1.02 (0.57-1.83)
1.29 (0.84-1.99)0.38 (0.22-0.65)0.71 (0.22-2.35)
0.77 (0.59-1.00)
Cisplatin-based combinations:BonoFreihaOttoSkinnerLehmannStadlerSubtotal (I2 = 0%; P = .880)Single agent cisplatin:StruderSubtotal (I2 = .%; P = .)Gemcitabine-cisplatin combinations:ItalianSpanishSubtotal (I2 = 91.8%; P = 0)
Overall (I2 = 46.5%; P = .060)
Favors Surgery AloneFavors Adjuvant Chemotherapy 1
NOTE: Weights are from random-effects analysis.
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SWOG-8710: Neoadjuvant CT Is Standard of Care for Muscle-Invasive Bladder Cancer
Grossman HB, et al. N Engl J Med. 2003;349:859-866.
Median OS Benefit: 2.6 yrs
MVAC + cystectomyCystectomy alone
Patients at Risk, nMVAC + cystectomyCystectomy alone
Survival EventMVAC +
Cystectomy(n = 153)
Cystectomy Alone
(n = 154)
Deaths, n 90 100
Median OS, mos
77 46
Surv
ival
(%
)
Mos After Randomization
0
20
40
60
80
100
0 24 48 72 96 120 144 168
153154
11288
9267
7550
4637
2318
675
th E
SO-E
SMO
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Clini
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NCCN Guidelines: NAC ± RT is The SOC in Stage II-IIIA UC
Stage II and IIIA
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Cisplatin-Based Neoadjuvant CT
1. Dash A, et al. Cancer. 2008;113:2471-2477. 2. Tully CM, et al. ASCO GU 2014. Abstract 355. 3. Anari F, et al. Eur Urol Oncol. 2018;1:54-60. 4. Iyer G, et al. J Clin Oncol. 2018;36:1949-1956.5. Blick C, et al. Cancer. 2012;118:3920-3927. 6. Plimack ER, et al. J Clin Oncol. 2014;32:1895-1901.7. Choueiri TK, et al. J Clin Oncol. 2014;32:1889-1894.
CharacteristicGem/Cis[1]
(n = 42)Gem/Cis[2]
(n = 154)DD Gem/Cis[3]
(n = 31)DD Gem/Cis[4]
(n = 46)AMVAC[5]
(n = 80)AMVAC[6]
(n = 40)DD MVAC[7]
(n = 39)
Study type Retrospective Retrospective Prospective Prospective Retrospective Prospective Prospective
Cycles, n 4 4 3 6 3-4 3 4
Wks, n 12 12 6 12 6-8 6 8
pCR (pT0), % 26 21 32 15 43 38 26
PR (< pT2), % 36 46 45 57 ~ 61 53 49
Median days from CT start to surgery
138 120 65 ~ 114+ 75 68 ~ 98
Grade 3/4 AEs, % NR NR 35 37 27 18 10
Progression free at 2 yrs, %
64 ~ 68 ~ 68 ~ 76 65 78 ~ 47
Alive at 2 yrs,* % 73 ~ 75 ~ 77 ~ 87 77 83 ≤ 80
*vs 58% with cystectomy alone.
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CharacteristicPembrolizumab
(n = 43)[1]Atezolizumab
(n = 68)[2]
Eligibility criteria T2-T3b; N1 allowed T2-T4a; N0 only
Cisplatin eligible, % 100 0
Received neoadjuvant CT, %
12 0
Duration of neoadjuvant checkpoint inhibition
3 cycles (9 wks) 2 cycles (6 wks)
Safe Yes Yes
Pathological CR (pT0), % 40 29
Available biomarker data Yes Yes
Neoadjuvant Checkpoint Inhibition in Bladder Cancer: Early Results of Phase II Trials
1. Necchi A, et al. ASCO 2018. Abstract 4507. 2. Powles T, et al. ASCO 2018. Abstract 4506.
Encouraging results; long-term outcomes needed before clinical use
pT0 Rates With CT:
Gem/Cis,15% to 32%
DD MVAC,26% to 43%
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RETAIN BLADDER: Risk-Adapted Treatment After Neoadjuvant CT for Bladder Cancer
• Single-arm, open-label phase II trial
• Primary endpoint: metastasis-free survival at Yr 2
Geynisman DM, et al. ASCO GU 2018. Abstract TPS537. ClinicalTrials.gov. NCT02710734.
Adult patients with primary urothelial or
predominantly urothelial
carcinoma of the bladder, cT2-4a N0M0 disease,
ECOG PS 0-2(N = 38)
TURBT 1
AMVAC x 3
TURBT 2
*Any alteration in ATM, RB1, FANCC, ERCC2.†Patient and physician choice.
No residual tumor/cT0 AND
mutation* positive
≥ cT3
cT2
Activesurveillance
Intravesicle txor chemo-RT
or cystectomy†
Cystectomy
Chemo-RTor cystectomy†
cTa or cTis or cT1 or positive cytology
OR cT0 and mutation* negative
Immunotherapy
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CONCLUSIONS• Urothelial Carcinoma is a Chemosensitive Disease.
• Cisplatin-Ineligible Patients Represents a Poor-Risk Prognostic Group: InmuneCheckpoint Inhibitors (hopefully) Can Change The Natural History of The Disease.
• Neoadjuvant Chemotherapy ± RT is the Standard of Care in Stage II and IIIA bladder cancer.
• ICI are Moving from Second-Line/Post-Platinum Systemic Treatment to NeoadjuvantSetting.
• Better Biomarkers for Response to ICI and Chemotherapy are needed.5th E
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THANKS FOR YOUR ATTENTION!
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