Advanced & metastatic bladder cancer - Dr Alok Gupta

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Advanced & Metastatic Bladder Cancer
Dr Alok Gupta
MD, DM,
Associate Director & Head
Medical and Hemato Oncology
Medanta Lucknow
Ex-Asst. Professor, AIIMS, New Delhi

Case 1
 Mr P S, 74 year male, Ex army person, Ex Smoker, No comorbidities.
 Evaluated for Painless Hematuria. No other symptoms. PS-1.
 USG: Multiple (at least 4 to 5 in number) soft tissue polypidal growth
are noted in the urinary bladder, in left lateral wall and posterior wall.
Largest measuring about 3.9 x 2.8 cm in the left lateral wall. No
hydroureteronephrosis.
 TURBT: High grade Invasive urothelial carcinoma. differentiation.
Tumor invades underlying muscularis propria. LVI/PNI: not seen.
 Pet CT scan: Pelvic nodes, RP + Mediastinal nodes, Multiple Lung
mets.
 Hb -13, Creat- 0.7, Creat clearance – 75, EF-66%
 Diagnosis: Metastatic High Grade Urothelial Carcinoma.

How will you treat?
1. Gemcitabine + Cisplatin
2. Gemcitabine + Carboplatin
3. MVAC
4. Immunotherapy (Pembro OR Atezo)
5. Single agent Cisplatin

Question for Panelists
 How do you select first line therapy in metastatic bladder
cancer?

Cisplatin Ineligibilty
1. ECOG performance status 2 or greater or a Karnofsky Performance
Status of 60 to 70 percent or less
2. Creatinine clearance less than 60 mL/min
3. Hearing loss (measured at audiometry) of 25 dB at two contiguous
frequencies
4. Grade 2 or greater peripheral neuropathy (ie, sensory alteration or
paresthesia, including tingling, but not interfering with activities of
daily living)
5. New York Heart Association class III or greater heart failure

 Which is the preferred regimen and why?
1. MVAC
2. Gem Cis
3. PCG
4. HD-MVAC
5. Single agent cisplatin
6. Gemcitabine carboplatin

Cisplatin Based Regimens in metastatic bladder cancer
Regimen RR CR PFS months OS months
Cisplatin 12 - 4 8
MVAC 40-50% 9-12% 7-10 13-14
Gemcitabine
Cisplatin
44-50% 9-12% 7-9 14
Paclitaxel
Gemcitabine
Cisplatin
56% 8 16
HD MVAC 64% 21% 9.5 15.1
Gemcitabine
Carboplatin
41% - 6 9

 If this patient had T3N2M0 disease, what would be the
intent and plan of treatment?

2nd Case Scenario
 Same patient. If he had T2 DM, Diabetic nephropathy,
Creat – 1.9, Creat clearance – 35ml/min.
 Which is the preferred regimen and why?
1. Gemcitabine + Carboplatin
2. Methotrexate + carboplatin + Vinblastine (MCAVI)
3. Pembrolizumab
4. Atezolizumab

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
0
0 4 8 12 16 20 24
Mos
Patients at Risk, n
370
28 32
283 223 173 147 86 38 11 11
OS(%)
100
80
60
40
20
0
0 4 8 12 16 20 24
Mos
Patients 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.

Treatment Options for Cisplatin Ineligible Patients
Regimen Phase RR CR PFS months OS months
Gemcitabine
Carboplatin
III 41% - 6 9
MCAVI III 30% 4 8
Pembrolizumab
Keynote 052
II 29%
CPS<10 - 20%
CPS>10 – 47%
7% - 11.3
CPS<10 – 9.7
CPS>10 – 18.5
Atezolizumab
Imvigor 210
cohort1
II 23%
IC2/3: 28
IC1/2/3: 24
9% - 16

 How frequently do you test for PD-L1 expression for
deciding treatment in cisplatin ineligible patients?
 What are the methods/antibodies used?

3rd Case Scenario
 Metastatic Bladder cancer, 85 year old with T2Dm and
HTN. Not fit for chemotherapy?
 Which is the preferred treatment option?
1. Best Supportive Care
2. Pembrolizumab
3. Atezolizumab

4th Case Scenario
 Our patient, Mr P S, 74 year male, Ex army person, No
comorbidities.
 Received 3+3 cycles of gemcitabine + Cisplatin. Partial
Response.
 Disease progression at 9 months.
 Metastatic High Grade Urothelial Carcinoma – Post
Platinum progression

 Which is your preferred 2nd line treatment and why?
1. Chemotherapy – Paclitaxel, Docetaxel, Pemetrexed, vinflunine.
2. Immunotherapy – Pembrolizumab, Atezolizumab, Durvalumab,
Nivolumab, Avelumab.

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]
ORR(%,95%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]

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(%,95%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]

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 or
Vinflunine 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)

Pembrolizum
ab
Chemotherap
y
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 32
0
20
40
60
80OS(%)
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)

KEYNOTE-045: ORR
de Wit R, et al. ESMO 2017. Abstract LBA37_PR.
21.1%
11.0%
PR
CR
7.8%
13.3%
Pembrolizumab
(n = 270)
Chemotherapy
(n = 272)
2.9%
8.1%
ORR(%,95%CI)
All Patients
20.3%
6.7%
6.8%
13.5%
Pembrolizumab
(n = 74)
Chemotherapy
(n = 90)
2.2%
4.4%
ORR(%,95%CI)
PD-L1 Positive (CPS ≥ 10)
0
5
10
15
20
25
30
35
0
5
10
15
20
25
30
35

IMvigor211 Study Design
 Primary endpoint
 OS, tested hierarchically
in pre-specified populations
Atezolizumab
1200 mgq3w
R
1:1
No crossoverpermitted per
protocol
Survival
follow-up
Lossof
clinical benefit
RECISTv1.1
progression
KeyEligibility Criteria
• mUCwith progression during orfollowing platinum-based
chemotherapy
– ≤ 2 prior lines of therapy
• Measurable diseaseper RECISTv1.1
• ECOGPS0-1
• Evaluablesamplefor PD-L1testing
• TCChistology asprimary component
(N =931)
StratificationFactors
• No. of risk factorsa(0 vs.1/2/3)
• Liver metastases(yesvs. no)
• PD-L1status (0/1 vs.2/3)
• Chemotherapy (vinflunine vs. taxanes)
 Additional endpoints
 Efficacy: RECIST v1.1 ORR, PFS and DOR
 Safety
 PROs: EORTC QLQ-C30
Chemotherapy
(investigator’s choice)
21
• Vinflunineq3w
• Docetaxelq3w
• Paclitaxelq3w
aDefinedby time from prior chemotherapy<3 mo, ECOGperformancestatus>0 and hemoglobin <10 g/dL.

OS Analysis: IC2/3 Population
20
Events/
Patients
Median OS
(95%CI)
12-mo OSRate
(95%CI)
Atezolizumab 72/116 11.1 mo (8.6,15.5) 46%(37, 56)
Chemotherapy 88/118 10.6 mo (8.4,12.2) 41%(32, 50)
10 12 14 16 18 208
HR = 0.87 (95% CI: 0.63, 1.21)
P = 0.41
0 2 4 6 2422
100
OverallSurvival
80
60
40
20
0
No. atRisk Month s
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
22

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 Targe
t
Schedul
e
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

First-line Therapy for Metastatic UC: What We
Know
 Chemotherapy is active in this space
 Cisplatin-eligible patients should get cisplatin
 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
‒ Access to such diagnostic tests is variable, limited at many
institutions

 What is your take on the recently presented data of Switch
maintenance immunotherapy in metastatic bladder
cancer?

Checkpoint Inhibitors as Maintenance Therapy in mUC
 HCRN GU14-182:
multicenter, randomized,
double-blind phase II study[1]
 Primary endpoint: 6-mo PFS
 JAVELIN Bladder 100:
multicenter, randomized,
open-label phase III study[2]
 Primary endpoint: OS
1. ClinicalTrials.gov. NCT02500121. 2. ClinicalTrials.gov. NCT02603432.
Patients with
metastatic UC
and at least SD
on first-line CT
(N = 200)
Pembrolizumab
Placebo
PD
MAINTENANCE
Pembrolizumab
Patients with locally
advanced or
metastatic UC and no
PD after
first-line CT
(N = 668)
Avelumab + BSC
BSC Only
MAINTENANCE

 EV-201: Enfortumab Vedotin in Advanced Urothelial Cancer
Previously Treated With Platinum Chemotherapy and Immune
Checkpoint Inhibitors?
 Enfortumab vedotin is an antibody–drug conjugate to Nectin-4 that
delivers the cytotoxic agent MMAE to tumor cells expressing Nectin-
4, thereby disrupting microtubules and resulting in cell cycle arrest
and apoptosis

EV-201: Study Design
 Single-arm , multicenter, pivotal phase II trial with 2 patient cohorts
 Primary endpoint: ORR (per BICR)
 Secondary endpoints: DoR, PFS, OS, safety
Petrylak. ASCO 2019. Abstr LBA4505. NCT03219333.
Patients with previously treated,
unresectable locally advanced or
metastatic urothelial cancer, prior
anti–PD-1/PD-L1 antibody, progression
on most recent therapy, ECOG PS 0/1
(cohort 1)
or 0-2 (cohort 2)
Enfortumab Vedotin
1.25 mg/kg IV on Days 1, 8, 15
28-day cycles
 Cohort 1: prior platinum chemotherapy; n = 125
 Cohort 2: no prior platinum and cisplatin ineligible

EV-201 (Cohort 1): ORR
 Nectin-4 expression
detected in all tested
pts (median H-score
290)
– H-score scale: 0-300Petrylak. ASCO 2019. Abstr LBA4505.
Response, n
(%)
Cohort 1
(n = 125)
ORR 55 (44)
Best overall
response per
RECIST
 CR 15 (12)
 PR 40 (32)
 SD 35 (28)
Change in Tumor Size From Baseline100
80
60
40
20
0
-20
-80
-60
-40
-100
ChangeFromBaseline(%)
 Tumor shrinkage in 84% of patients

EV-201 (Cohort 1): PFS and OS
Petrylak. ASCO 2019. Abstr LBA4505.
Patients at Risk, n
Cohort 1 125 116 91 84 72 65 51 47 30 22 8 7 3 2
Patients at Risk, n
Cohort 1 125 122 121 113 111 101 96 91 82 61 36 24 18 9 8
2 1
Mos
100
80
60
40
20
0
PFS(%)
543210 6 7 8 9 1011121314
Median PFS: 5.8 mos
(95% CI: 4.9-7.5)
PFS
15161718
Mos
100
80
60
40
20
0OS(%)
543210 6 7 8 9 1011121314
Median OS: 11.7 mos
(95% CI: 9.1-NR)
OS
15161718

Summary
31
• 1st Line – Cisplatin Eligible Cisplatin based combination chemotherapy.
• 1st Line – Cisplatin Ineligible PD-L1 testing as per recommended test. If PD-L1 is high
then consider immunotherapy (Phase III data pending). If PD-L1 low/not available then
carboplatin based combination chemotherapy.
• 1st Line – Chemotherapy Ineligible Can Consider Immunotherapy
• 2nd Line We have 5 IO drugs with some data for use in mUC but only one with
phase III trial data to support its use (Pembrolizumab). Biomarker studies seem to
show a relationship but not clear
• 3rd Line  Enfortumab Vedotin appears promising in phase 2 trail
• Accelerated approval does not guarantee phase 3 trial success
• More IO drugs and combination trials are ongoing. Cost will play a big role in usage of
IO agents

Thank You
Dr Alok Gupta MD, DM,
Consultant Medical Oncologist
Max Super Speciality Hospital, Saket

Advanced & metastatic bladder cancer - Dr Alok Gupta

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