Immunotherapy in CA Bladder

Dr Mithilesh Yadav
Mch Resident
Introduction
Neoadjuvant Setting
 TCC histology and cT 3bN0 stage
 3 cycles of Pembrolizumab 200 mg every 3 weeks before RC

 Primary end point in the intention-to-treat population :

Pathologic complete response (pT0).

 Biomarker analyses: PD-L1 expression

 February 2017 to March 2018
 Neoadjuvant pembrolizumab
‒ 42% of patients with pT0

 Pembrolizumab could be a
worthwhile neo-adjuvant Rx for
MIBC when limited to patients
with
‒ PD-L1–positive
‒ High-TMB tumors (TMB scores ≥ 15)
• DFS- 68%
• OS- 77%
• Pathological
complete
response 85%
Adjuvant and metastasis setting-
1. Pembrolizumab
2. Atezolizumab
3. Nivolumab
4. Avelumab
5. Durvalumab
PEMBROLIZUMAB

• PD 1 receptor
inhibitor
 2017
• Open-label, Phase 3 trial ; 542 patients
• Recurred or progressed after platinum
• Pembrolizumab 200 mg every 3 weeks vs Chemotherapy
Pembrolizumab Chemotherapy

Median OS 10.3 months 7.4 months

PFS ( no difference)

Adverse events ( Any grade) 60.9% 90.2%

 KEYNOTE-045: Study Design
 International, randomized, open-label phase III study

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)
Adult patients with predominantly
transitional cell UC of the renal Pembrolizumab
pelvis, ureter, bladder, or urethra; 200 mg IV Q3W
PD after (n = 270)
Treatment continued for
1-2 lines of platinum-based CT or 2 yrs or until PD,
recurrence < 12 mos after Paclitaxel 175 mg/m2 IV Q3W or
unacceptable toxicity, or
perioperative platinum-based CT; Docetaxel 75 mg/m2 IV Q3W or
withdrawal of consent
ECOG PS 0-2(N = 542) Vinflunine 320 mg/m2 IV Q3W
(n = 272)
 Primary endpoints: OS, PFS
 Secondary endpoints: ORR, DoR, safety
Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026.
 2019
• Median follow-up as of 26 October 2017 was 27.7 months
Pembrolizumab Chemotherapy

Median 1- and 2-year OS 44.2% and 26.9% 29.8% and 14.3%

PFS ( Although no difference) 1- and 2-year PFS rates were

higher
Objective response rate 21.1% 11.0%

Median duration of response Not reached 4.4 months; (range 1.4+

(range 1.6+ to 30.0+ months) to 29.9+ months)

Adverse events ( Any grade) 62.0% 90%

• 519/542 were included in HRQoL analyses 2018

Pembrolizumab Chemotherapy

Time to deterioration(TTD) in global 3.5 months 2.3 months

health status/quality-of-life score
(Median)

Mean (95% CI) change from baseline 0.69 28.36

to week 15 in global health (22.40 to 3.77) (211.84 to 24.89)
status/QOL score
Atezolizumab

Targets the ligand

PD-L1 to restore
antitumour T-cell
activity
• Few options exist for patients with locally advanced or
metastatic TCC after progression with platinum-based
chemotherapy
• Atezolizumab(467) 1200 mg or chemotherapy(464) iv 3 weekly
• Between Jan 13, 2015, and Feb 15, 2016
• 931 patients from 198 sites
• Did not meet its primary endpoint of improved OS for
patients with high PD-L1 expression (IC score 2/3) with 11.1
months vs. 10. 6 months (0.87, 95% CI: 0.63-1.21, p = 0.41)
• But OS was numerically improved in the ITT population in an
exploratory analysis (8.6 months vs. 8.0 months, HR: 0.85,
95% CI: 0.73-0.99)
• Nov 2016 - Mar 2018 (median follow-up 12.7mo)
• 1004 patients with locally advanced or metastatic urothelial
or nonurothelial urinary tract carcinoma
• Tolerability of atezolizumab in a real-world pretreated
population with urinary tract carcinoma.
NIVOLUMAB
• Nivolumab 3 mg/kg IV every 2 weeks until disease progression and clinical
deterioration, unacceptable toxicity, or other protocol-defined reasons
• March 9, 2015, and Oct 16, 20 15, 270 patients from 63 sites in 11 countries
• Median follow-up for overall survival was 7·00 months (IQR 2·96–8·77).
PD L1 expression Confirmed
objective response

Overall 52/265
≥ 5% 23/81
≥ 1% 29/122
< 1% 23/143
• 44 patients
• Median follow up of 16.5 months (IQR, 15.8 to 16.7 months).
• Confirmed objective response rate : 18.2% (95% CI, 8.2% to 32.7%; 5 complete
responses and 3 partial responses)
• Median duration of response was not reached (95% CI, 12.1 weeks to not estimable),
and responses were ongoing in six patients (75.0%), including four of five complete
responses.
• Median PFS: 11.6 weeks (95% CI, 6.1 to 17.4 weeks)
• Median OS: 13.7 months (95% CI, 8.5 months to not estimable), with a 12-
month OS rate of 54.3% (95% CI, 37.9% to 68.1%).
• Avelumab was well tolerated and associated with durable responses and prolonged
 EV-201: Study Design
 Single-arm , multicenter, pivotal phase II trial with 2 patient cohorts

Patients with previously treated,

unresectable locally advanced or
Enfortumab Vedotin
metastatic urothelial cancer, prior anti–
1.25 mg/kg IV on Days 1, 8, 15
PD-1/PD-L1 antibody, progression on
28-day cycles
most recent therapy, ECOG PS 0/1 (cohort
1)
or 0-2 (cohort 2)
 Cohort 1: prior platinum chemotherapy; n = 125
 Cohort 2: no prior platinum and cisplatin ineligible

 Primary endpoint: ORR (per BICR)

 Secondary endpoints: DoR, PFS, OS, safety
Petrylak. ASCO 2019. Abstr LBA4505. NCT03219333.
 EV-201 (Cohort 1): ORR
Cohort 1 100 Change in Tumor Size From Baseline
Response, n (%)
(n = 125) 80  Tumor shrinkage in 84% of patients
ORR 55 (44)

Change From Baseline (%)

60
Best overall
response per 40
RECIST
20
 CR 15 (12) 0
 PR 40 (32) -20
 SD 35 (28)
-40
 Nectin-4 expression -60
detected in all tested pts -80
(median H-score 290) -100
– H-score scale: 0-300
Petrylak. ASCO 2019. Abstr LBA4505.
EV302/KeynoteA39
• EV-302 is a phase 3, global, open-
label, randomized trial

• Blinded independent central review

(BICR)

• The trial was sponsored by Astellas

Pharma US; Merck Sharp and
Dohme, a subsidiary of Merck; and
Seagen.
 EV-302/KEYNOTE-A39: PFS per BICR
(Coprimary Endpoint)
100 + + EV + Pembro Chemotherapy
+++ Outcome (n = 442) (n = 444)
+++++
+++ ++
80 ++ +
+++ ++ mPFS, mo (95% CI) 12.5 (10.4-16.6) 6.3 (6.2-6.5)
+++ +
++++ +++ ++++
60 +++ +++
+++++++
HR (95% CI) 0.45 (0.38-0.54; P <.00001)
PFS (%)

++ ++ +++++++ ++
++ ++++++++++++++++ +
40 ++++++ ++++++++
++ +++
+ ++
+++
+ ++ + + +
++
+++++
20 +++ ++++
+++ ++++
+ ++++++ +++ + ++ +
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Mo
Patients at Risk, n
EV + Pembro 442 409 361 303 253 204 167 132 102 73 45 33 17 6 3 1
Chemotherapy 444 380 297 213 124 78 56 41 30 19 8 6 5 3 2 1 1

Powles. ESMO 2023. Abstr LBA6. Reproduced with permission. Slide credit: clinicaloptions.com
 EV-302/KEYNOTE-A39: OS (Coprimary Endpoint)
EV + Pembro Chemotherapy
100 ++ ++++ Outcome
(n = 442) (n = 444)
++ ++++ +
+ ++++++++ mOS, mo (95% CI) 31.5 (25.4-NR) 16.1 (13.9-18.3)
80 + +++++++++++++ HR (95% CI) 0.47 (0.38-0.58; P <.00001)
++++ +++++++++++++
++++++ +++ ++
++
+++
+++++++++
++
++++++ ++++++++++++++++++
60 +++++++ +++++++++++++
++++++
OS (%)

++++++ + ++++ + ++ ++
+++++++
+++++++
40 ++++++++++++
+++++++ +++++++++++++++++ + + +
++ + + +
20

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38
Mo
Patients at Risk, n
EV + Pembro 442 426 409 394 376 331 270 222 182 141 108 67 36 22 12 8 1 1 1
Chemotherapy 444 423 393 356 317 263 209 164 125 90 60 37 25 18 12 7 6 2 1
Median follow-up: 17.2 mo
Powles. ESMO 2023. Abstr LBA6. Reproduced with permission. Slide credit: clinicaloptions.com
Checkpoint Inhibitors as Maintenance Therapy in mUC
 HCRN GU14-182: multicenter,  JAVELIN Bladder 100:
randomized, double-blind phase multicenter, randomized,
II study[1] open-label phase III study[2]
MAINTENANCE MAINTENANCE

Patients with Patients with locally

Pembrolizumab advanced or metastatic Avelumab + BSC
metastatic UC
and at least SD UC and no PD after
on first-line CT PD first-line CT
Placebo Pembrolizumab BSC Only
(N = 200) (N = 668)

 Primary endpoint: 6-mo PFS  Primary endpoint: OS

1. ClinicalTrials.gov. NCT02500121. 2. ClinicalTrials.gov. NCT02603432.

Current
Recommendations
• 2 Groups-
– Combination therapy eligible- ECOG performance status
0-2, GFR ≥ 30 ml/min and adequate organ functions based on
eligibility for treatment with Enfortumab vedotin and Pembrolizumab

– Combination therapy not eligible- refuse treatment

with EV including patients with uncontrolled diabetes, peripheral
neuropathy grade ≥ 2 and pre-existing significant skin disorders.
Not fit/accepting combination therapy
 Summary
Neoadjuvant therapy- in clinical trialsetting only

Adjuvant therapy- FDA has approved nivolumab for

high risk of recurrence whereas the EMA has
approved adjuvant nivolumab for the treatment of
adults with muscle-invasive UC (MIUC) with tumour
cell PD-L1 expression ≥ 1%.

Metastatic disease- 1st line- EV plus Pembrolizumab

combination, or platinum-based chemotherapy
switch, maintenance treatment with IO (avelumab) Thanks…..