IMMUNE THERAPY IN BLADDER CANCER.€¦ · Atezolizumab NCT02807636 (IMvigor130):1 N=1,200 ......

IMMUNE THERAPY IN BLADDER

CANCER.

Thomas Powles

Director of Barts Cancer Centre

Renal Cancer Lead: London Cancer

Disclosures

Advisory role: BMS, Roche, Merck, AZ, Pfizer, Lilly, Incyte, Seattle

Genetics.

Research funding: AZ, Roche, Novarits.

Honoraria: Novartis, BMS, Roche, AZ Merck, Pfizer, Lilly.

Pembrolizumab vs chemotherapy in platinum

refractory disease

CPS = combined positive score.

Key Eligibility Criteria

• Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra

• Transitional cell predominant

• PD after 1–2 lines of platinum-based chemo or recurrence within 12 months of perioperative platinum-based therapy

• ECOG PS 0–2

• Provision of tumor sample for biomarker assessment

Pembrolizumab

200 mg IV Q3W

for 2 years

Paclitaxel 175 mg/m2 Q3WOR

Docetaxel 75 mg/m2 Q3WOR

Vinflunine 320 mg/m2 Q3W

R(1:1)

N = 542

Key end points:

Primary: OS and PFS in total and PD-L1 CPS ≥10%

populations

Secondary: ORR and DOR in total and PD-L1 CPS ≥10%

populations; safety in total population

N = 270

N = 272

Primary endpoint forKN-045: overall survival for all

patients

Data cutoff date: Sep 7, 2016.Bellmunt J, et al, NEJM 2016)

Events, n HR (95% CI) P

Pembro 155 0.73 (0.59–0.91) 0.0022

Chemo 179

43.9%

30.7%

Median (95% CI)

10.3 mo (8.0–11.8)

7.4 mo (6.1–8.3)

0 2 4 6 8 10 12 14 16 18 20 22 24

0

10

20

30

40

50

60

70

80

90

100

Time, months

OS

(%

)

270 226 194 169 147 131 87 54 27 13 4 0 0

272 232 171 138 109 89 55 27 14 3 0 0 0

No. at risk

RR 21% vs 11%

Mersberger et al

2019 EUA

Algorithm for first line chemotherapy for metastatic UC

(until recently).

Gemcitabine/cisplatin Eligible for cisplatin based therapy

Ineligible for cisplatin based therapyImmune therapy or

Gemcitabine/carboplatin

Algorithm for first line chemotherapy for metastatic UC

from July 2018

• ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PFS, progression-free survival.

• 1. NCT02807636. Available at: http://www.clinicaltrials.gov (accessed November 2017); 2. NCT02516241. Available at: http://www.clinicaltrials.gov (accessed November 2017);3. NCT02853305. Available at: http://www.clinicaltrials.gov (accessed November 2017); 4. NCT03036098. Available at: http://www.clinicaltrials.gov (accessed November 2017).

MSDOncology

Cisplatin + gemcitabine OR

carboplatin + gemcitabine

AtezolizumabNCT02807636 (IMvigor130):1 N=1,200

• First-line cisplatin-ineligible, locally advanced/metastatic

• ECOG PS ≤2

Co-primary endpoints: PFS, OS and safety

Platinum-based chemotherapy + atezolizumabR

DurvalumabNCT02516241 (DANUBE):2 N=1,005

• First-line unresectable stage IV

• Eligible/ineligible for cisplatin-based chemotherapy

Durvalumab + tremelimumab

Co-primary endpoints: PFS and OS



R



Pembrolizumab + cisplatin/gemcitabine OR

Pembrolizumab + carboplatin/gemcitabineNCT02853305 (KEYNOTE-361):3 N=990

• First-line unresectable or metastatic

• ECOG PS ≤2

Pembrolizumab


R



Nivolumab + ipilimumabNCT03036098 (CheckMate-901):4 N=897

• First-line unresectable or metastatic

• ECOG PS ≤1

Nivolumab + cisplatin + gemcitabine


R

Key first-line Phase III trials of anti-PD-1/PD-L1 antibodies in urothelial cancer1–4

Multiple randomised trials of immune therapy with

chemotherapy in first-line metastatic UC

Immune therapy

Chemotherapy

Different front-line

randomised trials exploring

immune combinations in

metastatic UC

Chemotherapy + immune therapy

Chemotherapy = gemcitabine + cisplatin or carboplatin

Immune therapy = atezolizumab, pembrolizumab,

nivolumab

Pembrolizumab +

chemotherapy in metastatic

NSCLC

Ghandi et al NEJM 2018

R

How responsive should bladder cancer be to immune

therapy?

Xu et; al Science 2018

Randomized double-blind phase II study of

maintenance pembrolizumab versus placebo after

first-line chemotherapy in patients with metastatic

urothelial cancer: HCRN GU14-182Matthew D. Galsky, Sumanta K. Pal, Amir Mortazavi, Matthew I. Milowsky, Saby George, Sumati Gupta, Mark T. Fleming, Long H. Dang, Daniel M. Geynisman, Radhika Walling, Robert S. Alter, Erwin L. Robin, Jue Wang, Shilpa Gupta, David D. Chism, Joel Picus, George Philips, David I.

Quinn, Noah M. Hahn, Menggang YuIcahn School of Medicine at Mount Sinai; City of Hope National Medical Center, Duarte, CA; Ohio State University; University of North Carolina at Chapel Hill School of Medicine; Roswell Park Cancer Institute; Huntsman Cancer Institute-University of Utah Health Care;

Virginia Oncology Associates; University of Florida; Fox Chase Cancer Center; Community Cancer Center; John Theurer Cancer Center at Hackensack University Medical Center; University of Arizona Cancer Center at Dignity Health St. Joseph's Hospital and

Medical Center; Masonic Cancer Center, University of Minnesota; Vanderbilt University Medical Center; Washington University School of Medicine; Georgetown University Hospital; USC Norris Comprehensive Cancer Center; Johns Hopkins University School of

Medicine; University of Wisconsin; Hoosier Cancer Research Network

15Matthew D. Galsky, MD

Matthew D. Galsky, MD

Metastatic UC

At least stable

disease

≤ 8 cycles of

platinum-based

chemotherapy

RandomizedStratification

Lymph-node only

metastases (Y/N)

Response to 1st line

chemo (CR/PR vs SD)

Placebo q3 weeks x up to 24

months

Pembrolizumab 200 mg IV q3

weeks x up to 24 months

HCRN GU14-182

Progression


CharacteristicPlacebo

(n=52)

Pembrolizumab

(n=55)p

Age, median (range) 65 (44-87) 68 (41-83) 0.2

Male 81% 71% 0.3

Visceral metastases 62% 71% 0.3

1st line chemotherapy

median # cycles 6 5 0.3

complete/partial response 69% 73% 0.8

cisplatin-based 77% 65% 0.5

Baseline Characteristics


CharacteristicPlacebo

(n=52)

Pembrolizumab

(n=55)

Not evaluable (baseline CR) 10 9

Overall response 12% 22%

Partial response 12% 13%

Complete response 0 9%

Stable disease 29% 35%

Progressive disease 54% 33%

Unknown 5% 10%

Objective Response Rate (RECIST 1.1)


Adverse Events (select treatment-emergent in ≥5%)

AE TermPlacebo (n=52) Pembrolizumab (n=55)

Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4

Any adverse event 58% 35% 0% 38% 42% 11%

Fatigue 39% 0% 0% 31% 7% 0%

Anorexia 14% 0% 0% 16% 2% 0%

Dry mouth 0% 0% 0% 11% 0% 0%

ALT increased 2% 0% 0% 11% 4% 2%

AST increased 10% 0% 0% 15% 5% 0%

Diarrhea 19% 0% 0% 35% 0% 0%

Hypothyroidism 4% 0% 0% 9% 0% 0%

Pruritis 13% 0% 0% 22% 2% 0%

Rash 8% 0% 0% 22% 0% 0%

Dyspnea 14% 0% 0% 22% 5% 0%

Renal insufficiency 24% 0% 0% 29% 2% 0%

* One patient randomized to pembrolizumab developed fatal immune-related hepatitis


Progression-free Survival

Median PFS and 95% CI

Placebo: 3.2 (2.8, 5.5)

Pembrolizumab: 5.4 (3.6, 9.2)

Hazard Ratio: 0.64 (0.41,

0.98)

Log rank p = 0.038

CTLA-4 + PD-L1 in previously treated UC

R

Durvalumab and

tremelimumab

DANUBE: Randomised phase III trial

of durvalumab with or without

tremelimumab vs chemotherapy in 1st

line mUC

Durvalumab

Tremelimumab

Ipilimumab 3

Nivolumab 1

(3/1)

Ipilimumab 1

Nivolumab 3

(1/3)

Pembroliz.

monotherapy

KN-045

Population Platinum

refractory

Platinum

refractory

Platinum

refractory

Platinum

refractory

Number 168 92 104 266

Phase II I I III

ORR 21% 38% 26% 21%

ORR PD-

L1+ve29% 58% 33% 21%

PFS 1.9 4.3 2.6 2.1

Toxicity

(grade 3)28% 39% 31% 15%

Median OS9 .5 months

(8–19)

15.3 months

(10–27)

7.4 months

(5–11)

10.3 months

(8–12)

Gemcitabine/carboplatin

Gemcitabine/cisplatin

Durvalumab

Bellmunt J NEJM 2016

Balar A AACR 2015

Sharma P ASCO 2018

Siefker-Radtke et al ASCO GU 2019

Bladder cancer originates in the inner lining, then

spreads through outer layers of the bladder wall

American Cancer Society 2014: Bladder Cancer

Lamina

propria

Urothelium

UrethraSpread to

adjacent

organs

Perivesical

fat

Musculari

s propria

Ureters

Urothelial cell

carcinoma

For internal use only

Neoadjuvant atezolizumab in operable urothelial cancer%

pC

Rra

te

All comers* PD-L1 positive PD-L1

negative

20/68 10/25 5/31

29%(95% CI: 19% - 42%)

40%(95% CI: 21% - 61%)

16%(95% CI: 5% - 34%)

Granulomatous

reaction

Foam cell

macrophages

Powles et al ASCO 2018

PURE-01: DDR/RB1-GA, PD-L1 CPS and pathologic

response

Presented By Andrea Necchi at 2018 ASCO Annual Meeting

Muscle invasive studies.

Platinum eligible

Platinum ineligible

Neoadjuvant chemotherapy +/-Durvalumab

Neoadjuvant chemotherapy +/- pembrolizumab

Neoadjuvant pembrolizumab vs placebo

Neoadjuvant NKTR+nivolumab vs placebo

Adjuvant therapy Atezolizumab vs placebo

Nivolumab vs placebo

Pembrolizumab vs placebo

The Future for patients with operable UC

Cystectomy

Bladder sparing

approach

Diagnostic testing

Immune biomarker

DNA alterations

RNA taxonomy

Circulating biomarkers

diagnosis

Immune therapy

Immune/targeted

Immune/

chemotherapy/ADC

Targeted alone Targeted alone

Immune therapy

Immune/

chemotherapy/ADC

Immune/targeted

Neoadjuvant Adjuvant

Phase III

Phase II

Second generation biomarker analysis – Tumor mutational burden

CPS = combined positive score. Powles et al Lancet 2017

Key Eligibility Criteria

• Urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra

• Transitional cell predominant

• PD after 1–2 lines of platinum-based chemo or recurrence within 12 months of perioperative platinum-based therapy

• ECOG PS 0–1

• Provision of tumor sample for biomarker assessment

Atezolizumab

1200 mg IV Q3W

Chemotherapy

R(1:1)

N =234

RNA sequencing and and Foundation One mutational analysis.

N = 460

N = 460

Tumor Mutation Burden (TMB) does not correlate with

PD-L1 unlike T effector signatures

Presented by: Powles T, IMvigor211.31

TMB, tumor mutation burden. 1. Lawrence Nature 2013. 2. Kandoth Nature 2013. 3. TCGA Nature 2014. 4. Powles Lancet 2017.

Teffector vs. PD-L1 IC

R = 0.61

TMB vs. PD-L1 IC

R = 0.13

Raw PD-L1 Expression (IHC)

Mu

tatio

ns/M

b

tGE

3

OS by TMB in bladder cancer: A predictive biomarker

32

a Median scores were used to define assessment cutoffs: TMB-high (≥ median) or TMB-low (< median). Median TMB in the biomarker-evaluable population was 9.65 mutations/Mb.

Reprinted from The Lancet, Powles T, et al. 2017 Dec 18. [Epub], © 2017, with permission from Elsevier.

33

Based on TMB-evaluable population (n = 544). DDR, DNA Damage Response.

• DDR mutations (gene set) correlated with increased TMB (Wilcoxon rank sum test P = 0.0016)

• However, tumors with DDR mutations did not enrich for increased efficacy in the atezolizumab arm

• Multiple factors contribute to TMB– e.g., DDR, APOBECs, proliferation

FoundationO

ne

Panel of K

now

n/L

ikely

DD

R M

uta

tio

ns

Perc

ent

TMB

Pathway

mutation

burden:

DDR Mutations and Efficacy

FGF-3 inhibitor in selected patients with urothelial

cancer.

R

Erdafitinib

pembrolizumab

THOR: Randomised phase III erdafitinib vs chemotherapy

or pembrolizumab in biomarker +ve UC

Erdafitinib INCB054828

Population Platinum

refractory

Platinum

refractory

Number 99 100

Phase II II

biomarker Mutations and

fusions

Mixed (2 cohorts)

RR 40% (30% with

FDA)

25%

PFS

months

5.5 months

(4.2-6)

na

Toxicity

(grade 3)

Stomatitis

Nail tox.

Hypophosphatemia

Alopecia

Fatigue

Hypophoshatemia.

Median OS 9 .5 months

(8-19)

NA

chemotherapy

R

Erdafitinib

Prior IO therapy

No

yes

Siefker-Radtke et al ASCO 2018

Powles T ESMO 2018 (Review)

CALGB 90601 (Alliance): Randomized, double blind,

placebo-controlled phase III trial comparing

gemcitabine and cisplatin with bevacizumab or

placebo in patients with metastatic urothelial

carcinoma.

Jonathan E. Rosenberg, Karla V. Ballman, Susan Halabi, Colleen Watt, Olwen M.

Hahn, Preston D. Steen, Robert Dreicer, Thomas W. Flaig, Walter M. Stadler,

Christopher Sweeney, Amir Mortazavi, Michael J. Morris on behalf of Alliance and

NCTN Investigators

35

GCPGCB

Pe

rce

nt

Alive

0 10 20 30 40 50

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Stratified Logrank P-value: 0.17

14.3 (12.1-16.2)Reference254 (212)GCP

14.5 (13.5-16.2)0.87 (0.72-1.06)252 (207)GCB

Median (95% CI)HR (95% CI)Total (Events)Arm

252 173 84 56 39 24254 156 75 48 34 19

Patients-at-Risk

Bevacizumab did not improve overall survival

in combination with gemcitabine and

cisplatin

PFS was improved with bevacizumab

GCPGCB

Pe

rce

nt

Alive

an

d D

ise

as

e-F

ree

0 10 20 30 40 50

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50

Time (Months)

0

10

20

30

40

50

60

70

80

90

100

Stratified Logrank P-value: 0.013

6.6 (6.2-7.1)Reference254 (229)GCP

7.7 (6.9-8.3)0.79 (0.66-0.95)252 (229)GCB

Median (95% CI)HR (95% CI)Total (Events)Arm

252 82 37 20 16 12254 58 24 17 13 7

Patients-at-Risk

Antibody drug conjugates (ADC) in Urothelial Cancer.

R

Efortumab

Vedotin

Taxane

Randomised phase III of efortumab vedotin

in IO and chemotherapy refractory disease

Efortumab

Vedotin

Sacitumab

govitecan

ASG-ISME Chemo.

(>1st line)

mAb Target Nectin TROP-2 SLITRK6 microtubule

Payload MMAE SN-38 MMAE NA

Phase II I I III

Patients 112 44 42 442

RR (%) 41% 31% 33% 13

Toxicity

(grade 3-4)

Hyponatramia

(7%)

Neutropoenia

(38%)

Fatigue

(44%)

Neutropaeia

(13%)

Median OS 13.6 months

11-15.8

16.1 months

9-31

NA 8.0 months

7.6-8.4

Targeted

antibody Linker

molecule

cytotoxic

Rosenberg ASCO 2018

Petrylak Ann Onc 2016

Tagawa ASCOGU2018

Powles Lancet 2018

Summary

Immune checkpoint inhibitors have not yet

fulfilled their potential in the first line setting.

Biomarkers have complicated this.

Targeted therapy and ADCs are catching up

quickly.

Trials in the Ta-T4a setting are ongoing and

hold promise.

IMMUNE THERAPY IN BLADDER CANCER.€¦ · Atezolizumab NCT02807636 (IMvigor130):1 N=1,200 ......

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