Metastatic UC: Immunotherapy · IMvigor130—SIU 2019: presented by Dr Aristotelis Bamias...

ESMO PRECEPTORSHIP ON METASTATIC BLADDER AND KIDNEY CANCERLugano, 29-30 November 2019

Aristotle Bamias MD PhD

Professor of Therapeutics-Internal Medicine-Oncology

Director of the 2nd Propaedeutic Dept of Internal Medicine,

Medical School, National & Kapodistrian University of Athens

ATTIKON University Hospital

Athens, GREECE

Metastatic UC: Immunotherapy

DISCLOSURE OF INTEREST

Honoraria, Advisory, Steering Committee, Research Support:

ROCHE, AZ, BMS, MSD, NOVARTIS, PFIZER, JANSSEN

OUTLINE

Background

1st-line

Relapsed disease

Selection

Guidelines

◆ It is nearly 40 years since Bacillus Calmette–Guérin (BCG) was first used as an immunotherapy to treat superficial

bladder cancer.

◆ Bladder cancer was the first malignancy with an approved immunotherapy

◆ Cancer survivors had higher incidence of TB

◆ BCG was internalized by healthy and malignant urothelial cells

◆ Stimulates an inflammatory response

◆ Cytokines and chemokines released → triggers recruitment of immune cells into bladder wall

◆ Intravesical BCG2:

◆ First used in 1976 for NMIBC

◆ Current recommended treatment for NMIBC

Bladder Cancer & Immunotherapy

Morales A, et al. J Urol. 1976;116(2): 180–183.

The cancer immuno-editing concept

Schreiber RD, et al. Science. 2011;331(6024):1565-1570. Cancer Immuno-Editing

Stimulatory and Inhibitory MoleculesDuring Immune Tumor Surveillance

Chen DS, et al. Immunity. 2013;39:1-10.

Cancer antigen presentationTNF-α IL-10IL-1 IL-4 IFN- α IL-13CD40L/CD40CDNATPHMGB1TLR

Killing of cancer cellsIFN-γT cell granule contentPD-L1/PD-1 LAG-3PD-L1/B7.1 ArginaseIDO MICA/MICBTGF-β TIM-3/phospholipidsBTLAVISTA

Trafficking of T cells to tumorsCX3CL1 CXCL10 CXCL9 CCL5

Priming and activationCD28/B7.1CD137/CD137LOX40/OX40LCD27/CD70HVEMGITRIL-2IL-12CTLA-4/B7.1PD-L1/PD-1PD-L1/B7.1prostaglandins

Lymph node

Blood vessel

Tumor

InhibitorsStimulatory factors

3

4

Infiltration of T cells into tumorsLFA1/ICAM1SelectinsVEGFEndothelin B receptor

5

Recognition of cancer cells by T cellsT-cell receptorReduced pMHC on cancer cells

6

7Release of cancer cell antigensImmunogenic cell deathTolerogenic cell death

1

2

CTLA-4 and PD-1/L1 Checkpoint Blockade

Ribas A. N Engl J Med. 2012;366(26):2517-2519.

Priming phase (lymph node)

Effector phase (peripheral tissue)

T-cell migration

Dendritic cell T cell

MHC TCR

B7

CD28

CTLA-4

T cell Cancercell

MHCTCR

PD-1

PD-L1

T cellCancer

cellDendritic cell T cell

B7

In healthy tissue, CTLA-4 is functioning as a dominant”off-switch”

PD-1 pathway functions in the effector phase, to prevent “collateral damage.” Cancercells have exploited this to shut off T cells

Immune checkpoint inhibitors

PD-1 Inhibitors:

• Pembrolizumab (humanized IgG4)

• Nivolumab (human IgG4)

PD-L1 Inhibitors:

• Atezolizumab (human IgG1)

• Durvalumab (human IgG1)

• Avelumab (human IgG1)

CTLA-4 Inhibitors

• Ipilimumab (human IgG1)

OUTLINE

Background

1st-line

Relapsed disease

Selection

Guidelines

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 11O

S (%

)

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.

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

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

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

http://www.clinicaloptions.com/

DANUBE

CheckMate901

R

A

N

D

O

M

I

Z

E

n=897

Participants with untreated metastatic or unresectable

urothelial cancer

Stratify by

(i) PD-L1<1%,

(ii) cisplatin-

ineligibility

(iii) liver metastasis

Part 1Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg

Q3W X 4 cycles

Gemcitabine-cisplatin OR Gemcitabine-carboplatin

x 6 cycles

Part 1Nivolumab 1 mg/kg +

Chemotherapy Q3W X 6 cycles

Part 2Nivolumab 480 mg

Q4W

Part 2Nivolumab 480 mg

Q4W

Follow-up

Visit 1

and

Visit 2

&

Survival

Follow-up

Aristotelis Bamias,1 Enrique Grande,2 José Ángel Arranz Arija,3 Maria De Santis,4Ian D. Davis,5 Ugo De Giorgi,6 Marina Mencinger,7 Eiji Kikuchi,8 Xavier García-del-Muro,9 Mahmut Gumus,10 Mustafa Özgüroğlu,11 Arash Rezazadeh Kalebasty,12 Se Hoon Park,13 Boris Alekseev,14 Fabio Augusto Schutz,15 Jian-Ri Li,16 Almut Mecke,17

Sanjeev Mariathasan,18 AnnChristine Thåström,18 Matthew D. Galsky19

1National & Kapodistrian University of Athens, Athens, Greece; 2MD Anderson Cancer Center Madrid, Madrid, Spain; 3Hospital General Universitario Gregorio Marañón, Madrid, Spain; 4Charité University Hospital, Berlin, Germany, and Department of Urology, Medical University, Vienna, Austria; 5Eastern Health/Monash University, Melbourne, Australia; 6Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy; 7Institute of Oncology Ljubljana, Ljubljana, Slovenia; 8Keio University, Tokyo, Japan; 9Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain; 10Istanbul Medeniyet University, Goztepe Research Hospital, Istanbul, Turkey; 11Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey; 12Norton Cancer Institute, Louisville, KY, USA; 13Sungkyunkwan University Samsung Medical Center, Seoul, Korea; 14P. Herzen Oncology Research Institute, Moscow, Russia; 15Beneficência Portuguesa de São Paulo, São Paulo, Brazil; 16Taichung Veterans General Hospital/HungKuang University, Taichung, Taiwan; 17F. Hoffmann-La Roche Ltd, Basel, Switzerland; 18Genentech, Inc., South San Francisco, CA, USA; 19Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY, USA

IMvigor130: Efficacy and Safety of Atezolizumab With or Without Chemotherapy in Previously Untreated Metastatic Urothelial Carcinoma

IMvigor130—SIU 2019: presented by Dr Aristotelis Bamias

Metastatic urothelial carcinoma (mUC) and IMvigor130

• PD-L1 and PD-1 inhibitors are the first new systemic therapies for mUC, both for 1L treatment of cisplatin-ineligible patients and for patients experiencing disease progression despite platinum-based chemotherapy (plt/gem)1-8

• In July 2018, the FDA and EMA revised the 1L label for atezolizumab (anti─PD-L1) and pembrolizumab (anti─PD-1) based on IDMC assessments9-12

• Here we report final PFS and interim OS results for IMvigor130, assessing atezolizumab alone or in combination with plt/gem vs placebo + plt/gem in 1L mUC

plt/gem, cisplatin or carboplatin plus gemcitabine.Grande et al. LBA14 ESMO 2019. 1. Gartrell Urol Oncol 2017; 2. Balar Lancet 2017; 3. Balar Lancet Oncol 2017; 4. Powles Lancet2018; 5. Rosenberg Lancet 2016; 6. Massard J Clin Oncol 2016; 7. Sharma Lancet Oncol 2017; 8. Apolo J Clin Oncol 2017; 9. TECENTRIQ USPI 2019; 10. TECENTRIQ SmPC 2019; 11. KEYTRUDA USPI 2019; 12. KEYTRUDA SmPC 2019.

Placebo + plt/gem (Arm C)

Atezo + plt/gem (Arm A)

Atezo monotherapy (Arm B)

• Locally advanced or mUC• No prior systemic therapy

in the metastatic setting• ECOG PS ≤ 2• 1L platinum-eligible• N = 1200• Randomised 1:1:1

Co-primary endpoints:

• PFS (Arm A vs C; Investigator-assessed per RECIST 1.1)

• OS (Arm A vs C, Arm B vs C)


IMvigor130 statistical testing hierarchy

ITT, intent to treat.a Timing of this final PFS and interim OS analysis was planned after ≈ 667 PFS events were observed in ITT (Arms A + C). Final OS analysis will be triggered by number of OS events observed in ITT (Arms A + C). The efficacy boundaries at interim and final OS analyses were determined based on the O'Brien Fleming alpha spending function.

Arm CPlacebo + plt/gem

Arm AAtezo + plt/gem

Arm BAtezo monotherapy

One-sided α = 0.025

FINAL PFS(1) PFS A vs C ITT

α = 0.01

α = 0.01

OS(2) OS A vs C ITTa

If (1) is negative: α = 0.015If (1) is positive: α = 0.025

If (2) is positive:

α = 0.015

α recycling if (1) is positive

(3) Further testing on OSOS B vs C (ITT, IC2/3)


IMvigor130 baseline characteristics

Grande et al. LBA14 ESMO 2019. a n = 359 for comparisons to atezo monotherapy arm. b Per Galsky criteria per protocol, excluding New York Heart Association functional classification. c Of the patients considered cisplatin eligible at study entry, 52% received carboplatin, while 10% of patients who were cisplatin ineligible received cisplatin.

CharacteristicAtezo + plt/gem

(n = 451)Placebo + plt/gem

(n = 400)aAtezo

(n = 362)Median age (range), y 69 (31-87) 67 (33-89) 67 (36-87)ECOG PS, n (%)

0 182 (40) 173 (43) 157 (43)1 209 (46) 187 (47) 174 (48)2 60 (13) 40 (10) 31 (9)

Bajorin risk factor score, n (%)0 176 (39) 162 (41) 151 (42)1 169 (37) 149 (37) 134 (37)2 and/or liver mets 106 (24) 89 (22) 77 (21)

PD-L1 status on IC, n (%)IC2/3 108 (24) 91 (23) 88 (24)IC1 195 (43) 179 (45) 160 (44)IC0 148 (33) 130 (33) 114 (31)

Cisplatin ineligibilityb 204 (45) 140 (35) 107 (30)Renal impairment 113 (25) 94 (24) 65 (18)

Investigator choice of chemotherapyc

Carboplatin 314 (70) 264 (66) 227 (63)Cisplatin 137 (30) 136 (34) 135 (37)


Final PFS: ITT (Arm A vs Arm C)

Grande et al. LBA14 ESMO 2019. NE, not estimable. Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients).

100908070605040302010

0

PFS

(%)

0 3 6 9 12 15 18 21 24 27 30 33

Months

6.3 mo(6.2, 7.0)

8.2 mo(6.5, 8.3)


(n = 451)


(n = 400)PFS events, n (%) 334 (74) 326 (82)Stratified HR (95% CI)

0.82 (0.70, 0.96)P = 0.007 (one-sided)

No. at RiskAtezo + plt/gem 451 345 282 160 111 74 42 22 10 4 2 NE

Placebo + plt/gem 400 317 246 116 73 40 18 11 4 NE NE NE


Interim OS: ITT (Arm A vs Arm C)

Grande et al. LBA14 ESMO 2019. Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients). a 5% of patients from Arm A and 20% of patients from Arm C received non-protocol immunotherapy. b Did not cross the interim efficacy boundary of 0.007 per the O’Brien-Fleming alpha spending function.

100908070605040302010

0

OS

(%)

0 3 6 9 12 15 18 21 24 27 30 33

Months

13.4 mo(12.0, 15.2)

16.0 mo(13.9, 18.9)

Atezo + plt/gem 451 408 360 301 229 163 117 72 36 16 3 NEPlacebo + plt/gem 400 359 308 255 182 123 79 49 25 8 NE NE


(n = 451)


(n = 400)OS eventsa, n (%) 235 (52) 228 (57)Stratified HR (95% CI)

0.83 (0.69, 1.00)P = 0.027 (one-sided)b

No. at Risk


Confirmed ORR and DOR

Grande et al. LBA14 ESMO 2019. Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients). a Objective response–evaluable patients: n = 447 in atezo + plt/gem, n = 397 in placebo + plt/gem, n = 359 in atezo.b n = 212 in atezo + plt/gem, n = 174 in placebo + plt/gem, n = 82 in atezo.

0

10

20

30

40

50

60

OR

Ra

(%)

47%

23%

44%

35%

17%

37%

13% 7% 6%CR:PR:

Atezo + plt/gem

Placebo + plt/gem Atezo

DORb, median(95% CI), mo

8.5(7.2,10.4)

7.6(6.3, 8.5)

NE(15.9, NE)


Interim OS for Monotherapy: ITT (Arm B vs Arm C)

Grande et al. LBA14 ESMO 2019. Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients). a Comparison only includes patients concurrently enroled with Arm B.

13.1 mo(11.7, 15.1)

No. at Risk

100908070605040302010

0

OS

(%)

0 3 6 9 12 15 18 21 24 27 30 33

Months

15.7 mo(13.1, 17.8)

Atezo 360 285 245 216 173 120 72 42 16 NE NE NEPlacebo + plt/gem 359 322 274 224 158 103 62 35 15 3 NE NE

Arm BAtezo

(n = 360)


(n = 359)a

OS events, n (%) 191 (53) 198 (55)Stratified HR (95% CI) 1.02 (0.83, 1.24)


Safety summary

Grande et al. LBA14 ESMO 2019. AE, adverse event. Safety-evaluable population. Data cutoff, 31 May 2019; median survival follow-up 11.8 months (all patients). a This patient was randomised to atezo + plt/gem and received atezo; they had an AE of pyrexia that day, and gemcitabine and carboplatin were marked as ‘drug withdrawn’. Since no chemotherapy was given, this patient was included in the atezo monotherapy arm for safety analysis.

AE, n (%) Atezo + plt/gem(n = 453)

Placebo + plt/gem(n = 390)

Atezo(n = 354)

Any grade, all cause 451 (100) 386 (99) 329 (93)Grade 3-4 383 (85) 334 (86) 148 (42)Grade 5 29 (6) 20 (5) 28 (8)

Any grade, treatment related 434 (96) 373 (96) 211 (60)Grade 3-4 367 (81) 315 (81) 54 (15)Grade 5 9 (2) 4 (1) 3 (1)

Any grade, serious 234 (52) 191 (49) 152 (43)Treatment-related serious AEs 144 (32) 101 (26) 44 (12)

Any grade leading to any treatment discontinuation 156 (34) 132 (34) 22 (6)Atezo or placebo discontinuation 50 (11) 27 (7) 21 (6)Cisplatin discontinuation 53 (12) 52 (13) 0Carboplatin discontinuation 90 (20) 79 (20) 1 (< 1)a

Gemcitabine discontinuation 117 (26) 100 (26) 1 (< 1)a

Any grade leading to any dose reduction or interruption 363 (80) 304 (78) 112 (32)

OUTLINE

Background

1st-line

Relapsed disease

Selection

Guidelines

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)


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

Phase III IMvigor211 Trial Design

◆ Key exploratory endpoint: relationship between tumor immune specific– or disease-related

biomarkers and efficacy

◆ Objectives of this analysis: compare clinical outcomes in ITT and PD-L1 subgroups vs those defined

by immune transcriptional gene expression (tGE) signatures and tumor mutational burden (TMB)

ClinicalTrials.gov ID, NCT02302807. IC, tumor-infiltrating immune cell. a Stratification factors: 0 vs 1/2/3 risk factors (time from prior chemotherapy < 3 mo, ECOG PS > 0 and hemoglobin < 10 g/dL), yes vs no liver metastases, PD-L1 IC0/1 vs IC2/3 status, vinflunine vs taxane selection. b PD-L1

expression on IC assessed per VENTANA SP142 IHC assay: scored as IC3 (≥ 10%), IC2 (≥ 5% and < 10%).

Key Eligibility Criteria‒ mUC with progression during

or following platinum-based chemotherapy ▪ 2 prior lines of therapy

‒ ECOG PS 0-1‒ Sample for PD-L1 testing

(N = 931)

Atezolizumab 1200 mg q3w

Survival follow-up

Loss of clinical benefit

RECIST v1.1 progression

Investigator’s choice: vinflunine, docetaxel

or paclitaxel, q3w

R

1:1a

Primary endpoint: OS,hierarchically compared between

arms in PD-L1–selectedb and ITT pts

OS: IC2/3

OS: IC1/2/3

OS: ITT

Key secondary endpoints:

ORR, DOR, PFS

OS Analysis in PD-L1 IC2/3 Population

◆ Based on OS results

in the PD-L1 IC2/3

population, the primary

endpoint was not met

Powles Lancet, 2017. Median follow-up duration: 17.3 mo (range 0-24.5 mo).

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

Ove

rall

Surv

ival

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)

Immunotherapy for Postplatinum UC

ORR

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

35

30

25

20

15

10

5

0

Historical chemotherapyORR: ~ 10%

N = 462 N = 249 N = 191 N = 265 N = 270

Avelumab[2]Atezolizumab[1] Durvalumab[3] Nivolumab[4] Pembrolizumab[5]

OR

R (

%)

13.0

17 17.8 19.621.1

Post-Platinum UC

OS at 12 Mos


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


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.


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


OUTLINE

Background

1st-line

Relapsed disease

Selection

Guidelines

PD-L1 Is Expressed in a Range of Tumor Types

1. Sun WY, et al. J Transl Med. 2016;14:173. 2. Massard C, et al. J Clin Oncol. 2016;34(suppl): Abstract 4502. 3. Rebelatto MC, et al. J Clin Oncol. 2016;34(suppl): Abstract 8033. 4. Topalian SL, et al. Nat Rev Cancer. 2016; 16:275-287. 5.Darb-Esfahani S, et al. Oncotarget. 2015;7:1486-1499.

Melanoma4

Ovarian5

Lung Cancer3

SCCHN3

Bladder2Breast1

Examples of Tumor Types with Strong PD-L1 Staining (≥10% of cells):

Reprinted from J Transl Med. 14:173. Sun WY, Lee KY, Koo JS, Expression of PD-L1 in triple-negative breast cancer based on different immunohistochemical antibodies, © Sun WY, Lee KY, Koo JS 2016.

Adapted by permission from Macmillan Publishers Ltd: Nature Rev Cancer Topalian SL, et al. Nat Rev Cancer. 2016; 16:275-287, copyright 2016.

Adapted from Oncotarget 7(2) Darb-Esfahani S, et al. Prognostic impact of programmed cell death-1 (PD-1) PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma, Pages 1486-1499, Copyright @ 2016 Impact Journals, LLC.

Interim OS: PD-L1 status (Arm B vs Arm C)

Arm B

Atezo

(n = 272)

Arm C

Placebo + plt/gem

(n = 274)

OS events, n (%) 158 (58) 156 (57)

Unstratified HR (95% CI) 1.07 (0.86, 1.33)

PD-L1 IC0/1

OS

(%)

Months MonthsAtezo

Placebo + plt/gem

No. at Risk272 210 175 152 124 85 48 28 11 NE NE NE274 246 212 173 116 73 41 21 10 2 NE NE

Arm B

Atezo

(n = 88)

Arm C

Placebo + plt/gem

(n = 85)

OS events, n (%) 33 (38) 42 (49)

Stratified HR (95% CI) 0.68 (0.43, 1.08)

PD-L1 IC2/3

88 75 70 64 49 35 24 14 5 NE NE NE85 76 62 51 42 30 21 14 5 1 NE NE

Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients).

12.9 mo(11.3, 15.0)

13.5 mo(11.1, 16.4)

0 3 6 9 12 15 18 21 24 27 30 33

17.8 mo(10.0, NE)

NE(17.7, NE)

100908070605040302010

00 3 6 9 12 15 18 21 24 27 30 33

First-line Therapy for Metastatic UC

◆ 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

Interim OS: PD-L1 status (Arm B vs Arm C)

Arm B

Atezo

(n = 272)

Arm C

Placebo + plt/gem

(n = 274)

OS events, n (%) 158 (58) 156 (57)

Unstratified HR (95% CI) 1.07 (0.86, 1.33)

PD-L1 IC0/1

OS

(%)

Months MonthsAtezo

Placebo + plt/gem

No. at Risk272 210 175 152 124 85 48 28 11 NE NE NE274 246 212 173 116 73 41 21 10 2 NE NE

Arm B

Atezo

(n = 88)

Arm C

Placebo + plt/gem

(n = 85)

OS events, n (%) 33 (38) 42 (49)

Stratified HR (95% CI) 0.68 (0.43, 1.08)

PD-L1 IC2/3

88 75 70 64 49 35 24 14 5 NE NE NE85 76 62 51 42 30 21 14 5 1 NE NE

Data cutoff 31 May 2019; median survival follow-up 11.8 months (all patients).

12.9 mo(11.3, 15.0)

13.5 mo(11.1, 16.4)

0 3 6 9 12 15 18 21 24 27 30 33

17.8 mo(10.0, NE)

NE(17.7, NE)

100908070605040302010

00 3 6 9 12 15 18 21 24 27 30 33

The Cancer Genome Atlas Research Network Nature 507, 315-322 (2014) doi:10.1038/nature12965

Expression characteristics of bladder cancer.

Gene Signatures in the Tumor MicroenvironmentIMvigor210: TCGA Subtype in metastatic urothelial cancer

TIL, tumor-infiltrating lymphocyte. aHigh myeloid, inflammatory, activated stromal/fibroblast markers

Rosenberg JE, et al. Lancet. 2016;387(10031):1909-1920.

• IMvigor 210 subtypes have distict tumor-immune landscapes that reflect responsiveness to atezolizumab

OUTLINE

Background

1st-line

Relapsed disease

Selection

Guidelines

First-line cisplatin-ineligible, PD-L1 positive Platinum-refractory

Pembrolizumab [III, B] [I, A]

Atezolizumab [III, B] [II, B]

Nivolumab [III, B]

Avelumab [III, C]*

Durvalumab [III, C]*

ESMO GUIDELINES 2019

J. Bellmunt et al. Ann Oncol 2014;25:iii40-iii48© The Author 2014. Published by Oxford University Press on behalf of the European Society for

Medical Oncology. All rights reserved. For permissions, please email: [email protected].

CONCLUSIONS

• Immune checkpoint inhibitors represent the new standard for platinum-

pretreated mUC

• The role of these agents in 1st-line setting remains undetermined

• The utility of PD-L1 expression for patients selection also remains undetermined

Metastatic UC: Immunotherapy · IMvigor130—SIU 2019: presented by Dr Aristotelis Bamias...

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