CONGRESS HIGHLIGHTS: RENAL

AND BLADDER CANCER

Petri Bono
Medical Director, Helsinki University Hospital
and
Associate professor,University of Helsinki
esmo.org
 Disclosures
• Honoraria
- Pfizer, Novartis, BMS, MSD, Orion Pharma, Ipsen

• Stock ownership
- TILT Biotherapeutics

• Institutional financial interests

– Trial funding:Novartis, BMS, MSD, Orion Pharma, Ipsen

2
 Ten new agents available
for the treatment of mRCC
10 agents have been approved over the last 10 years: Median survival 28-
30 mos
Temsirolimus5 Lenvatinib

High-dose IL-22 Bevacizumab* + IFN-α6

Pazopanib8 Cabozantinib

Sunitinib4
IFN-α
Axitinib9 Nivolumab
Everolimus7
Sorafenib3

1992–2005 2006 2007 2008 2009 2010 2011 2012 2013-5 2016

*Dates indicate European Medicines Agency approval.

First-line Second-line

1. Ljungberg B et al. EAU Guidelines on RCC 2013 7. Motzer RJ et al. Cancer 2010;116:4256–4265
2. Fyfe G et al. J Clin Oncol 1995;13:688–696 8. Sternberg CN et al. J Clin Oncol
3. Escudier B et al. N Engl J Med 2007;356:125–134 9. Rini BI et al. Lancet 2011;378:1931–1939. IFN, interferon; IL, interleukin;
4. Motzer RJ et al. N Engl J Med 2007;356:115–124 mRCC, metastatic renal cell carcinoma.
5. Hudes G et al. N Engl J Med 2007;356:2271–2281
6. Escudier B et al. Lancet 2007;370:2103–2111
What have we learned?
◆ Targeteed agents improve ORR, PFS and very likely OS
◆ Checkpoint inhibitors (ICI) work well in mRCC including 2nd-3rd line
as well as 1st line
◆ ICI comination ipi + nivo work even better, OS benefit in the 1st line
◆ New strandard of care in intermediate and high-risk mRCC
◆ VEGFR TKI + ICI appear to have very high response rate and
VEGFR TKI may have also immunomodulatory effects
– ↑ immune cell tumor infiltration, ↓ immune suppressor cells
METASTATIC KIDNEY
CANCER

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 And phase 3 are expected shortly

Presented By Bernard Escudier at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
 JAVELIN RENAL 101: STUDY DESIGN

Key eligibility criteria: Avelumab 10 mg/kg IV Q2W

+
• Treatment-naive aRCC with
a clear cell component Axitinib 5 mg PO BID
Stratification:
N = 886 (6-week cycle)
• ≥ 1 measurable lesion as • ECOG PS (0 vs 1) R
defined by RECIST v1.1 • Geographic region 1:1
(USA vs Canada/Western
• Tumor tissue available for Europe vs ROW)
PD-L1 staining Sunitinib 50 mg PO QD
(4 weeks on, 2 weeks off)
• ECOG PS 0 or 1

BID, twice per day; ECOG PS, Eastern Cooperative Oncology Group performance status; IV, intravenous; PO, orally; Q2W, every 2 weeks; QD, once per day; ROW, rest of the world.
 Primary
endpoint
PRIMARY ENDPOINT #1 MET: PFS PER IRC IN THE PD-L1+ GROUP
100
Median PFS (95% CI), months
90 Avelumab + Axitinib 13.8 (11.1, NE)
Progression-free survival, % Sunitinib 7.2 (5.7, 9.7)
80
Stratified HR, 0.61 (95% CI: 0.475, 0.790)
70 P < .0001

60

50

40

30

20

10

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Months
Number at risk
Avel + Axit: 270 227 205 154 120 76 53 32 23 13 3 1 0
Sunitinib: 290 210 174 119 85 49 35 16 13 5 0
Minimum follow-up, 6 months. Median follow-up, 9.9 months (avelumab + axitinib) and 8.4 months (sunitinib).
The PFS analysis crossed the prespecified efficacy boundary based on the alpha-spending function (P = .001). NE, not estimable.
 Secondary
CONFIRMED OBJECTIVE RESPONSE endpoint

PD-L1+ group (N = 560) Overall population (N = 886)

Per IRC Avelumab + Axitinib Sunitinib Avelumab + Axitinib Sunitinib
(N = 270) (N = 290) (N = 442) (N = 444)
Objective response rate (95% CI), % 55 (49.0, 61.2) 26 (20.6, 30.9) 51 (46.6, 56.1) 26 (21.7, 30.0)
Best overall response, %*
Complete response 4 2 3 2
Partial response 51 23 48 24
Stable disease 27 43 30 46
Progressive disease 11 22 12 19
Not evaluable† 4 7 6 8
Patients with ongoing response, %‡ 73 65 70 71

Per investigator assessment

Objective response rate (95% CI), % 62 (55.8, 67.7) 30 (24.5, 35.3) 56 (51.1, 60.6) 30 (25.9, 34.7)
Best overall response, %
Complete response 4 3 3 2
Partial response 58 27 53 28
Median duration of response was not yet reached in either treatment arm in either population.
* Patients without target lesions at baseline per IRC who achieved non-complete response/non-progressive disease: 3% (avelumab + axitinib) and 2% (sunitinib) in the PD-L1+ group;
2% (avelumab + axitinib) and 2% (sunitinib) in the overall population. † Including patients with no postbaseline assessments. ‡ In patients with confirmed complete or partial response.
OS in the overall population
Median OS (95% CI), months
100 Avelumab + Axitinib Not reached
Sunitinib Not reached
90
Stratified HR, 0.78 (95% CI: 0.554, 1.084)
80 P = .0679
Overall survival, %

70

60

50

40
OS data are immature
30 • 14% of patients with event in the avelumab + axitinib arm
20 • 17% of patients with event in the sunitinib arm
10

0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time since treatment initiation, months
Number at risk
Avel + Axit: 442 426 412 396 319 252 187 121 93 70 27 8 1 0
Sunitinib: 444 426 401 373 295 224 175 113 84 59 17 5 1 0
Median follow-up, 12.0 months (avelumab + axitinib) and 11.5 months (sunitinib).
 Subgroup
PFS PER IRC IN KEY SUBGROUPS analysis

Subgroup Events/patient HR
Avelumab + Axitinib Sunitinib
Overall population 180/442 216/444 0.69

PD-L1 Positive 108/270 145/290 0.63

group* Negative 54/132 58/120 0.80

Prior Yes 143/352 172/355 0.67

nephrectomy No 37/90 44/89 0.75

Favorable 25/94 36/96 0.54

IMDC risk Intermediate 112/271 129/276 0.74
Poor 41/72 50/71 0.57

Favorable 29/96 36/100 0.65

MSKCC risk Intermediate 118/283 142/293 0.72
Poor 29/51 34/45 0.50

0 .2 1 .0 1 .4

Favors Avelumab + Axitinib Favors Sunitinib

* Among patients not evaluable for PD-L1 expression, PFS events occurred in 18/40 patients (avelumab + axitinib) vs 13/34 patients (sunitinib); HR, 0.83; 95% CI: 0.403, 1.699.
Treatment Related Adverse Events in Front Line metastatic ccRCC

Javelin: Gr 3-
5 51% and
gr 1-2 44%

Presented By Elizabeth Plimack at 2018 ASCO Annual Meeting

Response Rates in Front Line metastatic ccRCC <br />(all risk groups)

Javelin: 51%
(PD L1+ 55%)

Presented By Elizabeth Plimack at 2018 ASCO Annual Meeting

 15

VEGFR TKI + IO? VEGFR TKI + IO?

VEGFR TKI + IO?

Courtesy of B- Escudier and L Albiges. New 2018 ESMO RCC guideline will be published soon
Molecular correlates differentiate response to
atezolizumab + bevacizumab vs sunitinib:
results from a Phase III study (IMmotion151) in
untreated metastatic renal cell carcinoma
Brian I. Rini,1 Mahrukh Huseni,2 Michael B. Atkins,3 David F. McDermott,4 Thomas Powles,5
Bernard Escudier,6 Romain Banchereau,2 Li-Fen Liu,2 Ning Leng,2 Jinzhen Fan,2 Jennifer Doss,2
Stefani Nalle,2 Susheela Carroll,2 Shi Li,2 Christina Schiff,2 Marjorie Green,2 Robert J. Motzer7

1ClevelandClinic Taussig Cancer Institute, Cleveland, OH, USA; 2Genentech, Inc., South San Francisco, CA, USA;
3Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA; 4Beth Israel Deaconess Medical Center,
Boston, MA, USA; 5Barts Cancer Institute and the Royal Free Hospital, Queen Mary University of London, London, UK;
6Gustave Roussy, Villejuif, France; 7Memorial Sloan Kettering Cancer Center, New York, NY, USA

esmo.org
IMmotion151: Study Design 17

Key eligibility Atezolizumab 1200 mg IV q3wb

• Treatment-naive advanced +
Stratification
or metastatic RCC Bevacizumab 15 mg/kg IV q3wb
• MSKCC risk score N = 915
• Clear cell and/or R
• Liver metastases 1:1
sarcomatoid histology
• PD-L1 IC IHC status
• KPS ≥ 70
(< 1% vs ≥ 1%)a Sunitinib 50 mg PO qd
• Tumour tissue available for (4 weeks on, 2 weeks off)
PD-L1 staining

Co-primary endpoints Exploratory endpoints include:

• PFSc in PD-L1+ • Validation of gene signatures from IMmotion150 and their
• OS in ITT association with PFS
• Biomarker characterisation in MSKCC risk subgroups and
sarcomatoid tumours
IC, tumour-infiltrating immune cell; IHC, immunohistochemistry; ITT, intent-to-treat; IV, intravenous; KPS, Karnofsky performance status;
MSKCC, Memorial Sloan Kettering Cancer Center; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival;
PO, by mouth; q3w, every 3 weeks; QD, once a day; R, randomised; RCC, renal cell carcinoma; TME, tumour microenvironment. Rini B, et al. IMmotion151 Biomarkers.
a ≥ 1% IC: 40% prevalence using SP142 IHC assay. b No dose reduction for atezolizumab or bevacizumab. c Investigator assessed PFS per RECIST v1.1. ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
 IMmotion150: Molecular Correlates of Differential 18

Response to Atezolizumab ± Bevacizumab vs Sunitinib

◆ Relative expression of Angiogenesis and T-

effector gene signatures identified differential
PFS benefits for atezolizumab ±
bevacizumab
vs sunitinib

– Sunitinib showed improved PFS in

AngiogenesisHigh vs AngiogenesisLow
subsets

– Atezolizumab + bevacizumab improved

PFS vs sunitinib in T-effectorHigh
and AngiogenesisLow tumours

– Atezolizumab + bevacizumab improved

PFS vs atezolizumab in T-effectorHigh
MyeloidHigh tumours

Rini B, et al. IMmotion151 Biomarkers.

McDermott DM, et al. Nat Med. 2018. ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
IMmotion151: Gene Signature Analysis Scheme 19

IMmotion150 (n = 263)
Identification of gene signatures based on association with clinical outcome
• Teff: CD8a, IFNG, PRF1, EOMES, CD274
• Angio: VEGFA, KDR, ESM1, PECAM1, CD34, ANGPTL4

Absolute cutoff selection based on PFS HR

• Teff cutoffs: 2.93 (40% prevalence)
• Angio cutoff: 5.82 (50% prevalence)

IMmotion151 (n = 823)
Pre-specified analysis of association with PFS
• Unstratified HR and log-rank tests were used for PFS analyses
in biomarker-evaluable patients
Rini B, et al. IMmotion151 Biomarkers.
ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
Atezolizumab + Bevacizumab Improved PFS vs 21

Sunitinib in the AngiogenesisLow Subset

Angiogenesis
AngiogenesisLow AngiogenesisHigh
1 Sunitinib (n = 151) 1 Sunitinib (n = 265)
Atezo + bev (n = 177) Atezo + bev (n = 230)
0.9 0.9
0.8 0.8
0.7 0.7
0.6 0.6
PFS

PFS
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
5.95 8.94 10.12 12.45
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
Months Months
HR (95% CI)
AngiogenesisLow AngiogenesisHigh
Atezo + bev vs
0.68 (0.52, 0.88) 0.95 (0.76, 1.19)
sunitinib

Rini B, et al. IMmotion151 Biomarkers.

ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
Sunitinib Demonstrated Improved PFS in 22

AngiogenesisHigh vs AngiogenesisLow Subsets

Angiogenesis
Sunitinib Atezolizumab + Bevacizumab
1 AngiogenesisLow (n = 151) 1 AngiogenesisLow (n = 177)
AngiogenesisHigh (n = 265) AngiogenesisHigh (n = 230)
0.9 0.9
0.8 0.8
0.7 0.7
0.6 0.6
PFS

PFS
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
5.95 10.12 8.94 12.45
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
Months Months
HR (95% CI)
Sunitinib Atezo + Bev
Angiogenesis
0.59 (0.47, 0.75) 0.86 (0.67, 1.1)
(High vs Low)

Rini B, et al. IMmotion151 Biomarkers.

ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
Atezolizumab + Bevacizumab Demonstrated 23

Improved PFS vs Sunitinib in TeffHigh Subset

Immune
T-effectorLow T-effectorHigh
1 Sunitinib (n = 234) 1 Sunitinib (n = 182)
Atezo + bev (n = 243) Atezo + bev (n = 164)
0.9 0.9
0.8 0.8
0.7 0.7
0.6 0.6
PFS

PFS
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
8.41 9.72 8.34 12.45
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
Months Months
HR (95% CI)
T-effectorLow T-effectorHigh
Atezo + bev vs
0.91 (0.73, 1.14) 0.76 (0.59, 0.99)
sunitinib

◆ T-effector gene signature did not differentiate PFS within the sunitinib or atezolizumab + bevacizumab
treatment arms Rini B, et al. IMmotion151 Biomarkers.
ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
Subgroup PFS Analyses in PD-L1+ and 24

All Evaluable Patientsa

Baseline Factor n HR

MSKCC Favourable 61 0.70

MSKCC Intermediate/Poor 291 0.74

PD-L1+
Sarcomatoid 84 0.48
Non-Sarcomatoid 267 0.86

MSKCC Favourable 156 0.94

All evaluable MSKCC Intermediate/Poor 667 0.82

patients Sarcomatoid 134 0.57
Non-Sarcomatoid 688 0.92

0.2 1.0 2
Hazard Ratio
Favours Atezo + bev Favours Sunitinib
Rini B, et al. IMmotion151 Biomarkers.
a Biomarker-evaluable population. ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
 Angiogenesis Gene Expression Is Higher in Favourable 25

MSKCC Risk Group

Angiogenesis Gene Signature T-effector Gene Signature PD-L1 Expression

P = 8.26e-05 P = 0.1 P = 0.35
100% 100% 100%

26% AngioLow TeffLow Negative

AngioHigh TeffHigh Positive
75% 43% 75% 75%
57% 61% 57%
Patients (%)

Patients (%)

Patients (%)
64%

50% 50% 50%

74%

57%
25% 25% 43% 25%
36% 39% 43%

0% 0% 0%
Favourable Intermediate/Poor Favourable Intermediate/Poor Favourable Intermediate/Poor
n = 156 n = 667 n = 156 n = 667 n = 156 n = 667

Rini B, et al. IMmotion151 Biomarkers.

ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
Summary 26

◆ Pre-specified analyses in IMmotion151 validated Angiogenesis and T-effector

gene signatures identified in IMmotion150

◆ MSKCC favourable-risk patients are characterised by a predominant AngiogenesisHigh

gene signature

◆ Sarcomatoid RCC is characterised by an AngiogenesisLow gene signature,

a T-effectorHigh gene signature / higher PD-L1 expression and enhanced clinical benefit
with atezolizumab + bevacizumab

◆ Findings from this study further the understanding of RCC biology and inform future
strategies to enable personalised therapy according to risk groups

Rini B, et al. IMmotion151 Biomarkers.

ESMO 2018 [abstract LBA31]. http://bit.ly/2yaVgyI
BLADDER/UROTHELIAL
CANCER

esmo.org
 Systemic therapy for urothelial cancer
Approval of 5 new immunotherapeutic agents

Paclitaxel (Ph II) Atezolizumab (Ph II)

Vinflunine
Docetaxel (Ph II) Durvalumab (Ph I/II)
Gemcitabine
Avelumab (Ph I)
Gemcitabine + carboplatin vs
MCaVi Nivolumab (Ph II)
+ cisplatin
HD-MVAC Gemcitabine Pembrolizumab (Ph III)
+ cisplatin
MVAC (Ph II) Gemcitabine + paclitaxel
+ paclitaxel

1989 1993 1997 2001 2005 2009 2013 2016 2017

 Slide 40

Presented By Andrea Apolo at 2018 ASCO Annual Meeting

 Nivolumab Alone or in Combination With
Ipilimumab in Patients With Platinum-Pretreated
Metastatic Urothelial Carcinoma, Including the
Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg
Expansion From CheckMate 032
Jonathan E. Rosenberg,1 Padmanee Sharma,2 Filippo de Braud,3 Umberto Basso,4 Emiliano Calvo,5
Petri Bono,6 Michael Morse,7 Paolo A. Ascierto,8 Jose Lopez-Martin,9 Peter Brossart,10
Kristoffer Rohrberg,11 Noemi Reguart,12 Wen Hong Lin,13 Stephanie Meadows-Shropshire,13
Abdel Saci,13 Margaret Callahan,1 Arlene Siefker-Radtke2
1Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2MD Anderson Cancer Center, University of Texas, Houston, TX, USA; 3Istituto Nazionale dei Tumori, Milan, Italy;
4Istituto Oncologico Veneto IOV IRCCS, Padua, Italy; 5START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain;
6Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland; 7Duke University Medical Center, Durham, NC, USA;
8Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy; 9Hospital Universitario 12 de Octubre, Madrid, Spain; 10University Hospital of Bonn, Bonn, Germany;
11Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; 12Hospital Clinic of Barcelona, Barcelona, Spain; 13Bristol-Myers Squibb, Princeton, NJ, USA

LBA32
 ◆ CheckMate 032

Study Design
32

Open-label, multicenter, phase 1/2 study (NCT01928394)

Nivolumab 3 mg/kg Endpoints:
IV Q2W
Pretreated patientsa
with
(N = 78)
locally advanced or
• Primary
metastatic urothelial
carcinoma Investigator-assessed confirmed
–

Nivolumab 3 mg/kg + ORR by RECIST v1.1b

• Progressive disease ipilimumab 1 mg/kg Nivolumab 3
after ≥1 prior platinum- DOR
–
IV Q3W for 4 cycles mg/kg
based therapy (N = 104) IV Q2W
• ECOG performance • Secondary
status ≤1 PFS –

• Measurable disease per Nivolumab 1 mg/kg + OS –

RECIST v1.1 ipilimumab 3 mg/kg

IV Q3W for 4 cycles Safety –

(N = 92) • Exploratory
ORR by PD-L1 expression
• Tumor measurements: CT or MRI every 6 weeks (±1 week) from first dose for the first 24 weeks, then every 12 weeks
–

(±1 week) status

aPatients could have refused chemotherapy. bAlso reported per BICR.

Treatment beyond progression was permitted if treatment was tolerated and prespecified clinical benefit was noted. Patients receiving combination treatment may undergo a re-exposure with
nivolumab/ipilimumab if they had a subsequent documented progression after achieving an initial objective response (partial or complete response) or stable disease of ≥3 months, and met
protocol-defined criteria.
Sharma P, et al. Lancet Oncol 2016;17:1590–1598. 32
BICR, blinded independent committee review; DOR, duration of response; PD-L1, programmed death ligand 1.
 ◆ CheckMate 032

33

Best Overall Response per Investigator

NIVO3 NIVO3+IPI1 NIVO1+IPI3
Characteristic (N = 78) (N = 104) (N = 92)
Confirmed ORR, % 25.6 26.9 38.0
95% CI 16.4–36.8 18.7–36.5 28.1–48.8
Best overall response, n (%)
Complete response 8 (10) 8 (8) 6 (7)
Partial response 12 (15) 20 (19) 29 (32)
Stable disease 21 (27) 24 (23) 23 (25)
Progressive disease 30 (38) 44 (42) 20 (22)
Unable to determine 7 (9) 8 (8) 12 (13)
Not reported 0 0 2 (2)

33
 ◆ CheckMate 032

ORR Overall and by Baseline Tumor PD-L1 Expression 34

per BICR
80 54.8
NIVO3 (N = 78)
(36.0–72.7)
70 NIVO1+IPI3 (N = 92)

60
ORR, % (95% CI)

37.0
50 (27.1–47.7)
19.2
20.9 21.4
(6.6–39.4)
40 20.5 (10.0–36.0) (10.3–36.8)
(12.2–31.2)
30

20

10
NIVO3 NIVO1+IPI3 NIVO3 NIVO1+IPI3 NIVO3 NIVO1+IPI3
0
n = 78 n = 92 n = 43 n = 42 n = 26 n = 31
Overall PD-L1 <1% PD-L1 ≥1%
PD-L1 Expression
BICR was done only for NIVO3 and NIVO1+IPI3 to confirm differences in investigator-assessed ORR.
34
 ◆ CheckMate 032

Best Tumor Change From Baseline in 35

Target Lesion per Investigator

NIVO3 NIVO3+IPI1 NIVO1+IPI3

Median tumor reduction Median tumor reduction Median tumor reduction

from baseline (%) from baseline (%) from baseline (%)
75
baseline target lesions (%)

75 75
1.9 0 −30.0
Maximum response in

50 50 50
25 25 25
0 0 0
–25 –25 –25
–50 –50 –50
–75 –75 –75
–100 –100 –100
Patients Patients Patients

Includes patients with target lesion at baseline and at ≥1 on-treatment tumor assessment. Negative or positive value means maximum tumor reduction or minimum tumor increase. Best reduction is
based on evaluable target lesion measurements up to progression or start of subsequent therapy/crossover. Horizontal reference line indicates the 30% reduction consistent with a RECIST v1.1
response. Square represents % change truncated to 100%. 35
 ◆ CheckMate 032

Progression-Free Survival per Investigator 36

Progression-free survival (probability)

1.0 NIVO3
NIVO3 NIVO3+IPI1 NIVO1+IPI3
NIVO3+IPI1 (N = 78) (N = 104) (N = 92)
0.9 NIVO1+IPI3
Events, n (%) 67 (86) 86 (83) 65 (71)
0.8

0.7 Median PFS 2.8 2.6 4.9

(95% CI), months (1.5–5.3) (1.4–3.9) (2.7–6.6)
0.6

0.5

0.4

0.3

0.2 42%
36% 26%
0.1 23%
32% 18%
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Months
Number at risk
NIVO3 78 34 27 20 12 11 11 11 10 9 8 8 7 5 3 1 0
NIVO3+IPI1 104 42 30 22 21 18 18 17 14 13 13 12 9 2 1 0 0
NIVO1+IPI3 92 50 34 25 15 9 6 6 6 3 2 1 1 1 1 1 0
36
 ◆ CheckMate 032

Overall Survival 37

1.0 NIVO3
NIVO3 NIVO3+IPI1 NIVO1+IPI3
NIVO3+IPI1 (N = 78) (N = 104) (N = 92)
0.9
Overall survival (probability)

NIVO1+IPI3
Events, n (%) 56 (72) 81 (78) 46 (50)
0.8

0.7 Median OS 9.9 7.4 15.3

(95% CI), months (7.3–21.1) (5.6–11.0) (10.1–27.6)
0.6

0.5

0.4

0.3 69% 57%

0.2 67% 47%
0.1
59% 38%
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Months
Number at risk
NIVO3 78 61 54 41 36 32 30 29 28 24 22 22 19 16 9 4 0 0
NIVO3+IPI1 104 86 61 46 39 32 31 30 28 26 26 22 19 15 5 0 0 0
NIVO1+IPI3 92 73 60 48 33 23 13 12 12 11 8 2 2 2 2 1 1 0
37
 OTHER EMERGING TREATMENT STRATEGIES IN
METASTATIC UROTHELIAL CANCER

• Combination VEGF inhibition + chemotherapy

• FGFR inhibitors
• Antibody Drug Conjugates

esmo.org
Pembrolizumab for High-Risk
Non–Muscle Invasive Bladder Cancer
Unresponsive to Bacillus Calmette-Guérin:
Results From an Interim Analysis of
KEYNOTE-057

R. de Wit; G. Kulkarni; E. Uchio; E. A. Singer; L. Krieger; P. Grivas; D. F. Bajorin;

H. K. Seo; L. Mourey; A. M. Kamat; H. Nishiyama; E. Kapadia; K. Nam; T. L.
Frenkl; A. V. Balar

esmo.org
 KEYNOTE-057: Single-Arm, Open-Label
Phase 2 Study (NCT02625961)
Patients Primary End Points
Evaluations with
• HR NMIBC patients unresponsive cystoscopy, cytology, ± • CR (absence of HR
to BCG who refuse or are ineligible biopsy Q12W × 2 y, NMIBC) in Cohort A
for cystectomy then Q24W × 2 y and • DFS in Cohort B
• Patients with papillary disease Pembrolizumab once yearly thereafter
must have fully resected disease at 200 mg Q3W and
Secondary End Points
study entry
CT urogram Q24W × 2 y • CR (absence of any
• Two cohorts or more frequently as disease ‒ high-risk or
• Cohort A (n = 130): CIS with or clinically indicated low-risk NMIBC) in
with out papillary disease cohort A
(high-grade Ta or T1) • DOR in cohort A
• Cohort B (n = 130): papillary • Safety/tolerability
disease (high-grade Ta or any Continue assessments
T1) without CIS and pembrolizumab until
recurrence of high-risk
If no persistence or recurrence of HR NMIBC at any assessment NMIBC, PD, or
24 months of treatment
complete
If HR NMIBC present at any assessment Discontinue treatment;
enter survival follow-up
 Overall Response Rate at Month 3 a
N = 103
Response
N % 95% CI
CR 40 38.8 29.4-48.9
Non-CR 57 55.3 45.2-65.1
Persistentb 47 45.6 35.8-55.7
NMIBC stage progressionc 9 8.7 4.1-15.9
Extravesical diseased 1 1.0 0.0-5.3
Progression to T2 0 0 ―
Nonevaluablee 6 5.8 2.2-12.2
aSummary of overall responses of high-risk NMIBC per central assessment at month 3 in all patients who received ≥1 dose of trial treatment, had baseline evaluations, and also had ≥1
postbaseline disease assessment. bDefined as patients with CIS at baseline who at month 3 also had CIS ± papillary tumor. cIncrease in stage from CIS and/or high-grade Ta at baseline to T1
disease. dDefined as presence of lesions suspicious for locally advanced or metastatic bladder cancer on imaging. dPatient developed new liver lesions on imaging and was later found to have a
second primary malignancy of pancreatic cancer. Subsequent review of the baseline scan showed subtle findings that, in retrospect, could be attributed to pancreatic cancer. ePatients whose
protocol-specified efficacy assessments were missing or who discontinued from the trial for reasons other than PD are considered not evaluable for efficacy.
Database cutoff: July 18, 2018.
 Duration of Response for Patients Who
Achieved CR at Month 3 a
100%
• Median (range) CR duration
100
80% • Not reached (0+ to 14.1+ months)
Remaining in CR, %

• 80% had a CR duration of ≥6 months

80

54%
60

40

20

0
0 2 4 6 8 10 12 14 16

No. at risk Months

40 30 24 17 10 6 4 1 0
a1month = 30.4367 days.
Database cutoff: July 18, 2018.
 Summary of UC treatment in 2018

● There is uncertainty in the frontline setting with cis-ineligible pts with

pembrolizumab/atezolizumab: Not recommended for PD-L1 –ve patients
● IO combo looks promising but ph 3 results are lacking. IO+chemo combination
frontline studies are already awaited
● FGFR inhibitor, antobody drug conjugate likely to move to earlier line but trials
are ongoing
● Pembrolizumab has activity in the non-muscle invasive disease and remains to be
further studied in this setting (KEYNOTE-676 phase 3)
THANK YOU!

petri.bono@hus.fi