1. KEYNOTE-052: Updated Findings on First-line Pembrolizumab in Cisplatin-Ineligible Advanced Urothelial Cancer
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. KEYNOTE-052: Background
Cisplatin-based therapy improves survival in metastatic UC[1]
Alternative regimens required for pts ineligible for cisplatin-based therapy due to age-related comorbidities
Available alternative chemotherapy regimens associated with poor outcomes and unfavorable toxicity[2]
Phase II data on anti–PD-L1 agent atezolizumab suggested clinical activity in untreated cisplatin-ineligible pts with advanced/metastatic UC (ORR: 23%)[3]
KEYNOTE-052 assessed safety, efficacy of anti–PD-1 antibody pembrolizumab in untreated cisplatin-ineligible pts with advanced UC
Preliminary analysis: ORR 24% (95% CI: ) after median follow-up 8 mos[4]
Current analysis reports additional follow-up, median: 9.5 mos (range: mos)[5]
UC, urothelial cancer.
1. von der Masse H, et al. J Clin Oncol. 2005;23: De Santis M, et al. J Clin Oncol. 2012;30: Balar AV, et al. Lancet. 2017;389: Balar A, et al. ESMO Abstract LBA O’Donnell P, et al. ASCO Abstract 4502.
Slide credit: clinicaloptions.com

3. KEYNOTE-052: Study Design
Multicenter, open-label, single-arm phase II study
Primary endpoint: ORR
Secondary endpoints: DoR, PFS, OS, safety, PD-L1 expression
Exploratory objective: assess relationship between biomarkers and response
Pts with advanced UC, no previous chemotherapy for metastatic disease, ECOG PS 0-2, and ineligible for cisplatin*
(N = 370)
Followed for up to 24 mos of therapy, confirmed PD, intolerable toxicity, or withdrawal of consent
Pembrolizumab
200 mg Q3W
Biomarker assessment conducted on pretreatment samples.
Data cutoff: 3/9/17
CrCl, creatinine clearance; DoR, duration or response; ECOG, Eastern Cooperative Oncology Group; NYHA, New York Heart Association; PD, progressive disease; PS, performance status; UC, urothelial cancer.
*Cisplatin ineligibility: CrCl < 60 mL/min, ECOG PS 2, grade ≥ 2 neuropathy or hearing loss, NYHA class III heart failure.
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract 4502.

4. KEYNOTE-052: Baseline Characteristics
Pembrolizumab
(N = 370)
Median age, yrs (range)
Age ≥ 80 yrs, n (%)
74 (34-94)
107 (29)
Male, n (%)
286 (77)
ECOG PS, n (%) 1 2
80 (22)
134 (36)
155 (42)
Primary tumor location
Upper tract
Lower tract
69 (19)
300 (81)
Liver metastases, n (%)
77 (21)
Characteristic
Pembrolizumab
(N = 370)
Metastases location, n (%)
Lymph node only
Visceral disease
51 (14)
315 (85)
Previous adj/neo-adj platinum-based chemotherapy, n (%)
37 (10)
Cisplatin ineligibility, n (%)
Renal dysfunction
ECOG PS 2
ECOG PS 2 and renal dysfunction
Other
183 (50)
120 (32)
34 (9)
33 (9)
adj, adjuvant; ECOG, Eastern Cooperative Oncology Group; neo-adj, neo-adjuvant; PS, performance status.
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract 4502.

5. KEYNOTE-052: Confirmed ORR (Primary Endpoint)
Response
Pembrolizumab
(N = 370) n* %
95% CI
ORR
108 29
25-42 CR 27 7
5-10 PR 81 22
18-27 SD 67 18
14-22 PD
155 42
37-47
DoR, duration of response; NR, not reached; PD, progressive disease; SD, stable disease; TTR, time to response.
*No assessment in 31 pts; 9 pts were not evaluable
ORR increased 5% with longer follow-up: CR in 10 additional pts, PR in 9 additional pts
58% pts had reduction in tumor size
Median TTR: 2 mos (range: 1-9 mos); median DoR: NR (95% CI: 12 mos to NR)
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract 4502.

6. KEYNOTE-052: ORR Subgroup Analyses
n/N
59/191 49/179 97/330 11/40
66/214 42/156 18/69 90/300 14/77 94/293 25/51 81/315 34/120 52/183 11/34 11/33
% (95% CI)
31 (24-38) 27 (21-35) 29 (25-35) 28 (15-44) 31 (25-38) 27 (20-35) 26 (16-38) 30 (25-36) 18 (10-29) 32 (27-38) 49 (35-63) 26 (21-31) 28 (21-37) 28 (22-36) 32 (17-51) 33 (18-52)
Age
ECOG PS
Disease location
Liver metastases
Metastases location
Reason for cisplatin ineligibility
< 75 yrs
≥ 75 yrs < 85 yrs
≥ 85 yrs
0-1 2
Upper tract
Lower tract
Present
Absent
Lymph node only
Visceral disease ECOG PS 2
Renal dysfunction
ECOG PS 2/renal dysfunction
Other
ECOG, Eastern Cooperative Oncology Group; PS, performance status. 10 20 30 40 50 60 70
ORR retained across multiple subgroups
ORR, % (95% CI)
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract Reproduced with permission.

7. KEYNOTE-052: Treatment Exposure and DoR
Median TTR: 2 mos (range: 1-9 mos)
Median DoR: NR (95% CI: 12 mos to NR)
67% of responses ongoing at data cutoff
CR or PR PD
Treatment ongoing
DoR, duration or response; NR, not reached; PD, progressive disease; TTR, time to response. 8 16 24 32 40 48 56 64 72 80 88 96
Wks
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract Reproduced with permission.

8. KEYNOTE-052: ORR by PD-L1 Expression
Response
PD-L1 CPS < 10%
PD-L1 CPS ≥ 10% n %
95% CI
Training set*
(n = 66)
(n = 30)
ORR 11 17
9-28 37
20-56 CR 3 5
1-13 4 13
4-31 PR 8 12
5-23 7 23
10-42 SD 9
6-24 PD 35 53
40-65
Validation set*
(n = 185)
(n = 80) 42
17-29 41 51
40-63
1-6 14 18
10-28 20
15-27 27 34
24-45 19
14-25 15
11-29 86 47
37-54 24
15-35
CPS, combined positive score; PD, progressive disease; SD, stable disease.
*Training set: threshold for high PD-L1 expression defined in first 100 enrolled pts. Validation set includes remaining evaluable pts.
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract 4502.

9. KEYNOTE-052: TRAEs Discontinued due to AEs: 7%
Any-Grade TRAEs
(≥ 5% of Pts), n (%)
Pembrolizumab
(N = 370)
Any
243 (66)
Fatigue
67 (18)
Pruritus
62 (17)
Rash
44 (12)
Decreased appetite
37 (10)
Hypothyroidism
35 (10)
Diarrhea
32 (9)
Nausea
31 (8)
Grade 3-5 TRAEs
(≥ 3 Pts), n (%)
Pembrolizumab
(N = 370)
Any
70 (19)
Fatigue
8 (2)
Colitis
6 (2)
Muscle weakness
5 (1)
Increased alkaline phosphate
5 (10
Diarrhea
4 (1)
Pneumonitis
Increased AST
Asthenia
3 (1)
Hepatitis
Increased ALT
ALT, alanine aminotransferase; AST, aspartate aminotransferase; irAE, immune-related adverse event; TRAE, treatment-related adverse event.
Discontinued due to AEs: 7%
1 death due to TRAE (myositis)
Most irAEs grade 1-2 (most common: hypothyroidism)
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract 4502.

10. 18-Gene T-Cell Inflamed GEP Score
18-gene GEP score significantly associated with response (P < .0001)
Response significantly associated with all genes (P < .05)
T-cell inflamed GEP score identified in 31 of 81 responders who were not identified by PD-L1 CPS testing
PD-L1 and T-Cell Inflamed GEP and Response
31/81 responders
39/81 responders
1.0
0.500
0.8
0.6
0.000
Sensitivity
18-Gene GEP Score
0.4
-0.318
18-gene GEP AUC: (95% CI: )
IHC PD-L1 AUC: (95% CI: )
1-sided P = .1288
-0.500
0.2
9/81 responders
2/81 responders
AUC, area under the concentration curve; CPS, combined positive score; GEP, gene expression profile.
-1.000
1.0
0.8
0.6
0.4
0.2 10 25 50 75
100
IHC PD-L1 CPS
Specificity
Nonresponder
Responder
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract Reproduced with permission.

11. Conclusions
In untreated cisplatin-ineligible pts with advanced UC, pembrolizumab demonstrated significant clinical activity
ORR: 29% (95% CI: 25-42) after median follow-up: 9.5 mos (range: mos)
ORR increased with longer treatment duration; median DoR: NR (95% CI: 12 mos to NR)
Safety profile similar to previous data for pembrolizumab
ORR increased in pts with PD-L1 expression (CPS ≥ 10%)
ORR in pts with CPS ≥ 10%: 51% (validation set)
T-cell inflamed GEP score identified responders not identified with PD-L1 testing
CPS, combined positive score; DoR, duration of response; NR, not reached; UC, urothelial cancer; GEP, gene expression profile.
Slide credit: clinicaloptions.com
O’Donnell P, et al. ASCO Abstract 4502.
Slide credit: clinicaloptions.com

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