1. KEYNOTE-045: Updated Survival Analysis of Phase III Trial of Pembrolizumab vs Paclitaxel, Docetaxel, or Vinflunine in Pts With Advanced Urothelial Carcinoma
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-045: Background
Treatment of recurrent urothelial carcinoma challenging, with no universally accepted second-line therapy
Choices include vinflunine, taxanes, or checkpoint inhibitors
Pembrolizumab active, safe in advanced urothelial carcinoma with significant survival advantage vs CT in phase III KEYNOTE-045 at median follow-up of 14.1 mos[1]
Led to approval of pembrolizumab for pts with locally advanced or metastatic UC who have disease progression during or following platinum-based CT or within 12 mos of neoadjuvant or adjuvant treatment with platinum-based CT[2]
Current report updates survival data for KEYNOTE-045 with median follow- up of 18.5 mos (range: mos)[3]
CT, chemotherapy; UC, urothelial carcinoma.
1. Bellmunt J, et al. N Engl J Med. 2017;376:  2. Pembrolizumab [package insert].
3. Bajorin DF, et al. ASCO Abstract 4501.
Slide credit: clinicaloptions.com

3. KEYNOTE-045: Study Design
Randomized, open-label phase III study
Primary endpoints: OS, PFS; Secondary endpoints: ORR, DoR, TTR, safety
Response measured by blinded ICR per RECIST v1.1
Data cutoff: 1/18/17
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)
Pembrolizumab
200 mg IV Q3W
(n = 270)
Pts with predominantly transitional cell UC of 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
Paclitaxel 175 mg/m2 Q3W, or
Docetaxel 75 mg/m2 Q3W, or
Vinflunine 320 mg/m2 Q3W
(n = 272)
CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; Hb, hemoglobin; ICR, independent central review; PD, progressive disease; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response; UC, urothelial carcinoma.
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract 4501.

4. KEYNOTE-045: Baseline Characteristics
Pembro
(n = 270) CT
(n = 272)
Median age, yrs (range)
67 (29-88)
65 (26-84)
Male, n (%)
200 (74.1)
202 (74.3)
Upper tract disease, n (%)
38 (14.1)
37 (13.6)
ECOG PS, n (%) 1 2
120 (44.4)
143 (53.0)
2 (0.7)
106 (39.0)
158 (58.1)
4 (1.5)
Disease, n (%)
Visceral
Lymph node only
Liver metastases
241 (89.3)
28 (10.4)
91 (33.7)
234 (86.0)
38 (14.0)
95 (34.9)
Setting of most recent tx, n (%)
Neoadjuvant
Adjuvant
First line
Second line
Third line
19 (7.0)
12 (4.4)
184 (68.1)
55 (20.4)
22 (8.1)
31 (11.4)
59 (21.7)
Characteristic, n (%)
Pembro
(n = 270) CT
(n = 272)
Hemoglobin < 10 g/dL
43 (15.9)
44 (16.2)
≥ 3 mos since last therapy
167 (61.9)
168 (61.8)
PD-L1 CPS ≥ 10%
74 (27.4)
90 (33.1)
Prior platinum therapy
Cisplatin
Carboplatin
Oxaliplatin or nedaplatin
199 (73.7)
70 (25.9)
1 (0.4)
214 (78.7)
56 (20.6)
2 (0.7)
Smoking status
Never
Former
Current
104 (38.5)
136 (50.4)
29 (10.7)
83 (30.5)
148 (54.4)
38 (14.0)
Risk factors* 1 2
3-4
54 (20.0)
96 (35.6)
66 (24.4)
45 (16.7)
45 (16.5)
97 (35.7)
80 (29.4)
CPS, combined positive score; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; Hb, hemoglobin; Pembro, pembrolizumab; PS, performance status; tx, treatment.
*ECOG PS > 0, Hb < 10 g/dL, liver mets, < 3 mos since CT.
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract 4501.

5. OS in Pts With PD-L1* CPS ≥ 10%
KEYNOTE-045: OS
OS in All Pts
OS in Pts With PD-L1* CPS ≥ 10%
100
100
Pembro
(n = 270) CT
(n = 272)
Median OS, mos (95% CI)
10.3
( )
7.4
( ) 80 80 60
44.4%
30.2%
36.1%
20.5% 60
OS (%)
OS (%) 40 40 20 20
CPS, combined positive score; CT, chemotherapy; Pembro, pembrolizumab.
HR: 0.57 (95% CI: ; P = .0034)
HR: 0.70 (95% CI: ; P = .0004) 4 8 12 16 20 24 4 8 12 16 20 24
Mos
Mos
Pembro CT
270
272
194
171
147
109
116 73 79 46 27 15 4 1
Pembro CT 74 90 51 35 28 28 21 17 14 7 3 1
*Assayed with PD-L1 IHC 22C3 pharmDx.
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract Reproduced with permission.

6. KEYNOTE-045: PFS
PFS in All Pts
PFS at 18 mos 16.8% in pembro arm vs 3.5% with chemotherapy, inferring that survival benefit will not change over further observation
100
Pembro
(n = 270) CT
(n = 272)
Median PFS, mos (95% CI)
2.1
( )
3.3
( )
HR: 0.96 (95% CI: ; P = .32) 80 60
PFS (%)
28.8%
28.4%
17.6%
7.9%
16.8%
3.5% 40 20
CT, chemotherapy; Pembro, pembrolizumab. 4 8 12 16 20 24
Mos
Pembro CT
270
272 85 91 56 34 41 15 24 6 8 2
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract Reproduced with permission.

7. KEYNOTE-045: OS by Subgroup
467 75 66
475 99
193
146 90
164
362 84 87 n
542
413
126
186
356
443 87
335
207
527 6
Primary site
Lower tract
Upper tract
Visceral disease
Lymph node only
Risk factors* 1 2
3/4
CPS
≥ 10%
< 10%
Investigator’s choice†
Paclitaxel
Docetaxel
Vinflunine
Overall
Prior platinum therapy
Cisplatin
Carboplatin
Liver metastases
Present
Absent
Hemoglobin
≥ 10 g/dL
< 10 g/dL
Time from CT
≥ 3 mos
< 3 mos
ECOG PS
0/1 2
CPS, combined positive score; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; Pembro, pembrolizumab; PS, performance status. 1 2 3 4 5 1 2
Pembro CT
Pembro CT HR HR
*ECOG PS > 0, hemoglobin < 10 g/dL, liver mets, < 3 mos since CT.
†Pt numbers listed for CT arm only; comparison to all pts in pembro arm.
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract Reproduced with permission.

8. ORR in Pts With PD-L1* CPS ≥ 10%
KEYNOTE-045: ORR
ORR in All Pts
ORR in Pts With PD-L1* CPS ≥ 10% 30 30
21.1% CR PR
20.3% CR PR 25 25 20
7.8% 20
11.0%
6.8% 15 15
Pts, % (95% CI)
Pts, % (95% CI)
13.3%
6.7% 10
2.9% 10
13.5%
8.1% 5 5
2.2%
4.4%
Pembrolizumab
(n = 270)
Chemotherapy
(n = 272)
Pembrolizumab
(n = 74)
Chemotherapy
(n = 90)
*Assayed with PD-L1 IHC 22C3 pharmDx.
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract Reproduced with permission.

9. Time to Response in Pts Achieving CR/PR Remaining in Response (%)
KEYNOTE-045: DoR, TTR
Duration of Response
Time to Response in Pts Achieving CR/PR
100
CR or PR
PD or death
Treatment ongoing
Median DoR: NR (range: 1.6+ to mos) 80
Pembro
(n = 57) 60
Remaining in Response (%)
Median time to response:
2.1 mos (range: ) 40
Median DoR: 4.4 mos (range: 1.4+ to mos) 20
Pembrolizumab
Chemotherapy
CT, chemotherapy; DoR, duration of response; NR, not reached; PD, progressive disease; Pembro, pembrolizumab; TTR, time to response. CT
(n = 30)
Median time to response:
2.1 mos (range: ) 6 12 18 24
Mos
Pembro CT 57 30 45 7 33 5 7 2 8 16 24 32 40 48 56 64 72 80 88 96
104
Wks
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract Reproduced with permission.

10. KEYNOTE-045: Adverse Events
TRAEs Occurring in
≥ 10% of Pts in Either Arm
AEs of Interest Occurring in ≥ 2% of Pts in Either Arm
Pruritus
Fatigue
Nausea
Diarrhea
Decreased appetite
Asthenia
Anemia
Constipation
Peripheral neuropathy
Peripheral sensory neuropathy
Decreased neutrophils
Neutropenia*
Alopecia
Pembro CT
Grade
1-2
3-5
Hypothyroidism
Pneumonitis
Hyperthyroidism
Infusion-related reactions
Colitis
Severe skin reaction
Adrenal insufficiency
Nephritis
Thyroiditis
AE, adverse event; TRAE, treatment-related adverse event. 40 30 20 10 10 20 30 40 40 30 20 10 10 20 30 40
Pts (%)
Pts (%)
*7.5% rate of febrile neutropenia in pts receiving CT.
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract Reproduced with permission.

11. KEYNOTE-045: Conclusions
In pts with progressive metastatic or recurrent UC, pembrolizumab maintained survival, response, and toxicity advantages vs CT with longer median follow-up of mos
Median OS: 10.3 vs 7.4 mos, P = .0004
12-mo OS: 44.4% vs 30.2%; 18-mo OS: 36.1% vs 20.5%
Median DoR: NR vs 4.4 mos; response ≥ 12 mos: 69% vs 36%
ORR: 21% vs 11%
Lower rate of TRAEs (61.3% vs 90.2%), including grade ≥ 3 (16.5% vs 49.8%)
However, similar rates of PFS, median time to progression in both arms
Study investigators conclude that pembrolizumab provides viable non-CT strategy for pts with recurrent or advanced UC
Slide credit: clinicaloptions.com
Bajorin DF, et al. ASCO Abstract 4501.

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