1. Case Discussion
A 52-year-old man initially presented with nonmuscle-invasive bladder cancer
He received Bacillus calmette-guerin (BCG) therapy
After a couple of years, he was found to have diffuse adenopathy without renal dysfunction.
Biopsy of enlarged lymph nodes revealed metastatic urothelial cancer

2. Mechanism of Action of BCG
The innate immune response to intravesical BCG was characterized using a systems approach based on proteomic and cytometric screens
Blood and urine were collected from patients receiving intravesical BCG before and 2 and 4 h after BCG, at the first and third instillation.
Molecular analyte profiling revealed a prime/boost pattern to the innate response to intravesical BCG
36 statistically significant changes in the proteins induced during the third instillation compared to the initial treatment were identified
BCG has the ability to sensitize the tissue microenvironment to enhance innate responses.
Bisiaux A et al. J Urol 2009;181(4):

3. Case Discussion
A 52-year-old man initially presented with nonmuscle-invasive bladder cancer
He received Bacillus calmette-guerin (BCG) therapy
After a couple of years, he was found to have diffuse adenopathy without renal dysfunction.
Biopsy of enlarged lymph nodes revealed metastatic urothelial cancer
Patient received dose-dense MVAC  achieved an objective response

4. Case Discussion
A 52-year-old man initially presented with nonmuscle-invasive bladder cancer
He received Bacillus calmette-guerin (BCG) therapy
After a couple of years, he was found to have diffuse adenopathy without renal dysfunction.
Biopsy of enlarged lymph nodes revealed metastatic urothelial cancer
Patient received dose-dense MVAC  achieved an objective response  observation

5. Case Discussion
A 52-year-old man initially presented with nonmuscle-invasive bladder cancer
He received Bacillus calmette-guerin (BCG) therapy
After a couple of years, he was found to have diffuse adenopathy without renal dysfunction.
Biopsy of enlarged lymph nodes revealed metastatic urothelial cancer
Patient received dose-dense MVAC  achieved an objective response  observation
Patient developed disease progression and received chemotherapy
Currently on atezolizumab for 2+ years

6. IMvigor 210: A Phase II Trial of Atezolizumab in Advanced Urothelial Cancer (UC)
Cohort 1
(n = 119)
Eligibility
Inoperable locally advanced or metastatic UC
Available tumor sample for PD-L1 testing
Progression during or after platinum
ECOG PS ≤1
CrCl ≥30mL/min
Atezolizumab
1,200 mg (IV) q3wk
Cohort 2
(n = 310)
Cohort 2
All
(n = 310)
IC2/3
(n = 100)
IC1/2/3
(n = 207)
IC1
(n = 107)
IC0
(n = 103)
ORR
15%
26%
18%
10% 8%
Atezolizumab showed durable activity and good tolerability in Cohort 2
Rosenberg JE et al. Lancet 2016;387(10031): ; Hoffman-Censits J et al. Genitourinary Cancers Symposium 2016;Abstract 355.

7. Case Discussion
A 52-year-old man initially presented with nonmuscle-invasive bladder cancer
He received Bacillus calmette-guerin (BCG) therapy
After a couple of years, he was found to have diffuse adenopathy without renal dysfunction.
Biopsy of enlarged lymph nodes revealed metastatic urothelial cancer
Patient received dose-dense MVAC  achieved an objective response  observation
Patient developed disease progression and received chemotherapy
Currently on atezolizumab for 2+ years

8. IMvigor 210: Atezolizumab as First-Line Therapy in Cisplatin-Ineligible Advanced Urothelial Cancer (UC)
Eligibility
Inoperable locally advanced or metastatic UC
Chemotherapy-naïve, ineligible for cisplatin-based chemotherapy (Cohort 1)
Available tumor sample for PD-L1 testing
Cohort 1
(n = 119)
Atezolizumab
1,200 mg (IV) q3wk
Cohort 2
(n = 310)
Cohort 1
All
(n = 119)
IC2/3
(n = 32)
IC1/2/3
(n = 80)
IC1
(n = 48)
IC0
(n = 39)
ORR
23%
28%
24%
21%
Median OS: All patients (n = 119): 15.9 mo
IC 0/1 (n = 87): 19.1 mo
IC 2/3 (n = 32): 12.3 mo
Balar AV et al. Lancet 2017;389(10064):67-76.

9. Nivolumab monotherapy
CheckMate 275: A Phase II Trial of Nivolumab in Metastatic Urothelial Cancer
Eligibility (n = 270)
Metastatic or surgically unresectable locally advanced urothelial cancer
Progression/recurrence after ≥1 platinum-based chemo
Nivolumab monotherapy
3 mg/kg
Clinical outcome
n = 265
Confirmed ORR
19.6%
Nivolumab monotherapy provided meaningful clinical benefit irrespective of PD-L1 expression and was associated with an acceptable safety profile. 
Sharma P et al. Lancet Oncol 2017;18(3):

10. Pembrolizumab for up to 2 years Paclitaxel or docetaxel or vinflunine
KEYNOTE-045: A Phase III Trial of Pembrolizumab in Advanced Urothelial Cancer
Eligibility (n = 542)
Advanced urothelial cancer
≤2 prior lines of therapy
ECOG PS ≤2
Pembrolizumab for up to 2 years
200 mg q3wk R
1:1
Paclitaxel or docetaxel or vinflunine
Outcome
Pembro
(n = 270)
Chemo
(n = 272) HR
p-value
Median OS
10.3 mo
7.4 mo
0.73
0.002
ORR
21.1%
11.4% —
0.001
Bellmunt J et al. N Engl J Med 2017;376(11):

11. Study 1108: A Phase III Trial of Durvalumab Monotherapy in Urothelial Bladder Cancer
Response
ORR
DCR at ≥12 weeks
All evaluable patients (n = 42)
13 (31%)
20 (48%)
PD-L1-positive (n = 28)
13 (46%)
16 (57%)
PD-L1-negative (n = 14)
4 (29%)
PD-L1 positive = ≥25% TCs or ICs
PD-L1 negative = <25% TCs or ICs
Massard C et al. Proc ASCO 2016;Abstract 4502.

12. Ongoing Adjuvant Trials of Immune Checkpoint Inhibitors for Urothelial Cancer
Trial name
Phase N
Treatment
CheckMate 274
(NCT )
III
640
Nivolumab
Placebo
IMvigor010
(NCT )
700
Atezolizumab
Observation
Clinicaltrials.gov (Accessed May 2017).

13. Ongoing Trials of Immune Checkpoint Inhibitors as First-Line Therapy for Urothelial Cancer
Trial name
Phase N
Treatment
NCT
III
1,005
Durvalumab
Durvalumab + tremelimumab
SOC chemotherapy
JAVELIN Bladder 100
(NCT )
668
Avelumab + BSC
BSC only
CheckMate 901
(NCT )
690
Nivolumab + ipilimumab
SOC = standard of care; BSC = best supportive care
Clinicaltrials.gov (Accessed May 2017).

14. Preliminary Results from the Phase II Trial of Cabozantinib in Advanced Urothelial Cancer
Cohort 1
n = 42
ORR
19.1%
Median OS
8.0 mo
Median PFS
3.7 mo
Apolo AB et al. Proc ASCO 2016;Abstract 4534.

15. Pembrolizumab for up to 2 years Paclitaxel or docetaxel or vinflunine
KEYNOTE-045: A Phase III Trial of Pembrolizumab in Advanced Urothelial Cancer
Eligibility (n = 542)
Advanced urothelial cancer
≤2 prior lines of therapy
ECOG PS ≤2
Pembrolizumab for up to 2 years
200 mg q3wk R
1:1
Paclitaxel or docetaxel or vinflunine
Median OS
Pembro
(n = 270)
Chemo
(n = 272) HR
p-value
All patients
10.3 mo
7.4 mo
0.73
0.002
HR < 1.0 favors pembrolizumab
Current smokers (HR = 0.32); former smokers (HR = 0.71); never smokers (HR = 1.06)
Bellmunt J et al. N Engl J Med 2017;376(11):

16. Perspective on the Differences Among the Anti-PD-1/PD-L1 Inhibitors
“I don’t think there’s really any difference that we can measure or see based on the data sets we have between any of these inhibitors. I think they all work on the same axis. They all essentially do the same thing. There may be slight differences in toxicity profile, but we’re going to need more data to really sort that out. I think they’re very similar. And I think, also, similar combinations are being looked at, as well, with all of these.” Elizabeth Plimack, MD

17. ASSURE (ECOG-ACRIN E2805): A Phase III Trial of Adjuvant Sunitinib or Sorafenib for High-Risk Nonmetastatic Renal Cell Carcinoma (RCC)
Outcome1
Sunitinib
(n = 647)
Sorafenib
(n = 649)
Placebo
Median DFS
5.8 years
6.1 years
6.6 years
No significant differences in DFS
S-TRAC: A Phase III Trial of Adjuvant Sunitinib in High-Risk RCC After Nephrectomy
Outcome2
Sunitinib
(n = 309)
Placebo
(n = 306) HR
p-value
Median DFS
6.8 years
5.6 years
0.76
0.03
1 Haas NB et al. Lancet 2016;387(10032): ; 2 Ravaud A et al. N Engl J Med 2016;375(23):

18. Management of Sunitinib-Associated Hand-Foot Skin Reaction (HFSR)
HFSR really interferes with people’s activities of daily living.
We are very proactive with having the patients see a dermatologist who’s well versed with the management of HFSR.
We maximize the use of topical ointments.
We encourage the use of soft-soled shoes.
However, if it continues to be problematic, we dose reduce because the patients need to be active and have a good quality of life.
Robert J Motzer, MD

19. METEOR: A Phase III Trial of Cabozantinib vs Everolimus in Advanced RCC
60 mg QD
(n = 330)
Eligibility (n = 658)
Advanced RCC
Prior treatment with ≥1 VEGFR inhibitor R
1:1
Everolimus
10 mg QD
(n = 328)
Outcome
Cabozantinib
(n = 330)
Everolimus
(n = 328) HR
p-value
Median OS
21.4 mo
16.5 mo
0.66
Median PFS
7.4 mo
3.9 mo
0.51
<0.0001
ORR
17% 3% —
Choueiri TK et al. Lancet Oncol 2016;17(7):

20. CABOSUN: A Phase II Trial of First-Line Cabozantinib vs Sunitinib in Advanced RCC
Eligibility (n = 157)
Untreated metastatic RCC
Clear cell histology
Poor or intermediate risk
ECOG PS ≤2
Cabozantinib
60 mg QD
(n = 79) R
1:1
Sunitinib
50 mg QD; 4 wks on; 2 wks off
(n = 78)
Outcome
Cabozantinib
(n = 79)
Sunitinib
(n = 78) HR
p-value
Median OS
30.3 mo
21.8 mo
0.80
Not reported
Median PFS
8.2 mo
5.6 mo
0.66
0.012
ORR
46%
18% —
Choueiri TK et al. J Clin Oncol 2017;35(6):591-7.

21. COMPARZ: A Phase III Trial of First-Line Pazopanib vs Sunitinib in Advanced RCC
Eligibility (n = 1,110)
Locally advanced or metastatic RCC
Clear cell histology
No prior systemic therapy for advanced RCC
Pazopanib
800 mg QD
(n = 557) R
1:1
Sunitinib
50 mg QD; 4 wks on; 2 wks off
(n = 553)
Outcome
Pazopanib
(n = 557)
Sunitinib
(n = 553) HR
p-value
Median OS1
28.3 mo
29.1 mo
0.92
0.24
Median PFS2
8.4 mo
9.5 mo
1.05
Not reported
HR for PFS met the predefined criterion for noninferiority
1 Motzer RJ et al. N Engl J Med 2014;370(18): ; 2 N Engl J Med 2013;369(8):

22. A Phase I/II Trial of Lenvatinib vs Everolimus in Advanced RCC
Eligibility (n = 153)
Unresectable locally advanced or metastatic RCC
Clear cell histology
1 prior VEGF-targeted therapy
Lenvatinib
(n = 52) R
Everolimus
(n = 50)
Lenvatinib + everolimus
(n = 51)
Outcome
Lenvatinib
(n = 52)
Everolimus
(n = 50)
Lenvatinib/everolimus
(n = 51)
Median OS
19.1 mo
15.4 mo
25.5 mo*
Median PFS
7.4 mo*
5.5 mo
14.6 mo*
* Statistically significant difference vs everolimus
Motzer RJ et al. Lancet Oncol 2015;16(15):

23. CheckMate 025: A Phase III Trial of Nivolumab vs Everolimus in Advanced RCC
Eligibility (n = 821)
Locally advanced or metastatic RCC
Clear cell histology
≤2 prior anti-angiogenic therapies
Nivolumab
(n = 410) R
Everolimus
(n = 411)
Outcome
Nivolumab
(n = 410)
Everolimus
(n = 411) HR
p-value
Median OS
25.0 mo
19.6 mo
0.73
0.002
Median PFS
4.6 mo
4.4 mo
0.88
0.11
ORR
25% 5% —
<0.001
HR for OS met the predefined criterion for superiority
Motzer RJ et al. N Engl J Med 2015;373(19):

24. Toxicities Associated with Immune Checkpoint Inhibitors
Colitis
Hypophysitis
Hypothyroidism
Adrenal insufficiency
Dermatologic side effects
Neuropathies
Hepatitis
Pneumonitis

25. Lenvatinib/everolimus
Results from a Phase I/II Trial of Lenvatinib vs Everolimus in Advanced RCC
Outcome
Lenvatinib
(n = 52)
Everolimus
(n = 50)
Lenvatinib/everolimus
(n = 51)
Median OS
19.1 mo
15.4 mo
25.5 mo*
Median PFS
7.4 mo*
5.5 mo
14.6 mo*
ORR
14 (27%)
3 (6%)
22 (43%)*
* Statistically significant difference vs everolimus
Motzer RJ et al. Lancet Oncol 2015;16(15):

26. Lenvatinib/everolimus
Results from a Phase I/II Trial of Lenvatinib vs Everolimus in Advanced RCC
Outcome
Lenvatinib
(n = 52)
Everolimus
(n = 50)
Lenvatinib/everolimus
(n = 51)
Median OS
19.1 mo
15.4 mo
25.5 mo*
Median PFS
7.4 mo*
5.5 mo
14.6 mo*
ORR
14 (27%)
3 (6%)
22 (43%)*
* Statistically significant difference vs everolimus
Motzer RJ et al. Lancet Oncol 2015;16(15):

27. CheckMate 025: A Phase III Trial of Nivolumab vs Everolimus in Advanced RCC
Eligibility (n = 821)
Locally advanced or metastatic RCC
Clear cell histology
≤2 prior anti-angiogenic therapies
Nivolumab
(n = 410) R
Everolimus
(n = 411)
Outcome
Nivolumab
(n = 410)
Everolimus
(n = 411) HR
p-value
Median OS
25.0 mo
19.6 mo
0.73
0.002
Median PFS
4.6 mo
4.4 mo
0.88
0.11
ORR
25% 5% —
<0.001
HR for OS met the predefined criterion for superiority
Motzer RJ et al. N Engl J Med 2015;373(19):

28. A Phase I Trial of Axitinib and Pembrolizumab in Advanced RCC
Eligibility (n = 52)
Previously untreated advanced RCC
Clear cell histology
Axitinib + pembrolizumab
Clinical outcome
n = 52
ORR
35 (67.3%)
Median PFS is not yet mature 
Atkins MB et al. Proc ESMO 2016;Abstract 773PD.