1. Clinical Application of Immune Checkpoint Inhibitors in Bladder Cancer
This program is supported by educational grants from Genentech and Merck.

2. Key Issues and Controversies in Immunotherapy for Advanced Bladder Cancer: Quiz Round 4
Elizabeth R. Plimack, MD, MS
Director, Genitourinary Clinical Research
Associate Professor Hematology/Oncology Fox Chase Cancer Center
Temple Health Philadelphia, Pennsylvania

3. About These Slides
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Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

4. Faculty Program Director:
Daniel P. Petrylak, MD Professor of Medicine
Medical Oncology
Director, Prostate and GU Medical Oncology
Director, Prostate Cancer Translational Research Group
Yale Cancer Center
New Haven, Connecticut
Elizabeth R. Plimack, MD, MS Director, Genitourinary Clinical Research Associate Professor, Department of Hematology/Oncology Fox Chase Cancer Center Temple Health Philadelphia, Pennsylvania
David I. Quinn, MBBS, PhD, FRACP, FACP Associate Professor of Medicine Division of Cancer Medicine and Blood Diseases The University of Southern California Medical Director USC Norris Cancer Hospital and Clinics Los Angeles, California Jonathan E. Rosenberg, MD Associate Attending Physician Genitourinary Oncology Service Division of Solid Tumor Oncology Department of Medicine Memorial Sloan Kettering Cancer Center New York, New York
This slide lists the faculty who were involved in the production of these slides.

5. Faculty Disclosures
Daniel P. Petrylak, MD, has disclosed that he has received consulting fees from Bayer, Bellicum, Dendreon, Exelixis, Ferring, Johnson & Johnson, Medivation, Millennium, Pfizer, Roche Laboratories, sanofi-aventis, and Tyme; has received funds for research support from Agensys, Celgene, Dendreon, Eli Lilly, Johnson & Johnson, Millennium, Oncogenex, Progenics, sanofi- aventis; and has ownership interest in Bellicum and Tyme. Elizabeth R. Plimack, MD, MS, has disclosed that she has received consulting fees from Acceleron, Bristol-Myers Squibb, Genentech, Eli Lilly, Novartis, Pfizer, Roche, and Synergene and funds for research support from AstraZeneca, Bristol-Myers Squibb, and Merck.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

6. Faculty Disclosures
David I. Quinn, MBBS, PhD, FRACP, FACP, has disclosed that he has received consulting fees from Astellas, AstraZeneca, Bayer, Exelixis, Genentech, Merck, Novartis, Peloton, Pfizer, Sanofi, Serono, and Vertex. Jonathan E. Rosenberg, MD, has disclosed that he has intellectual property rights/patents from Somatic ERCC2 mutation and platinum sensitivity; has received consulting fees from Agensys, Eli Lilly, Genentech/Roche, OncoGeneX, and sanofi- aventis; and has ownership interest in Illumina and Merck.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

7. Evolution of Systemic Therapy for Urothelial Cancer
Docetaxel
Gemcitabine + cisplatin
Atezolizumab
Accelerated MVAC
Standard
MVAC
1989
Paclitaxel
Vinflunine
Today
1997
1999
2001
2003
2005
2007
2009
2011
2013
2015
2016
EMA, European Medicines Agency; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin.
Cisplatin
FDA
approved
1978
Gemcitabine
EMA approved
Atezolizumab
FDA approved
5/18/2016
Vinflunine
EMA approved
Durvalumab
breakthrough therapy designation
2/17/2016
Sternberg CN, Yagoda A, et al. Cancer 1989;64: McCaffrey JA, et al. J Clin Oncol 1997;15: von der Maase H, et al. J Clin Oncol 2005;23: Sternberg CN, et al. J Clin Oncol 2001;19: Vaughn DJ, et al. J Clin Oncol 2002;20: Bellmunt J, et al. J Clin Oncol 2009;27: Rosenberg JE, et al. Lancet. 2016;387:
Slide credit: clinicaloptions.com

8. Systemic Therapy for UBC Before 2016
Nonmuscle Invasive
Neoadjuvant
Adjuvant
First-line Metastatic
Next-line Metastatic
No systemic therapy
Gem + cisplatin A-MVAC (cisplatin)
Gem + cisplatin
A-MVAC (cisplatin) or
Gem + carbo
Paclitaxel
Docetaxel
Vinflunine*
Cisplatin
ORR 50% to 60%;
median OS: 15 mos;
1-yr OS: 60%
Carboplatin
ORR: 36%;
median OS: 9 mos;
1-yr OS: 37%
A-MVAC, accelerated methotrexate, vinblastine, doxorubicin, and cisplatin; Carbo, carboplatin; Gem, gemcitabine; UBC, urothelial bladder cancer
ORR: 12% median; OS: 7 mos; *1-yr OS: 26%
Slide credit: clinicaloptions.com
NCCN Guidelines. Bladder cancer. v

9. Systemic Therapy for UBC Now
Nonmuscle Invasive[1]
Neoadjuvant
Adjuvant[1]
First-line Metastatic[1]
Second-line
Metastatic[2]
Next-line Metastatic[1]
No systemic therapy
Gem + cisplatin A-MVAC (cisplatin)
Gem + cisplatin
A-MVAC (Cisplatin) or
Gem + carbo
Atezolizumab
Paclitaxel
Docetaxel
Vinflunine*
Cisplatin
ORR 50% to 60%;
median OS: 15 mos;
1-yr OS: 60%
Carboplatin
ORR: 36%;
median OS: 9 mos;
1-yr OS: 37%
AMVAC, accelerated methotrexate, vinblastine, doxorubicin, and cisplatin; Carbo, carboplatin; Gem, gemcitabine; UBC, urothelial bladder cancer
ORR: 15%;
median OS: 8 mos;
1-yr: OS 37%
ORR: 12% median; OS: 7 mos; *1-yr OS: 26%
1. NCCN Guidelines. Bladder cancer. v Dreicer R, et al. ASCO Abstract 4515.

10. Testing for PD-L1: How Does It Fit Into Clinical Practice?

11. PD-L1 Testing: No Standardized AssayV
ATEZOLIZUMAB[1,2]: Immune Cells Only
PEMBROLIZUMAB[3]
IC, immune cells.
Tumor cells
Tumor + inflammatory cells
1. Rosenberg JE, et al. Lancet. 2016;387: Rosenberg JE, et al. European Cancer Conference Abstract 21LBA. 3. Plimack ER, et al. ASCO Abstract 4502.
Slide credit: clinicaloptions.com

12. PD-L1 and Response in the Postplatinum Therapy Setting
Atezolizumab[1] Phase II
PD-L1, n (%)
ORR CR PR SD PD
IC1/2/3 (n = 207)
37 (18)
13 (6)
24 (12)
34 (16)
107 (52)
All pts (n = 310)
45 (15)
15 (5)
30 (10)
59 (19)
159 (51)
IC0 (n = 103)
8 (8)
2 (2)
6 (6)
25 (24)
52 (50)
Pembrolizumab[2] Phase I basket (n = 33)
PD-L1+ defined as ≥ 1% PDL1 in tumor or stroma by IHC; 100% were positive
Response rate: 28% in PD-L1–positive group, and overall
Nivolumab[3] Phase I basket (n = 78)
PD-L1+ defined as ≥ 1% expression; 37% were positive
Response rate: 24% in PD-L1–positive group, and overall
IC, immune cell; GU, genitourinary; PD, progressive disease; SD, stable disease; TC, T cell.
Durvalumab[4] Phase I basket (n = 42)
PD-L1+ defined as ≥ 25% of TC or IC staining for PD-L1; 66% were positive
Response rate: 46% in PD-L1–positive group; 31% overall
1. Rosenberg JE, et al. Lancet. 2016;387: Plimack ER, et al. ASCO Abstract Sharma P, et al. ASCO Abstract Massard C, et al. ASCO Abstract 4502.
Slide credit: clinicaloptions.com

13. High PD-L1 Level Loses Relevance Across Atezolizumab Studies
Response Rate
0.60
0.50
0.40
0.30
0.20
0.10
Phase I[1]
Phase II (postplatinum)[2]
PD-L1 high (IC 2/3)
PD-L1 low (IC 0/1)
GU, genitourinary; IC, immune cell.
1. Petrylak DP, et al. ASCO Abstract Dreicer R, et al. ASCO Abstract 4515.
Slide credit: clinicaloptions.com

14. PDL1 Low (IC 0/1) Pts Still Respond to Atezolizumab
Response Rate
0.60
0.50
0.40
0.30
0.20
0.10
Phase I[1]
Phase II (postplatinum)[2]
PD-L1 high (IC 2/3)
PD-L1 low (IC 0/1)
Historical
response rate with second-line chemotherapy
~ 12%
GU, genitourinary; IC, immune cell.
1. Petrylak DP, et al. ASCO Abstract Dreicer R, et al. ASCO Abstract 4515.
Slide credit: clinicaloptions.com

15. What Is FDA “Breakthrough Status,” and What Does It Mean for the Future of PD-L1 Inhibitors in Bladder Cancer?

16. FDA “Breakthrough Therapy” Designation
A mechanism of identifying drugs with sufficient early evidence of efficacy to justify a “seamless” development program
Allows for:
Closer communication with the FDA regarding the drug’s development
Review of expansion of “basket” cohorts from phase I or phase II trials for filing consideration
Potential approval based on single-arm data
Requirements:
Serious condition
Lack of existing therapies
Preliminary clinical evidence demonstrating substantial improvement over available therapies with respect to clinically significant endpoints
Subsequent confirmatory data
Slide credit: clinicaloptions.com
Prowell TM, et al. N Engl J Med. 2016;374:

17. “Breakthrough Therapy” Granted to 2 Immunotherapies for Bladder Cancer
Atezolizumab
June 2014
Durvalumab
February 2016
Slide credit: clinicaloptions.com

18. FDA Accelerated Approval
When studying a new drug, it can sometimes take many yrs to learn whether a drug actually provides a real effect
Accelerated approval is allowed for drugs for serious conditions that fill an unmet medical need based on effects on a surrogate or an intermediate clinical endpoint
The drug company will still need to conduct studies to confirm findings related to definitive endpoints (eg, OS) to maintain continued approval
Atezolizumab
FDA approved (accelerated) for bladder cancer in May 2016.
Surrogate endpoint: response rate
Slide credit: clinicaloptions.com

19. When Is the Optimal Time to Introduce Immunotherapy in Bladder Cancer?

20. Atezolizumab: FDA Approved in May 2016 for Bladder Cancer
The first agent in its class approved to treat bladder cancer
Approved for locally advanced or metastatic urothelial carcinoma
Disease progression during or following platinum- based chemotherapy or
Disease progression within 12 mos of neoadjuvant or adjuvant treatment with platinum-based chemotherapy
Accelerated approval may be contingent on confirmatory trials
Slide credit: clinicaloptions.com
Atezolizumab [package insert]

21. FDA Indication for Atezolizumab in Bladder Cancer: Second-line Postplatinum
Agent
RR, %
Median OS, Mos
12-Mo OS, %
Atezolizumab[1] 15 8 37
Docetaxel[2] 13 9
N/A
Paclitaxel[3] 10 7
Vinflunine[4] 26
RR, response rate.
1. Dreicer R, et al. ASCO Abstract 4515.
2. McCaffrey JA, et al. J Clin Oncol. 1997;15:
3. Vaughn DJ, et al. J Clin Oncol. 2002;20:
4. Bellmunt J, et al. J Clin Oncol. 2009;27:
Slide credit: clinicaloptions.com

22. Is Receipt of Chemotherapy Prior to Immunotherapy Important Biologically?
Potential immunogenic effects of chemotherapy
Release of tumor antigens
Translocate CRT to surface of tumor cell, an “eat me” signal to DCs  phagocytosis
Cause secretion of ATP “find me” signal to DCs
Release dsRNA  autonomous secretion of type I interferons “revving” the immune response
Deplete regulatory T cells and/or myeloid-derived suppressor cells
ATP, adenosine triphosphate; CRT, calreticulin; CRTR, calreticulin receptor; DC, dendritic cells; dsRNA, double-stranded RNA.
Slide credit: clinicaloptions.com
Emens LA, et al. Cancer Immunol Res 2015;3:

23. Survival with First-line Gem/Cis vs MVAC in Bladder Cancer (Phase III)
1.0
Gemcitabine + Cisplatin
5-yr PFS 9.8%
5-yr OS 13.0%
0.9
Median OS, Mos
Gem/cis: 14.0 (95% CI: ) MVAC: 15.2 (95% CI: ) HR: 1.09 (P = .44)
0.8
0.7
0.6
Gem/cis MVAC
Proportion Surviving
0.5
0.4
0.3
0.2
0.1
Cis, cisplatin; Gem, gemcitabine; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; 12 24 36 48 60 72 84
Mos
Pts at Risk, n
50 62
36 40
30 34
23 29
7 9
0 1
Gem/cis MVAC
Slide credit: clinicaloptions.com
Von der Maase H, et al. J Clin Oncol. 2005;

24. High-Dose MVAC/G-CSF vs MVAC as First-line Therapy for UC: Survival
7-yr update of phase III EORTC study in advanced TCC (N = 263)
Progression-Free Survival
Overall Survival
HD MVAC ( )
MVAC ( )
100
HD MVAC ( )
MVAC ( )
100
Median, mos 5-yr, % (95% CI)
Median, mos 5-yr, % (95% CI) 80 80 60 60
HR: log-rank P = .017
HR: 0.76
log-rank P = .042
Alive Without Progression (%)
Alive (%) 40 40
Treatment MVAC HD MVAC
Treatment MVAC HD MVAC 20 20
MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; GSCF, granulocyte-stimulating colony factor; HD, high dose; UC, urothelial carcinoma. 2 4 6 8 10 12 2 4 6 8 10 12
Yrs
Yrs O N
Pts at Risk, n 14 32 O N
Pts at Risk, n 32 45
11 22
7 18
4 6
2 0
15 29
11 23
4 8
2 0
5-yr PFS (HD MVAC): ~ 17%
5-yr OS (HD MVAC): 22%
Slide credit: clinicaloptions.com
Sternberg CN, et al. Eur J Cancer. 2006;42:50-54.

25. First-line Gem/Carbo vs M-CAVI in Cisplatin-Ineligible Bladder Cancer: OS
EORTC 30986: randomized phase II/II trial in advanced urothelial cancer (N = 238)
Treatment MCAVI Gem/carbo
First-line Gem/Carbo
ORR: 36%
Median OS: 9.3 mos
1-yr OS: 37%
5-yr OS:
close to zero
100 80
Log-rank test P = .64 60
Survival (%) 40 20
Carbo, carboplatin; Gem, gemcitabine; MCAVI, methotrexate plus carboplatin plus vinblastine 1 2 3 4 5 6 7
Yrs
Treatment MCAVI Gem/carbo O N
Pt at Risk, n 37 44
13 15
7 5
3 2
1 2
1 1
Slide credit: clinicaloptions.com
De Santis M, et al. J Clin Oncol. 2012;30:

26. IMVigor210: First-line Atezolizumab in Cisplatin-Ineligible Advanced Bladder Cancer
Cohort 1 of single-arm phase II trial
Primary endpoint: response
Secondary endpoints: duration of response, PFS, OS, safety, antitherapeutic antibodies, Cmax of atezolizumab
ORR: 24% overall; 28% in PD-L1 IC2/3 group
Median OS: 14.8 mos; 1-yr OS: 57%
Treatment continued until loss of clinical benefit or unmanageable toxicity
Treatment-naive and cisplatin- eligible pts with locally advanced or metastatic UC
(N = 429)
Atezolizumab
1200 mg IV Q3W
Historical comparator: First-line gem/carbo (ORR: 36%; median OS: 9.3 mos; 1-yr OS: 37%)
Carbo, carboplatin; Carbo, carboplatin; Cmax, maximum serum concentration; GU, genitourinary; UC, urothelial carcinoma.
Slide credit: clinicaloptions.com
Balar AV, et al. ASCO Abstract LBA4500.

27. Should PD-1 Pathway Inhibition Be Moved Up to First Line?
For pts eligible for cisplatin: no
No data yet in this setting
Cisplatin provides durable benefit for some, remains standard of care until randomized trials show superiority of PD-1 inhibition
For pts not eligible for cisplatin: not yet
FDA indication for atezolizumab is postplatinum (cisplatin or carboplatin)
Data from cisplatin-ineligible cohort of IMvigor 210 show encouraging median OS of mos and 1-yr OS of 57% vs historical median and 1-yr OS of 9.3 mos and 37% with gemcitabine/carboplatin
Important considerations when evaluating frontline cis-ineligible data
What is efficacy compared to historic controls with gem/carbo?
Is there a toxicity advantage to atezolizumab over gem/carbo?
Is there a longer tail to the OS curve with atezolizumab?
GU, genitourinary; gem, gemcitabine; carbo, carboplatin.
Slide credit: clinicaloptions.com
Balar AV, et al. ASCO Abstract LBA4500.

28. Important Unanswered Questions

29. Ongoing Trials of PD-1 Pathway Inhibitors in Bladder Cancer
Nonmuscle-invasive bladder cancer
Muscle-invasive bladder cancer
Metastatic urothelial cancer
Low grade
High grade
Neoadjuvant
Adjuvant
Cisplatin eligible
Cisplatin ineligible
Atezolizumab
pembro + chemo
Atezolizumab*
nivolumab*
Durvalumab +
tremelimumab*
Pembrolizumab
In development
Pembrolizumab + BCG
First Line
Trimodality
Maintenance
Pembrolizumab
+ RT
Avelumab*
pembrolizumab
Second Line and Beyond
BCG, Bacillus Calmette-Guérin; pembro, pembrolizumab; RT, radiation therapy.
BCG-unresponsive
Platinum refractory
Pembrolizumab
Pembrolizumab vs chemo*
atezolizumab vs chemo*
*Phase III
Slide credit: clinicaloptions.com
Schema adapted from Fakhrejahani F, et al. Curr Opin Urol. 2015;25:

30. Actively Accruing Second-line (and Beyond) Clinical Trials in Metastatic UCIT
No prior
immunotherapy
Chemo
Prior
immunotherapy
allowed
Non IT
combination
Targeted
therapy
UC, urothelial carcinoma; IT, immunotherapy.
Unmet need: Trials specifically tailored to pts who relapse after or are refractory to immunotherapy
Slide credit: clinicaloptions.com
ClinicalTrials.gov.

31. Clinical Issues in Immunotherapy for Bladder Cancer: Conclusions
Checkpoint inhibitors are changing therapeutic landscape for metastatic/advanced UBC
Currently only one approved in platinum-refractory setting outside of a clinical trial
Questionable utility of testing for PD-L1 expression.  No standardized assay
New USFDA pathways allow for early review of single- arm data to determine breakthrough status and potentially accelerated approval of these agents
BCG, Bacillus Calmette-Guérin.
Slide credit: clinicaloptions.com

32. Clinical Issues in Immunotherapy for Bladder Cancer: Conclusions
What is the most appropriate setting for checkpoint inhibition in urothelial carcinoma?
Current indication is postplatinum metastatic
Trials ongoing in frontline for cis-ineligible pts, maintenance for cis-eligible, and nonmetastatic UC
For pts refractory to PD-1 pathway inhibition or who relapse after treatment, few immunotherapy trials exist 
Does prior immunotherapy with one agent preclude response to a different agent or combination regimen?
What is the best approach in this setting?
BCG, Bacillus Calmette-Guérin.
Slide credit: clinicaloptions.com

33. Go Online for More CCO Coverage of Bladder Cancer!
Downloadable slidesets on the clinical application of immunotherapy in bladder cancer On-demand Webcast from the live symposium CME-certified Expert Analysis of key ASCO 2016 abstracts on GU and other malignancies
clinicaloptions.com/oncology