Bladder

Raising Expectations in Bladder Cancer Treatment

UNMET NEED

Bladder cancer is the sixth most common cancer in the US2

79,030 new cases estimated in 20172

90% of bladder cancers are urothelial carcinomas (UCs)3

Percentage of all bladder tumors at diagnosis2

Non–muscle-invasive bladder cancer (NMIBC) - 51%

Muscle-invasive bladder cancer (MIBC) - 41%

Metastatic urothelial carcinoma (mUC) - 4%

For patients with bladder cancer, outcomes have not improved over the last two decades2

Challenges remain at each stage of treatment

NMIBC

31% to 78% of patients with NMIBC will experience a recurrence or new occurrence of UC within 5 years4

MIBC

The standard of care for MIBC comprises of cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy and bilateral pelvic lymph node dissection. High metastatic relapse rates still occur after radical cystectomy, which indicates that MIBC is a systemic disease at diagnosis in many patients5

mUC

The current 1L treatment recommendation is cisplatin-based combination chemotherapy, which places a toxic burden on patients. Only one immunotherapy agent is listed as category 1 for 2L mUC, according to NCCN guidelines6

TAKE A DEEPER LOOK at the unmet needs in the management of bladder cancer

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HARNESSING THE IMMUNE SYSTEM

The mutational burden of bladder cancer may be associated with increased immunogenic response

Bladder cancer has the fourth highest mutational burden among several tumor types.7

There is a need to enhance the body’s natural immune response in bladder cancer.10

Various immune-based antitumor approaches are being explored11,12

vaccine

Therapeutic vaccines

Antigens introduced into the body resulting in an immune response, activating cytotoxic T cells or inducing antibody production13

vaccine

Innate immune cell activation

Modulating immune response by targeting effector immune cells and antigen-presenting cells, thus initiating a T-cell immune response14

vaccine

Oncolytic viruses

Oncolytic viruses are injected into the tumor site, directly killing tumor cells and inducing a systemic immune response15,16

vaccine

Immune checkpoint inhibitors

Targets key immune checkpoints to harness the innate immune response to eliminate tumor cells14

The path forward with immune checkpoint inhibitors

Immune checkpoint inhibitors, such as PD-L1 and CTLA-4, are the most widely studied systemic immune-based approach for the treatment of bladder cancer.17 Currently, there are five immune checkpoint inhibitors approved to treat metastatic UC.18 There are several ongoing clinical trials of checkpoint inhibitors in either monotherapy or combination therapy in earlier lines or stages of disease.19

New Understandings in Bladder Cancer and the Role of the Immune System

New Understandings in Bladder Cancer and the Role of the Immune System

NCCN=National Comprehensive Cancer Network; PD-L1=programmed cell death ligand-1; CTLA-4=cytotoxic T-lymphocyte–associated antigen 4.

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

References

1. FDA approves new, targeted treatment for bladder cancer [press release]. Silver Spring, MD: Food and Drug Administration; May 18, 2016. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm501762.htm. Accessed June 26, 2017. 2. National Cancer Institute. Cancer stat facts: bladder cancer. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed June 26, 2017. 3. Cancer.net. Bladder cancer. http://www.cancer.net/cancer-types/bladdercancer/. Accessed June 26, 2017. 4. Sylvester RJ, Van der meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466-475. 5. Funt SA, Rosenberg JE. Systemic, perioperative management of muscle-invasive bladder cancer and future horizons. Nat Rev Clin Oncol. 2017;14(4):221-234. 6. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer v.5.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed June 26, 2017. To view the most recent and complete version of the guidelines, go online to NCCN.org. 7. Rajasagi M, Shukla SA, Fritsch EF, et al. 2014. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood. 2014;124(3):453-462. 8. Choudhury NJ, Kiyotani K, Yap KL, et al. Low T-cell receptor diversity, high somatic mutation burden, and high neoantigen load as predictors of clinical outcome in muscle-invasive bladder cancer. Eur Urol Focus. 2016;2(4):445-452. 9. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471): 333-339. 10. Intlekofer AM, Thompson CB. At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. J Leukoc Biol. 2013;94(1):25-39. 11. Muthigi A, George AK, Brancato SJ, Agarwal PK. Novel immunotherapeutic approaches to the treatment of urothelial carcinoma. Ther Adv Urol. 2016;8(3):203-214. 12. ClinicalTrials.gov. A phase 1/2 study of in situ vaccination with tremelimumab and IV durvalumab plus polyICLC in subjects with advanced, measurable, biopsy-accessible cancers. https://clinicaltrials.gov/ct2/show/NCT02643303. Accessed June 28, 2017. 13. National Cancer Institute. Cancer vaccines. https://www.cancer.gov /about-cancer/causes-prevention/vaccines-fact-sheet. Accessed July 18, 2017. 14. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73. 15. Hoos A. Development of immuno-oncology drugs—from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov. 2016;15(4):235–247. 16. Chiocca EA, Rabkin SD. Oncolytic viruses and their application to cancer immunotherapy. Cancer Immunol Res. 2014;2(4):295–300. 17. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=Bladder+Cancer&term=astrazeneca&cntry1=&state1=&Search=Search&recrs=a. Accessed June 28, 2017. 18. National Cancer Institute. FDA approves immunotherapy drugs for patients with bladder cancer. https://www.cancer.gov/newsevents /cancer-currents-blog/2017/approvals-fda-checkpoint-bladder. Accessed July 18, 2017. 19. AstraZeneca. Clinical trials appendix Q1 2017 results update. https://www.astrazeneca.com/content/dam/az/PDF/2017/QR1/Q1_2017_Results_Clinical_Trial_Appendix.pdf. Accessed July 7, 2017.