Unmet need in bladder cancer
Bladder cancer is the 4th most common form of cancer in men in the US. Four times more men are diagnosed with bladder cancer than women. The median age of diagnosis is 73 years old1. In 2023 there will be 82,290 new cases1.
75% of bladder cancer is non-muscle invasive bladder cancer (NMIBC) and 25% is classified as muscle invasive bladder cancer (MIBC).
Bladder cancer is a highly recurrent and progressive disease that is costly to the health care system because of the intense follow up schedule.
Staging of Bladder Cancer:
Non-muscle Invasive Bladder Cancer (NMIBC):
Patients with high-grade NMIBC, are treated with surgical removal of their lesions and intravesical treatment with BCG2. There is a great need for a local, well tolerated, and effective bladder preserving option for patients with intermediate risk as well as high risk BCG unresponsive NMIBC. In 70% of patients with BCG unresponsive disease, BCG fails to treat the disease. FDA approved therapeutic options that are available are Valrubicin and KEYTRUDA® A ADSTILADRIN® C was approved by the FDA in December 2022, but it is not currently available. Valrubicin received approval in 1998, but reported low response rates and durability of response. In 2020, KEYTRUDA® A, a systemic treatment received approval, however, it has not been widely adopted due to unfavorable toxicity. This leaves most patients with their only treatment option being bladder removal (cystectomy). Cystectomy is associated with negative outcomes, mortality, and a reduced quality of life4,5,6,7. Ninety (90) days following discharge after cystectomy, 80% of patients have complications and 37% of those are major complications7. There is a 20%-30% readmissions rate within 30 days, a 3%-4% morbidity rate at 90 days following cystectomy. In fact, only 6% of eligible patients with BCG unresponsive disease undergo a cystectomy, with high-grade T1 disease4,5,6,7. Patients report preferring bladder preservation, and in many cases due to co-morbid conditions, are not eligible for such a demanding surgery3. For more information on bladder cancer go to Bladder Cancer Advocacy Network at www.BCAN.org.
In Studies in patients with BCG unresponsive NMIBC:
Cretostimogene grenadenorepvec (CG0070) is being investigated in a global Phase 3 trial (BOND-003) as a monotherapy for the treatment of BCG-unresponsive, Non-Muscle Invasive Bladder Cancer (NMIBC). Most patients with high-risk NMIBC (CIS with or without Ta/T1, Ta or T1) who do not respond to BCG intravesical therapy (standard of care). For information on Bond-003 study design click on image from the video. For information on the study click here.
Muscle Invasive Bladder Cancer (MIBC):
Approximately 20% of newly diagnosed bladder cancer cases are MIBC2. Up to 45% of high-risk NMIBC patients progress to MIBC within 5 years2,8. Annual cost of care is 70% higher for MIBC than yearly cost of care for NMIBC patients9. Delaying progression is significant because MIBC is associated with higher mortality. The 5-year mortality rates for T2, T3, and T4 patients are 56%, 72%, and 91% respectively2,8. Cisplatin is the cornerstone of neoadjuvant chemotherapy, though up to 50% MIBC patients are cisplatin-ineligible due to decreased renal function, and neuropathy11. Checkpoint therapy has become the standard-of-care for patients who are cisplatin ineligible and have high PD-L1 expression11,12,13,14. Pathological Complete Response (pCR) rate is a surrogate for survival in MIBC patients treated with neoadjuvant therapy. For more information on bladder cancer go to Bladder Cancer Advocacy Network at www.BCAN.org
Combination Trial for the Treatment of MIBC:
Cretostimogene grenadenorepvec (CG0070) is also in a single-arm, multi-center trial Phase 1b study (CORE-002), to evaluate the safety and efficacy of the neo-adjuvant combination of cretostimogene grenadenorepvec (CG0070) plus OPDIVO® B(nivolumab) in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for cisplatin-based chemotherapy. Primary endpoints of the trial will be safety and pathological complete response rate.
Unique Mechanism of Action
1. Cancer of the Urinary Bladder – Cancer Stat Facts. SEER. https://seer.cancer.gov/statfacts/html/urinb.html. Accessed October, 2022.
2. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, Pruthi R, Quale DZ, Ritch CR, Seigne JD, Skinner EC, Smith ND, McKiernan JM (2016). Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 196:1021-1029.
3. Mossanen M, Wang Y, Szymaniak J, et al. Evaluating the cost of surveillance for non-muscle-invasive bladder cancer: an analysis based on risk categories. World J Urol. 2019;37(10):2059-2065.
4. Berger I, Xia L, Wirtalla C, Dowzicky P, Guzzo TJ, Kelz RR. 30-day readmission after radical cystectomy: Identifying targets for improvement using the phases of surgical care. Can Urol Assoc J. 2018;13(7):E190-e201.
5. Sadowski DJ, Warner H, Scaife S, McVary KT, Alanee SR. 30-day all-cause hospital readmission after cystectomy: No worse for rural Medicare residents. Urol Oncol. 2018;36(3):89.e87-89.e11.
6. Pak JS, Lee JJ, Bilal K, Finkelstein M, Palese MA. Utilization trends and short-term outcomes of robotic versus open radical cystectomy for bladder cancer. Urology. 2017;103:117-123.
7. Maiboma SL, Poulsena AM, Thind PO, Sallinga ML, Sallinga LN, Kehletb H, Brassoa K, Joensena UN, (2021). Morbidity and Days Alive and Out of Hospital Within 90 Days Following Radical Cystectomy for Bladder Cancer. European Journal of Urology 28(28) 1-8. www.sciencedirect.com
8. Richard J Sylvester 1, Adrian P M van der Meijden, Willem Oosterlinck, J Alfred Witjes, Christian Bouffioux, Louis Denis, Donald W W Newling, Karlheinz Kurth. 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 Uro. 2006 Mar;49(3):466-5; discussion 475-7. doi: 10.1016/j.eururo.2005.12.031. Epub 2006 Jan 17.
9. K D Sievert 1, B Amend, U Nagele, D Schilling, J Bedke, M Horstmann, J Hennenlotter, S Kruck, A Stenzl. Economic aspects of bladder cancer: what are the benefits and costs? World J Urol. 2009 Jun;27(3):295-300. doi: 10.1007/s00345-009-0395-z. Epub 2009 Mar 7.
10. Atreya Dash 1, Matthew D Galsky, Andrew J Vickers, Angel M Serio, Theresa M Koppie, Guido Dalbagni, Bernard H Bochner Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder Cancer. 2006 Aug 1;107(3):506-13. doi: 10.1002/cncr.22031.
11. Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucianò R, Colecchia M, Giannatempo P, Mortarini R, Bianchi M, Farè E, Monopoli F, Colombo R, Gallina A, Salonia A, Messina A, Ali SM, Madison R, Ross JS, Chung JH, Salvioni R, Mariani L, Montorsi F. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study J Clin Oncol. 2018 Dec 1;36(34):3353-3360. doi: 10.1200/JCO.18.01148. Epub 2018 Oct 20.
12. Powles, T., Kockx, M., Rodriguez-Vida, A. et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab inoperable urothelial carcinoma in the ABACUS trial. Nat Med 25, 1706–1714 (2019). https://doi.org/10.1038/s41591-019-0628-7
13. van Dijk, Nick, et al. “Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial.” Nature Medicine 26.12 (2020): 1839-1844. https://doi.org/10.1038/s41591-020-1085-z.
14. Gao, J., Navai, N., Alhalabi, O. et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med 26, 1845–1851 (2020). https://doi.org/10.1038/s41591-020-1086-y
A KEYTRUDA is a registered trademark of Merck Sharp and Dohme.
B OPDIVO is a registered trademark of Bristol-Myers Squibb Company.
C ADSTILADRIN is a trademark of FERRING B.V.