(UroToday.com) Dr. J. Alfred Witjes kicked off the thematic session of immunotherapy in urothelial cancer with a talk on non-muscle invasive bladder cancer (NMIBC). Below I highlight his key points.
Immunotherapy for NMIBC has a long history. This is the first cancer treated with immunotherapy. It all started with the creation of BCG by Albert Calmette and Camille Guerin. In 1976, Morales notes a 12-fold reduction in recurrence in 9 bladder cancer patients (he used 6 doses in 6 weeks because that’s all he was able to get from the company!). In 1977 and 1980, Lamm reported successes in controlled animal studies and a successful randomized controlled trial (SWOG). In the 1980s-90’s, there were multiple RCTs demonstrating the BCG was superior to chemotherapy (SWOG, EORTC, CUETO, Nordic, Finnbladder).
To date, while we know that the immune system is involved to clear mechanism of action of BCG is not known. It does involve recruitment of both immune cells (macrophages, neutrophils) but also cytokines. Regardless BCG remains the first-line therapy for NMIBC.
Alternative historical options (historical):
1. BCG+Interferon – was the North American standard for BCG failure, but only had one good phase 2 study and the results were never validated in a larger study.1
2. Sequential MMC/BCG – in Finnbladder IV study, sequential MMC/BCG was better than alternating BCG/IFN
3. BCG variations to lower side effects
a. Mycobacterium cell wall nucleic acid complex - Morales et al.2 – 35% 1-year DFS. No active mycobacterium, so less toxic. But also less effective.
b. Several gamma-irradiated mycobacteria – induced antitumor activity in vivo. Less toxic. But also less effective.
4. Mistletoe extract – Rose et al.3
- Phase 1 dose escalation study.
- 1 year recurrence rate was 26.3%
- phase 3 study launched
5. Diptheria Toxin=A BC-819
- 6 week induction and 1 week maintenance
- 33% CR of marker lesion, 64% with no new recurrence
6. KLH (vs MMC) – RCT that looked at KLH vs. MMC for intermediate/high risk NMIBC
- RFS was better with MMC
- Progression was uncommon in both arms
7. Bropirimine – oral IFN signaling inducer
- Witjes et al.4 – 92% CR rate vs. 100% for BCG
- No additional effect with BCG
Unfortunately, never pursued further.
8. Imiquimod – safe, mild toxicity. Stopped at a phase 1 trial.
Current alternative options:
1. Instilladrin (nadoferagene firadenovac): non-replicating adenoviral vector with human IFN-a2b gene and Syn3 à incorporation of virus into cellular DNA à synthesis and expression
- 1 intravesical instillation per 3 months, for up to 12 months
- Phase 3 results5 demonstrate 53.4% CR at 3 months. 45% maintained CR. Relatively low toxicity
- Better results in papillary tumors
2. Checkpoint inhibitors – pembrolizumab
- Keynote 0576 – IV treatment q3weeks for 2 years. 38.8% CR at 3 momths, of which 72.5% remained CR at 14 months.
Some ongoing trials:
15 ongoing trials for BCG non-responders (5 in BCG naïve)
- There are numerous other checkpoint inhibitor trials ongoing for NMIBC
- Includes monotherapy, combination IO/IO therapy and IO therapy with radiation
Presented by: J. Alfred Witjes, MD, Ph.D., Full professor at the Radboud Institute for Molecular Life Sciences, Faculty of Medical Sciences, Chair of Oncological Urology, Radboud University Medical Centre, Nijmegen, Netherlands
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.
References:
1. Rosevear HM, Lightfoot AJ, Birusingh KK, et al.; National BCG/Interferon Investigator Group. Factors affecting response to bacillus Calmette-Guérin plus interferon for urothelial carcinoma in situ. J Urol. 2011 Sep;186(3):817-23. doi: 10.1016/j.juro.2011.04.073. Epub 2011 Jul 23. PMID: 21788050.
2. Morales A, Herr H, Steinberg G, et al.. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette-Guérin. J Urol. 2015 Apr;193(4):1135-43. doi: 10.1016/j.juro.2014.09.109. Epub 2014 Oct 5. PMID: 25286009.
3. Rose A, El-Leithy T, vom Dorp F., et al. Mistletoe Plant Extract in Patients with Nonmuscle Invasive Bladder Cancer: Results of a Phase Ib/IIa Single Group Dose Escalation Study. J Urol. 2015 Oct;194(4):939-43. doi: 10.1016/j.juro.2015.04.073. Epub 2015 Apr 22. PMID: 25910967.
4. Witjes WP, König M, Boeminghaus FP, et al.. Results of a European comparative randomized study comparing oral bropirimine versus intravesical BCG treatment in BCG-naive patients with carcinoma in situ of the urinary bladder. European Bropirimine Study Group. Eur Urol. 1999 Dec;36(6):576-81. doi: 10.1159/000020051. PMID: 10559611.