In our recently published article,2 we conducted a narrative review of the literature to summarize the rationale and outcomes of clinical trials investigating ICIs and novel targeted approaches for both BCG-naïve and BCG-unresponsive disease. Despite NMIBC has been less investigated as compared to muscle-invasive disease, it has been recognized also as an immunogenic tumor, and PD-1/PD-L1 expression has been shown to correlate to higher tumor grade, increased risk of recurrence, and lower response to BCG therapy.3–5
The pivotal study of systemic IO in BCG-unresponsive NMIBC was the KEYNOTE-057.6 The encouraging results of this trial led to the FDA-approval of pembrolizumab for NMIBC patients harboring carcinoma in situ (CIS), as 40.6% (95% CI: 30.7–51.1) of patients achieved a 3-mo complete response (CR) with a median duration of response of 16.2 months. Moreover, pembrolizumab systemic treatment was safe as it was related only to 12.7% grade 3-4 adverse events (AEs) according to Clavien-Dindo (C-D) classification. In a similar cohort of high-risk BCG-unresponsive NMIBC with or without CIS, the phase II trial SWOG 1605 is testing atezolizumab.7 In a subset of 75 patients with CIS, 41.1% (95% CI: 29.7%–53.2%) and 26% (95% CI: 16.5%–37.6%) experienced a 3-mo and 6-mo CR, respectively. AEs were identified in 83.6% of patients, with 12.3% developing grade 3-5 C-D complications and one treatment-related death. Based on the results of KEYNOTE-057 and SWOG1605 trials, many other studies are currently exploring IO for BCG-unresponsive disease, evaluating ICIs alone or in association with other therapies.
With the aim to obtain similar oncological outcomes, while avoiding common immune-related AEs due to systemic treatment, other clinical trials are testing the effect of ICIs alone or combined with other drugs also by intravesical administration. Particularly, intravesical gene therapy has been implemented to find new therapeutic solutions for bladder cancer treatment in the last few years. For instance, NCT02365818 and NCT04452591 trials are currently evaluating the safety and efficacy status of CG0070, a tumor-selective adenovirus that encodes granulocyte-monocyte colony-stimulating factor (GM-CSF) and preferentially replicates in bladder cancer cells with defective retinoblastoma-1 tumor suppressor protein. Similarly, following the results of the phase II NCT01687244 trial, the non-replicating recombinant adenovirus gene transfer vector rAd-IFN/Syn-3 (Nadofaragene firadenovec) consisting of the human interferon-α-2b (IFN-α-2b) gene with the excipient Syn-3, has been tested in a phase III trial. At 12-mo, among patients with CIS (n = 103), 25 (24.3%) (95%CI, 16.4–33.7) maintained CR, while in the high-grade Ta or T1 cohort (n = 48), 21 patients (43.8%) (95% CI, 29.5–58.8) were free from high-grade recurrence.8 Results from trials testing novel treatment options in patients who failed BCG therapy also triggered the research in the BCG-naïve setting. Although there are no results available, several ongoing trials, testing different ICIs treatment combinations, are currently enrolling BCG-naïve patients, as shown in Table 1.
Table 1. Clinical trials testing ICIs for BCG-naïve patients
We are about to enter an exciting time also for NMIBC treatment, providing soon novel therapies to improve quality of life and possibly survival outcomes. However, critical information is still required prior to define a new standard-of-care in real-world practice. For instance, long-term safety data of novel targeted therapies in early-disease patients are immature, and the impact of the associated costs for the healthcare system, compared to RC, is lacking. Moreover, although targeted therapies may guarantee a better quality of life for NMIBC patients as compared to RC, these drugs are associated with high rates of AEs. Therefore, randomized phase III trials will be necessary also for NMIBC to offer reliable bladder-sparing solutions.
Written by: Giuseppe Basile,1 Filippo Pederzoli,1 Marco Bandini,1 Daniele Raggi,4 Andrea Gallina,1 Andrea Salonia,1 Alberto Briganti,1 Francesco Montorsi,1 Philippe E. Spiess2, and Andrea Necchi3,4
1Urological Research Institute (URI), Unit of Urology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy; 2Moffitt Cancer Center and Research Institute, Tampa, FL, USA;3San Raffaele Hospital and Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; 4Fondazione IRCCS Istituto Nazionale dei Tumori
- Babjuk M, Burger M, Compérat EM, et al. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. European Urology. 2019;76(5):639-657. doi:10.1016/j.eururo.2019.08.016
- Basile G, Pederzoli F, Bandini M, et al. Intermediate- and high-risk nonmuscle invasive bladder cancer: Where do we stand? Urologic Oncology: Seminars and Original Investigations. Published online March 2021. doi:10.1016/j.urolonc.2021.02.020
- Bellmunt J, Mullane SA, Werner L, et al. Association of PD-L1 expression on tumor-infiltrating mononuclear cells and overall survival in patients with urothelial carcinoma. Annals of Oncology. 2015;26(4):812-817. doi:10.1093/annonc/mdv009
- Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: Associations with localized stage progression. Cancer. 2007;109(8):1499-1505. doi:10.1002/cncr.22588
- Hashizume A, Umemoto S, Yokose T, et al. Enhanced expression of PD-L1 in non-muscle-invasive bladder cancer after treatment with Bacillus Calmette-Guerin. Oncotarget. 2018;9(75):34066-34078. doi:10.18632/oncotarget.26122
- Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057. Journal of Clinical Oncology. 2020;38(15_suppl):5041-5041. doi:10.1200/jco.2020.38.15_suppl.5041
- Black PC, Tangen C, Singh P, et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). Journal of Clinical Oncology. 2020;38(15_suppl):5022-5022. doi:10.1200/jco.2020.38.15_suppl.5022
- Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. The Lancet Oncology. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4
Read the Abstract