SUBDUE-1: sub-urothelial immunotherapy to balance effectiveness and safety in Bacillus Calmette-Guérin-unresponsive non-muscle invasive bladder cancer?

Hayne and colleagues performed SUBDUE-1, a phase Ib study to explore the safety profile of a sub-urothelial durvalumab injection among bladder cancer patients (1). They recruited 11 patients with chemotherapy- and immunotherapy-naïve [prior Bacillus Calmette-Guérin (BCG) treatment allowed] high-grade localized bladder cancer planned to undergo radical cystectomy. The study included patients with both muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). However, 9 out of the 11 patients recruited had NMIBC, with 4 having prior exposure to BCG. This essentially makes the study at least partially a phase I investigation into BCG-unresponsive NMIBC. Durvalumab was injected in a dose-escalation design into the bladder (either 25, 75 or 150 mg diluted in 25 mL and distributed across 25 grid-like injections at least 2 weeks before the surgery). Cold-cup biopsies from four quadrants and from any tumors were taken immediately before the injection and immediately before the surgery. In addition to pathological and immunohistochemical analyses, the investigators collected patient-reported outcomes as well as blood samples before and after injection.

Using the National Cancer Institute Common Terminology Criteria for Adverse Events (Version 4.0), a total of 14 adverse events were reported: 10 were grade 1, 3 were grade 2, and 1 was grade 3. None of the adverse events were classified as immune-related. The investigators did not observe any significant changes in patient-reported outcomes or circulating immune cell populations but detected a dose-dependent increase in CD69 total macrophages and CD164 M2 macrophages suggesting a local immunological effect.

The authors should be commended for their excellent efforts to investigate the promise of sub-urothelial immune checkpoint inhibitor (ICI) injection as a novel delivery mechanism. The hypothesis of sub-urothelial durvalumab safety has been corroborated in this report. Although one patient with TaHG tumor and concurrent carcinoma in situ (CIS) demonstrated no evidence of disease at cystectomy, SUBDUE-1 was clearly not designed to provide any efficacy signals. It is therefore important to contextualize the SUBDUE-1 results with prior studies that evaluated the systemic and intravesical administration of ICI in BCG-unresponsive non-muscle invasive bladder cancer where efficacy (and safety) were the primary objectives.

Systemic ICI administration in BCG unresponsive NMIBC has been reported in KEYNOTE-057 (2) and SWOG S1605 (3), both of which demonstrated modest efficacy (complete response rate: 41% at 3 months as assessed by cystoscopy/cytology in KEYNOTE-057, 27% at 6 months as assessed by mandatory biopsy in SWOG S1605) with a non-negligible safety profile [treatment-related adverse events (grade ≥3): 13% in KEYNOTE-057, 16% in SWOG S1605]. Notably, three patients (2%) in the SWOG S1605 trial died from treatment-related adverse effects, raising concerns about the risk/benefit ratio of intravenous ICI in this patient population. In contrast, intravesical ICI administration studies among various recurring types of non-muscle invasive bladder cancer (4-6), including BCG-unresponsive disease, have not shown any concerning safety signals with a general lack of treatment-related grade ≥3 adverse events, the single exception being one grade 5 adverse event, a potentially treatment-related myasthenia gravis (pembrolizumab/BCG in NCT02808143). Unfortunately, these intravesical studies either were not designed to demonstrate efficacy, demonstrated poor efficacy or have not yet published their final results, leaving the utility of intravesical ICI unanswered.

As the safety profile of sub-urothelial durvalumab seems to be more comparable to that of intravesical ICI administration, one might hypothesize limited anti-tumor activity in future phase II studies. Such a pessimistic interpretation may not be justified given the preclinical data associated with sub-urothelial/intra-tumoral ICI injection. For example, Van Hooren and colleagues (7) studied ICI (CTLA-4) injections in mice with orthotopic bladder cancer. They performed ultrasound-guided intratumoral CTLA-4 antibody injections and demonstrated tumor regression with more than tenfold reduction in systemic antibody levels in comparison to intravenous or subcutaneous administration. These data, along with those from SUBDUE-1, suggest the need for future phase II evaluation.

However, even if a future phase II study is successful in demonstrating that the sub-urothelial administration of durvalumab can sufficiently unleash the immune system for an anti-neoplastic response, the next challenge for such a therapy would be to compete in the space of BCG-unresponsive non-muscle invasive bladder cancer. While it is not impossible to reach the single-arm efficacy thresholds used by the United States Food and Drug Administration (FDA) to grant approval in this disease space (complete response of 40–50% at 6 months and at least 30% at 18–24 months for BCG unresponsive CIS) (8), cost-effectiveness may prove challenging. Furthermore, as more agents become FDA-approved and established in the BCG unresponsive space, it is very possible that the FDA will change its registration policies by asking for randomized controlled studies to be performed. Potential comparators could be systemic pembrolizumab (efficacy/safety discussed earlier) (2), the other FDA-approved agents intravesical nadofaragene firadenovec (46% high-grade recurrence-free survival at 12 months; 4% grade ≥3 adverse events) (9) and intravesical nogapendekin alfa inbakicept plus BCG (45% complete response at 12 months; safety: 2% grade ≥3 adverse events) (10) or off-label use of sequential gemcitabine/docetaxel (67% high-grade recurrence-free survival at 12 months within BCG-unresponsive cohort; no grade ≥3 adverse events) (11).

Despite the aforementioned limitations and anticipated challenges ahead, we are very curious to see the results of a potential phase II study exploring the promising hypothesis of sub-urothelial ICI administration in BCG-unresponsive non-muscle invasive bladder cancer.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-143/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-143/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Hayne D, Ong K, Swarbrick N, et al. The SUB-urothelial DUrvalumab InjEction-1 (SUBDUE-1) trial: first-in-human trial in patients with bladder cancer. BJU Int 2024;134:283-90. [Crossref] [PubMed]
2. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol 2021;22:919-30. [Crossref] [PubMed]
3. Black PC, Tangen CM, Singh P, et al. Phase 2 Trial of Atezolizumab in Bacillus Calmette-Guérin-unresponsive High-risk Non-muscle-invasive Bladder Cancer: SWOG S1605. Eur Urol 2023;84:536-44. [Crossref] [PubMed]
4. Woodcock VK, Chen JL, Purshouse K, et al. PemBla: A Phase 1 study of intravesical pembrolizumab in recurrent non-muscle-invasive bladder cancer. BJUI Compass 2023;4:322-30. [Crossref] [PubMed]
5. Meghani K, Cooley LF, Choy B, et al. First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin. Eur Urol 2022;82:602-10. [Crossref] [PubMed]
6. Fragkoulis C, Fragkiadis E, Sakellakis M, et al. Intravesical administration of durvalumab to patients with high risk non muscle invasive bladder cancer after BCG failure. A phase II trial by the Hellenic GU Cancer Group. Eur Urol 2023;83:S604. [Crossref]
7. van Hooren L, Sandin LC, Moskalev I, et al. Local checkpoint inhibition of CTLA-4 as a monotherapy or in combination with anti-PD1 prevents the growth of murine bladder cancer. Eur J Immunol 2017;47:385-93. [Crossref] [PubMed]
8. Jarow JP, Lerner SP, Kluetz PG, et al. Clinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop. Urology 2014;83:262-4. [Crossref] [PubMed]
9. 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. Lancet Oncol 2021;22:107-17. [Crossref] [PubMed]
10. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer. NEJM Evid 2023;2:EVIDoa2200167.
11. Chevuru PT, McElree IM, Mott SL, et al. Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer. Urol Oncol 2023;41:148.e1-7. [Crossref] [PubMed]