Bladder cancer is the fourth most common malignancy in the United States, with 81,180 new cases diagnosed in 2022.¹ Between 75% and 80% of newly diagnosed bladder cancer cases are nonmuscle-invasive bladder cancer (NMIBC). In NMIBC, the tumor is localized to the bladder’s inner lining and does not involve the deeper muscle layers.2 The estimated 5-year survival rate for NMIBC is 96%, and the main goals of treatment are to prevent recurrence and progression to muscle-invasive bladder cancer or metastatic disease while preserving health-related quality of life.^1,2

First-line Treatment of Nonmuscle-invasive Bladder Cancer: Opportunities and Challenges

Initial management of nonmuscle-invasive bladder cancer (NMIBC) depends primarily on risk stratification subsequent to transurethral resection of bladder tumor.^2,3 Single-instillation perioperative intravesical chemotherapy is preferred for low-risk disease, induction intravesical therapy for intermediate-risk disease, and radical cystectomy or induction intravesical bacillus Calmette-Guérin (BCG) followed by maintenance instillations for high-risk (HR) NMIBC.⁴

NMIBC is clinically and pathologically heterogeneous, which contributes to wide variability in the risk of progression and recurrence after treatment.⁴ Although 70%-75% of patients with HR-NMIBC have complete response (CR) to BCG therapy, nearly half develop recurrence or become BCG-unresponsive.^5,6 Approximately 20% of patients treated with BCG have progression to muscle-invasive disease within 48 months.⁵

As a result of an ongoing global shortage of BCG, patients may receive fewer courses of BCG or experience delays in BCG therapy, exacerbating their risks of recurrence and progression.^2,5 Radical cystectomy and pelvic lymph node dissection is an alternative to BCG and is preferred for patients with very HR features or after BCG failure, but it is associated with significant perioperative morbidity and impact on quality of life.^2,7 Given the national BCG shortage and the concerning complications of radical cystectomy, more effective and better-tolerated therapies for HR-NMIBC are urgently needed.

The Evolving Role for Immune Checkpoint Inhibitors in HR-NMIBC

In January 2020, the Food and Drug Administration approved single-agent pembrolizumab, an immune checkpoint inhibitor (ICI) that targets programmed cell death protein 1(PD-1), for patients with BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors (Ta/T1) for patients who are not eligible for, or refuse, radical cystectomy.⁵ Approval was based on results of the phase 2 KEYNOTE-057 trial, which established pembrolizumab’s antitumor activity in a difficult-to-treat cohort of 96 patients with BCG-unresponsive CIS who refused or were ineligible for radical cystectomy. Overall, 41% of patients had a CR at 3 months, 46% of whom maintained a CR for at least 1 year.⁶ National Comprehensive Cancer Network (NCCN) bladder cancer guidelines include pembrolizumab as an option for select patients with BCG-unresponsive CIS.²

PD-1 is an immune checkpoint receptor expressed on activated T cells that mediates immune responses. Binding of programmed death-ligand 1(PD-L1) to PD-1 on immune cells inhibits T-cell activity and promotes cancer cell survival.⁸ In NMIBC, dysregulation of the PD-1/PD-L1 pathway is associated with recurrence, progression, and BCG resistance.⁹ PD-L1 expression is upregulated in patients with bladder cancer, and human studies have observed correlations between higher levels of PD-L1 in bladder cancer and lower rates of 5-year recurrence-free and overall survival.^8,9

BCG therapy appears to increase PD-L1 expression in bladder cancer tissue significantly, especially in patients with BCG-unresponsive tumors.^8,9 Thus, an emerging strategy for NMIBC is to combine PD-1/PD-L1 pathway blockade with BCG therapy. In preclinical studies, the combination exhibited potent antitumor activity.⁸ Ongoing clinical trials are evaluating whether adding an anti-PD-1 or PD-L1 ICI to BCG therapy can improve outcomes in people with HR-NMIBC in the first line and beyond (Table 1).

Table 1. Select Ongoing Phase 3 Trials of bacillus Calmette-Guérin Therapy Plus Programmed Cell Death Protein-1/Programmed Death-ligand 1 Blockade for High-risk Nonmuscle-invasive Bladder Cancer (ClinicalTrials.gov)

Other Emerging Immunotherapy Approaches in HR-NMIBC

In December 2022, the Food and Drug Administration approved nadofaragene firadenovec-vncg gene therapy for adults with BCG-unresponsive HR-NMIBC with CIS.¹⁰ Nadofaragene firadenovec uses a nonreplicating adenovirus vector to deliver a copy of the human interferon alfa-2b gene to urothelial cells.⁷ It is administered intravesically once every 3 months.¹⁰ Approval was based on findings from Study CS-003, a phase 3 single-arm trial that included 98 evaluable patients with BCG-unresponsive HR-NMIBC with CIS.¹⁰ Overall, 51% of patients achieved a CR, 46% of whom maintained a CR for at least 1 year. NCCN guidelines include nadofaragene firadenovec as an option for HR-NMIBC after BCG failure in patients with CIS with or without papillary carcinoma or without CIS but with high-grade papillary Ta/T1-only tumors.²

Other novel immunotherapy strategies are in various stages of development for HR-NMIBC. Ongoing clinical trials are evaluating gene therapies, anticancer vaccines, targeted agents, and ICI-based approaches (Table 2).

Table 2. Select Trials of Novel Immunotherapy Strategies for High-risk Nonmuscle-invasive Bladder Cancer (ClinicalTrials.gov)

Salvage Therapy for BCG-unresponsive NMIBC

The Figure outlines salvage options for BCG-unresponsive NMIBC. It is based on recently published data and current NCCN guidelines, and incorporates approved and investigational approaches.

Urologists Should Consider a Multi- and Interdisciplinary Team Approach to Management of NMIBC With Immunotherapy

Incorporating immunotherapy for NMIBC into real-world clinical practice requires careful planning and honest balanced discussions with partners, care teams, and colleagues across disciplines to enable informed shared decision-making. It is important for urologists and other clinicians involved in treatment planning and patient management to understand best practices for immunotherapy use in NMIBC, including educating and monitoring patients, as well as identifying and carefully managing adverse events.

Urologists should establish partnering relationships with representatives from specialties including medical and radiation oncology, pathology, radiology, nursing, and oncologic pharmacy, among others. Maintaining these multidisciplinary relationships is critical for optimizing patients’ experiences, satisfaction, and clinical outcomes.¹¹

Disclosures

Petros Grivas, MD, PhD: Consultant or advisor for 4D Pharma, Aadi Bioscience, Astellas, Asieris Pharmaceuticals, AstraZeneca, BostonGene, Bristol Myers Squibb, CG Oncology, Dyania Health, Exelixis, Fresenius Kabi, Genentech, Gilead Sciences, Guardant Health, ImmunityBio, Infinity Pharmaceuticals, Janssen, Lucence, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, PureTech, QED Therapeutics, Regeneron, Roche, Seattle Genetics, Silverback Therapeutics, Strata Oncology, UroGen Pharma. Institutional research funding from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm Group, G1 Therapeutics, Gilead Sciences, GlaxoSmithKline, Merck KGaA, Mirati Therapeutics, MSD, Pfizer, QED Therapeutics. Noah M. Hahn, MD: Consultant or advisor for AstraZeneca, Merck, EMD Serono, Seattle Genetics, Incyte, Janssen, Pfizer, BioGears, Protara Therapeutics, Verity Pharma, Astellas, Natera, Mirati, Trya Biosciences, ImmunityBio; Institutional research funding from AstraZeneca, Incyte, Inovio, Genentech, BMS, Merck, Seattle Genetics, Astex, Ikena Oncology, CG Oncology, HTG Molecular Diagnostics. Neal Shore, MD, FACS: Consultant or advisor for AbbVie, Alessa, Arquer, Astellas, Astra Zeneca, Bayer, BMS, Clarity, Cold Genesys, Dendreon, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, Photocure, Pfizer, Promaxo, Protara, Sanofi, SesenBio, Telix, Tolmar, Vaxiion; Speaker or speakers bureau: Bayer, Astellas, Janssen, Pfizer; Institutional research funding and served as contracted research for AbbVie, Alessa, Arquer, Astellas, Astra Zeneca, Bayer, BMS, Clarity, Cold Genesys, Dendreon, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Merck, Minomic, Myovant, Myriad, NGM, Nonagen, Novartis, Photocure, Pfizer, Promaxo, Protara, Sanofi, SesenBio, Telix, Tolmar, Vaxiion.