Bladder cancer is a prevalent and burdensome cancer, with nearly 83,000 new diagnoses expected in 2021.1 Approximately 75% of patients present with localized, non–muscle-invasive bladder cancer (NMIBC).¹ The current standard of care for intermediate- and high-risk NMIBC is resection of all visible disease followed by induction intravesical treatment with bacillus Calmette-Guérin (BCG), and then maintenance therapy for up to 3 years.^2,3 Prospective data have supported the first-line use of BCG for more than 20 years.^4-6

High-risk NMIBC is a resource-intensive entity, with a clinical hallmark being frequent recurrences and risk of progression, resulting in a substantial therapy burden for patients.^2-7 Although intravesical treatment BCG has long been the standard of care for NMIBC, BCG failure occurs in 30% to 50% of patients, with limited salvage options. At present, only 2 agents currently have FDA approval for use in BCG-unresponsive disease: valrubicin and pembrolizumab (Keytruda), both of which have response rates of 50% or less.^8,9

When faced with this challenging clinical scenario, it is important to understand salient definitions surrounding BCG failure, as differing criteria over time can make interpretation of study data and recommendations difficult. In 2018, the FDA set forth formal definitions of post-BCG high-risk NMIBC.¹⁰

Importantly, “adequate” BCG in the context of these definitions means receipt of at least 5 to 6 doses at induction and 2 to 3 doses of maintenance, or at least 5 to 6 BCG treatments at initial induction and 2 to 6 instillations on a second induction course.10 For patients meeting these criteria, additional courses of BCG are unlikely to induce remission. For the purposes of the remainder of this review, our focus will be on salvage intravesical, surgical, and systemic immunotherapy options for BCG-unresponsive NMIBC.

Intravesical options for BCG-unresponsive NMIBC

Valrubicin. Valrubicin is the onlychemotherapeutic agent currently approved for intravesical therapy in patients with BCG-unresponsive carcinoma in situ (CIS), based upon an 18% complete response (CR) rate in a study of 230 BCG-unresponsive NMIBC patients undergoing 6 or 9 weeks of valrubicin.¹¹ Disease-free survival (DFS) was merely 4% at 2 years in this trial.¹¹ The FDA label specifically indicates use in patients “for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.”¹² This relatively narrow indication as well as the poor overall long-term performance as salvage therapy has resulted in limited adoption of valrubicin in contemporary management.

Gemcitabine. Gemcitabine, given by intravesical route, is an off-label chemotherapy utilized in the setting of BCG-unresponsive disease. In a study by Dalbagni et al, CR was 50% at 6 months, although 12-month DFS was only 21%.¹³ Similarly, a randomized trial by Di Lorenzo and colleagues compared additional BCG induction vs intravesical gemcitabine instillation in 80 patients with BCG-unresponsive disease, utilizing a 6-week induction course and 3 weekly maintenance instillations at 3, 6, and 12 months for both treatment arms. Recurrence-free survival (RFS) was greater in the gemcitabine group at 2 years than in the repeat BCG group (19% vs 3%). Importantly, 33% and 37% of patients in the gemcitabine and BCG groups, respectively, had disease progression requiring radical cystectomy (RC).¹⁴ Although no trial has identified an optimal format for therapy, gemcitabine dosing and frequency is extrapolated from the experience with BCG and is typically instilled on the same schedule as BCG, with 6 induction courses and maintenance.

Docetaxel/paclitaxel. Docetaxel and paclitaxel are also off-label chemotherapy options with at least moderate evidence for salvage intravesical use in BCG-unresponsive disease. In a small phase 1 trial of docetaxel in 18 patients with BCG-unresponsive disease, a 22% CR was observed at a median follow-up of 43 months, with 56% of patients initially having no visible disease on initial cystoscopy or biopsy after treatment.¹⁵ Unfortunately, longer-term follow-up demonstrated an overall treatment failure rate of 61% requiring additional interventions (including RC), with median DFS of 13.3 months.¹⁶ Likewise, intravesical paclitaxel was evaluated in a small phase 1 trial of 16 patients with BCG-unresponsive CIS; the CR rate was 60% at 8-week evaluation. Long-term results with use of paclitaxel are uncertain.¹⁷

Gemcitabine/docetaxel. Given the results of single-agent gemcitabine and docetaxel in the previously discussed trials, the combination was investigated as salvage treatment for patients who were unfit or unwilling to undergo RC for BCG-unresponsive NMIBC. A 2019 retrospective analysis by Steinberg and colleagues reported on 276 patients who received combination intravesical gemcitabine and docetaxel therapy for BCG-unresponsive disease, including recurrent high-grade (HG) T1 disease with or without CIS. RFS rates at 1 and 2 years were 60% and 46%, respectively, with 15.6% of patients progressing to RC at a median time of 11.3 months from induction.¹⁸

Surgical options for BCG-unresponsive NMIBC

In 2021, RC remains a guideline-recommended standard of care first-line option for patients with high-risk, BCG-unresponsive NMIBC, and it improves survival.^2,3,19,20 There are many compelling studies demonstrating the adverse oncologic risks of delayed surgical management in BCG-unresponsive NMIBC.^19-21 Specifically, in patients with BCG-unresponsive HG T1 disease, cancer-specific and overall survival were inferior in patients who underwent delayed (>2 years) vs early RC.^22,23 Likewise, Bianco et al demonstrated that for patients with pT1 disease, with or without CIS, treated with RC, 27% were up-staged on surgical pathology to muscle-invasive bladder cancer (MIBC), including 12% with nodal disease.²⁴

The use of RC for T1 recurrent disease after BCG treatment has a decreased 5-year cumulative incidence of death compared with patients treated with re-resection and more BCG.²⁵ Finally, patients with initial high-risk NMIBC who progress to MIBC and undergo RC have been found to have a worse prognosis than patients with de novo MIBC, demonstrating the danger of delaying timely intervention in this population.^26,27 Thus, considering timely management with RC after reaching a state of BCG-unresponsiveness is a key decision point for patients with high-risk NMIBC. Nevertheless, one must acknowledge the continued challenges surrounding patient selection for RC in populations with increasingly complicated medical comorbidities. Furthermore, the long-term quality-of-life and lifestyle impacts of RC and urinary diversion remain a barrier for many patients.

The role of systemic therapy

Despite a long-standing indication for platinum-based chemotherapy treatment in the first-line setting for advanced bladder cancer, there is currently no role for systemic chemotherapy in the management of BCG-unresponsive NMIBC. Recently, immunotherapy checkpoint inhibitors have led to improved outcomes in advanced bladder cancer when compared to the use of second-line chemotherapy regimens following receipt of a platinum-based regimen. Additionally, the use of immunotherapy is appropriate in the first-line setting for those who are deemed platinum-ineligible or who have PD-L1 expression. There are 5 PD-1/PD-L1 inhibitors approved for use in advanced bladder cancer; however, not all patients achieve or maintain benefit from these treatments. The idea of possible success of systemic immunotherapy in BCG-unresponsive NMIBC has roots in the biology of NMIBC. HG bladder cancer has one of the highest tumor mutational burdens, which is known to be a feature of tumors more likely to respond to checkpoint inhibition. Additionally, BCG, an immunomodulating agent, has been the backbone of treatment for HG NMIBC for more than 45 years.²⁸

Multiple studies have explored the use of immunotherapy in NMIBC. KEYNOTE-057 (NCT02625961) was a single-arm phase 2 trial involving 103 patients with BCG-refractory NMIBC who were not candidates for, or refused, RC. Patients received pembrolizumab 200 mg intravenously (IV) 3 times a week for 24 months or until disease progression. Assessment for response occurred after 3 months. A total of 38.8% (95% CI, 29.4%-48.9%) achieved CR, and 80.2% maintained CR for longer than 6 months. There was no progression to muscle-invasive or metastatic disease at the time of analysis. No new safety signals arose; 18.4% had immune-related adverse events (AEs), and 1 treatment-related death from colitis occurred.²⁹ The results of KEYNOTE-057 led to FDA approval for pembrolizumab in BCG-unresponsive, high-risk NMIBC.

Similarly, SWOG 1605 (NCT02844816) evaluated atezolizumab (Tecentriq) 1200 mg IV 3 times a week for 1 year in a single-arm, phase 2 study of patients with BCG-unresponsive high-risk NMIBC who were unfit for, or declined, RC. The primary outcome was pathologic CR (pCR) rate at 6 months by mandatory biopsy. Results for a subset of 75 patients with CIS, with or without concomitant Ta or T1 disease, were presented at the virtual American Society of Clinical Oncology 2020 Annual Meeting. The pCR rate at 3 months was 41.1% (95% CI, 29.7%-53.2%) and 26% (95% CI, 16.5%-37.6%) at 6 months. No new safety signals were noted, with 12.3% of patients experiencing at least a grade 3 AE; there was 1 immune-related death from myasthenia gravis.³⁰

PD-L1 expression in the tumor microenvironment may lead to attenuated response to BCG. KEYNOTE-676 (NCT03711032) is a phase 3 randomized study evaluating the efficacy and safety of BCG with or without pembrolizumab in patients with relapsed or refractory high-risk NMIBC following standard BCG therapy. The primary end point is CR rate in patients with CIS.^31,32

Clinical trials and pipeline therapies

Multiple other trials are underway to investigate various agents in BCG-unresponsive bladder cancer. Below are highlighted several important studies that are either underway or have reported preliminary results.

Durvalumab (Imfinzi). The Hoosier Cancer Research Network is currently conducting a multiarm, multistage, multicenter phase 1/2 study (ADAPT BLADDER) investigating the efficacy and safety of IV durvalumab plus BCG with or without external beam radiation therapy in BCG-unresponsive NMIBC. After the recommended phase 2 dose is identified, the primary end point for the phase 2 expansion will be progression-free survival at 6 months. Recruitment is ongoing and preliminary results are expected by September 2022.³³

Nadofaragene firadenovec. Nadofaragene firadenovec is a recombinant adenovirus delivering human interferon-α cDNA into bladder epithelium along with Syn3, a polyamide surfactant that enhances the viral transduction of the urothelium; this results in local interferon-α production, which in turn produces tumor regression.^34-36 Based on success of preclinical studies and a phase 1 trial on intravesical formulation of this agent, a phase 3 trial was conducted to further examine efficacy in CIS (with or without a HG Ta or T1 tumor).^36,37 In total, 55 (53.4%) of 103 patients with CIS (with or without a HG Ta or T1 tumor) who were included for efficacy analysis had response within 3 months of the first dose, and this response was maintained in 25 (45.5%) of 55 patients at 12 months. Micturition urgency was the most common AE and there were no treatment-related deaths.³⁸

^CG0070. CG0070 is an oncolytic immunotherapy using an adenovirus engineered to preferentially replicate in, and destroy, RB pathway defective cells using the E2F-1 promoter element to limit virus replication and expression of the immunomodulatory transgene granulocyte-macrophage colony-stimulating factor.³⁹ Preclinical and phase 1 studies on intravesical CG0070 showed both safety and efficacy in NMIBC.³⁸ Packiam and others conducted a phase 2, open-label, single-arm study to evaluate its efficacy; 45 patients who had received at least 2 prior courses of intravesical therapy for CIS, with at least 1 being a course of BCG, were evaluated, and CR at 6 months was 47% (95% CI, 32%-62%).⁴⁰

IL-15 superagonist complex (N803).N-803 is an interleukin-15–based immunostimulatory protein complex that activates and proliferates natural killer cells and CD8+ T cells.⁴¹ A recent study of 80 patients with BCG-unresponsive CIS who were treated with N803 plus BCG showed 72% CR; 59% remained in CR at 12 months and median duration of CR was 19.2 months (range, 7.6-26.4). The combination was safe and well tolerated with only 9 patients experiencing an AE higher than grade 3.⁴²

Conclusions

A significant increase in the number of effective treatments for advanced bladder cancer have been developed in recent years. Although the treatment landscape of NMIBC has simultaneously been evolving, only pembrolizumab has gained FDA approval in BCG-unresponsive disease. As understanding of the mechanism for BCG resistance, and the variability of post-BCG disease states, has increased, multiple investigational agents have been developed and are being studied. The paucity of accepted and effective therapeutics in the BCG-unresponsive setting highlights the necessity for clinical trial participation to answer clinical questions and expand the spectrum of effective treatments in this population.

Smelser is a clinical instructor and Society of Urologic Oncology fellow, Yasin is a genitourinary oncology fellow, and Davis is an associate professor of medicine and urology and vice president for Cancer Care Network and Strategy at Vanderbilt University Medical Center, Nashville, Tennessee.

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