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The Current Treatment Landscape of BCG-unresponsive Non-Muscle Invasive Bladder Cancer: N-803 and Viral/Bacterial-Based Therapies

Introduction


Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard-of-care, guideline recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and disease progression.1-3 However, despite adequate BCG, up to 50% of patients develop a BCG-refractory, relapsing, or failure state.4 Currently, radical cystectomy remains the gold standard approach in this setting.1 However, many patients are either unfit or refuse cystectomy.

Given the shortage of options in this disease space, along with the modest efficacy of Valstar (21% complete response with a median response duration of one year),5 the FDA issued a guidance document to promote the development of drugs and biologics for BCG-unresponsive NMIBC:6
  • Persistent or recurrent CIS within 12 months of adequate BCG therapy
  • Recurrent high-grade Ta/T1 disease within six months of completion of adequate BCG therapy
  • High-grade T1 disease detected on the first evaluation following an induction BCG course
Since then, there has been the approval of two additional agents for BCG unresponsive NMIBC: Keytruda® (pembrolizumab) in January 20207 and Adstiladrin (nadofaragene firadenovec) in December 2022.8 Given the increased PD-L1 expression in BCG-unresponsive NMIBC cells, which has been implicated in adaptive immune response-related resistance mechanisms,9 a significant amount of research has focused on the use of anti-PD-1/PD-L1 immune checkpoint inhibitors for these patients. However, both short- and medium-term complete response rates have remained modest,10-12 and, as such, even more “novel” agents in this disease space are sorely needed.

In this Center of Excellence article, we will discuss the currently available evidence and ongoing studies for Nogapendekin alfa-inbakicept (NAI), and viral/bacterial-based therapies in the BCG unresponsive NMIBC disease space.


NAI (N-803)

There is emerging evidence that impaired T-cell and cytotoxic cellular response play a key role in the development of BCG failure. N-803 is an interleukin-15 (IL-15) superagonist that acts as an activation and proliferation factor for natural killer and effector/memory T-cells. Given that BCG has been shown to establish ‘trained immunity’ as the molecular basis for its immunotherapeutic effect in bladder cancer, it has been hypothesized that NAI (Anktiva; ImmunityBio) could further enhance the immune response by mediating a second, unrelated stimulus.

QUILT-3.032 is an ongoing, open label, multicenter, single arm trial that is evaluating intravesical NAI plus BCG or NAI alone in patients with BCG-unresponsive, high-grade NMIBC.13 This study includes three patient cohorts:

  • Cohort A (CIS +/- papillary disease): Intravesical NAI (400 μg/instillation) + BCG (50 mg/installation) given once weekly for 6 consecutive weeks (induction)
  • Cohort B (High grade Ta/T1 papillary disease): NAI + BCG
  • Cohort C (CIS +/- papillary): NAI alone
Surveillance included a cystoscopy plus a urinary cytology every 3 months for the first 24 months, followed by every six months thereafter until 60 months. Importantly, biopsy was mandated at week 12 in all patients, irrespective of cystoscopy or cytology findings. Re-induction was offered to patients without a complete response, conditional on the absence of T1 or worse disease in the specimen. These patients would then undergo a mandatory 6-months biopsy. The primary endpoints in Cohorts A and C were 3- and 6-months complete response, defined by one of the following three scenarios:

  • Negative cystoscopy and cytology (including atypical)
  • Biopsy-proven benign or low-grade Ta disease and negative cytology
  • Negative cystoscopy with malignant urinary cytology, if cancer was found in the upper tract or prostatic urethra and random bladder biopsies were negative
In Cohort A (n=82), a complete response was observed in 71% of patients (13/58 responders required a re-induction). Response rates were as follows:

  • 3 months: 55%
  • 6 months: 56%
  • 12 months: 45%
The median duration of response in complete responders was 26.6 months. The 24-months progression-free, overall, and disease-specific survival rates were 85%, 94%, and 100% respectively.

figure-1-BCG-unrepsonsive-NIMBC.jpg

In 72 evaluable patients in Cohort B, the median disease-free survival was 19.3 months, with disease-free survival rates as follows:

  • 12 months: 55.4%
  • 18 months: 51.1%
  • 24 months: 48.3%
The 24-months progression-free, overall, and disease-specific survival rates were 88.8%, 91.7%, and 97.7%, respectively.

In the 10 evaluable patients in Cohort C, a complete response at 3 months was observed in only 2 (20%) patients with NAI alone. Of the 8 initial non-responders, 6 underwent re-induction with only 1/6 demonstrating evidence of a complete response at 6 months. On the basis of protocol-defined stopping rules, the independent data monitoring committee recommended that cohort C be discontinued for futility.

The most common treatment-related adverse events with the combination of NAI + BCG were lower genitourinary in nature (dysuria, pollakiuria, hematuria). The incidence of grade 3 or worse adverse events was 23%, most frequently hematuria and urinary tract infections (2% each). One patient experienced a grade 5 treatment-related adverse event (cardiac arrest with subsequent death) and 3 had evidence of immune-related adverse events.13


Viral and Bacterial-Based Therapy

Nadofaragene Firadenovec (rAd-IFNα/Syn3)

Interferon alpha-2b has previously been shown to have limited efficacy for NMIBC patients in the post-BCG setting, with this limited response likely secondary to the short exposure time.14 Nadofaragene firadenovec (Adstiladrin®; Ferring) consists of (i) rAd-IFNα, a non-replicating recombinant adenovirus vector-based gene therapy that delivers a copy of the human interferon alfa-2b gene to urothelial cells and (ii) Syn3, a polyamide surfactant that enhances the viral transduction of the urothelium. This allows for a prolonged exposure to interferon alph-2b, enhancing its local anti-tumor activity.15

In 2021, Boorjian et al. published the results of an open label, multicenter, repeat-dose, single arm phase 3 trial that evaluated nadofaragene firadenovec in adult patients with BCG-unresponsive NMIBC. This study included two patient cohorts:

  • CIS (+/- papillary Ta/T1 disease)
  • High grade Ta or T1 disease
Eligible patients were required to have all visible tumors resected and no evidence of upper tract or prostatic urothelial disease or unilateral hydronephrosis secondary to the underlying tumor. Instillation included 75 ml of nadofaragene firadenovec (3 × 10¹¹ viral particles per mL) intravesically. Patients underwent a repeat cystoscopy and cytology every 3 months. In the absence of high-grade recurrence, repeat administration was performed at three, six, and nine months. Patients with high-grade recurrences were withdrawn from the study, and re-induction was not permitted. At 12 months following treatment initiation, patients were mandated to have a systematic biopsy of five sites (dome, trigone, right/left lateral, and posterior walls). If this biopsy was negative, patients were allowed to continue treatment, administered every three months thereafter.

This trial enrolled 157 patients (CIS: 107; high-grade Ta/T1: 50), with a median age of 71 years. This was a heavily pre-treated patient cohort, with 50% of patients having previously received at least three prior BCG courses. At a median follow-up of 19.7 months, 53.4% of patients in the CIS cohort had a complete response (all noted at month 3). The median duration of complete response was 9.7 months, with 24.3% remaining high grade recurrence-free at 12 months. Five patients (5%) progressed to muscle invasive disease.

figure-2-BCG-unrepsonsive-NIMBC.jpg

In the high-grade Ta/T1 cohort, the 3-months high-grade recurrence-free rate was 72.9%, with 43.8% of patients remaining recurrence-free at 12 months. The median duration of high-grade recurrence-free survival was 12.4 months.

In the overall cohort, 26% of patients had undergone a cystectomy by 12 months follow-up, with a median time to cystectomy of 8.6 months. None of the patients experienced a grade 4-5 adverse event. Grade 3 adverse events occurred in 4% of patients, most commonly lower genitourinary in etiology (bladder spasm, micturition urgency, and urinary incontinence).15

CG0070

Cretostimogene Grenadenorepvec (CG0070) is an adenovirus serotype 5-based oncolytic vaccine engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF) and selectively replicate in tumor cells with a mutated/deficient retinoblastoma (RB) gene. CG0070 induces cell lysis via immunogenic cell death, augmented in the presence of GM-CSF.

figure-3-BCG-unrepsonsive-NIMBC.jpg

CG0070 monotherapy was initially evaluated in a phase 1 trial (V0046) of 35 patients with high-risk, BCG-failure NMIBC (CIS-containing or papillary). CG0070 demonstrated a complete response rate of 46% at 3 months and met the safety/efficacy outcomes, with the target dose and schedule identified for a subsequent phase 2 study.16 Next, CG0070 was evaluated in a phase II trial of 46 BCG-unresponsive NMIBC patients (BOND-002). A complete response was achieved in 30/46 patients (65%) at any time, with durable complete responses of 44% and 28% at 6 and 12 months, respectively. Notably, outcomes were better for those with CIS-containing disease. The most common grade 3 treatment-related adverse events were dysuria (3%) and hypotension (1.5%), with no grade 4-5 events observed.17 Given the promising results of this phase II trial, CG0070 monotherapy will be evaluated in a phase III trial of patients with CIS-containing, BCG-unresponsive NMIBC (BOND-003; NCT04452591):

figure-4-BCG-unrepsonsive-NIMBC.jpg

Given its mechanism of action, it has been hypothesized that CG0070 may have a synergistic mechanism of action with PD-1/L1 inhibitors. Accordingly, CORE1 was designed as an open label, single arm phase II trial evaluating the combination of CG0070 plus pembrolizumab in 35 patients with high-risk, BCG-unresponsive NMIBC (CIS-containing). All patients received CG0070 induction weekly (1x1012 vp/mL) for 6 weeks, followed by a second induction course weekly for 3 weeks in responders and 6 weeks in non-responders. All responders subsequently received a maintenance course weekly for 3 weeks. Patients concurrently received pembrolizumab every 6 weeks (as opposed to the usual 3 weeks) at a dose of 400 mg through year 2. This was a heavily pre-treated cohort with a median number of 12 prior BCG installations. 80% of the patients had pure CIS. The overall complete response rate was 85% in the 34 evaluable patients. Significantly, this response was maintained in the majority of these patients, with the following complete response rates:

  • 6 months: 82% (27/33)
  • 9 months: 81% (25/31)
  • 12 months: 68% (17/25)
With regards to adverse events, these were predominantly transient, grade 1-2 local genitourinary in nature. Grade 3 adverse events were observed in 4 patients (11%), and there were no grade 4-5 events.18


TARA-002


TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. The chemical characteristics of TARA-002 are intended to be comparable to OK-432, which is approved in Japan and Taiwan for the treatment of several different cancers (head and neck, gastric, and lung cancer). The antitumor activity of TARA-002 is thought to occur via direct cytotoxicity and by stimulation of immunocompetent cells through the induction of helper T-cell type-1 cytokines, which then recruit cytotoxic T lymphocytes to tumor cells.

ADVANCED-1 is a dose-escalated, phase 1a/b study that is currently recruiting high-grade NMIBC patients (CIS or high-grade Ta) who are either unable to obtain BCG or have received at least one prior dose of BCG or intravesical chemotherapy. Patients will receive up to 3 dose levels of TARA-002 (10, 20, and 40 KE), administered in 6 weekly intravesical instillations with patients followed for six weeks thereafter. The study objective is to determine the safety, tolerability, and preliminary efficacy of TARA-002 in patients with CIS or high-grade Ta.19

ADVANCED-2 is a phase 1b/2, dose expansion, open-label study that will evaluate the safety and efficacy of TARA-002 administered intravesically for the treatment of subjects with CIS (± Ta/T1) with active disease.20 The study will enroll 102 patients stratified into one of two cohorts based on their prior BCG experience:

  • Cohort A (n=27): Subjects unable to obtain BCG or who have not received BCG in the 24 months prior to their CIS diagnosis
  • Cohort B (n=75): Patients with BCG-unresponsive CIS
The trial design is as follows:
figure-5-BCG-unrepsonsive-NIMBC.jpg


Oportuzumab monatox (Vicinium)


Oportuzumab monatox (Vicinium) is a recombinant fusion protein comprising a humanized anti-EpCAM single-chain antibody linked to Pseudomonas exotoxin A. Once bound to the cancer cell, Vicinium is internalized, and the toxin moiety is released into the cytosol where it induces apoptosis.

In 2012, the results of a phase II trial evaluating Vicinium in patients with NMIBC who had failed prior BCG treatment were published. This trial included 46 patients who received either a 6 (Cohort 1) or 12-weekly (Cohort 2) induction course of Vicinium (30 mg), followed by 3 weekly maintenance regimen every 3 months for up to 3 cycles. This agent was associated with a 3-month complete response rate of 44%, with a median duration of response of 9 to 13 months.21

More recently, Vicinium was evaluated in the setting of a phase multicenter, phase 3 trial whereby patients with BCG-unresponsive NMIBC were administered induction, followed by maintenance Vicinium. During induction, Vicinium was instilled for 2 hours twice weekly for 6 weeks, then weekly for 6 weeks. Disease-free patients at 3 months received maintenance every 2 weeks for up to 2 years. Patients were assessed every 13 weeks, with a response defined as negative cytology along with normal cystoscopy or absence of high-grade disease on biopsy. Similar to the earlier phase II trial, the 3-month complete response rate was 40% in CIS patients. The median duration of response was 9.4 months, and 52% remained disease-free for 12 months after starting treatment. Conversely, among patients with papillary disease, the recurrence-free rates were:

  • 3 months: 71%
  • 6 months: 58%
  • 12 months: 50%
  • 24 months: 37%
20.2% of patients underwent a subsequent radical cystectomy with patients having a complete response at 3 months having a longer time to radical cystectomy (34 versus 20.7 months, p<0.001). Vicinium was generally well-tolerated with 52% of patients experiencing treatment-related adverse events, the majority being grade 1-2. There were four treatment-related severe adverse events, which included grade 2 pyrexia, grade 3 acute kidney injury, grade 4 cholestatic hepatitis, and grade 5 renal failure. Only 3% of the patients discontinued treatment due to adverse events.22


Conclusions

We have witnessed the emergence of novel anti-viral/bacterial-based therapies in the BCG unresponsive NMIBC disease space, with promising efficacy and safety profiles. These novel agents induce prolonged immune responses that overcome some of the limitations inherent to older agents. In particular, the combination of CG-0070 and pembrolizumab, via a dual, synergistic mechanism of action, appears to be promising in this disease space. Further to these immune-based therapies, we are also witnessing the emergence of the next generation of intravesical chemotherapeutic options in this disease space, with alternate mechanisms of action and novel methods of administration. Ideally, several of these new agents will soon receive FDA approval.

table-1-BCG-unrepsonsive-NIMBC.jpg

Published August 2023
Written by: Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, ON and Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia, USA
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  15. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, 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(1):107–117.
  16. Friedlander TW, Weinberg VK, Yeung A, et al. Activity of intravesical CG0070 in Rb-inactive superficial bladder cancer after BCG failure: Updated results of a phase I/II trial. J Clin Oncol. 2012 (Supplement).
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  20. Sun W, Bandari J, Zummo J, et al. Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer. J Clin Oncol. 2023;41(Suppl):TPS4618.
  21. Kowalski M, Guindon J, Brazas L, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. J Urol. 2012;188(5):1712-8.
  22. Shore N, O’Donnell M, Keane T, et al. PD03-02: Phase 3 Results of Vicinium in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer. J Urol. 2020;Supp 4:e72.
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