ADSTILADRIN TE Articles

(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on bladder cancer, and a presentation by Dr. Min Yang discussing a cost effectiveness analysis of nadofaragene firadenovec for the treatment of high-risk, BCG–unresponsive, non-muscle invasive bladder cancer from a United States third-party payer perspective. Bladder cancer is the second most common cancer in the urinary tract in the United States, with 75% restricted to the superficial layers of the bladder and termed as non-muscle invasive bladder cancer. For decades, BCG has been the standard of care for high risk non-muscle invasive bladder cancer patients, however, bladder preserving treatments are limited after BCG failure. Nadofaragene firadenovec, an interferon-alfa-2b encoding gene therapy, is approved for the treatment of high-risk BCG-unresponsive non-muscle invasive bladder cancer with CIS with or without papillary tumors (CIS ± Ta/T1):

San Francisco, California (UroToday.com) For patients with BCG unresponsive non-muscle invasive bladder cancer, the standard of care for patients who are operative candidates is a radical cystectomy. However, not all patients may be cystectomy candidates, often for a multitude of reasons, including coexisting comorbidities as well as personal considerations and quality of life.¹ Thus, there is an unmet need in this space for better local or systemic therapies which may prevent progression of bladder cancer to muscle-invasive or metastatic disease.

(UroToday.com) The 2024 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium includes a urothelial carcinoma session featuring trials in progress and a presentation by Dr. Sia Daneshmand discussing the trial design of ABLE-41 assessing nadofaragene firadenovec-vncg early use and outcomes in a real-world setting in the United States. BCG is the first line standard of care for patients with non–muscle-invasive bladder cancer (NMIBC), however approximately one-third of patients initially responding to BCG experience recurrence and/or progression in the first year after treatment.¹ Thus, local, effective, bladder-preserving options are needed for patients with BCG-unresponsive NMIBC.

(UroToday.com) The 2024 GU ASCO annual meeting featured a urothelial carcinoma session and a presentation by Dr. Vikram Narayan discussing urinary minimal residual disease detection predicting recurrence in BCG-unresponsive non-muscle-invasive bladder cancer (NIMBC) and quantifying molecular response to nadofaragene firadenovec. Urinary minimal residual disease profiling uses next-generation sequencing to identify mutations associated with urothelial carcinoma and can be used to predict recurrence and assess response to therapy. Nadofaragene firadenovec is a novel intravesical therapy recently approved for BCG-unresponsive NMIBC.¹ This study sought to evaluate the utility of urinary minimal residual disease to identify molecular response to nadofaragene in patients with high-grade BCG-refractory or relapsed NMIBC.

1. Was patient outcome and safety jeopardized by salvage treatment withNadofaragene firadenovec (Adstiladrin®)?
2. Was survival of patients who failed to respond toNadofaragene firadenovec (Adstiladrin®) threatened?
3. What was the longer term outcome for patients who achieved a complete response at 12 months?
4. In patients who achieved a complete response at 12 months, were these patients able to avoid radical cystectomy?

(UroToday.com) The 2022 Annual Meeting of the American Urological Association (AUA) was host to The International Bladder Cancer Group (IBCG) AUA Bladder Cancer Forum which featured a State-of-the-Art lecture by Dr. Seth Lerner regarding the current state of BCG unresponsive disease.

(UroToday.com) The 2024 American Urological Association (AUA) annual meeting held in San Antonio, TX was host to the Bladder Cancer Non-invasive podium session. Dr. Vikram Narayan presented the final results from the 60-month follow-up of the phase 3 trial evaluating the efficacy of intravesical Nadofaragene Firadenovec-vcng for patients with Bacillus Calmette-Guerin (BCG)-unresponsive carcinoma in situ (CIS) of the bladder.

(UroToday.com) The 2024 American Urological Association (AUA) Annual Meeting held in San Antonio, TX was host to a non-invasive bladder cancer moderated poster session. Dr. Vikram Narayan presented an analysis of urinary minimal residual disease detection for predicting recurrent in BCG unresponsive non-muscle invasive bladder cancer and quantifying molecular response to nadofaragene firadenovec.

(UroToday.com) As part of the “Game-changing Session 2” plenary presentation at the European Association of Urology (EAU) Virtual Annual Meeting, Dr. Neal Shore presented results of the phase III trial of nadofaregene firadenovec in patients with high-grade, bacillus calmette-guerin or BCG-unresponsive non-muscle invasive bladder cancer on behalf of Dr. Boorjian, Dr. Dinney, and the Society of Urologic Oncology (SUO) Clinical Trials Consortium (SUO CTC).

(UroToday.com) The 2024 European Association of Urology (EAU) annual meeting featured a session on non-muscle invasive bladder cancer, and a presentation by Dr. Colin Dinney discussing 36 month follow-up from the phase 3 trial assessing the efficacy of intravesical nadofaragene firadenovec-vncg for patients with BCG-unresponsive non-muscle-invasive bladder cancer.

• Ferring’s novel adenovirus vector-based gene therapy Adstiladrin^® (nadofaragene firadenovec-vncg) is the first gene therapy approved for bladder cancer
• Efficacy and safety of Adstiladrin supported by Phase 3 results demonstrating that more than half of patients (51% of CIS ± Ta/T1 cohort) achieved a complete response (CR) at three months and of these, 46% continued to remain free of high-grade recurrence at 12 months
• Bladder cancer is the sixth most common cancer in the U.S.; Adstiladrin provides NMIBC patients a valuable alternative compared to an invasive bladder removal surgery

• Patients with high-risk, non-muscle invasive bladder cancer now have greater access to the first and only FDA-approved intravesical gene therapy
• With full supply of ADSTILADRIN ahead of schedule, Ferring ends the temporary ADSTILADRIN Early Experience Program
• Enrollment in ABLE-41 U.S. Real-World Evidence Study is ongoing

Bladder cancer is a prevalent malignancy with limited therapeutic options, particularly for patients who are unresponsive to Bacillus Calmette-Guérin (BCG). The approval of interferon-α (IFNα) gene therapy with nadofaragene firadenovec (Adstiladrin®), the first gene therapy for genitourinary malignancies, has provided a promising alternative.

This article reviews the research and milestones that led to the development and approval of nadofaragene firadenovec. Bladder cancer is well-suited for gene therapy due to direct access to the bladder and the availability of urine and tissue samples for monitoring.

• 36-month follow-up data from the Phase 3 study demonstrate one-quarter of patients with high-risk, BCG-unresponsive NMIBC remained free of high-grade recurrence
• Trial showed a 90% three-year overall survival rate, with more than half of cystectomy-free patients at 36 months
• Follow-up analysis of the Phase 3 study continues with five-year treatment and monitoring

A newly published systematic review and meta-analysis: Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non–muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis 

Athens, Greece (Urotoday.com) Dr. Badrinath Konety presented on intravesical therapy for non-muscle invasive bladder cancer (NMIBC). The current risk-based therapy entails:

• Low risk – surveillance or mitomycin
• Intermediate risk – mitomycin or BCG
• High risk – BCG (and mitomycin as a second choice)

15 years after treatment, 37%, 27% and 34% of patients with high-risk superficial bladder cancer have been shown to be alive with no evidence of disease, dead of other causes, and dead of disease, respectively.¹

BCG therapy does not always work, and there are several definitions of disease recurrence following BCG therapy:¹

1. BCG failure is defined as recurrence after adequate BCG treatment
2. BCG Relapse is defined as recurrence after a tumor-free period:

• Early if it is less than 1 year
• Late if it is more than 2 years

3. BCG Refractory – no tumor-free interval on BCG treatment after induction
4. BCG intolerant – Unable to tolerate BCG induction

In the next part of his talk, Dr. Konety discussed the various additional options for the intravesical treatment of NMIBC.

He began describing the Hyperthermic intravesical chemotherapy (HIVEC) option, which uses mitomycin. It is given at 43 degrees Celsius intravesically for 60 minutes by “Combat Medical”. In a study assessing 40 NMIBC intermediate-risk patients, 24 received this therapy at a neoadjuvant setting (before transurethral resection of bladder tumor [TURBT] for a duration of 8 weeks), and 16 patients received it at the adjuvant setting post-TURBT every week for 4 weeks and then every 6 months).²

The results demonstrated 62% and 33% complete and partial response, respectively, at the neoadjuvant setting and a 21% recurrence rate at 4 years. For the adjuvant setting – 12.5% recurrence rate at 2 years.²

Another more novel option is the Synergo device. In this option, before administering the instillation itself the bladder is heated, instead of the intravesical instillation being heated (Mitomycin). In a study assessing 190 intermediate- and high-risk patients in 11 centers, patients received 1-year maintenance therapy with either the Synergo device or standard intravesical BCG instillations.³ The study was closed early and, in the intention to treat analysis no difference was seen with the Synergo device compared to BCG. However, there was a significant difference in the per-protocol analysis, showing a lower recurrence rate for Synergo.³ The overall adverse event rate was lower with BCG.

Another option is Valrubicin. In a nonrandomized study including 90 patients, the complete response rate was 21% with a 7% durable response at 30-month median follow-up.⁴ Overall this drug was well-tolerated, and it has been FDA approved only for BCG refractory carcinoma in situ (CIS).⁴

The combination of gemcitabine and docetaxel was discussed next. In a study of 45 patients, of which 41/45 had previous BCG therapy, 62% had reported symptoms, and 16% had treatment alteration, with 10 patients undergoing radical cystectomy.⁵

There are several other early phase studies assessing novel medications. These include:

1. CG0070, a GMCSF expressing adenovirus, showing a 49% cure durable for 10 months^6,7
2. Photodynamic therapy with hexaminolevulinate (HAL) – a phase 1 study with 12 patients has been done. A total of 45% of the patients were recurrence-free at 12 months.⁸
3. Nadofaragene firadenovec (Adstiladrin®)- (rAd-interferon-alpha/Syn3; nadofaragene firadenovec), a new drug given at two dose levels, with early results showing a 35% recurrence-free survival at one year, and 41% recurrence-free-survival in patients treated with more than 3 courses of BCG⁹
4. Vicinium (VISTA trial) – a phase 3 study (NCT02449239) assessing Vicinium, which is an EpCAM antibody + pseudomonas toxin A. It seems that over 95% of bladder cancer patients express EpCAM in their bladder. In this study, the newly studied drug resulted in a 39% complete response rate for 273 days, with an adverse event rate of 46% - mostly being dysuria, hematuria and urinary tract infection¹⁰
5. Other ongoing studies include those investigating the efficacy of ALT 803 (IL-15 super antagonist), Imiquimod (TMX-101), and Vaccinia virus

In the last section of the talk, Dr. Konety discussed some of the work being done involving immunotherapy in the setting of NMIBC (Figure 1). In the Keynote-057, high-risk NMIBC patients with papillary or with CIS +/- papillary disease, unresponsive to BCG, who declined or cannot undergo cystectomy were treated with pembrolizumab. Initial results at the 3-month time point showed a complete response rate of 40.2% (Figure 2).

Figure 2 – KEYNOTE 057 trial design:

Dr. Konety concluded his talk giving his personal view on how to treat NMIBC patients:

• High risk with good performance status – offer radical cystectomy
• High risk with poor performance status or not agreeable to cystectomy – offer salvage therapy or trials
• Intermediate risk – salvage chemotherapy and trials, and later radical cystectomy
• Low risk – chemotherapy, BCG and then salvage or repeated fulguration

Presented by: Badrinath Konety, MD, MBA, CEO of the University of Minnesota Physicians, Vice Dean for Clinical Affairs at the University of Minnesota Medical School. Professor, Department of Urology, Director, Institute for Prostate and Urologic Cancers, Minnesota, United States

Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, New-York, USA @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece  

References:

1. Steinberg RL, Thomas LJ, Mott SL, O'Donnell MA. Bacillus Calmette-Guérin (BCG) Treatment Failures with Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition for BCG Unresponsive Disease. Bladder Cancer 2016; 2(2): 215-24.
2. Sousa A, Pineiro I, Rodriguez S, et al. Recirculant hyperthermic IntraVEsical chemotherapy (HIVEC) in intermediate-high-risk non-muscle-invasive bladder cancer. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group 2016; 32(4): 374-80.
3. Arends TJ, Nativ O, Maffezzini M, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guerin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol 2016; 69(6): 1046-52.
4. Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. The Journal of urology 2000; 163(3): 761-7.
5. Steinberg RL, Thomas LJ, O'Donnell MA, Nepple KG. Sequential Intravesical Gemcitabine and Docetaxel for the Salvage Treatment of Non-Muscle Invasive Bladder Cancer. Bladder Cancer 2015; 1(1): 65-72.
6. Dinney CP, Fisher MB, Navai N, et al. Phase I trial of intravesical recombinant adenovirus mediated interferon-alpha2b formulated in Syn3 for Bacillus Calmette-Guerin failures in nonmuscle invasive bladder cancer. The Journal of urology 2013; 190(3): 850-6.
7. Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. The Journal of urology 2012; 188(6): 2391-7.
8. Bader MJ, Stepp H, Beyer W, et al. Photodynamic therapy of bladder cancer - a phase I study using hexaminolevulinate (HAL). Urologic oncology 2013; 31(7): 1178-83.
9. Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd–IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin–Refractory or Relapsed Non–Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. Journal of Clinical Oncology 2017; 35(30): 3410-6.
10. Dickstein R, Wu N, Cowan B, et al. LBA27 PHASE 3 STUDY OF VICINIUM IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER: INITIAL RESULTS. Journal of Urology 2018; 199(4S): e1167-e.

Washington, DC (UroToday.com) During the bladder cancer session at the Society of Urologic Oncology Meeting on Thursday, December 5^th, Dr. Colin Dinney presented the results of a phase III clinical trial for Adstiladrin® (rAd-INFa/syn3) in BCG unresponsive non-muscle invasive bladder cancer.

(UroToday.com) The 2023 Society of Urologic Oncology (SUO) annual meeting held in Washington, D.C. between November 28^th and December 1^st, 2023, was host to a poster/abstract session. Dr. Stephen Boorjian presented the 36 months follow-up results of the phase 3 trial evaluating the efficacy of intravesical nadofaragene firadenovec-vcng for patients with Bacillus Calmette-Guerin (BCG)-unresponsive carcinoma in situ (CIS) of the bladder.