Adstiladrin (nadofaragene firadenovec-vncg)

P4, N=25, Not yet recruiting, Ferring Pharmaceuticals

uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials.

P=N/A, N=800, Recruiting, Ferring Pharmaceuticals | Trial completion date: Dec 2026 --> Dec 2025 | Trial primary completion date: Dec 2026 --> Dec 2025

uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials.

The estimated follow-up period is 24 months, until study discontinuation, or withdrawal. Final results from this large, prospective, multi-institutional, real-world registry providing early use and outcomes of nadofaragene firadenovec are expected December 2026.

Three drugs-pembrolizumab, valrubicin, and most recently, nadofaragene firadenovec-vncg-have been FDA approved for the treatment of BCG-unresponsive NMIBC in patients who are ineligible for or decline RC. Despite the challenges faced in finding effective therapies, many potential treatments are currently under investigation. Addressing the landscape of biomarkers, mechanisms of progression, BCG resistance, and trial design challenges in HR-NMIBC is essential for the discovery of new targets and the development of effective treatments.

Treatment options for patients with bacillus Calmette-Guérin (BCG)-unresponsive CIS who refuse/are ineligible for radical cystectomy include pembrolizumab, intravesical chemotherapy, or nadofaragene firadenovec. Data from this trial provide first evidence of occurrence of FGFR alterations in CIS and demonstrate the promising and durable efficacy of an FGFR inhibitor such as erdafitinib in patients with BCG-unresponsive CIS with FGFR alterations. Safety data were consistent with the known safety profile of erdafitinib.

Funding: Research is supported in part by A.I. Virtanen Institute for Molecular Sciences (Kuopio, Finland) and MD Anderson CCSG program (P30 016672).; Introduction: Interferon alpha (IFNα) gene therapy with Nadofaragene firadenovec is emerging as a promising therapeutic option for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC). Combination therapy with IFNα or -β and Gemcitabine led to superior cell cycle arrest and apoptosis in murine BLCA cell lines. The observed differences between the effects of IFNα and IFNβ merit further investigation to optimize intravesical gene therapy. Future in-vitro and in-vivo experiments using human and murine BLCA models are ongoing to direct future clinical development of intravesical gene therapy.

Intravesical nadofaragene firadenovec, administered once every three months, demonstrated a sustained durability of response in patients with BCG-unresponsive CIS±Ta/T1 papillary disease. Nadofaragene firadenovec represents a novel treatment option for BCG-unresponsive NMIBC with a favorable benefit-to-risk ratio. *All patients had passed 36 months at data cutoff on 09 September 2021.

P=N/A; Not yet recruiting --> Recruiting

Ongoing research focuses on improving patient selection, identifying biomarkers for response prediction, exploring alternative vectors for enhanced transfection efficiency, and developing combination strategies targeting resistance mechanisms. The approval of nadofaragene firadenovec marks a significant milestone in the field of gene therapy for bladder cancer, and future developments hold promise for further enhancing its efficacy and impact.

P=N/A; N=800; Not yet recruiting; Sponsor:Ferring Pharmaceuticals

In December 2022, nadofaragene firadenovec received its first global approval in the USA for the treatment of high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumours in adults. This article summarizes the milestones in the development of nadofaragene firadenovec leading to this first approval for this indication.

Ongoing and planned studies evaluating other novel approaches (eg, enfortumab vedotin, erdafitinib, nadofaragene firadenovec) for BCG-unresponsive NMIBC MODULE 2: The Role of Immune Checkpoint Inhibitors as Adjuvant and Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer (MIBC)rnrn1...Recent FDA approval of adjuvant nivolumab and identification of appropriate candidates for treatment 4...Current role of atezolizumab and pembrolizumab as first-line treatment for mUBC, importance of chemotherapy eligibility and PD-L1 status in selecting patients for this strategy 2. Key efficacy and safety data with maintenance avelumab after front-line chemotherapy for mUBC, appropriate incorporation into patient care 3...Preliminary data from the Phase I/II NORSE study of erdafitinib in combination with the investigational anti-PD-1 antibody cetrelimab for patients with previously untreated mUBC with FGFR3 or FGFR2 genetic alterations who are not eligible for cisplatin MODULE 4: The Selection and Sequencing of Therapy for Relapsed/Refractory mUBC 1...Emerging results from cohort 3 of the TROPHY U-01 trial combining sacituzumab govitecan and pembrolizumab 4...Optimal integration of enfortumab vedotin, sacituzumab govitecan and erdafitinib into therapy for progressive mUBCrnIncidence, severity and management of adverse events reported with enfortumab vedotin, sacituzumab govitecan or erdafitinib 6. Frequency of HER2 expression in UBC, mechanism of action of disitamab vedotin and available data and ongoing evaluation for patients with HER2-positive disease 7. Other promising agents and strategies under investigation for mUBC (eg, trastuzumab deruxtecan, futibatinib, infigratinib, cabozantinib) Target Audience This activity has been designed to meet the educational needs of medical and radiation oncologists, urologists and other allied healthcare professionals involved in the treatment of bladder cancer...RESEARCH TO PRACTICE CME PLANNING COMMITTEE MEMBERS, STAFF AND REVIEWERS — Planners, scientific staff and independent reviewers for Research To Practice have no relevant conflicts of interest to disclose. Supporters This activity is supported by educational grants from Astellas and Seagen Inc, AstraZeneca Pharmaceuticals LP, Gilead Sciences Inc, and Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC.

Most recently, two organoids have been successfully established and expanded in suspension culture with 2-4% Matrigel supplementation, improving scalability and decreasing organoid doubling time. Conclusions : Patient-derived tumor organoids represent a novel preclinical model for evaluating the direct cytotoxicity of Nadofaragene firadenevec, and optimization of organoid growth in suspension culture improves capacity for real-time evaluation of individual tumor sensitivities to novel therapeutics.

GemRIS is an implantable novel form of intravesical drug delivery of gemcitabine and is currently being investigated with cetrelimab, a checkpoint inhibitor, in patients with high-risk NMIBC and MIBC...Nadofaragene firadenovec (rAd-IFN-α/Syn3) is a recombinant adenovirus that induces release of interferon-alpha in the urothelium...N-803 is an interleukin (IL)-15 analogue, which has been investigated in a phase 1b study in combination with BCG and has shown durable complete response in all nine patients for 72 months. It was granted breakthrough designation status by the FDA in 2019.

In high-grade, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer, nadofaragene firadenovec, a non-replicating adenovirus administered locally to express the IFNα2b transgene, embodies a novel approach to deploy the therapeutic activity of type I IFNs while minimizing systemic toxicities...We found that constitutive activation of the type I IFN signaling pathway is a biomarker for resistance to both transcriptional response and direct cytotoxic effects of IFNα. We present several genes that discriminate between sensitive and resistant tumor cells, suggesting they should be explored for utility as biomarkers in future clinical trials of type I IFN-based anti-tumor therapies.

Patient-derived tumor organoids represent a novel preclinical model for evaluating the direct cytotoxicity of nadofaragene firadenovec, and optimization of organoid growth in suspension culture improves capacity for real-time evaluation of individual tumor sensitivities to novel therapeutics. Current studies are evaluating baseline and post-treatment organoid gene expression profiles and developing organoid-based orthotopic murine xenograft disease models.

Nadofaragene firadenovec instilled intravesically once every 3 mos demonstrates sustained durability of response with longer follow-up in pts with HG, BCG-unresponsive NMIBC. Clinical trial information: NCT02773849.

Nadofaragene firadenovec was well tolerated and demonstrates durability of response in pts with HG Ta/T1, BCG-unresponsive NMIBC in 24 mos follow-up after first intravesical treatment. Clinical trial information: NCT02773849.

Secondary analysis of the prospective, multicenter phase 3 nadofaragene firadenovec trial in BCG-unresponsive NMIBC indicates a role for assaying baseline and on-treatment Ab titers. A combination of Ab titer and fold-change levels can potentially predict response to this novel therapeutic in a patient population with urgent unmet clinical need.

Nadofaregene firadenovec was well tolerated and achieved an encouraging, durable HGRF survival in high-grade BCG-unresponsive NMIBC pts with PD. This demonstrates a clinically meaningful benefit in a pt population for whom to date non-surgical treatment options have remained limited. Clinical trial information: NCT02773849.