Dr Narayan on the Utility of Nadofaragene Firadenovec in NMIBC and Beyond

Vikram M. Narayan, MD, assistant professor, Department of Urology, Emory University School of Medicine, Winship Cancer Institute; director, Urologic Oncology, Grady Memorial Hospital, discusses key takeaways regarding the utility of nadofaragene firadenovec-vncg (Adstiladrin) in patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC).

final 5-year analysis of a phase 3 trial (NCT02773849)

 investigating nadofaragene firadenovec in this patient population, understanding how to use this agent in other treatment arenas remains at the forefront of consideration, Narayan says. When considering what the future holds for the use of nadofaragene firadenovec in other patient populations, Narayan states that there is ongoing research exploring the use of this agent in patients with low-grade upper tract urothelial cancer. In this setting, the drug is administered using a balloon catheter to help maintain it in the renal pelvis, he explains.

Additionally, there is interest in using nadofaragene firadenovec in patients with intermediate-risk bladder cancer, specifically in the non–high-risk BCG-unresponsive patient population, where there is significant unmet need, Narayan continues, adding that recurrent low-grade disease is another potential area of interest for the investigation of this agent. Nadofaragene firadenovec is being evaluated in various other urothelial cancer patient populations as well, he emphasizes.

Furthermore, there is a focus on better stratifying patients with high-risk, low-risk, and intermediate-risk disease using biomarkers, Narayan expands. Urinary biomarkers have been studied with the UroAmp test, and data from phase 2 trials with nadofaragene firadenovec were presented at the 

, he elucidates. The goal is to replicate these findings with phase 3 data to further validate them, Narayan notes. This approach will enable future clinical trials to go beyond categorizing patients simply by the presence of carcinoma in situ or papillary disease, allowing for a more detailed understanding of the specific mutations and minimal residual disease levels that are present in each patient, Narayan adds, concluding by saying that this ongoing research will be crucial for identifying which patients are best suited for these treatments.

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Vikram M. Narayan, MD, discusses the utility of nadofaragene firadenovec in patients with non–muscle-invasive bladder cancer and beyond.

Dr Narayan on Long-Term Results With Nadofaragene Firadenovec in NMIBC

Vikram M. Narayan, MD, assistant professor, Department of Urology, Emory University School of Medicine, Winship Cancer Institute; director, Urologic Oncology, Grady Memorial Hospital, discusses results from the final 5-year analysis of a phase 3 trial (NCT02773849) investigating nadofaragene firadenovec-vncg (Adstiladrin) in patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC).

These 5-year follow-up data are important because they represent the longest follow-up to date of any intravesical gene therapy, a novel class of drugs for the treatment of patients with BCG-unresponsive NMIBC, Narayan says. Regarding safety, investigators observed no new safety signals at 5 years of follow-up, and only 2% of patients discontinued nadofaragene firadenovec because of an adverse effect (AE), Narayan explains. Furthermore, no grade 4 or 5 treatment-related AEs were noted, Narayan emphasizes.

Regarding efficacy, among the patients with carcinoma in situ (CIS) who achieved a complete response (CR) at 3 months, 10.9% remained high-grade recurrence free (HGRF) at 57 months. Among the patients with only high-grade Ta/T1 disease who were HGRF at 3 months, 20.0% maintained their CR at 57 months. A total of 25% of patients with CIS and 49% of those with Ta/T1 disease had an ongoing response. This was defined as the absence of disease recurrence at their last disease assessment, although some patients were lost to follow-up, Narayan adds.

Regarding the bladder preservation rates observed in this study, Narayan provides the caveat that bladder preservation often cannot be attributed to 1 specific cause and that many patients in the study who progressed on nadofaragene firadenovec could have received subsequent treatments that helped to preserve their bladder. However, among the patients with CIS, 43.2% (95% CI, 32.3%-53.7%) had a cystectomy-free survival (CFS) at month 60. Moreover, the 60-month CFS rate was 76.3% (95% CI, 64.6%-84.5%) among patients with only high-grade Ta/T1 disease. The 5-year follow-up data from this study indicate that nadofaragene firadenovec is a safe alternative to cystectomy, which is welcome news for patients, Narayan concludes.

Vikram M. Narayan, MD, discusses the final 5-year analysis of a phase 3 trial of nadofaragene firadenovec in patients with BCG-unresponsive NMIBC.

Dr Narayan on the Mechanism of Action of Nadofaragene Firadenovec in NMIBC

Vikram Narayan, MD, director, Urological Oncology, Grady Memorial Hospital; assistant professor, Department of Urology, Emory University School of Medicine, Winship Cancer Institute, 

discusses the mechanism of action of nadofaragene firadenovec-vncg

 (Adstiladrin) in patients with high-risk BCG-unresponsive non–muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

Nadofaragene firadenovec operates through a mechanism of action that involves a non-replicating adenovirus carrying interferon alfa-2b (IFNα-2b) and Syn3, Narayan begins. Historically, IFNα-2b has been administered intravesically either alone or in conjunction with BCG for bladder cancer management, albeit with limited effectiveness, according to Narayan. However, nadofaragene firadenovec introduces a novel treatment approach by using an adenoviral vector to deliver IFNα-2b directly into urothelial cells, he explains. By exploiting the innate abilities of urothelial cells, nadofaragene firadenovec creates a localized "bioreactor" within the bladder, continuously generating IFNα-2b protein and sustaining its therapeutic impact over time, Narayan states.

The inclusion of Syn3 in nadofaragene firadenovec serves an important role in enhancing the agent’s efficacy and facilitating better penetration and uptake of the therapeutic components, overcoming a historical barrier that hindered the effectiveness of interferon therapy when administered alone, he expands. This synergy between the adenoviral vector and Syn3 underscores the multifaceted approach of nadofaragene firadenovec in combating bladder cancer, Narayan elucidates.

The pleiotropic effects of IFNα-2b further contribute to the efficacy of nadofaragene firadenovec by eliciting a range of immunostimulatory and immunomodulatory responses, he reports. These effects include apoptosis, inhibition of angiogenesis, and augmentation of natural killer cell activity against bladder cancer cells, Narayan says. The culmination of these responses leads to widespread tumor cell death and underpins the promising complete response (CR) rates observed in a phase 3 study of nadofaragene firadenovec, Narayan adds.

Despite the notable CR rates achieved with nadofaragene firadenovec, ongoing research efforts aim to refine and optimize its therapeutic outcomes, he continues. Enhancements may involve exploring combination therapies to augment its effects or potentially readministering the treatment to bolster long-term CR rates, Narayan says. Although the current results with this agent are promising, continued research and innovation are essential to further elucidate the full potential of nadofaragene firadenovec in the management of bladder cancer, he concludes.

Vikram Narayan, MD, discusses the mechanism of action of nadofaragene firadenovec in patients with high-risk non–muscle invasive bladder cancer.

Vikram Narayan, MD

Articles

Dr Narayan on the Utility of Nadofaragene Firadenovec in NMIBC and Beyond

Dr Narayan on Long-Term Results With Nadofaragene Firadenovec in NMIBC

Dr Narayan on the Mechanism of Action of Nadofaragene Firadenovec in NMIBC