BCG Unresponsive NMIBC - Intravesical Nadofaragene Firadenovec Gene Therapy

Dear All,

Recently much has been discussed on BCG unresponsive NMIBC with varying Treatment options being considered. EAU (2020) in its guideline for NMIBC has given the current options for BCG failure.

Guidelines for the treatment of BCG failure (EAU 2020)


Treatment options

Strength rating


Radical cystectomy (RC)

Enrollment in clinical trials assessing new treatment strategies

Bladder-preserving strategies in patients unsuitable or refusing RC





Late BCG relapsing:

T1Ta/HG recurrence > 6 months or CIS > 12 months of last BCG exposure


Radical cystectomy or repeat BCG course according to individual situation

Bladder-preserving strategies




LG recurrence after BCG for primary

Repeat BCG or intravesical chemotherapy

Radical cystectomy



Treatment of recurrent NMIBC after intravesical BCG remains challenging. Although the standard of care is radical cystectomy, many patients are unsuitable for surgery due to their advanced age and/or frailty, or simply refuse to undergo the procedure. The development of bladder sparing agents in this disease space has been hampered by the heterogeneity in the patient population, poor definition of disease states, a lack of appropriate control arms, and consensus on trial endpoints. High-risk NMIBCs show a greater propensity for disease recurrence and/or progression to muscle-invasive tumors, even after optimal BCG immunotherapy. NMIBC requires a better risk stratification due to clinical and molecular heterogeneity also in BCG responsiveness, which poses a major challenge for clinical decision-making. Genitourinary cancers are the most likely responsive to immunotherapy; however, about 20–30% of bladder cancers have unfavourable to very unfavourable prognoses.

The only intravesical drug approved by the FDA for carcinoma in situ (CIS) after failure to BCG is Valrubicin. Recently, the FDA has approved intravenous Pembrolizumab, following the publication of preliminary data from the KEYNOTE-057 study. Atezolizumab has demonstrated similar preliminary efficacy results. Only microwave-induced chemo-hyperthermia and EMDA-MMC (Electromotive Drug Administration) are recognized as alternatives in European guidelines. Other options under investigation are taxanes and gemcitabine, alone or in combination, device-assisted intravesical chemo-hyperthermia and Recombinant Viruses. The results of new drugs are promising, with a large number of trials underway.

Stephen A Boorjian, Badrinath R Konety, Ashish M Kamat and host of others (2020, Lancet Oncology, Published Online 27th Nov) published the results of ‘BCG Unresponsive NMIBC - Intravesical Nadofaragene Firadenovec Gene Therapy) (PDF provided).

Intravesical Nadofaragene Firadenovec for patients with BCG-unresponsive NMIBC showed first of its kind efficacy for Gene Therapy resulting in favourable Benefit-Risk Profile. The data from this study support the use of Intravesical Nadofaragene Firadenovec for a historically difficult-to-treat disease.

One of the advantages claimed is the dosing Schedule. The recommended Schedule of one Intravesical Treatment every three months made it convenient for both patients and the treating clinicians. The safety profile to this therapy was acceptable with very few discontinuing treatment. No treatment related deaths were recorded.

Will this become the option of choice in future for this heterogenous Group where BCG is unresponsive or where early BCG failures are recognized? It is too early to predict as more data from other studies are required. However, if radical Cystectomy option for these patients can be eliminated, that itself will be of great benefit. 



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  • Dr. Roy Chally
    Dr. Roy Chally
    13 Dec 2020 01:28:48 PM

       We used give interferon Alpha for BCG failures. This was not effective in our hands. 

    Interferon is a glycoprotein expressed by cells against viral infection. In this study adenovirus is the vector to carry the interferon. Unlike interferon administered intravesically the adenovirus will get into the epithelial cell and release interferon. Here the virus is in the cell and body will produce antibodies against. ( the systemic effect?)The virus in the cell will also induce the body to produce interferon.

          This is a single arm study. The intravesical instillation is every 3m for 4yrs if no recurrence is seen at 3 monthly review. This paper presents data at the end of 1 year. 

         In the natural history of progression of noninvasive bladder to invasive bladder cancer is around 5%. In the this paper progression rate is same. 

        There was a 69% recurrence in this group. This is quite high. What happened to this group is not mentioned. 

         The side effect profile is a cause for worry. Cystitis due to adenovirus is well known. 25 % of patients expelled part of the medication by the side of catheter. Did this affect efficacy is not clear from the paper.

           The results are with patients who had received at least one dose. The data of patients who completed the treatment and those who got excluded due to recurrence or noncompliance are not clear. 

           This medication is administered after total resection of tumour in the bladder. The genomic structure of cancer and host vary from patient to patient. So to convince, I feel that a control arm is needed. 



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