BCG Unresponsive NMIBC - Intravesical Nadofaragene Firadenovec Gene Therapy
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)
Radical cystectomy (RC)
clinical trials assessing new treatment strategies
strategies in patients unsuitable or refusing RC
Late BCG relapsing:
recurrence > 6 months or CIS > 12 months of last BCG exposure
Radical cystectomy or repeat BCG
course according to individual situation
LG recurrence after BCG for primary
Repeat BCG or
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 20â€“30% of bladder cancers have unfavourable to very unfavourable
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 â€˜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.