Editing Non-Muscle Invasive Bladder Cancer (section)

== BCG failure ==

* See [https://onlinelibrary.wiley.com/cms/asset/37df5090-9112-44c8-bd9c-6ac7a3851707/iju14153-fig-0001-m.jpg Figure]

=== Categories of BCG failure (4) ===

* 2016 International Bladder Cancer Group Definitions[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321095/table/T5/]
# '''<span style="color:#ff0000">BCG-intolerant</span>'''
#* '''Disease persistence as a result of inability to receive adequate BCG* because of toxicity.''' 
#**Adequate BCG is defined as at least 5-6 weekly instillations of an induction course followed by at least one maintenance cycle (consisting of at least 2 out of 3 weekly BCG treatments) or a second induction cycle (whereby at least 2 of 6 weekly instillations were received).
# '''<span style="color:#ff0000">BCG-relapsing</span>'''
#* '''<span style="color:#ff0000">Recurrence of high-grade disease after achieving a disease-free state at 6 months after adequate BCG.'''
#**Sub-stratified into early (<12 months) vs. intermediate (12-24 months) vs. late (>24 months)
#*** Prognosis improved with increasing duration of disease-free interval
# '''<span style="color:#ff0000">BCG-refractory</span>'''
#* '''<span style="color:#ff0000">Persistent high-grade disease at 6 months despite adequate BCG treatment</span>'''
#*'''<span style="color:#ff0000">Any stage or grade progression by 3 months after the first BCG cycle</span>''' (eg. initial Ta/TaHG or CIS then 3 months BCG then T1HG)
#** BCG-refractory patients are at increased risk of progression and worse 5-year survival rates when compared to patients with a complete response to induction therapy
# '''<span style="color:#ff0000">BCG-unresponsive</span>'''
#*'''<span style="color:#ff0000">Includes</span>''' 
#**'''<span style="color:#ff0000">All BCG refractory tumours</span>'''
#**'''<span style="color:#ff0000">BCG-relapse within 6 months of last BCG exposure</span>'''
#**'''<span style="color:#ff0000">CIS within 12 months of completion of adequate BCG exposure</span>'''
#* BCG-unresponsive disease implies patients being previously treated with adequate BCG (see above)
#* '''Meant to denote a subgroup of patients at highest risk of recurrence and progression for whom additional BCG therapy is not a feasible option.'''

* BCG resistant (described in 2015 CUA NMIBC Guidelines)
** Recurrence or persistence of disease at 3 months after induction cycle but of lesser stage or grade which subsequently is no longer present at 6 months
* Prognosis: BCG intolerance > BCG relapsing > BCG refractory (worst prognosis)
* '''<span style="color:#ff0000">Low-grade recurrences during or after BCG are not considered BCG failure</span>'''

=== Management options in BCG unresponsive disease ===

* '''<span style="color:#ff0000">See</span> [[CUA/AUA: Non-muscle Invasive Bladder Cancer (2021 CUA/2016 AUA))|2016 AUA/2021 CUA NMBIC]] <span style="color:#ff0000">Guideline Notes</span>'''
* '''<span style="color:#ff0000">Standard of care: radical cystectomy + lymph node dissection'''
** '''<span style="color:#ff0000">BCG-unresponsive with CIS or HG Ta: a second-line intravesical therapy might be considered before radical cystectomy'''
* '''<span style="color:#ff0000">BCG-unresponsive with CIS who are unfit for or refuse to undergo radical cystectomy (4):'''
*# '''<span style="color:#ff0000">Intravenous pembrolizumab'''
*# '''<span style="color:#ff0000">Intravesical oportuzumab monatox'''
*# '''<span style="color:#ff0000">Intravesical nadofaragene firadenovec'''
*# '''<span style="color:#ff0000">BCG plus N-803'''
** Chemoradiation should not be recommended for patients with BCG-unresponsive CIS
* '''<span style="color:#ff0000">BCG-unresponsive who are unfit for or refuse to undergo radical cystectomy[https://pubmed.ncbi.nlm.nih.gov/33938798/]''' 
*# '''<span style="color:#ff0000">Clinical trial'''
*# '''<span style="color:#ff0000">Sequential intravesical gemcitabine/docetaxel[https://pubmed.ncbi.nlm.nih.gov/31821066/ §] (induction plus maintenance)'''
*# '''<span style="color:#ff0000">Other combination intravesical therapy (e.g., sequential gemcitabine/MMC, BCG + interferon if available)'''
*# '''<span style="color:#ff0000">Single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine)'''
*#* For BCG-unresponsive patients undergoing intravesical chemotherapy, sequential combination of drugs is favoured instead of single-agent regimens
*#* See [https://www.cua.org/system/files/Guideline-Files/7367_NMIBC%2520Guideline_Epub.pdf Table 5] from 2021 CUA NMIBC Guidelines for dosing
*# '''<span style="color:#ff0000">Repeat induction BCG'''
*#* '''In patients with NMIBC treated with an induction course of BCG (without maintenance) who later develop recurrence of disease (BCG relapse), a second induction course may achieve 30-50% response rates.'''
*#** '''<span style="color:#ff0000">>2 BCG induction courses is not recommended due to high failure rate</span>''' <br>

* '''<span style="color:#ff0000">Pembrolizumab'''
** Systemic immunotherapy for NMIBC
** '''MOA: PD-1 checkpoint inhibitor'''
** Dose: 200 mg IV q3weeks for up to 24 months
** '''<span style="color:#ff00ff">KEYNOTE-057 (Lancet Oncology 2021)'''
*** Population: 96 patients with BCG-unresponsive CIS who were ineligible for or declined to undergo radical cystectomy
****BCG-unresponsive disease was defined as
*****Stage progression at 3 months (or up to 4 weeks either side) despite adequate BCG induction therapy alone OR
*****Persistent high-risk non-muscle-invasive bladder cancer at 6 months (or up to 4 weeks either side) after adequate BCG therapy OR
*****Recurrent high-risk non-muscle-invasive bladder cancer within 9 months after the last BCG instillation despite adequate BCG therapy.
*** '''Single arm study''': 200 mg of pembrolizumab IV q3 weeks for 24 months or until recurrence, progression or limiting toxicity
*** Primary outcome: clinical complete response rate (absence of high-risk non-muscle-invasive bladder cancer or progressive disease), assessed by cystoscopy and urine cytology approximately 3 months after the first dose of study drug.
*** Results
**** Median follow-up: 36.4 months
**** Complete response in 39 patients (41%) at 3 months
**** Median duration of response was 16.2 months
****Median duration of treatment was 4.2 months
*****91% discontinued treatment; primary reasons for discontinuation were persistent disease and recurrent disease or stage progression to T1 disease
****49% of initial responders and non-responders who discontinued pembrolizumab subsequently underwent radical cystectomy
**** Adverse events
*****Treatment-related adverse events in 66% of patients
******13% of patients had grade 3 or 4 treatment-related adverse events
******22% of patients had immune-related adverse events of any grade
*****Most common treatment-related adverse events: hyponatremia (3%), arthralgia (2%)
*****Most common serious treatment-related adverse events: pneumonitis (3%), colitis (2%)
*****Treatment-related adverse events led to pembrolizumab interruption in 13% of patients
*** [https://pubmed.ncbi.nlm.nih.gov/34051177/ Balar, Arjun V., et al.] "Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study." ''The Lancet Oncology'' (2021).
* '''<span style="color:#ff0000">Nadofaragene firadenovec (Adstiladrin)</span>'''
** MOA: a non-replicating adenovirus vector (rAd-INFa/Syn3) together with recombinant IFN-alpha2b. When given intravesically, the virus is transduced into bladder cells and the IFN-alpha2b gene is incorporated by the DNA. IFNalpha2b protein, which has antitumour activity, is then produced.
*** '''<span style="color:#ff00ff">Single-arm trial</span>'''
*** Population: 157 patients with BCG-unresponsive non-muscle-invasive bladder cancer
*** Results:
**** 53% of patients with (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 46% of 55 patients at 12 months.
*** [https://pubmed.ncbi.nlm.nih.gov/33253641/ Boorjian, Stephen A., et al.] "Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial." ''The Lancet Oncology'' 22.1 (2021): 107-117.
* '''Oportuzumab monatox (Vicineum)'''
** MOA: specific antibody to Epithelial Cell Adhesion Molecule (EpCAM) fused to a Pseudomonas toxin that binds specifically to bladder cancer cells.
* '''BCG plus N-803'''
** MOA: N-803 is an IL-15 superagonist antibody cytokine fusion protein that can be co-administered intravesically with BCG to induce activation and proliferation of endogenous natural killer (NK) cells and CD8+ T-cells without inducing a T-reg response.