Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 Review Article Non-muscle-invasive bladder cancer: An overview of potential new treatment options Neal D. Shore, M.D.a, Joan Palou Redorta, M.D.b, Gregoire Robert, M.D.c, Thomas E. Hutson, M.D.d, Rossano Cesari, Pharm.D.e, Subramanian Hariharan, M.D.f,  Oscar Rodrıguez Faba, M.D.b, Alberto Briganti, M.D.g, Gary D. Steinberg, M.D.h,* a Carolina Urologic Research Center, Myrtle Beach, SC, USA b Department of Urology, Fundaci o Puigvert, Universitat Aut onoma de Barcelona, Barcelona, Spain c Department of Urology, CHU Bordeaux, University of Bordeaux, Bordeaux, France d Texas Oncology, Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA e Pfizer Oncology, Milan, Italy f Pfizer Oncology, New York, NY, USA g Department of Urology, Vita Salute San Raffaele University, Milan, Italy h Perlmutter Cancer Center, an NCI-designated Comprehensive Cancer Center Goldstein Bladder Cancer Program, NYU Langone Health, NYU Urology Associates, New York University, New York, NY, USA Received 22 February 2021; received in revised form 29 April 2021; accepted 9 May 2021 Abstract Aim: This review article summarizes the current clinical practice guidelines around disease definitions and risk stratifications, and the treatment of non-muscle-invasive bladder cancer (NMIBC). Recently completed and ongoing clinical trials of novel and investigational therapies in Bacillus Calmette-Guerin (BCG)-naı̈ve, BCG-recurrent, and BCG-unresponsive patient populations are also described, e.g., those involving immune checkpoint inhibitors, targeted therapies, other chemotherapy regimens, vaccines, and viral- or bacterial-based treatments. Finally, a brief overview of enhanced cystoscopy and drug delivery systems for the diagnosis and treatment of NMIBC is provided. Background: A global shortage of access to BCG is affecting the management of BCG-naı̈ve and BCG-recurrent/unresponsive NMIBC; hence, there is an urgent need to assist patients and urologists to enhance the treatment of this disease. Methods: Searches of ClinicalTrials.gov, PubMed, and Google Scholar were conducted. Published guidance and conference proceed- ings from major congresses were reviewed. Conclusion: Treatment strategies for NMIBC are generally consistent across guidelines. Several novel therapies have demonstrated promising antitumor activity in clinical trials, including in high-risk or BCG-unresponsive disease. The detection, diagnosis, surveillance, and treatment of NMIBC have also been improved through enhanced disease detection. Ó 2021 Pfizer Inc. and the Author(s). Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Keywords: BCG; Bladder cancer; Immune checkpoint inhibitors; Non-muscle-invasive; Targeted therapy Funding: Medical writing support was provided by Anne Marie McGoni- 1. Introduction gal, PhD, and Vardit Dror, PhD, of Engage Scientific Solutions, and was funded by Pfizer. Pfizer provided a formal review of the publication, including for medical accuracy. The authors were not paid for the develop- Bladder cancer is the eleventh most common cancer ment of this manuscript. The authors had final authority, including on the worldwide, and the fifth and sixth most prevalent cancer in choice of journal, on all aspects of the manuscript content and the European Union and United States, respectively, with development. urothelial carcinoma the most common histology [1,2]. *Corresponding author. Tel.: 929-455-5907 E-mail address: Gary.Steinberg@nyulangone.org (G.D. Steinberg). Bladder cancer stratification can be binary, based upon https://doi.org/10.1016/j.urolonc.2021.05.015 1078-1439/Ó 2021 Pfizer Inc. and the Author(s). Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 643 depth of penetration, i.e., muscle-invasive (MIBC) and non- 1.1. Treatment guidelines muscle-invasive (NMIBC) bladder cancer. NMIBC accounts for »75% of newly diagnosed urothelial cell car- There is a large overlap in AUA/SUO and EAU treatment cinoma of the bladder [3-5]. guidelines (Fig. 1 and 2). A comparison of all major guide- NMIBC is a heterogeneous disease, with a wide range lines is reported in Table 1 [6-9,18]. There is a general con- of progression and recurrence rates that depend on sev- sensus on patient risk stratification into low-, intermediate-, eral clinical and pathologic factors [6-9]. Intravesical or high-risk subgroups, with low-grade solitary tumors cate- Bacillus Calmette-Guerin (BCG) is an efficacious treat- gorized as low-risk, and high-grade/T1/carcinoma in situ ment for NMIBC, and was the first therapy to reduce the (CIS) categorized as high-risk, although the AUA catego- risk of recurrence and progression in high-risk NMIBC rizes high-grade Ta ≤3-cm tumors as intermediate-risk. [6-9]. Depending on risk, »70% of patients may achieve Tumors in between these 2 definitions are usually assigned a complete response (CR); however, up to 60% of as intermediate-risk [6-9,18]. patients may experience recurrence after 1 year [10]. In The SOC initial treatment of a bladder lesion involves high-risk patients, »20% may progress to MIBC within transurethral resection of bladder tumor (TURBT) followed 48 months, despite BCG treatment [11]. The current by intravesical chemotherapy or BCG, depending on patient worldwide shortage of BCG has resulted in rationing/ risk group [6-9,18]. A single instillation of chemotherapy is prioritizing schema in clinics, which may lead to generally recommended post-TURBT in patients who are increased rates of both disease recurrence and progres- presumed to be low- or intermediate-risk. Once risk stratifi- sion in patients with NMIBC [12-14]. Due to BCG cation is confirmed, observation and/or intravesical chemo- shortages, patients are receiving fewer courses of BCG, therapy is the suggested first-line therapy for low-risk potentially increasing the proportion of patients under- patients. Intravesical BCG is typically reserved for high- going cystectomy [13]. The BCG shortage has also risk patients in the first-line setting, or as an option for inter- impacted clinical trial access and eligibility [13]. mediate-risk patients [6-9,18]. In response to BCG short- Only 2 treatments for NMIBC have been approved by ages, AUA/SUO, EAU, and NCCN guidelines have advised the US Food and Drug Administration (FDA) or European that BCG should be reserved for high-risk patients only, Medicines Agency for NMIBC in the past 30 years − valru- and intermediate-risk patients can be treated with intravesi- bicin (anthracycline) in September 1998, followed by pem- cal chemotherapy as an alternative to BCG in the first-line brolizumab (anti-programmed cell death protein-1 [PD-1]) setting [6,19,20]. Induction BCG instillations are given in January 2020 [15,16]. A lack of consensus on clinical once weekly for 6 weeks. Intermediate-/high-risk patients trial endpoints and appropriate control arms has slowed may also receive an extended period of maintenance ther- research advancements, along with the challenges of enroll- apy, although there is currently no consensus on the dura- ing patients in early-stage clinical trials [17]. Following tion of maintenance therapy [6-9,18]. BCG failure in high-risk NMIBC, the standard of care Different options exist upon failure of first-line treat- (SOC) is radical cystectomy [6-9]. Given the BCG shortage ment, i.e., following failure of intravesical chemotherapy or and the morbidities of radical cystectomy, there is an urgent BCG, and are largely dependent on the response to prior need for new therapies for high-risk NMIBC. therapy [6-9,18]. Radical cystectomy is generally recom- This review summarizes the current landscape of transla- mended following BCG treatment failure. tional research and clinical trials in BCG-naı̈ve, BCG- recurrent, and BCG-unresponsive NMIBC populations, and 1.2. Histological variants in NMIBC discusses possible alternative treatments to BCG for NMIBC. ClinicalTrials.gov and PubMed (MEDLINE) liter- An increasingly important consideration in the treatment ature searches were conducted to identify relevant ongoing of NMIBC is the impact of histological variants on treat- and planned clinical trials and publications in “non-muscle- ment outcomes. Despite evidence that the presence of these invasive bladder cancer” for the 3 categories of “BCG- histological variants is often linked to poorer prognoses, naı̈ve,” “BCG-recurrent,” and “BCG-non-responsive/unre- including an increased risk of disease recurrence and pro- sponsive.” Supplementary searches were also performed in gression, the identification and diagnosis of variants during Google Scholar. Published guidance and conference pro- TURBT remains challenging in clinical practice [21-25]. ceedings from major urology and oncology congresses Currently, radical cystectomy is the main option for patients (European Association of Urology [EAU], American Uro- with NMIBC presenting with histological variants, with logical Association [AUA], Society of Urological Oncology intravesical BCG an option for select variants [21,23,24]. [SUO], National Comprehensive Cancer Network [NCCN], Studies in urothelial cancer have shown that certain his- National Institute for Health and Care Excellence, and Soci- tological variants are associated with molecular subtypes. ety for Immunotherapy of Cancer) on NMIBC were also These molecular subtypes could provide new or alternative reviewed, as well as the International Bladder Cancer targeted therapy options and/or be more susceptible to treat- Group definitions on BCG-recurrent or BCG-unresponsive ment with chemotherapy, existing targeted agents, or ICIs disease. [26-30]. Therefore, further investigation is needed to 644 N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 identify which histological variants of NMIBC may be (N=2,099) reported that BCG-Connaught reduced the recur- more susceptible to certain treatments, particularly investi- rence rate vs. BCG-Tice without maintenance, but the con- gational agents directed against specific molecular targets verse was true when maintenance therapy was administered and/or immunophenotypes. [33]. Additionally, 5-year recurrence-free survival (RFS) was significantly greater with BCG-Connaught vs. BCG- 1.3. BCG strains Tice [34]. A network meta-analysis of 65 randomized clini- cal trials found that, although there were differences in effi- The mechanism of action of BCG is complex and is cacy among BCG strains vs. chemotherapy, no BCG strain thought to involve both urothelial cells and cells of the showed clear superiority over another [35]. A retrospective immune system [31]. Urothelial cells internalize BCG, review of clinical data (N=321) reported no difference in secrete chemokines and cytokines, and present BCG and/or progression-free survival or RFS between BCG-Tice and antigens to the immune system. Cells of the immune system BCG-Moreau strains [36]. The assessment (N=844) of tox- (including but not limited to CD4+ and CD8+ lymphocytes, icity caused by BCG-Tice, BCG-Moreau, and BCG-RIVM natural killer (NK) cells, and macrophages) eliminate blad- showed patients who received BCG-Tice had mostly mild der cancer cells via the direct action of BCG, direct cytotox- adverse events vs. those who received the other 2 strains, icity, and secretion of soluble factors such as tumor necrosis and BCG-RIVM caused more severe complications [37]. A factor−related apoptosis-inducing ligand) [31]. It is likely phase 3 study (NCT03091660) comparing Tokyo-172 strain that BCG strains act via similar mechanisms, but minor dif- with the BCG-Tice solution is ongoing (estimated comple- ferences may exist. Evidence for differences in clinical tion: February 2025). Patients with high-grade, BCG-naı̈ve characteristics among BCG strains in the treatment of NMIBC are randomized 1:1:1 to intravesical BCG-Tice, NMIBC is limited, predominantly due to a paucity of head- intravesical BCG-Tokyo-172, or intradermal BCG-Tokyo- to-head clinical trials [32]. A retrospective review 172 followed by intravesical BCG-Tokyo-172 [38]. Fig. 1. Overview of AUA/SUO treatment guidelines for NMIBC. AUA = American Urological Association; BCG = Bacillus Calmette-Guerin; MIBC = mus- cle-invasive bladder cancer; NMIBC = non-muscle-invasive bladder cancer; SUO = Society of Urologic Oncology; TURBT = transurethral resection of blad- der tumor N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 645 2. Completed and ongoing clinical trials 5-year survival rates [47]. The anti-PD-1/PD-L1 antibod- ies sasanlimab (subcutaneous administration), durvalu- BCG-naı̈ve patients are those who have never been mab, and atezolizumab are being investigated in treated with BCG. Definitions for BCG-recurrent or BCG- combination with BCG in phase 3 trials in high-risk, unresponsive disease are outlined in Table 2. A number of BCG-naı̈ve NMIBC (Table 3). Subcutaneous sasanlimab active and ongoing clinical trials are exploring the efficacy +BCG is being evaluated in the 3-arm CREST trial (no of new treatments for NMIBC in these disease settings prior BCG ≤2 years), including a BCG maintenance- (Table 3). sparing approach. Primary endpoint is event-free survival (EFS), with estimated study completion in December 2.1. BCG-na€ıve 2026. Durvalumab+BCG is being evaluated in the POTOMAC trial (no prior BCG ≤3 years). Primary end- 2.1.1. Immune checkpoint inhibitors (ICIs)/ point is disease-free survival (DFS), with estimated study immunomodulators completion in November 2024. The ALBAN trial is Increased expression of programmed cell death investigating atezolizumab+BCG vs. BCG in addition to ligand-1 (PD-L1) is a mechanism used by tumors to 1-year BCG bladder instillation. Primary endpoint is evade the immune response [40-44]. In bladder cancer RFS, with estimated study completion in February 2028. cells, PD-L1 expression increased in response to BCG Two single-center trials evaluating atezolizumab+BCG [45]. In high-risk NMIBC, PD-L1 expression in tumor and pembrolizumab are ongoing (Table 3). cells and the T-cell population in the tumor microenvi- Interleukin (IL)-15 stimulates the activation, development, ronment were both predictive factors of BCG response and proliferation of CD8+ T cells and NK cells, but not regu- [46]. PD-1 and PD-L1 expression appeared to be induced latory T cells [49-51]. ALT-803 (N-803) is an IL-15 receptor following BCG in patients with NMIBC [47,48]. Further- superagonist that has antineoplastic activity by promoting more, high PD-L1 expression in BCG-relapsing tumors innate and adaptive immune responses [49-51]. A synergistic was associated with disease progression and reduced effect of ALT-803+BCG was observed in a rat bladder Fig. 2. Overview of EAU treatment guidelines for NMIBC. BCG = Bacillus Calmette-Guerin; CIS = carcinoma in situ; EAU = European Association of Urology; MIBC = muscle-invasive bladder cancer; NMIBC = non-muscle-invasive bladder cancer; TURBT = transurethral resection of bladder tumor 646 N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 Table 1 Summary of treatment strategies across major guidelines AUA/SUO EAU NCCN NICE SITC Smoking None explicitly stated Counsel patients to stop Recommended to stop None explicitly stated None explicitly stated smoking smoking Risk stratification − Low  Low-grade solitary Ta  Low-grade, primary, Same as AUA/SUO  Solitary, low-grade Ta  Solitary, primary ≤3 cm solitary, TaG1 (papillary guidelines ≤3 cm low-grade Ta  Papillary urothelial urothelial neoplasm of  Papillary urothelial neoplasm of low low malignant potential) neoplasm of low malignant potential  <3 cm malignant potential  No CIS Risk stratification −  Recurrence within 1 y, All tumors not defined in Same as AUA/SUO  Solitary, low-grade Ta Up to 2 of the following: Intermediate low-grade Ta the low- and high-risk guidelines >3 cm  Histologically confirmed  Low-grade solitary Ta categories  Low-grade Ta, multiple and/or recurrent >3 cm multifocal low-grade Ta tumors  Low-grade Ta,  High-grade pTaG2 multifocal  Any pTaG2, grade not  High-grade Ta, ≤3 cm further specified  Low-grade T1  Any low-risk NMIBC recurring within <12 mo of last tumor occurrence Risk stratification − High  High-grade T1  T1 tumor Same as AUA/SUO  High-grade T1 or Ta  Any T1, high-grade, and/  Any recurrent, high-  High-grade tumor guidelines  CIS or CIS grade Ta  CIS  Any aggressive variants  High-grade Ta, >3 cm  Multiple, recurrent, and (or multifocal) large (>3 cm) TaG1G2/  Any CIS low-grade tumors (all  Any BCG failure in features must be present) high-grade disease  Any variant histology  Any lymphovascular invasion  Any high-grade prostatic urethral involvement TURBT Recommended Recommended, followed Recommended, and Recommended Recommended, and by pathology consider intravesical consider intravesical investigation chemotherapy within 24 immunotherapy ≥2 wk h of TURBT after TURBT Second TURBT  After incomplete initial  After incomplete or  After incomplete initial  Within 6 wk in low-risk  4−6 wk in all high-grade resection doubt regarding resection patients if initial T1  In high-risk, high-grade completeness of initial  No muscle in the setting resection does not  4−6 wk in selected high- Ta tumors TURBT of high-grade tumor include detrusor muscle grade Ta (per EAU  If indicated, perform  If there is no muscle in  Large or multifocal  In high-risk tumors guidelines) within 2−6 wk after the initial specimen, lesions within 6 wk of initial initial resection except in Ta low-grade/  Any T1 tumor resection G1 tumors and primary CIS  In T1 tumors  If indicated, perform within 2−6 wk after initial resection Treatment of primary or  Low-risk tumor: should  Low- or intermediate-risk  cTa low-grade tumor:  Low-risk tumor: consider  Low-risk tumor and low- BCG-naı̈ve tumors not administer induction tumor with low previous observation or 6-wk intravesical grade Ta: observation intravesical therapy recurrence rate and course of intravesical chemotherapy  Intermediate-risk tumor  Low- or intermediate- EORTC recurrence score therapy concurrent with initial and 1−2 additional risk tumor: consider a <5: consider single  cTa high-grade tumor: TURBT criteria: intravesical single postoperative instillation of BCG (preferred),  Intermediate-risk tumor: therapy, preferably BCG instillation of chemotherapy observation, or consider ≥6 courses of induction and ≥1-y intravesical  Intermediate-risk tumor intravesical intravesical maintenance. Other chemotherapy within with/without immediate chemotherapy chemotherapy options are observation 24 h of TURBT, except instillation  cT1 tumor with residual  High-risk tumor: or chemotherapy in the case of suspected chemotherapy: disease: BCG or intravesical BCG or  Intermediate-risk tumor perforation or extensive intravesical BCG or cystectomy radical cystectomy and ≥3 additional resection intravesical  CT1 tumor without criteria or high-risk  Intermediate-risk tumor: chemotherapy for ≤1 y residual disease: BCG tumor: intravesical consider 6-wk course of  High-risk tumor: (preferred), observation, therapy, preferably BCG induction intravesical intravesical BCG for or intravesical induction and ≥3 y chemotherapy or 1−3 y or radical chemotherapy maintenance. Other immunotherapy cystectomy in patients at  Any Tis tumor: BCG options are  High-risk tumor with highest risk of tumor chemotherapy or clinical newly diagnosed CIS, progression trial (continued) N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 647 Table 1 (Continued) AUA/SUO EAU NCCN NICE SITC high-grade T1, or high- risk Ta urothelial carcinoma: consider 6-wk induction course of BCG  Intermediate-risk tumor with CR to induction intravesical chemotherapy or induction BCG: consider maintenance therapy (BCG maintenance for 1 y)  High-risk tumor with CR to induction BCG: consider BCG maintenance for 3 y Treatment following Intermediate- or high-risk Consider BCG instillations Cystoscopy-positive: None explicitly stated None explicitly stated failure of prior tumor: consider biopsy adjuvant intravesical intravesical and an upper tract therapy, cystectomy, or chemotherapy evaluation prior to pembrolizumab additional intravesical therapy Persistent cTa, cT1, or Tis tumors: second induction course of induction therapy, followed by TURBT  If no residual disease: maintenance BCG for those who received prior BCG  If residual disease: cystectomy, concurrent chemoradiation, change intravesical agent, or clinical trial enrollment Cytology-positive: intravesical BCG followed by maintenance BCG  BCG-unresponsive: cystectomy, change intravesical agent, or clinical trial enrollment Pembrolizumab can be considered in select patients  Intermediate- or high-risk  BCG-unresponsive: See previous Radical cystectomy or BCG failure pattern tumor with persistent or radical cystectomy, further intravesical (resistant, refractory, or recurrent Ta or CIS clinical trial enrollment therapy relapsing) should be disease: consider second or bladder-preserving considered in decisions course of BCG strategies about further therapy  Patient fit for surgery  Late BCG-relapsing: with high-grade T1 radical cystectomy or disease: consider radical repeat BCG, or bladder- cystectomy preserving strategies  Intolerance or  Low-grade recurrence documented recurrence after BCG for primary on TURBT within 6 mo: intermediate-risk tumor: should not prescribe repeat BCG or additional BCG intravesical  Persistent or recurrent chemotherapy, or radical intermediate- or high- cystectomy risk NMIBC, unwilling or unfit for cystectomy: consider clinical trial enrollment or intravesical chemotherapy (continued) 648 N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 Table 1 (Continued) AUA/SUO EAU NCCN NICE SITC Radical cystectomy Recommended in low- or Recommended in high-risk Recommended in high- Recommended in high- None explicitly stated intermediate-risk tumors tumors or following grade tumors or grade tumors or following failure of other BCG failure following treatment following treatment options or in high-risk failure failure tumors AUA = American Urological Association; BCG = Bacillus Calmette-Guerin; CIS = carcinoma in situ; CR = complete response; EAU = European Association of Urology; EORTC = European Organisation for Research and Treatment of Cancer; NCCN = National Comprehensive Cancer Network; NICE = National Institute for Health and Care Excellence; NMIBC = non-muscle- invasive bladder cancer; SITC = Society for Immunotherapy of Cancer; SUO = Society of Urologic Oncology; Tis = tumor in situ; TURB = transurethral resection of bladder; TURBT = transurethral resection of bladder tumor. Table 2 Definitions of BCG-recurrent and BCG-unresponsive disease BCG-recurrent or -relapsing Disease BCG-unresponsive or -refractory Disease International Bladder Cancer Group [17] BCG-relapsing: recurrence of high-grade disease after BCG-unresponsive: includes BCG-refractory and BCG- achieving a disease-free state at 6 mo following relapsing (<6 mo since last BCG exposure) disease. adequate BCG treatment Subgroup of patients at highest risk of recurrence and progression and for whom additional BCG treatment is not feasible option BCG-refractory: persistent high-grade disease at 6 mo despite adequate BCG treatment. Includes any stage or grade progression by 3 mo after first BCG cycle FDA [39] See BCG-unresponsive BCG-unresponsive: ≥1 of the following:  Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary disease/tumor invades the subepithelial connective tissue) disease <12 mo following adequate BCG treatment  Recurrent high-grade Ta/T1 disease <6 mo follow- ing adequate BCG treatment  T1 high-grade disease at the first evaluation after BCG induction EAU [9] BCG-relapsing: recurrence of G3/high-grade BCG-refractory: (WHO guidelines) tumor after completion  T1G3/high-grade tumor at 3 mo of BCG maintenance, despite initial response  TaG3/high-grade tumor after 3 mo and at 6 mo, after either re-induction or first course of maintenance  CIS (without concomitant papillary tumor) at 3 mo and persists at 6 mo after re-induction  High-grade tumor during BCG maintenance BCG-unresponsive:  BCG-refractory  T1Ta/high-grade relapse <6 mo following adequate BCG treatment  Development of CIS <12 mo following adequate BCG treatment SITC [18] BCG-relapsing: recurrence of high-grade disease after BCG refractory: persistent high-grade disease at 6 mo achieving a disease-free state at 6 mo following despite adequate BCG treatment. Also includes any adequate BCG treatment stage/grade progression by 3 mo after first BCG cycle BCG-resistant (not currently used but included for BCG unresponsive: includes BCG-refractory and BCG- clarification purposes): recurrent or persistent disease relapsing (within 6−9 mo of last BCG treatment). 3 mo after induction. In these cases, BCG resistance Patients for whom further BCG is not indicated and has resolved 6 mo after BCG re-treatment, with or radical cystectomy is a true option without transurethral resection Adequate BCG: received at least 5 out of 6 doses of induction therapy plus at least 2 out of 6 doses of a second induction course or 2 out of 3 doses of maintenance therapy. BCG = Bacillus Calmette-Guerin; CIS = carcinoma in situ; EAU = European Association of Urology; FDA = US Food and Drug Administration; SITC = Society for Immunotherapy of Cancer; WHO = World Health Organization. N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 649 cancer model [51]. In a phase 1/2 trial of ALT-803+BCG, 2.1.4. Chemotherapy 9 patients with intermediate-/high-risk NMIBC were disease- Per guidelines, intravesical chemotherapy is recom- free at 24 months [52] (Table 3). mended for first-line use in patients with low-risk NMIBC, or in intermediate-risk patients as an alternative to BCG in 2.1.2. Targeted therapies the case of BCG shortages [6-9]. Chemotherapy options Several targeted therapies have demonstrated preclini- include the DNA synthesis inhibitors mitomycin C (MMC) cal efficacy and are in early clinical investigation for and gemcitabine, and the anthracycline epirubicin, an inhib- BCG-naı̈ve NMIBC, including alpha1H, sirolimus (rapa- itor of nucleic acid and protein synthesis [6-9]. mycin), APL-1202, and sunitinib (Table 3). Alpha1H is a Patients with low-/intermediate-risk NMIBC treated synthetic peptide, consisting of the alpha1 domain of with intravesical pirarubicin reported 3-year RFS rates a-lactalbumin in complex with oleic acid, with tumorici- of 63.7−85.3% [67]. Intravesical gemcitabine improved dal activity. The mammalian target of rapamycin DFS vs. BCG in a retrospective analysis in a largely (mTOR) inhibitor sirolimus (rapamycin) has shown anti- BCG-naı̈ve NMIBC population (29% and 21% had prior tumor effects in preclinical bladder cancer studies BCG, respectively) [68]. Patients treated with sequential [53,54]. Furthermore, mTOR pathway activation could gemcitabine-docetaxel reported treatment success rates be a predictive biomarker for recurrence in high-risk of 96%, 89%, and 89% at 3 months, and 1 and 2 years, NMIBC [55]. APL-1202 is an inhibitor of methionine respectively [69]. Reports of gemcitabine+docetaxel in aminopeptidase II type (MetAP2) that has shown antian- NMIBC suggest that BCG-naı̈ve patients respond better giogenic and antineoplastic activities in preclinical stud- vs. patients with recurrent/relapsed disease [70,71]. In a ies [56]. In a phase 2 trial of sequential BCG-sunitinib phase 3 trial in intermediate- and high-risk superficial (pan tyrosine kinase inhibitor), 72% of patients with papillary bladder cancer, there was no difference in effi- high-grade NMIBC (no BCG ≤12 months) achieved cacy for patients treated with intravesical MMC-BCG CR at 3 months, with low rates of recurrence and progres- vs. MMC alone [72]. Various trials with other chemo- sion [57]. therapy regimens are ongoing (Table 3), including the ANZUP 1301 [73] and GEMDOCE trials. 2.1.3. Gene therapy, vaccines, viral-, and bacterial-based therapies 2.2. BCG-recurrent BC-819 (inodiftagene vixteplasmid) is a recombinant 2.2.1. ICIs/immunomodulators DNA plasmid carrying the gene for diphtheria toxin-A Pembrolizumab+BCG is being assessed in a single- chain under the regulation of the promoter of H19 gene, center phase 1 trial in high-risk, BCG-recurrent/persis- which is upregulated and expressed at high levels only in tent NMIBC [74]. In the phase 3 KEYNOTE-676 trial, tumor cells [58]. In a phase 2 trial, intravesical BCG+BC- patients with high-risk, recurrent/persistent NMIBC after 819 exhibited clinical activity and was well tolerated [59]. 1 BCG induction course will receive pembrolizumab+ Intercellular adhesion molecule 1 (ICAM-1) is upregulated BCG or BCG alone [75]. Primary endpoint is CR rate in in NMIBC [60,61]. In preclinical studies, the bio-selected patients with CIS, with estimated study completion in ICAM-1-targeted immunotherapeutic coxsackievirus A21 November 2024 [75]. The KEYNOTE-676 trial has (CVA21; CAVATAK) displayed oncolytic activity in recently been updated to include a BCG-naı̈ve population NMIBC cells [62]. In the phase 1 CANON trial, clinical (NCT03711032). Nivolumab+BCG vs. BCG is being activity of first-line CVA21 was observed [60,61]. In the evaluated in the phase 3 CheckMate 7G8 trial phase 1b KEYNOTE-200 trial, an objective response rate (NCT04149574) in high-risk, BCG-recurrent/persistent (ORR) of 31% and median overall survival of 11.2 months NMIBC ≤24 months after last BCG dose. Primary end- were reported following CVA21+pembrolizumab in point is EFS, with estimated study completion in August patients with advanced/metastatic bladder cancer [63]. 2030 (Table 3). Ty21a, a commercial vaccine for typhoid fever, TMX-101 is a new formulation of imiquimod, a toll-like improved survival in MB49 bladder tumor−bearing mice receptor agonist with immuno-stimulatory properties, opti- and induced infiltration of NK T cells with 1 dose, whereas mized for intravesical delivery. TMX-101 demonstrated BCG required multiple doses to elicit the same response promising antitumor activity in a phase 2 trial in recurrent [64,65]. A single-center study of intravesical Ty21a is CIS NMIBC (50% had received ≥2 prior courses of BCG) underway (Table 3). [76]. VAX014 is a recombinant bacterial minicell-based immunotherapy that targets 2 NMIBC-associated integrin 2.2.2. Targeted therapies heterodimers to destabilize tumor cell membranes. Preclini- cal studies demonstrated a dose-dependent ability of Mutations in fibroblast growth factor receptor (FGFR) VAX014 to prevent tumor implantation and development genes and dysregulation of FGFR signaling have been in a bladder cancer model [66]. implicated in urothelial carcinoma. Additionally, several Table 3 Activea clinical trials in patients with NMIBC 650 Intervention Population NCT Number/Name Phase Estimated Enrollment, n Primary Outcome Measures BCG-naı̈ve Immune checkpoint inhibitors/immunomodulators  IV pembrolizumab+intravesical BCG (induction and maintenance)  High-risk NMIBC NCT03711032 / 3 1525 (all study  EFS up to 5 y  Intravesical BCG (induction and maintenance)  BCG-naı̈ve KEYNOTE-676 cohorts)  SC sasanlimab+intravesical BCG (induction and maintenance)  High-risk NMIBC NCT04165317 / CREST 3 999  EFS from randomization up to N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663  SC sasanlimab+intravesical BCG (induction only)  No intravesical BCG within 2 y 55 mo  Intravesical BCG (induction and maintenance)  IV atezolizumab+intravesical BCG (induction and maintenance)  High-risk NMIBC NCT03799835 / ALBAN 3 614  RFS after 2 y  Intravesical BCG (induction and maintenance)  No prior BCG  IV durvalumab+intravesical BCG (induction and maintenance)  High-risk NMIBC NCT03528694 / 3 973  DFS up to 4 y  IV durvalumab+intravesical BCG (induction only)  BCG-naı̈ve or no BCG within 3 y POTOMAC  Intravesical BCG (induction and maintenance)  First-line IV pembrolizumab monotherapy  BCG-naı̈ve, high-risk T1 NMIBC NCT03504163 2 37  DFS at 6 mo  Refused cystectomy  Intravesical N-803+BCG  Intermediate or high-risk Ta, T1 NCT02138734 1/2 596  CR rate at 12 mo  Intravesical BCG or Tis stage NMIBC  DFS at 24 mo  No prior BCG  IV atezolizumab+intravesical BCG (induction and maintenance)  High-risk NMIBC NCT04134000 / 1 40  DLT up to 24 mo  BCG-naı̈ve or no BCG ≤3 y BladderGATE  RFS up to 24 mo Targeted therapies  Epirubicin+APL-120  Intermediate- or high-risk chemo- NCT04490993 3 359  EFS up to 30 mo  Epirubicin therapy-refractory NMIBC  No prior BCG or immunotherapy  Encapsulated rapamycin  Ta, Tis, or T1 NMIBC NCT04375813 2 166  RFS at 1 y  Placebo  No prior BCG  Change in urinary quality of life  Change in cognitive function  Time to recurrence  Intravesical alpha1H  NMIBC awaiting TURBT NCT03560479 1/2 52  AE profile  Intravesical placebo  No intravesical BCG or chemo-  Cell shedding therapy ≤12 mo  Change from baseline in charac- teristics of papillary tumors  Sirolimus+intravesical BCG  Ta, Tis, or T1 NMIBC NCT02753309 1 33  % change in systemic gamma-  Good candidate for BCG (prior delta T-cell frequency at 4 wk and BCG not specified) 3 mo  % change in systemic gamma- delta T-cell proliferation in response to BCG-specific antigens at 4 wk and 3 mo (continued) Table 3 (Continued) Intervention Population NCT Number/Name Phase Estimated Enrollment, n Primary Outcome Measures  % change in systemic Ag85 pep- tide-specific CD4 and CD8 T lym- phocytes measured using human IFN-g release at 4 wk and 3 mo Gene therapy, vaccines, viral- and bacterial-based N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663  Intravesical Ty21a  Low- or intermediate-risk NMIBC NCT03421236 1 25  AEs after 6 wk not requiring BCG therapy Chemotherapy  Intravesical MMC+BCG  High-grade pTa or stage pT1 NCT02948543 / 3 500  DFS up to 5 y  Intravesical BCG (any grade) NMIBC ANZUP 1301  No prior BCG  Oral lenalidomide+intravesical BCG  High-grade NMIBC NCT01373294 2 17  PFS at 1 y  Intravesical BCG  BCG ≤2 y (response not specified)  Intravesical gemcitabine+docetaxel  Intermediate- or high-risk, NCT04386746 / 2 26  CR rate at 3 mo BCG-naı̈ve NMIBC GEMDOCE  Intravesical MMC  NMIBC NCT03058757 2 78  RFS at 1 y  Prior BCG not specified  Intravesical paclitaxel  Low-grade, Ta NMIBC NCT03081858 1/2 15  MTD at 12 wk  Previous intravesical therapy  Marker lesion response rate at ≥6 mo 12 wk  Cisplatin-gemcitabine  T1b NMIBC NCT04245618 NA 50  Evaluation of benefit of neoadju-  Prior BCG not specified vant chemotherapy  Cisplatin-gemcitabine  Recurrent moderate-/high-risk NCT02716961 NA 208  Tumor progression up to 5 y NMIBC  Drug intervention complications  Prior BCG not specified up to 2 y BCG-recurrent Immune checkpoint inhibitors/immunomodulators  IV pembrolizumab+intravesical BCG (induction and maintenance)  High-risk NMIBC NCT03711032 / 3 1525  CR rate in patients with CIS by  Intravesical BCG (induction and maintenance)  Persistent or recurring after induc- KEYNOTE-676 (all study cohorts) BICR at »3.5 y tion BCG therapy  IV nivolumab+intravesical BCG  High-risk NMIBC NCT04149574 / 3 700  EFS at »3 y  Intravesical BCG  Persistent or recurring ≤24 mo CheckMate 7G8 following last BCG dose, but not BCG-unresponsive disease  IV pembrolizumab+intravesical BCG  High-risk NMIBC NCT02324582 / MARC 1 13  AEs up to 23 wk  Persistent or recurring after induc- tion BCG therapy 651 (continued) 652 Table 3 (Continued) Intervention Population NCT Number/Name Phase Estimated Enrollment, n Primary Outcome Measures Targeted therapies  Pemigatinib  Low- or intermediate-risk NMIBC NCT03914794 2 43  CR rate at 6 wk  Documented recurrence Chemotherapy N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663  Metformin  Low-grade primary or recurrent NCT03379909 / 2 49  Overall response at 3 mo NMIBC TROJAN  Intravesical gemcitabine+BCG  Relapsing but BCG-responsive NCT04179162 1/2 68  MTD up to 1 y high-grade, NMIBC ≤24 mo fol-  Proportion of patients disease-free lowing last BCG dose at 6 mo BCG-unresponsive Immune checkpoint inhibitors/immunomodulators  Intravesical ALT-803+BCG  CIS (with/without Ta or T1 dis- NCT03022825 / 2 183  CR at 24 mo ease) or high-grade Ta or T1 QUILT-3.032  Disease-free rate at 12 mo disease  BCG-unresponsive disease: per- sistent or recurrent CIS with/with- out recurrent Ta/T1 disease ≤12 mo of BCG; or recurrent high-grade Ta/T1 disease ≤6 mo of BCG; or T1 high-grade disease at first evaluation following BCG induction  IV pembrolizumab monotherapy  High-risk, BCG-unresponsive NCT02625961 / 2 260  CR rate up to 3 y NMIBC KEYNOTE-057  DFS rate up to 3 y  Ineligible for/refusal of radical cystectomy  IV pembrolizumab+intravesical gemcitabine  Persistent high-risk (high-grade NCT04164082 2 163  CR rate in CIS subpopulation at Ta, T1, or CIS) NMIBC ≤9 mo 6 mo of BCG  EFS at 18 mo  Ineligible for/refusal of radical cystectomy  IV nivolumab monotherapy  High-risk, BCG-unresponsive NCT03519256 / 2 358  Proportion of CIS patients with  IV nivolumab+oral BMS-986205 NMIBC CheckMate 9UT CR, per PRC, up to 5 y  IV nivolumab+intravesical BCG  Duration of CR, per PRC, in CIS  IV nivolumab+oral BMS-986205+intravesical BCG patients with CR up to 5 y  IV atezolizumab  High-grade Ta, T1, or CIS NCT02844816 / 2 202  CR rate in subset of patients with NMIBC SWOG S1605 CIS at 25 wk  BCG-unresponsive: persistent or  EFS up to 18 mo recurrent high-grade Ta/CIS ≤12 mo of BCG (at least (continued) Table 3 (Continued) Intervention Population NCT Number/Name Phase Estimated Enrollment, n Primary Outcome Measures induction and first maintenance or second induction; high-grade Ta tumors did not achieve disease- free state for ≥6 mo following last dose of BCG, or had CIS and did not achieve CR); or patient has N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 persistent or recurrent high-grade T1 ≤9 mo of BCG (at least induc- tion); or, disease-free state achieved at 6 mo after induction and maintenance/second induction BCG, but later experiences high- grade Ta/T1 recurrence (with or without concomitant CIS) ≤6 mo after BCG or recurrent CIS ≤12 mo after BCG  Ineligible for/refusal of radical cystectomy  Intravesical durvalumab  High-risk NMIBC NCT03759496 2 39  MTD of durvalumab (6 mo after  BCG-refractory: high-grade tumor trial initiation) appears during BCG therapy; or,  Possibility of rate of HGRF (6 mo high-grade, non-muscle-invasive after trial initiation) papillary tumor is present at 3 mo;  1-y HGRF rate or, if CIS (with/without papillary tumor) is present at 3 and 6 mo  Ineligible for/refusal of radical cystectomy  IV avelumab+radiotherapy  High-risk (high-grade, T1, or CIS) NCT03950362 / 2 67  High-risk RFS at 1 y NMIBC PREVERT  BCG-unresponsive: persistent high-grade disease at 6 mo despite BCG or recurrence of high-grade disease ≤6 mo of BCG  Ineligible for/refusal of radical cystectomy  BCG-refractory NMIBC: persistence of high-grade CIS at 6 mo NCT02901548 2 34  CR rate at Month 6 after BCG; or, stage/grade progression at 3 mo after induction BCG; or, recurrence of high-grade CIS after achieving disease-free state following BCG induction <9 mo after last BCG; or, persistent CIS noted on the bladder biop- sies ≤3 mo after completing ≥2 BCG induction and 1 maintenance in a 6-mo period, except for any patient with grade/stage progres- sion after induction BCG (continued) 653 654 Table 3 (Continued) Intervention Population NCT Number/Name Phase Estimated Enrollment, n Primary Outcome Measures  IV ALT-801+gemcitabine  High-risk (high grade Ta, T1, or NCT01625260 1/2 52  Safety profile at 12 wk CIS, tumor >4 cm or multifocal)  Tolerability at 12 wk NMIBC  Clinical benefit up to 13 wk  Refractory/relapsing of ≥1 prior BCG treatment  IV atezolizumab  High-risk, BCG-unresponsive NCT02792192 1/2 24  % patients with AEs from baseline N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663  IV atezolizumab+BCG NMIBC: persistence of high-grade up to end of study (»3.5 y) CIS at 6 mo after BCG; or, stage/  % patients with DLT BCG (up to grade progression at 3 mo after 21 days) induction BCG; or, recurrence of  MTD of BCG (up to 21 days) high-grade CIS after achieving  % patients with CR as assessed by disease-free state after BCG investigator at 6 mo induction <6 mo after last BCG  Includes BCG-recurrent and BCG-naı̈ve populations  IV durvalumab monotherapy  Phase 1: BCG-unresponsive NCT03317158 / 1/2 186  Phase 1: RP2D at 6 mo  IV durvalumab+intravesical BCG NMIBC: persistent or recurrent ADAPT-BLADDER  Phase 2: 6-mo RFS rates  IV durvalumab+external beam radiotherapy CIS with/without concurrent Ta or T1 tumors ≤12 mo of BCG; or, recurrent high-grade Ta or T1 tumors ≤6 mo of BCG  Phase 2: intermediate- or high-risk BCG-relapsing or persistent NMIBC  IV avelumab+intravesical BCG (induction and maintenance)  BCG-unresponsive NMIBC: NCT03892642 / ABC 1/2 27  Proportion of patients receiving tumor lesion present after prior complete induction course (8 wk) response  IV durvalumab+SC S-488210/S-488211  High-risk, BCG-unresponsive NCT04106115 / 1b/2 64  DLT at end of cycle 1 (29 days) NMIBC DURANCE  Pathological DFS rate 1 y after  Ineligible for/refusal of radical start of treatment cystectomy  Intravesical E7766  Intermediate-risk NMIBC NCT04109092 / 1 110  DLTs up to 6 wk  BCG-unresponsive: persistent or INPUT-102  AEs recurrent CIS alone or with recur-  CR rate at 3, 6, 12, 18, and 24 mo rent Ta/T1 disease ≤12 mo of BCG; or, recurrent high-grade Ta/ T1 disease ≤6 mo of BCG; or, T1 high-grade disease at first evalua- tion after BCG induction  Refusal of radical cystectomy (continued) Table 3 (Continued) Intervention Population NCT Number/Name Phase Estimated Enrollment, n Primary Outcome Measures  IV pembrolizumab+BCG solution  High-risk NMIBC NCT02808143 1 9  MTD up to 9 wk  Persistent high-grade disease or BCG-refractory: recurrence ≤6 mo of ≥2 courses of BCG; or, T1 high-grade disease at first N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 evaluation after BCG induction  IV durvalumab+vicinium  High-grade NMIBC NCT03258593 1 40  AEs in a 1-y period  BCG-unresponsive: per SUO and FDA Targeted therapies  Intravesical vicinium  CIS (with or without papillary NCT02449239 / VISTA 3 134  CR rate up to 24 mo disease), T1, or high-grade Ta NMIBC  BCG-refractory: persistent disease after BCG; or, recurrence after CR  Oral erdafitinib  High-risk, BCG-unresponsive NCT04172675 2 280  RFS up to 4 y  Investigator’s choice (intravesical gemcitabine or MMC) NMIBC  FGFR mutations or fusions  Ineligible for/refusal of radical cystectomy  APL-1202  High-risk NMIBC NCT04498702 2 41  RFS rate at 12 mo  Failed/relapsed on prior intravesi- cal BCG or chemotherapy Gene therapy, vaccines, viral- and bacterial-based  Intravesical nadofaragene firadenovec (AdstiladrinÒ )  CIS or Ta/T1 high-grade disease NCT02773849 3 157  CR rate at 12 mo in patients with with/without CIS NMIBC CIS  BCG-unresponsive: high-grade NMIBC unlikely to benefit from or receive further BCG. Includes: nonresponders; persistent high- grade recurrence ≤12 mo after BCG; relapse following CR after BCG; relapse with high-grade CIS ≤12 mo of BCG; relapse with high-grade Ta/T1 NMIBC ≤6 mo of BCG (continued) 655 656 Table 3 (Continued) Intervention Population NCT Number/Name Phase Estimated Enrollment, n Primary Outcome Measures  Intravesical BC-819  Intermediate-risk NMIBC, includ- NCT00595088 2 47  CR rate at 9 wk ing BCG failure  BCG failure: intolerance, such that treatment was discontinued or after ≥6 BCG instillations there is recurrent/persistent disease ≥3 mo N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 after BCG initiation  Intravesical CG0070+IV pembrolizumab  NMIBC with CIS (with/without NCT04387461 / 2 37  CR rate at 12 mo Ta/T1 disease) Core-001  BCG-unresponsive: persistent or recurrent CIS alone or with recur- rent Ta/T1 disease ≤12 months of BCG  Ineligible for/refusal of radical cystectomy Chemotherapy  Intravesical cabazitaxel, gemcitabine, cisplatin  BCG-unresponsive/recurrent NCT02202772 1 19  Serious AEs up to 6 wk NMIBC  BCG-refractory: persistent high- risk Ta, T1, and/or CIS after BCG induction  BCG-recurrent: recurrence after achieving a tumor-free status by 6 mo after at least BCG induction ≤18 mo after last BCG dose a Excludes completed trials, except those not yet published.AE = adverse event; BCG = Bacillus Calmette-Guerin; BICR = blinded independent central review; CIS = carcinoma in situ; CR = complete response; DFS = disease-free survival; DLT = dose-limiting toxicity; EFS = event-free survival; FDA = US Food and Drug Administration; FGFR = fibroblast growth factor receptor; HGRF = high-grade relapse-free; IFN = interferon; IV = intravenous; MMC = mitomycin C; MTD = maximum tolerated dose; NCT = National Clinical Trial; NMIBC = non-muscle-invasive bladder cancer; PFS = progression- free survival; PRC = Pathology Review Committee; RFS = relapse/recurrence-free survival; RP2D = recommended phase 2 dose; SC = subcutaneous; SUO = Society of Urologic Oncology; Tis = tumor in situ; TURBT = transurethral resection of bladder tumor. N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 657 FGFR inhibitors have shown clinical efficacy in advanced patients with CIS, 90% achieved CR [49]. In 16 patients bladder cancer [77]. BGJ398, an oral FGFR inhibitor, dem- with high-grade Ta/T1 papillary disease, DFS was 75% at 6 onstrated antitumor activity in intermediate-risk NMIBC months and 54% at 9 months [49]. [78]. The FGFR1-3 inhibitor pemigatinib is under investi- ALT-801 is a first-in-class fusion protein between IL-2 gation in a phase 2 trial (Table 3). and a T-cell receptor directed toward a p53 epitope dis- played on tumor cells. ALT-801 promotes the expression of 2.2.3. Chemotherapy IL-2 receptors on immune cells and subsequent trafficking of immune cells to tumors, leading to an enhanced antitu- BCG+intravesical gemcitabine is being investigated in a mor immune response [50,85]. Preliminary clinical activity phase 1/2 trial (Table 3). Metformin is being investigated in and immune responses were observed with ALT-801+gem- the phase 2 TROJAN trial in low-grade primary/recurrent citabine in a phase 1/2 trial [85]. NMIBC [79]. Following sequential MMC-BCG, 91.7% of The stimulator of interferon (IFN) genes (STING) path- patients with primary/recurrent NMIBC were disease-free way is a cytosolic DNA-sensing pathway that plays a cru- after 21.4 months’ follow-up in a phase 1 trial [80]. cial role in the activation of the innate and adaptive immune responses [86-89]. STING activates the innate 2.3. BCG-unresponsive immune system via the production of cytokines, such as Type 1 IFN, resulting in the generation of cytotoxic T-cell 2.3.1. ICIs/immunomodulators responses and T-cell infiltration, as well as the activation of Pembrolizumab was recently approved by the FDA for dendritic cells and antigen cross-presentation [86-89]. patients with high-risk, BCG-unresponsive NMIBC with E7766 is a novel STING agonist that has demonstrated CIS with or without papillary tumors and ineligible for/ potent antitumor immune responses in preclinical models elected not to undergo cystectomy [15]. This approval was of NMIBC insensitive to BCG and anti-PD-1 [90], and is based on the ongoing phase 2 KEYNOTE-057 trial evaluat- being investigated in the INPUT-102 trial (Table 3). ing pembrolizumab monotherapy in high-risk, BCG-unre- sponsive NMIBC [81]. After >2 years’ follow-up (N=96), 2.3.2. Targeted therapies the CR rate at 3 months was 40.6% and median duration of Erdafitinib is an FGFR 1-4 inhibitor being assessed vs. response (DOR) was 16.2 months [81]. Of 39 patients with intravesical chemotherapy in a phase 2 trial in patients with CR, 18 (46.2%) patients had a DOR ≥12 months. Of the 57 high-risk, BCG-unresponsive NMIBC who harbor FGFR nonresponders, 9 had stage progression at 3 months, and 3 mutations (Table 3). In a phase 1b study in patients with inter- of 36 patients who underwent cystectomy had progression mediate-/high-risk NMIBC, BCG+APL-1202 (MetAP2 inhib- to ≥T2 disease [81]. itor) was well tolerated [56]. A phase 2 trial of APL-1202 is In the phase 2 SWOG S1605 trial of atezolizumab (anti- ongoing. PD-L1) monotherapy in 74 patients with CIS, CR rates Vicinium (oportuzumab monatox) is a fusion protein were 41.1% and 26.0% at 3 and 6 months, respectively; the consisting of an epithelial cell adhesion molecule−specific trial has now closed as it failed to meet the primary end- antibody fragment fused to Pseudomonas exotoxin that point [82]. A number of other ICI trials are underway in exerts antitumor effects by inhibiting protein synthesis [91]. BCG-unresponsive NMIBC (Table 3), including the durva- In phase 1 and 2 studies of intravesical vicinium, a CR rate lumab+vicinium (fusion protein) trial and DURANCE, of 29−40% at 3 months was reported in patients with CIS evaluating durvalumab+S-488210/S-488211, a 5-peptide NMIBC [91]. The phase 3 VISTA trial was recently com- cancer vaccine that stimulates a cytotoxic T-lymphocyte pleted and vicinium was granted fast-track designation by response against tumor cells and leads to tumor cell lysis. the FDA. Initial phase results reported a 40% CR rate at Indoleamine 2,3-dioxygenases catalyze the conversion 3 months in evaluable CIS patients [92]. Of patients with of tryptophan into kynurenine. This leads to the activation CR at 3 months, 52% had CR for ≥12 months [92,93]. of regulatory T cells and myeloid-derived suppressor cells, and the suppression of NK cells and effector T cells [83]. 2.3.3. Gene therapy BMS-986205 (linrodostat) is an indoleamine 2,3-dioxyge- nase-1 inhibitor that restores and promotes the proliferation In a phase 2b trial of intravesical BC-819 in patients with and activation of various immune cells [83]. Preliminary intermediate-risk NMIBC, 33% had tumor ablation and efficacy was observed in patients with advanced bladder 64% had no new tumor growth at 3 months [58]. Another cancer treated with BMS-986205+nivolumab (anti-PD-1 phase 2 trial is ongoing (Table 3). therapy) [84]; the phase 2 CheckMate 9UT trial is now Nadofaragene firadenovec (AdstiladrinÒ ) is an intravesi- underway (Table 3). cal human IFN-a2b gene-mediated therapy that delivers the Based on preliminary results from the ongoing phase 2 IFN-a2b gene to increase IFN-a2b expression [94]. In a QUILT-3.032 trial, the FDA granted breakthrough therapy phase 3 study, a CR of 53.4% at 3 months was reported in designation to the IL-15 receptor superagonist ALT-803+ patients with CIS, with 24.3% remaining free of high-grade BCG for BCG-unresponsive NMIBC CIS [49]. Of 20 recurrence at 1 year [94]. In patients with high-grade Ta/T1 658 N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 alone, 72.9% and 43.8% were free from recurrence at 3 and electromotive drug administration (EMDA), conductive 12 months, respectively. Overall, responses were durable to hyperthermic chemotherapy, and radiofrequency-induced 1 year [94]. thermochemotherapeutic effect [50,107-109]. CG0070 is an oncolytic serotype 5 adenovirus with an EMDA uses an electrical current to promote intravesical E2F-1 promoter gene and granulocyte macrophage colony drug uptake through electroporation, electro-osmosis, and −stimulating factor gene that is replication-selective for ret- iontophoresis [107,108,110,111]. A systematic review sug- inoblastoma pathway-defective tumors [95]. CG0070 dem- gested EMDA-MMC may delay time to recurrence in select onstrated antitumor activity in preclinical bladder cancer populations [112]. Retrospective studies have shown that models [95]. In a phase 1 study of intravesical CG0070 in EMDA-MMC and sequential BCG-EMDA-MMC are NMIBC, CR was 48.6% [96]. In an interim analysis of a effective in NMIBC, including BCG-failure NMIBC phase 2 study of intravesical CG0070, the overall 6-month [109,113]. The effectiveness of BCG vs. sequential BCG- CR rate was 47% [97]. The overall 18-month CR rate was EMDA-MMC in preventing recurrence and progression of 23%: 35% in BCG-refractory and 17% in BCG-relapsed high-risk NMIBC is under investigation in a phase 3 trial disease [98]. CG0070+pembrolizumab is under investiga- (NCT03664869). tion in the Core-001 trial (Table 3). Hyperthermic intravesical chemotherapy (HIVEC) has demonstrated reduced recurrence and improved bladder 2.3.4. Chemotherapy preservation rates vs. intravesical chemotherapy [114]. More recent studies reported clinical efficacy in patients A meta-analysis of patients with NMIBC (all therapy with intermediate-/high-risk NMIBC treated with HIVEC lines) reported that intravesical chemotherapy+BCG (MMC and pirarubicin) [115-119]. Immediate Combat- improved clinical outcomes vs. BCG [99]. In a phase 1 trial HIVEC following TURBT is being investigated in a phase of patients treated with intravesical cabazitaxel, cisplatin, 1 trial (NCT03689478). and gemcitabine, partial and CR rates were 94% and 89%, Various trials have also evaluated the Synergo system of respectively. RFS was 83% and 64% at 1- and 2-years, microwave-induced chemohyperthermia, including in high- respectively [100]. A CR rate of 36% (median 41 months’ risk or recurrent NMIBC, with varying results [120-124]. follow-up) was reported in patients with BCG-recurrent Unfortunately, several phase 3 trials (NCT02471495; NMIBC treated with intravesical nab-paclitaxel in a phase NCT02254915; NCT00384891; NCT03335059) in NMIBC 2 trial [101]. Gemcitabine+docetaxel (an antimitotic agent) with the Synergo system have been terminated/withdrawn was evaluated in subgroups of BCG-unresponsive/recurrent in recent years. NMIBC with promising clinical efficacy observed [70,71]. Following treatment with reverse thermal hydrogel for- Of 59 patients with NMIBC, 63% had failed ≥2 induction mulated with MMC (UGN-102), 65% of patients achieved BCG. DFS was 49% and 29% at 1 and 2 years, respectively CR at 3 months in a phase 2 trial in intermediate-risk [71]. NMIBC (no BCG ≤2 years) [125]. TAR-200 (GemRIS device; TARIS Biomedical, Lexing- 2.4. Future and potential targets in NMIBC ton, MA) is a device that delivers a continuous and pro- longed dose of gemcitabine over a period of weeks [126]. The therapies reviewed in earlier sections represent The device slowly releases gemcitabine tablets via a semi- those that are currently in clinical trials for the treatment permeable silicone tube that functions as an osmotic pump, of NMIBC. Some recent studies have performed next- resulting in 60−70% of gemcitabine delivered over 2 weeks generation sequencing and multi-omics analyses on (vs. 2 hours for intravesical drugs) [126]. TAR-200 is under NMIBC tissue samples to identify potential new thera- investigation in several clinical trials, including in low-/ peutic targets for the treatment of NMIBC [102-106]. intermediate-risk NMIBC (NCT02720367). Different molecular and genetic features were observed Photodynamic therapy involves the administration of an between cohorts of samples, stratified according to appropriate wavelength of light and a photosensitizing NMIBC grading/risk or transcriptomic/proteomic sub- agent to destroy malignant tissue [50,108,127]. Studies types, that could translate into future molecular targets. have reported clinical benefit in patients with recurrent/ These targets include those involved in DNA damage refractory NMIBC who received photodynamic therapy repair, p53 pathways, cell cycle, chromatin remodeling, with 5-aminolevulinic acid or photoporphyrin [127-131]. and hormone receptor signaling [102-106]. The photodynamic therapy cis-Urocanic acid has shown antitumor effects in rat bladder cancer cells [132]. An ongo- 3. Intravesical drug delivery systems ing phase 1 trial (NCT01458847) in primary/recurrent NMIBC is evaluating cis-Urocanic acid. A phase 1 trial Intravesical device-assisted therapies use increased tem- (NCT03053635) of TLD-1433 and photodynamic therapy peratures to improve drug tissue penetration vs. passive-dif- was recently completed in high-risk, BCG-refractory fusion intravesical therapy. The most common include NMIBC, and a phase 2 trial (NCT03945162) is underway. N.D. Shore et al. / Urologic Oncology: Seminars and Original Investigations 39 (2021) 642−663 659 4. Lesion detection Disclosure The current SOC surveillance for NMIBC is cystoscopic evaluation using white light cystoscopy (WLC); however, it  Neal D. Shore: consultant/advisor for AbbVie, Amgen, is limited in CIS detection, and thus can lead to disease AstraZeneca, Bayer, Bristol-Myers Squibb, Ferring, recurrence or progression [6,8,133]. Blue light cystoscopy Janssen, Merck, Myovant, Novartis, Pfizer, Sanofi Gen- (BLC) uses an intravesical instillation of hexaminolevuli- zyme, Sesen Bio, Tolmar; research funding from Abb- nate and blue light to enhance tumor detection. In a meta- Vie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, analysis, BLC significantly improved tumor detection, with Ferring, Janssen, Merck, Myovant, Novartis, Pfizer, a subsequent reduction in tumor recurrence vs. WLC [134]. Sanofi Genzyme, Sesen Bio, Tolmar. Experience in Europe has shown advantages of BLC in  Joan Palou Redorta: consultant/advisor for Astellas, Jans- terms of locating additional lesions, and confirming tumor sen, Merck, Ferring, AstraZeneca, Sandoz, Novartis. ablation and no tumor recurrence [133]. Accessibility to  Gregoire Robert: nothing to disclose. BLC in the United States is different from Europe due to  Thomas E. Hutson: speaker/consultant for, and research restrictions on reimbursement. More recently, in a phase 3 funding from Pfizer, Astellas, Exelixis, Bristol-Myers trial, BLC was found to significantly improve the detection Squibb, AstraZeneca, Janssen, Eisai, Aveo. of recurrent bladder cancer, including CIS, when compared  Rossano Cesari and Subramanian Hariharan: employees with WLC; 20.6% of recurrence cases and 34.6% of CIS and stockholders of Pfizer. cases were seen only with BLC [135].   Oscar Rodrıguez Faba: nothing to disclose. Improving TURBT using en-bloc is an emerging alterna-  Alberto Briganti: consultant/advisor for Astellas, Jans- tive to standard TURBT, and could potentially improve sen, Merck, Ferring, AstraZeneca, Sandoz, Novartis. staging assessment, perioperative morbidity, and report on  Gary D. Steinberg: stock/other ownership in EpiVax clinical outcomes [9,136-139]. En-bloc uses a monopolar Oncology, UroGen; consultant/advisor for Heat Bio- or bipolar current Thulium:YAG or Holmium:YAG laser to logics, Cold Genesys, Photocure, Merck, Roche/Gen- provide high-quality resected specimens, with high rates of entech, Ciclomed, TARIS Biomedical, MDxHealth, detrusor muscle [9,136-139]. Fidia Farmaceuticals, UroGen, Ferring, Aduro, Boston Scientific, Bristol-Myers Squibb, AstraZeneca, Pfizer, Janssen, EpiVax Oncology, Natera, FKD, Ferring, 5. Conclusion enGene Bio, Sesen Bio, BioCanCell, Nucleix, Ipsen, Combat Medical, Astellas, FerGene; clinical trial pro- Across clinical practice guidelines, the initial SOC treat- tocol committee member for Merck, Bristol-Myers ment for NMIBC often involves TURBT followed by intra- Squibb, Janssen, Cold Genesys, Pfizer, Photocure, vesical chemotherapy or BCG, depending on patient risk Fidia Farmaceuticals. group. 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