Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette–Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation.
Agent/ Target |
NCT/ Acronym |
Phase | Primary Endpoint | Patients Enrolled | Median Follow Up | Results |
---|---|---|---|---|---|---|
Pembrolizumab * ICI Anti-PD1 IgG4/kappa |
NCT02625961 KEYNOTE-057 [28] |
II | CRR of high-risk NMIBC | Cohort A (CIS): 101 pts Cohort B (Non-CIS): 47 pts |
36.4 mos. | Cohort A: 41% (39 out of 96 pts, 95% CI 30.7–51.1%) |
Atezolizumab ICI Anti-PD-L1 IgG1 |
NCT02844816 SWOG S1605 [29] |
II | CRR at 25 weeks in CIS-cohort | CIS cohort: 70 pts pre-planned Non-CIS cohort: 65 pts pre-planned | NR | CIS cohort: 27% (20 out of 74 pts, 95% CI NR) |
Nadofaragene firadenovec rAd-IFNa2b/Syn3 |
NCT02773849 [30] | III | CRR at 12 mos. in CIS-cohort | CIS-cohort: 107 pts Non-CIS cohort: 50 pts |
19.7 mos. | CIS-cohort: 53.4% (55 out of 103 patients, 95% CI 43.3–63.3%) |
Oportuzumab Monatox EpCAM scFv linked to ETA |
NCT02449239 [ |
NCT/Acronym | Status | Phase | Drug(s) | Control | Primary Endpoints | |
---|---|---|---|---|---|---|
31 | ||||||
] | ||||||
III | CRR in CIS-cohort | 126 pts | CIS-cohort: 89 pts | NR | CIS-cohort: 40% (95% CI NR) |
(a) BCG-unresponsive or BCG-intolerant NMIBC | |||||
NCT05120622 Rideau |
Recruiting | 1, 2 | Durvalumab, tremelimumab | — | TRAEs, MTD |
NCT04738630 | Recruiting | 2 | HX008 (Pucotenlimab) | — | CRR, EFS |
NCT04706598 | Recruiting | 1, 2 | Camrelizumab | — | MTD, RFS |
NCT04640623 SunRISe-1 | Recruiting | 2 | TAR-200, Cetrelimab | TAR-200 or Cetrelimab | CRR |
NCT04387461 CORE-001 |
Recruiting | 2 | CG0070, Pembrolizumab | — | CRR |
NCT04164082 | Recruiting | 2 | Pembrolizumab, gemcitabine | — | CRR in CIS subpopulation, EFS |
NCT03950362 PREVERT | Not yet recruiting | 2 | Avelumab, RDT | — | RFS |
NCT03759496 | Recruiting | 2 | Durvalumab | — | MTD, RFS |
Recruiting | |||||
3 | |||||
Pembrolizumab | |||||
, BCG | |||||
BCG | |||||
CRR, EFS | |||||
NCT03528694 POTOMAC |
Active, not recruiting | 3 | Durvalumab, BCG | BCG | DFS |
NCT/Acronym | Status | Phase | Drug(s) | Target or Mechanism | Primary Endpoints | ||||
---|---|---|---|---|---|---|---|---|---|
(a) BCG-unresponsive or BCG-intolerant NMIBC | |||||||||
NCT05014139 | Not yet recruiting | 1 | Enfortumab Vedotin | ADC against Nectin-4 | TRAEs, DLT | ||||
NCT04917809 | Not yet recruiting | 2 | Erdafitinib | FGFR-TKI | ORR | ||||
NCT04799847 | Not yet recruiting | 1, 2 | Catumaxomab | Bispecific (anti-EpCAM, anti-CD3) Ab | DLT, TRAEs | ||||
NCT04498702 | Completed | 2 | APL-1202 | MetAP2 inhibitor | RFR | ||||
NCT04452591 BOND-003 |
Recruiting | 3 | CG0070 | Oncolytic adenovirus | CRR | ||||
NCT04172675 | Recruiting | 2 | Erdafitinib vs. gemcitabine/MMC | ||||||
NCT03519256 | |||||||||
CheckMate 9UT |
Active, not recruiting | 2 | Nivolumab, BMS-986205 (Linrodostat mesylate) | Nivolumab | CRR, DoR | ||||
FGFR-TKI | RFS | ||||||||
NCT03914794 | Recruiting | 2 | Pemigatinib | NCT03317158 ADAPT-BLADDER |
Recruiting | 1, 2 | Durvalumab, RDT | — | RP2D, RFS |
FGFR1-3-TKI | CRR | ||||||||
NCT03022825 QUILT-3.032 |
Recruiting | 2, 3 | BCG, ALT-803 | IL-15 superagonist | CRR, DFR | ||||
NCT02009332 | Completed | 1, 2 | Nab-sirolimus, gemcitabine | mTOR inhibitor | DLT, CRR | ||||
NCT01731652 | Completed | 2 | Vesimune | TLR-7 agonist | CRR | NCT04149574 CheckMate 7G8 |
Recruiting | 3 | Nivolumab, BCG |
NCT02371447 | BCG | EFS | |||||||
Active, not recruiting | 1, 2 | VPM1002BC | Modified BCG | NCT04106115 DURANCE |
Not yet recruiting | 1, 2 | Durvalumab, S-488210/S-488211 vaccine | — | DLT, DFSR |
NCT03892642 ABC Trial |
Active, not recruiting | 1, 2 | Avelumab, BCG | — | DLT | ||||
(b) BCG-naïve NMIBC | |||||||||
DLT, RFR | |||||||||
(b) BCG-naïve NMIBC | |||||||||
NCT04736394 ASCERTAIN |
Not yet recruiting | 3 | APL-1202 vs. epirubicin | MetAP2 inhibitor | EFS | NCT04922047 TACBIN-01 |
Recruiting | ||
NCT02138734 | Recruiting | 1, 2 | ALT-803, BCG | IL-15 superagonist | CRR, DFS | 1, 2 | Tislelizumab, BCG | — | DLT |
NCT04730232 | Recruiting | 2 | Tislelizumab, nab-paclitaxel | — | CRR | ||||
NCT04165317 * CREST |
Recruiting | 3 | Sasanlimab, BCG | BCG | EFS, CRR | ||||
NCT03799835 ALBAN |
Recruiting | 3 | Atezolizumab, 1y BCG | BCG | RFS | ||||
NCT03711032 * KEYNOTE-676 |