Table 2.
Emerging therapies for advanced/metastatic UC or NMIBC.
| Novel Agent | Primary Mechanism | UC Population Treated | Trial Phase | Study/Trial # |
|---|---|---|---|---|
| Toripalimab | PD-1 antibody | Advanced UC | I | Tang et al. (75) |
| Nivolumab with concomitant radiation | PD-1 antibody | Advanced UC that will undergo cystectomy | II | Schmid et al. (76) |
| Tremelimumab + Durvalumab |
CTLA-4 antibody PD-1 antibody |
Advanced UC | II | NCT02527434 |
| Enfortumab vedotin + Atezolizumab |
Antibody-drug conjugate PD-L1 ligand |
Advanced/metastatic UC |
Ib/II | NCT03869190 |
| Enoblituzumab | B7-H3 antibody | Refractory UC | I | NCT01391143 |
| Tislelizumab | PD-1 antibody | Advanced/metastatic UC | II | NCT04004221 |
| Rogaratinib | Pan-FGFR inhibitor | Advanced UC | I I |
Schuler et al. (77) NCT01976741 |
| Derazantanib | Pan-FGFR inhibitor | Advanced UC | I | Papadopoulos (78) |
| Infigratinib | Pan-FGFR inhibitor | Advanced UC | I | NCT01004224 |
| Carotuximab | Endoglin antibody | Advanced/metastatic UC | II | Apolo et al. (79) |
| Axitinib + Avelumab |
VEGFR inhibitor PD-L1 antibody |
Advanced/metastatic UC (cisplatin ineligible) | II | NCT03472560 |
| Ramucirumab | VEGFR inhibitor | Advanced UC refractory to prior therapy | I | Herbst et al. (80) |
| Tisotumab vedotin | Antibody-drug conjugate | Advanced/metastatic UC | I/II | De Bono et al. (81) |
| Ado-trastuzumab | Antibody-drug conjugate | Advanced UC | I | NCT02675829 |
| Afatanib | EGFR/HER2 inhibitor | Metastatic UC after platinum failure | II | Choudhury et al. (82) |
| II | NCT02122172 | |||
| II | NCT02780687 | |||
| Genestein | EGFR inhibitor | Advanced UC that will undergo cystectomy or TURBT | II | NCT00118040 |
| Everolimus | mTOR inhibitor | Metastatic UC progressing after 1-4 cytotoxic agents | II | Seront et al. (83) |
| Metastatic UC after platinum failure | II | Milowsky et al. (84) | ||
| Temsirolimus | mTOR inhibitor | Recurrent/metastatic UC after platinum | II | Pulido et al. (85) |
| Cabozantanib | Multikinase inhibitor | Metastatic UC refractory to platinum | II | Apolo et al. (86) |
| Sorafenib | Multikinase inhibitor | Metastatic UC that progressed after platinum | I | Shah et al. (87) |
| Pazopanib + Everolimus |
Multikinase inhibitor mTOR inhibitor |
Metastatic UC ineligible for platinum or progressed after platinum | I | Bellmunt et al. (88) |
| Regorafenib | Multikinase inhibitor | Metastatic UC that progressed after platinum | II | NCT02459119 |
| Merestinib | Multikinase inhibitor | Advanced/metastatic UC | I | NCT03027284 |
| Selumetinib | Multikinase inhibitor | Advanced/metastatic UC that progressed with prior therapy | Ib | NCT02546661 |
| Vistusertib | MTOR inhibitor | |||
| AZD4547 | FGFR 1/2/3 inhibitor | |||
| Adavosertib | WEE1 inhibitor | |||
| Olaparib | PARP inhibitor | |||
| Durvalumab | PD-L1 inhibitor | |||
| SGT-94 | RB94 plasmid | Metastatic UC with no available standard therapy | I | Siefker-Radke et al. (89) |
| Docetaxel + Apatorsen |
Microtubule inhibitor Hsp27 inhibitor |
Metastatic UC that relapsed after platinum | II | Rosenberg et al. (90) |
| Paclitaxel | Microtubule inhibitor | Advanced UC that progressed after cisplatin | II | Ogawa et al. (91) |
| Advanced UC after platinum and pembrolizumab failed | Furubayashi et al. (92) | |||
| Metastatic UC after cisplatin failed | Kobayashi et al. (93) | |||
| Cabazitaxel | Microtubule inhibitor | MIBC eligible for cystectomy | II | Challapalli et al. (94) |
| Pemetrexed | Folate antimetabolite | Advanced UC resistant to platinum | N/A | Bambury et al. (95) |
| Advanced UC | II | Choi et al. (96) | ||
| Advanced/metastatic UC | I | Cao et al. (97) | ||
| Metastatic UC refractory to platinum | I | Pappot et al. (98) | ||
| Apatorsen | Hsp27 inhibitor | Advanced, untreated UC | II | Bellmunt et al. (99) |
| Pralatrexate + Palbociclib |
DHFR inhibitor CDK 4/6 inhibitor |
Advanced UC | N/A | Wang et al. (100) |
| Flouorocyclo- -pentenyl cytosine |
Cytidine analog and methyltransferase inhibitor | Advanced UC | IIa | Adashek et al. (101), NCT02030067 |
| Olaparib + Durvalumab |
ADP ribose polymerase inhibitor PD-L1 inhibitor |
Unresectable metastatic UC ineligible for platinum | II | NCT03459846 |
| Resectable metastatic UC to undergo surgery | II | Rodriguez-Moreno et al. (102), NCT03534492 | ||
| FyCyd + THU |
Methytransferase inhibitor Cytidine deaminase inhibitor |
Unresectable or metastatic UC that progressed after platinum | II | NCT00978250 |
| CAR-T cells | Target specific tumor antigens | Relapsed and refractory UC | I | NCT03960060 |
| PF-04518600 + Utomilumab |
OX40 agonist 4-1BB agonist |
Advanced/metastatic UC | I | NCT02315066 |
| TAEST16001 | Target specific tumor antigens | Metastatic UC that failed multi-line treatment | I | NCT03159585 |
| Cytokine induced killer cells | Immune system stimulation | Advanced UC | II | NCT02489890 |
| Personalized peptide vaccination | Induce tumor immunity | Progressive advanced UC | I/II | Obara et al. (103) |
| Advanced/metastatic upper tract UC after platinum failure | II | Suekane et al. (104) | ||
| Metastatic UC refractory to platinum | II | Noguchi et al. (105) | ||
| Advanced/metastatic UC | I | NCT02897765 | ||
| Modified vaccinia Ankara virus + Pembrolizumab |
Augment host immune response PD-1 inhibitor |
Unresectable metastatic UC that failed prior therapy | I | NCT02432963 |
| CAVATAK | Oncolytic virus | Advanced/metastatic UC | I | NCT02043665 |
| Navoximod + Atezolizumab |
IDO1 inhibitor PD-L1 inhibitor |
Advanced UC | Ib | Jung et al. (106) |
| Epacadostat | IDO1 inhibitor | Advanced/metastatic UC | I/II | NCT02178722 |
| INCB001158 + Pembrolizumab |
Arginase inhibitor | Advanced/metastatic UC | I/II | NCT02903914 |
| Pirarubicin | DNA intercalator and topoisomerase inhibitor | NMIBC after TURBT | N/A | Huang et al. (107) |
| Cabazitaxel | Microtubule inhibitor | NMIBC that failed BCG | I | DeCastro et al. (108) |
| Apaziquone | DNA crosslinker | NMIBC after TURBT | III | NCT03224182 |
| III | NCT02563561 | |||
| Vicinium | Protein synthesis inhibitor | NMIBC in situ, or high grade papillary bladder cancer that failed BCG | III | NCT02449239 |
| Dendritic cells | Induce immune response | 3 NMIBC + 2 metastatic UC patients | I/II | Ogasawara et al. (109) |
| CAVATAK | Oncolytic virus | NMIBC scheduled for TURBT | I | Annels et al. (110) |
| Enadenotucirev | Oncolytic virus | NMIBC scheduled for TUBRT | I | Garcia-Carbonero et al. (111) |
| CG0070 | Oncolytic virus | High-grade NMIBC after BCG failure | II | NCT02365818 |
| PANVAC | Induce tumor immunity | High-grade NMIBC after BCG failure | I | NCT02015104 |
| Personalized peptide vaccination | Induce tumor immunity | NMIBC after TURBT | I | Obara et al. (112) |
| MAGE-A3 | Induce tumor immunity | NMIBC after TURBT | I | Derre et al. (113) |
| Infigratinib | FGFR-3 inhibitor | NMIBC after prior BCG therapy | N/A | NCT02657486 |
| Rapamycin (sirolimus) | mTOR inhibitor | NMIBC after BCG failure | I/II | NCT02009332 |
| NMIBC | II | NCT04375813 | ||
| APL-1202 | Methionine aminopeptidase II inhibitor | NMIBC resistant to one induction BCG course | Ib | NCT03672240 |
| Nadofaragene firadenovec | Interferon-alpha transmitted to tumor environment | High-grade NMIBC refractory to BCG or relapsed | II | Shore et al. (114) |
| III | NCT02773849 | |||
| Imiquimod | Toll-like receptor 7 agonist | NMIBC in situ | I | Arends et al. (115) |
| II | Donin et al. (116) |
The emerging therapeutic agents for UC with completed or ongoing phase I or II or incomplete III trials with novel molecular targets are listed below. To highlight the novel agents for UC management, standard chemotherapy agents involved in some studies were not included in this table.