Table Info

Table 1.

Selected ongoing clinical trials evaluating emerging targeted treatments in patients affected by advanced or metastatic urothelial carcinoma

Clinicaltrials.gov registration number/name	Phase	Drug	Type of drug	Population	Setting	Number of patients	Endpoints	Current Status	Estimated primary completion date
Anti-Nectin 4
NCT03288545 EV-103 trial	Phase I/IIb randomized, multi-cohort, open-label, multicenter study	Dose escalation/cohort A, cohort B, and K: EV + pembrolizumab Cohort D: EV + cisplatin Cohort E: EV + carboplatin Cohort F: EV + gemcitabine Cohort E: EV + platinum + pembrolizumab Cohort H: EV	ADC, CT, ICI	Locally advanced or metastatic UC	First-line and/or refractory	348	ORR, DOR, DCR, PFS, EFS, OS, safety	Active, not recruiting	31-12-2026
NCT05923190	Phase II non-randomized two arm open-label de-esclation pilot study	EV ± pembrolizumab	ADC and ICI	Metastatic UC	First-line and/or refractory	70	OS, time to next treatment	Recruiting	01-07-2028
NCT05845814	Phase 1/2 randomized, umbrella study	Arm A: EV + favezelimab/pembrolizumab Arm B: EV + vibostolimab/pembrolizumab Arm C: EV + pembrolizumab	ADC and ICI	Locally advanced or metastatic UC	First-line	390	ORR, DOR, PFS, OS, safety	Active, not recruiting	31-05-2027
NCT03869190	Phase Ib/II, open-label, multicenter, randomized, umbrella study	2 arms: atezolizumab + EV	ADC and ICI	Locally advanced or metastatic UC	Refractory	645	ORR, DOR, DCR, PFS, EFS, OS	Enrollement is closed	06-12-2024
NCT04561362	Phase I/II, multicenter, first-in-human, open-label dose-escalation study	Zelenectide pevedotin alone and in combination with pembrolizumab	Bicycle toxin conjugate +/– ICI	Locally advanced or metastatic UC	Refractory, first-line standard-of-care-ineligible	329	ORR, PFS, OS, DOR, safety	Recruiting	12-2025
Anti-TROP2
NCT04527991	Phase III, randomized, open-label study	SG vs. paclitaxel/docetaxel/vinflunine	ADC	Advanced or metastatic UC	Refractory	696	OS, PFS, ORR, CBR, DOR, safety, quality of life	Recruiting	20-2024
NCT03547973	Phase II open-label study	Cohort 3: SG + pembrolizumab Cohort 4: SG + cisplatin + avelumab/zimberelimab Cohort 5: SG + zimberelimab Cohort 6: SG +/– zimberelimab +/– domvanalimab	ADC and others	Advanced or metastatic UC	First-line and/or refractory	643	ORR, DOR, CBR, OS, PFS	Recruiting	07-2024
NCT04863885	Phase I/II non-randomized open label study	SG + nivolumab + ipilimumab	ADC and ICI	Metastatic urothelial bladder carcinoma	First-line, cisplatin-ineligible	46	ORR, DOR, PFS, OS	Active, not recruiting	11-10-2024
NCT03869190	Phase Ib/II, open-label, multicenter, randomized, umbrella study	1 arm: atzolizumab + SG	ADC and ICI	Locally advanced or metastatic UC	Refractory	645	ORR, DOR, DCR, PFS, EFS, OS	Closed enrollment	06-12-2024
NCT05327530	Phase II, multicenter, randomized, open label, parallel-arm, umbrella study	Arm B: avelumab + SG	ADC and TKI	Locally advanced or metastatic UC	Maintenance after first-line CT	252	ORR, DOR, PFS, OS, safety	Recruiting	23-01-2025
FGFR inhibitors
NCT05544552	Phase I-II, multicenter, open-label	TYRA-300	FGFR 3-selective TKI	Advanced UC with activating FGFR3 gene alterations	Refractory	310	MTD, RP2D, ORR	Recruiting	11-2026
NCT03390504 THOR	Phase III	Erdafitinib	FGFR inhibitor	Advanced UC and selected FGFR gene aberrations	Refractory	629	OS, PFS, ORR, DOR, safety	Active, not recruiting	11-09-2024
NCT05775874	Phase II, single-arm，open-label, multicenter study	Fexagratinib + tislelizumab	FGFR inhibitor	Metastatic or locally advanced UC harboring FGFR alterations	Advanced	80	Safety, objective remission rate	Recruiting	30-09-2025
NCT02699606	Phase II, open-label, multicenter	Erdafitinib	FGFR inhibitor	Advanced non-small-cell lung cancer, UC, gastric cancer, esophageal cancer, or cholangiocarcinoma	Refractory	35	ORR, PFS, OS, DOR, safety	Completed	15-03-2024
NCT04601857	Phase II	Futibatinib + pembrolizumab	FGFR inhibitor and others	Advanced or metastatic UC	First-line	46	ORR, DCR, DOR, PFS, OS, safety	Active, not recruiting	05-2024
NCT03473756 FORT-2	Phase Ib/II	Rogaratinib + atezolizumab	FGFR inhibitor and anti-PD-L1	Advanced or metastatic UC	First-line	37	Safety, efficacy, RP2D, PK	Active, not recruiting	30-08-2024
Anti Her-2
NCT02465060, NCT06136897 MATCH	Phase II, multicenter, non-randomized, open-label, multi-cohort	Genetic testing-directed monotherapies including: pertuzumab, trastuzumab, T-DM1, afatinib	MoAb, ADC	Her-2 amplified or mutated advanced unresectable or metastatic solid tumors, including UC	Refractory to standard treatment	6,452	ORR, OS, 6-months PFS	Active, not recruiting, has results arm B, J, Q	24-06-2024
NCT02122172	Phase II, multicenter, non-randomized, open-label	Afatinib	TKI	Her-2 amplified or mutated advanced unresectable or metastatic UC	Refractory to platinum +/– 1 other line	95	PFS, ORR	Active, recruiting	12-06-2024
NCT03602079	Phase I/II, multicenter, open-label	A166	ADC	Her-2 amplified or mutated metastatic solid tumors, including UC	Refractory	49	MTD, ORR, DLT, safety, Cmax	Completed	12-01-2022
NCT02675829	Phase II, multicenter, non-randomized, open-label	T-DM1	ADC	Her-2 amplified or mutated metastatic solid tumors, including UC	Advanced solid tumours	140	ORR	Active, recruiting	02-2025
NCT04482309 DESTINY-PanTumor02	Phase II, multicenter, non-randomized, open-label	T-DXd	ADC	Her-2 amplified or mutated advanced unresectable or metastatic solid tumors, including UC	Refractory	468	ORR, DOR, DCR, PFS, OS, safety	Active, not recruiting	30-07-2027
NCT04639219	Phase II, multicenter, non-randomized, non-label	T-DXd	ADC	Her-2 amplified or mutated advanced unresectable or metastatic solid tumors, including UC	Refractory	102	ORR, DOR, DCR, PFS, OS, safety	Active, not recruiting. Results posted	14-07-2026
NCT04839510	Phase II, multicenter, open-label	MRG002	ADC	Her-2 amplified or mutated advanced unresectable or metastatic UC	Refractory	58	ORR, DOR, TTR, DCR, PFS, OS, safety	NA	06-2022
NCT03809013	Phase II, multicenter, non-randomized open-label	DV	ADC	Her-2 amplified or mutated advanced unresectable or metastatic UC	Refractory	64	ORR, PFS, DOR, DCR, OS	Completed	05-06-2023
NCT04073602	Phase II, single center, non-randomized, open-label	DV	ADC	Her-2 amplified or mutated advanced unresectable or metastatic UC	Refractory	19	ORR, PFS, DOR, DCR, OS, safety	Completed	31-01-2023
NCT04319757	Phase Ib/II, multicenter, non-randomized, open-label	ACE 1702	NK cells	Her-2 amplified or mutated advanced unresectable or metastatic solid tumors, including UC	Refractory	36	DLT, safety	Active, recruiting	06-2024
NCT05318339	Phase II, multicenter, open-label	Trastuzumab + pyrotinib	MoAb + TKI	Her-2 amplified or mutated advanced unresectable or metastatic UC	Refractory	30	ORR, OS, PFS	Active, recruiting	10-12-2024
NCT04632992 MyTACTIC	Phase II, multicenter, non-randomized, open-label, multi-cohort	Cohort F and J: T-DM1 + atezolizumab Cohort G: trastuzumab + pertuzumab Cohort H: trastuzumab + pertuzumab + CT Cohort I: TDM1 + tucatinib	ADC + ICI, MoAbs, ADC + TKI	Her-2 amplified or mutated advanced unresectable or metastatic solid tumors, including UC	Refractory	252	ORR, PFS, DOR, OS, disease control, safety	Completed	27-02-2024
NCT04879329	Phase II, multicenter, open-label, multi-cohort	Cohort A, B, D: DV Cohort C and E: DV + pembrolizumab Cohort C randomized: DV + pembrolizumab vs. DV	ADC, ADC + ICI	Her-2 amplified or mutated advanced unresectable or metastatic UC	Cohort A, B, D: refractory Cohort C, E: I-line	332	ORR, safety, maximum and trough concentration, time to maximum concentration, DOR, PFS, DCR, OS	Active, recruiting	31-10-2024
NCT04644068 PETRA	Phase II, multicenter, open-label, multicohort	Module 1: AZD5305 Module 2: AZD5305 + paclitaxel Module 3: AZD5305 + carboplatin +/– paclitaxel Module 4: AZD5305 + T-DXd Module 5: AZD5305 + datopotamab-DXd Module 6: AZD5305 + camizestrant	PARPi, PARPi + CT, PARPi + ADC (including anti-Her-2)	Solid tumors, including UC	NA	804	Safety, DLT, best percentage change in target lesion, ORR, DOR, PFS, TTR, CA125 change, AUC, Cmax	Active, recruiting	15-12-2026
NCT05302284	Phase III, multicenter, randomized, open-label	DV + triplizumab vs. cisplatin/carboplatin + gemcitabine	ADC + ICI vs. CT	Her-2 amplified or mutated advanced unresectable or metastatic UC	First-line	452	OS, PFS, DOR, DCR	Active, recruiting	31-12-2026
NCT04278144	Phase I/II, multicenter, non-randomized, open-label	BDC-1001 +/– nivolumab	Immune-stimulating antibody conjugate +/– ICI	Her-2 amplified or mutated advanced unresectable or metastatic solid tumors, including UC	Refractory	390	Safety, MTD, DLT, ORR, DOR, DCR, PFS	Active, recruiting	31-01-2025
NCT04143711	Phase I/II, multicenter, non-randomized, open-label	DF1001	Trispecific antibody targeting Her-2, NK cells and T-cells	Her-2 amplified or mutated advanced unresectable or metastatic solid tumors, including UC (only in the escalation-expansion phases)	Refractory	378	DLT, ORR, safety, OS, DOR, PFS	Active, recruiting	10-2026
PARP inhibitors
NCT03869190	Phase Ib/II, open-label, multicenter, randomized umbrella study	Niraparib	PARPi and others	Locally advanced or metastatic UC	Refractory	645	ORR, PFS, OS, DOR, DCR, safety	Recruiting	06-12-2024
NCT04678362 TALASUR	Phase II	Talazoparib + avelumab	PARPi and others	Platinum-sensitive locally advanced or metastatic UC	First-line maintenance treatment	50	PFS, OS, DOR	Recruiting	12-2023
NCT03375307	Phase II	Olaparib	PARPi	Metastatic or advanced UC and other genitourinary tumors with DNA-repair defects	Refractory	150	ORR, PFS, OS	Recruiting	21-08-2024
NCT03448718	Phase II	Olaparib	PARPi	Metastatic UC harboring somatic DNA damage response (DDR) alterations	Refractory	19	ORR, PFS, OS, safety	Completed Results posted	15-10-2021
NCT03682289	Phase II	Ceralasertib alone and in combination with olaparib or durvalumab	PARPi and others	Locally advanced or metastatic selected solid tumor malignancies	Refractory	89	ORR, DOR, PFS, safety	Recruiting	31-07-2025
Multi-tyrosine-kinase inhibitors
NCT03425201 NICARAGUA	Phase I/II, multicenter, non-randomized, open-label	Cabozantinib + niraparib	Multi-TKI + PARPi	Advanced unresectable or metastatic UC or renal cell carcinoma	Refractory	20	MTD, PFS, satefy, ORR, DCR, DOR, OS	Active, not recruiting	04-2024
NCT03534804	Phase II, multicenter, non-randomized, open-label	Cabozantinib + pembrolizumab	Multi-TKI + ICI	Metastatic cisplatin-ineligible UC	First-line	34	ORR, 6-month PFS, OS, safety	Active, not recruiting	31-05-2024
NCT03866382	Phase II, non-randomized, open-label	Cabozantinib + nivolumab + ipilimumab	Multi-TKI + ICI	Metastatic rare genitourinary tumors	Refractory	224	ORR, PFS, OS, DCR, safety	Active, recruiting	28-02-2025
NCT05092958 MAIN-CAV	Phase III, multicenter, randomized, open-label	Cabozantinib + avelumab vs. avelumab	Multi-TKI + ICI vs. ICI	Advanced unresectable or metastatic UC	First-line maintenance treatment	654	OS, PFS, safety, tumor response, quality of life	Active, not recruiting	10-12-2024

ADC: antibody-drug conjugate; AUC: area under the curve; CAR: chimeric antigen receptor; CBR: clinical benefit rate; Cmax: maximum observed concentration; CT: chemotherapy; DCR: disease control rate; DLT: dose limiting toxicity; DOR: duration of response; DV: disitamab vedotin; EFS: event-free survival; EGFR: epidermal growth factor receptor; ICIs: immune checkpoint inhibitors; MTD: maximum tolerated dose; MoAb: monoclonal antibody; NA: not available; NK: natural killer; NMIBC: non-muscle-invasive bladder cancer; ORR: objective response rate; OS: overall survival; PARPi: poly(ADP-ribose) polymerase inhibitor; PFS: progression-free survival; RP2D: recommendend phase 2 dose; T-DXd: trastuzumab deruxtecan; T-DM1: trastuzumab emtansine; TKI: tyrosine kinase inhibitor; TTR: time to response; UC: urothelial carcinoma; UTUC: upper tract urothelial carcinoma; PD-L1: programmed cell death ligand-1; EV: enfortumab vedotin; FGFR: fibroblast growth factor receptor; Her-2: human epidermal growth factor receptor-2; PK: pharmacokinetics

Declarations

Author contributions

IT, GCG, and UV: Conceptualization, Investigation, Writing—original draft, Writing—review & editing. UV, FT, and GS: Validation, Writing—review & editing, Supervision. SM, LT, and MP: Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

Ursula Vogl received grant from Fond’Action; received institutional personal honoraria from Pfizer, Astellas, Janssen, Merck, MSD, BMS, Ipsen, Healthbook, Novartis AAA, Bayer, Grasso consulting, Vaccentis; received private personal honoraria from Healthbook, SAMO, Inselspital Bern, Kantonsspital Chur, Kantonsspital Baden, Ipsen; and received travel grant from Astra Zeneca and Janssen. Fabio Turco received travel grant from Bayer. All other authors declare the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Cancer Stat Facts: Bladder Cancer [Internet]. [Cited 2024 Aug 4]. Available from: https://seer.cancer.gov/statfacts/html/urinb.html

Pasin E, Josephson DY, Mitra AP, Cote RJ, Stein JP. Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. Rev Urol. 2008;10:31–43. [PubMed] [PMC]

Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196:1021–9. [DOI] [PubMed]

Flaig TW, Spiess PE, Abern M, Agarwal N, Bangs R, Buyyounouski MK, et al. NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024. J Natl Compr Canc Netw. 2024;22:216–25. [DOI] [PubMed]

Balar AV, Kamat AM, Kulkarni GS, Uchio EM, Boormans JL, Roumiguié M, 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. Lancet Oncol. 2021;22:919–30. [DOI] [PubMed]

Lee A. Nadofaragene Firadenovec: First Approval. Drugs. 2023;83:353–7. [DOI] [PubMed] [PMC]

Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021;384:2102–14. [DOI] [PubMed] [PMC]

Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383:1218–30. [DOI] [PubMed]

van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, et al.; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023;389:1778–89. [DOI] [PubMed]

10.

Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, et al.; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390:875–88. [DOI] [PubMed]

11.

Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, et al. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021;39:2474–85. [DOI] [PubMed] [PMC]

12.

Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, González-Martín A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024;42:47–58. [DOI] [PubMed] [PMC]

13.

Ross JS, Wang K, Khaira D, Ali SM, Fisher HA, Mian B, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016;122:702–11. [DOI] [PubMed]

14.

Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, et al.; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024;35:107–17. [DOI] [PubMed]

15.

Chan CJ, Andrews DM, Smyth MJ. Receptors that interact with nectin and nectin-like proteins in the immunosurveillance and immunotherapy of cancer. Curr Opin Immunol. 2012;24:246–51. [DOI] [PubMed]

16.

Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016;76:3003–13. [DOI] [PubMed]

17.

Tomiyama E, Fujita K, Rodriguez Pena MDC, Taheri D, Banno E, Kato T, et al. Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma. Int J Mol Sci. 2020;21:5390. [DOI] [PubMed] [PMC]

18.

Hoffman-Censits JH, Lombardo KA, Parimi V, Kamanda S, Choi W, Hahn NM, et al. Expression of Nectin-4 in Bladder Urothelial Carcinoma, in Morphologic Variants, and Nonurothelial Histotypes. Appl Immunohistochem Mol Morphol. 2021;29:619–25. [DOI] [PubMed] [PMC]

19.

Rosenberg J, Sridhar SS, Zhang J, Smith D, Ruether D, Flaig TW, et al. EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma. J Clin Oncol. 2020;38:1041–9. [DOI] [PubMed] [PMC]

20.

Rosenberg JE, O’Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019;37:2592–600. [DOI] [PubMed] [PMC]

21.

Yu EY, Petrylak DP, O’Donnell PH, Lee JL, van der Heijden MS, Loriot Y, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021;22:872–82. [DOI] [PubMed]

22.

Chang E, Weinstock C, Zhang L, Charlab R, Dorff SE, Gong Y, et al. FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma. Clin Cancer Res. 2021;27:922–7. [DOI] [PubMed]

23.

Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021;384:1125–35. [DOI] [PubMed] [PMC]

24.

O’Donnell PH, Milowsky MI, Petrylak DP, Hoimes CJ, Flaig TW, Mar N, et al. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023;41:4107–17. [DOI] [PubMed] [PMC]

25.

Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023;41:22–31. [DOI] [PubMed] [PMC]

26.

TW Friedlander, MI Milowsky, PH O’Donnell, DP Petrylak, CJ Hoimes, TW Flaig, et al. Enfortumab vedotin (EV) with or without pembrolizumab (P) in patients (pts) who are cisplatin-ineligible with previously untreated locally advanced or metastatic urothelial cancer (la/mUC): Additional 3-month follow-up on cohort K data. J Clin Oncol. 2023;41:4568. [DOI]

27.

Powles TB, van der Heijden MS, Gupta S, Perez Valderrama B, Galsky MD, Bedke J, et al. 1966MO - EV-302: Exploratory analysis of nectin-4 expression and response to 1L enfortumab vedotin (EV) + pembrolizumab (P) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC). Ann Oncol. 2024;35:S1137–38. [DOI]

28.

Vogl UM, Testi I, De Santis M. Front-line Platinum Continues To Have a Role in Advanced Bladder Cancer. Eur Urol Focus. 2024;10:217–8. [DOI]

29.

McGregor BA, Sonpavde GP, Kwak L, Regan MM, Gao X, Hvidsten H, et al. The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma. Ann Oncol. 2024;35:91–7. [DOI] [PubMed]

30.

Mudd GE, Scott H, Chen L, van Rietschoten K, Ivanova-Berndt G, Dzionek K, et al. Discovery of BT8009: A Nectin-4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer. J Med Chem. 2022;65:14337–47. [DOI] [PubMed] [PMC]

31.

Bennett G, Brown A, Mudd G, Huxley P, Van Rietschoten K, Pavan S, et al. MMAE Delivery Using the Bicycle Toxin Conjugate BT5528. Mol Cancer Ther. 2020;19:1385–94. [DOI] [PubMed]

32.

Baldini C, Goldschmidt V, Brana I, Doger B, Italiano A, Cousin S, et al. BT8009-100: A phase I/II study of novel bicyclic peptide and MMAE conjugate BT8009 in patients (pts) with advanced malignancies associated with nectin-4 expression, including urothelial cancer (UC). J Clin Oncol. 2023;41:498. [DOI]

33.

Klümper N, Tran NK, Zschäbitz S, Hahn O, Büttner T, Roghmann F, et al. NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer. J Clin Oncol. 2024;42:2446–55. [DOI] [PubMed] [PMC]

34.

Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015;6:84–105. [DOI] [PubMed] [PMC]

35.

Mathew Thomas V, Tripathi N, Agarwal N, Swami U. Current and emerging role of sacituzumab govitecan in the management of urothelial carcinoma. Expert Rev Anticancer Ther. 2022;22:335–41. [DOI] [PubMed]

36.

Stepan LP, Trueblood ES, Hale K, Babcook J, Borges L, Sutherland CL. Expression of Trop2 cell surface glycoprotein in normal and tumor tissues: potential implications as a cancer therapeutic target. J Histochem Cytochem. 2011;59:701–10. [DOI] [PubMed] [PMC]

37.

Faltas B, Goldenberg DM, Ocean AJ, Govindan SV, Wilhelm F, Sharkey RM, et al. Sacituzumab Govitecan, a Novel Antibody--Drug Conjugate, in Patients With Metastatic Platinum-Resistant Urothelial Carcinoma. Clin Genitourin Cancer. 2016;14:e75–9. [DOI] [PubMed]

38.

Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC). Oncotarget. 2015;6:22496–512. [DOI] [PubMed] [PMC]

39.

Bardia A, Messersmith WA, Kio EA, Berlin JD, Vahdat L, Masters GA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32:746–56. [DOI] [PubMed]

40.

Loriot Y, Petrylak DP, Rezazadeh Kalebasty A, Fléchon A, Jain RK, Gupta S, et al. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol. 2024;35:392–401. [DOI] [PubMed]

41.

Petrylak DP, Tagawa ST, Jain RK, Bupathi M, Balar AV, Rezazadeh A, et al. Primary analysis of TROPHY-U-01 cohort 2, a phase 2 study of sacituzumab govitecan (SG) in platinum (PT)-ineligible patients (pts) with metastatic urothelial cancer (mUC) that progressed after prior checkpoint inhibitor (CPI) therapy. J Clin Oncol. 2023;41:520. [DOI]

42.

Grivas P, Pouessel D, Park CH, Barthelemy P, Bupathi M, Petrylak DP, et al. Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3. J Clin Oncol. 2024;42:1415–25. [DOI]

43.

Grivas P, Tagawa ST, Bellmunt J, De Santis M, Duran I, Goebell PJ, et al. TROPiCS-04: Study of sacituzumab govitecan in metastatic or locally advanced unresectable urothelial cancer that has progressed after platinum and checkpoint inhibitor therapy. J Clin Oncol. 2021;39:TPS498. [DOI]

44.

Gilead Provides Update on Phase 3 TROPiCS-04 Study [Internet]. Gilead Sciences, Inc.; 1996-2024 [cited 2024 Aug 4]. Available from: https://www.gilead.com/news-and-press/press-room/press-releases/2024/5/gilead-provides-update-on-phase-3-tropics-04-study

45.

Ascione CM, Napolitano F, Esposito D, Servetto A, Belli S, Santaniello A, et al. Role of FGFR3 in bladder cancer: Treatment landscape and future challenges. Cancer Treat Rev. 2023;115:102530. [DOI]

46.

Sonpavde GP, Subbiah V. Unlocking precision oncology with FGFR inhibition in urothelial carcinoma. Ann Oncol. 2024;35:150–3. [DOI] [PubMed]

47.

Touat M, Ileana E, Postel-Vinay S, André F, Soria JC. Targeting FGFR Signaling in Cancer. Clin Cancer Res. 2015;21:2684–94. [DOI] [PubMed]

48.

Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol. 2019;16:105–22. [DOI] [PubMed]

49.

Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–29. [DOI] [PubMed]

50.

Robinson BD, Vlachostergios PJ, Bhinder B, Liu W, Li K, Moss TJ, et al. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun. 2019;10:2977. [DOI] [PubMed] [PMC]

51.

Necchi A, Madison R, Pal SK, Ross JS, Agarwal N, Sonpavde G, et al. Comprehensive Genomic Profiling of Upper-tract and Bladder Urothelial Carcinoma. Eur Urol Focus. 2021;7:1339–46. [DOI] [PubMed]

52.

Nadal R, Valderrama BP, Bellmunt J. Progress in systemic therapy for advanced-stage urothelial carcinoma. Nat Rev Clin Oncol. 2024;21:8–27. [DOI] [PubMed]

53.

Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al.; BLC2001 Study Group. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019;381:338–48. [DOI] [PubMed]

54.

Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, et al.; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022;23:248–58. [DOI] [PubMed]

55.

Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, et al. Management of Fibroblast Growth Factor Inhibitor Treatment-emergent Adverse Events of Interest in Patients with Locally Advanced or Metastatic Urothelial Carcinoma. Eur Urol Open Sci. 2023;50:1–9. [DOI] [PubMed] [PMC]

56.

Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023;389:1961–71. [DOI]

57.

Siefker-Radtke AO, Powles T, Moreno V, Kang TW, Cicin I, Girvin A, et al. Erdafitinib (ERDA) vs ERDA plus cetrelimab (ERDA+CET) for patients (pts) with metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa): Final results from the phase 2 Norse study. J Clin Oncol. 2023:16:4504. [DOI]

58.

Lamont FR, Tomlinson DC, Cooper PA, Shnyder SD, Chester JD, Knowles MA. Small molecule FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo. Br J Cancer. 2011;104:75–82. [DOI] [PubMed] [PMC]

59.

Milowsky MI, Dittrich C, Durán I, Jagdev S, Millard FE, Sweeney CJ, et al. Phase 2 trial of dovitinib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma. Eur J Cancer. 2014;50:3145–52. [DOI] [PubMed]

60.

Papadopoulos KP, El-Rayes BF, Tolcher AW, Patnaik A, Rasco DW, Harvey RD, et al. A Phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumours. Br J Cancer. 2017;117:1592–9. [DOI] [PubMed] [PMC]

61.

Chaudhry A, Sternberg CN, De Santis M, Bellmunt J, Necchi A, Powles T, et al. FIDES-02, a phase Ib/II study of derazantinib (DZB) as monotherapy and combination therapy with atezolizumab (A) in patients with surgically unresectable or metastaticurothelial cancer (UC) and FGFR genetic aberrations. J Clin Oncol. 2020;38:TPS590. [DOI]

62.

Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011;54:7066–83. [DOI]

63.

Nogova L, Sequist LV, Perez Garcia JM, Andre F, Delord JP, Hidalgo M, et al. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin Oncol. 2017;35:157–65. [DOI] [PubMed] [PMC]

64.

Lyou Y, Rosenberg JE, Hoffman-Censits J, Quinn DI, Petrylak D, Galsky M, et al. Infigratinib in Early-Line and Salvage Therapy for FGFR3-Altered Metastatic Urothelial Carcinoma. Clin Genitourin Cancer. 2022;20:35–42. [DOI] [PubMed] [PMC]

65.

Schuler M, Cho BC, Sayehli CM, Navarro A, Soo RA, Richly H, et al. Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20:1454–66. [DOI] [PubMed]

66.

Sternberg CN, Petrylak DP, Bellmunt J, Nishiyama H, Necchi A, Gurney H, et al. FORT-1: Phase II/III Study of Rogaratinib Versus Chemotherapy in Patients With Locally Advanced or Metastatic Urothelial Carcinoma Selected Based on FGFR1/3 mRNA Expression. J Clin Oncol. 2023;41:629–39. [DOI] [PubMed] [PMC]

67.

Rosenberg JE, Gajate P, Morales-Barrera R, Lee JL, Necchi A, Penel N, et al. Safety and efficacy of rogaratinib in combination with atezolizumab in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (UC) and FGFR mRNA overexpression in the phase Ib/II FORT-2 study. J Clin Oncol. 2021;39:4521. [DOI]

68.

Liu PCC, Koblish H, Wu L, Bowman K, Diamond S, DiMatteo D, et al. INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. PLoS One. 2020;15:e0231877. [DOI] [PubMed] [PMC]

69.

Subbiah V, Iannotti NO, Gutierrez M, Smith DC, Féliz L, Lihou CF, et al. FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Ann Oncol. 2022;33:522–33. [DOI] [PubMed]

70.

Necchi A, Pouessel D, Leibowitz R, Gupta S, Fléchon A, García-Donas J, et al. Pemigatinib for metastatic or surgically unresectable urothelial carcinoma with FGF/FGFR genomic alterations: final results from FIGHT-201. Ann Oncol. 2024;35:200–10. [DOI] [PubMed]

71.

Galsky MD, Powles T, Dreicer R, Kitamura H, Asatiani E, Howe J, et al. FIGHT-205: Phase II study of first-line pemigatinib (PEMI) plus pembrolizumab (PEMBRO) versus PEMI alone versus standard of care (SOC) for cisplatin (CIS)—Ineligible urothelial carcinoma (UC) with FGFR3 mutation or rearrangement. J Clin Oncol. 2020;38:TPS592. [DOI]

72.

Sootome H, Fujita H, Ito K, Ochiiwa H, Fujioka Y, Ito K, et al. Futibatinib Is a Novel Irreversible FGFR 1-4 Inhibitor That Shows Selective Antitumor Activity against FGFR-Deregulated Tumors. Cancer Res. 2020;80:4986–97. [DOI] [PubMed]

73.

Meric-Bernstam F, Bahleda R, Hierro C, Sanson M, Bridgewater J, Arkenau HT, et al. Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study. Cancer Discov. 2022;12:402–15. [DOI] [PubMed] [PMC]

74.

Koshkin VS, Sonpavde GP, Hwang C, Mellado B, Tomlinson G, Shimura M, et al. Futibatinib plus pembrolizumab in patients (pts) with advanced or metastatic urothelial carcinoma (mUC): Preliminary safety results from a phase 2 study. J Clin Oncol. 2022;40:501. [DOI]

75.

Cleary JM, Iyer G, Oh DY, Mellinghoff IK, Goyal L, Ng MCH, et al. Final results from the phase I study expansion cohort of the selective FGFR inhibitor Debio 1,347 in patients with solid tumors harboring an FGFR gene fusion. J Clin Oncol. 2020;38:3603. [DOI]

76.

Hyman DM, Goyal L, Grivas P, Meric-Bernstam F, Tabernero J, Hu Y, et al. FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology. J Clin Oncol. 2019;37:TPS3157. [DOI]

77.

Martínez-Torrecuadrada J, Cifuentes G, López-Serra P, Saenz P, Martínez A, Casal JI. Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Clin Cancer Res. 2005;11:6280–90. [DOI] [PubMed]

78.

Bellmunt J, Picus J, Kohli M, Arriaga Y, Milowsky MI, Currie G, et al. FIERCE-21: Phase 1b/2 study of docetaxel + b-701, a selective inhibitor of FGFR3, in relapsed or refractory (R/R) metastatic urothelial carcinoma (mUCC). J Clin Oncol. 2018;36:4534. [DOI]

79.

Mellado B, Castellano D, Pang S, Urun Y, Park SH, Vaishampayan U, et al. Interim analysis of the fierce-21 phase 2 (P2) study of vofatamab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC). J Clin Oncol. 2019;37:4547. [DOI]

80.

Siefker-Radtke AO, Lugowska I, Tupikowski K, Andric ZG, Rezazadeh Kalebasty A, Curigliano G, et al. 917P - Clinical activity of vofatamab (V), an FGFR3 selective antibody in combination with pembrolizumab (P) in metastatic urothelial carcinoma (mUC), updated interim analysis of FIERCE-22. Ann Oncol. 2019;30:v365. [DOI]

81.

Qing J, Du X, Chen Y, Chan P, Li H, Wu P, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. J Clin Invest. 2009;119:1216–29. [DOI] [PubMed] [PMC]

82.

Surguladze D, Pennello A, Ren X, Mack T, Rigby A, Balderes P, et al. Abstract 4835: LY3076226, a novel anti-FGFR3 antibody drug conjugate exhibits potent and durable anti-tumor activity in tumor models harboring FGFR3 mutations or fusions. Cancer Res. 2019;79:4835. [DOI]

83.

Kollmannsberger C, Britten CD, Olszanski AJ, Walker JA, Zang W, Willard MD, et al. A phase 1 study of LY3076226, a fibroblast growth factor receptor 3 (FGFR3) antibody-drug conjugate, in patients with advanced or metastatic cancer. Invest New Drugs. 2021;39:1613–23. [DOI] [PubMed]

84.

Chae YK, Hong F, Vaklavas C, Cheng HH, Hammerman P, Mitchell EP, et al. Phase II Study of AZD4547 in Patients With Tumors Harboring Aberrations in the FGFR Pathway: Results From the NCI-MATCH Trial (EAY131) Subprotocol W. J Clin Oncol. 2020;38:2407–17. [DOI] [PubMed] [PMC]

85.

Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26:6469–87. [DOI] [PubMed] [PMC]

86.

Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. [DOI] [PubMed] [PMC]

87.

Kiss B, Wyatt AW, Douglas J, Skuginna V, Mo F, Anderson S, et al. Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy. Sci Rep. 2017;7:42713. [DOI] [PubMed] [PMC]

88.

Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al.; American Society of Clinical Oncology; College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013. [DOI] [PubMed]

89.

Albarrán V, Rosero DI, Chamorro J, Pozas J, San Román M, Barrill AM, et al. Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates. Int J Mol Sci. 2022;23:12659. [DOI] [PubMed] [PMC]

90.

Scherrer E, Kang A, Bloudek LM, Koshkin VS. HER2 expression in urothelial carcinoma, a systematic literature review. Front Oncol. 2022;12:1011885. [DOI] [PubMed] [PMC]

91.

Rosli N, Mahasin M, Mohd Saleh MF, Abd Shukor N. The prognostic significance of HER2 expression in urothelial carcinoma. Malays J Pathol. 2022;44:245–52. [PubMed]

92.

Dadhania V, Zhang M, Zhang L, Bondaruk J, Majewski T, Siefker-Radtke A, et al. Meta-Analysis of the Luminal and Basal Subtypes of Bladder Cancer and the Identification of Signature Immunohistochemical Markers for Clinical Use. EBioMedicine. 2016;12:105–17. [DOI] [PubMed] [PMC]

93.

Ye J, Liao X, Qiu Y, Wei Q, Bao Y. A systematic review and meta-analysis for human epidermal growth factor receptor 2 on upper tract urothelial carcinoma patients. Tumori. 2024;110:25–33. [DOI] [PubMed]

94.

Fleischmann A, Rotzer D, Seiler R, Studer UE, Thalmann GN. Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. Eur Urol. 2011;60:350–7. [DOI] [PubMed]

95.

Zhao J, Xu W, Zhang Z, Song R, Zeng S, Sun Y, et al. Prognostic role of HER2 expression in bladder cancer: a systematic review and meta-analysis. Int Urol Nephrol. 2015;47:87–94. [DOI] [PubMed]

96.

Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN Jr, et al.; National Cancer Institute. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute trial. J Clin Oncol. 2007;25:2218–24. [DOI] [PubMed]

97.

Oudard S, Culine S, Vano Y, Goldwasser F, Théodore C, Nguyen T, et al. Multicentre randomised phase II trial of gemcitabine+platinum, with or without trastuzumab, in advanced or metastatic urothelial carcinoma overexpressing Her2. Eur J Cancer. 2015;51:45–54. [DOI]

98.

Michaelson MD, Hu C, Pham HT, Dahl DM, Lee-Wu C, Swanson GP, et al. A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524). Int J Radiat Oncol Biol Phys. 2017;97:995–1001. [DOI] [PubMed] [PMC]

99.

Sweeney CJ, Hainsworth JD, Bose R, Burris HA, Kurzrock R, Swanton C, et al. MyPathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment of a Tissue-Agnostic Cohort of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors. J Clin Oncol. 2024;42:258–65. [DOI] [PubMed] [PMC]

100.

Galsky MD, Von Hoff DD, Neubauer M, Anderson T, Fleming M, Nagarwala Y, et al. Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors. Invest New Drugs. 2012;30:695–701. [DOI] [PubMed]

101.

Wülfing C, Machiels JP, Richel DJ, Grimm MO, Treiber U, De Groot MR, et al. A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma. Cancer. 2009;115:2881–90. [DOI] [PubMed]

102.

Cerbone L, Sternberg CN, Sengeløv L, Agerbaek M, Van Herpen C, Marreaud S, et al. Results from a Phase I Study of Lapatinib with Gemcitabine and Cisplatin in Advanced or Metastatic Bladder Cancer: EORTC Trial 30061. Oncology. 2016;90:21–8. [DOI] [PubMed]

103.

Tang S, Dorff TB, Tsao-Wei DD, Massopust K, Ketchens C, Hu J, et al. Single arm phase II study of docetaxel and lapatinib in metastatic urothelial cancer: USC trial 4B-10-4. J Clin Oncol. 2016;34:424. [DOI]

104.

Powles T, Huddart RA, Elliott T, Sarker SJ, Ackerman C, Jones R, et al. Phase III, Double-Blind, Randomized Trial That Compared Maintenance Lapatinib Versus Placebo After First-Line Chemotherapy in Patients With Human Epidermal Growth Factor Receptor 1/2-Positive Metastatic Bladder Cancer. J Clin Oncol. 2017;35:48–55. [DOI] [PubMed]

105.

Choudhury NJ, Campanile A, Antic T, Yap KL, Fitzpatrick CA, Wade JL 3rd, et al. Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations. J Clin Oncol. 2016;34:2165–71. [DOI] [PubMed] [PMC]

106.

Bedard PL, Li S, Wisinski KB, Yang ES, Limaye SA, Mitchell EP, et al. Phase II Study of Afatinib in Patients With Tumors With Human Epidermal Growth Factor Receptor 2-Activating Mutations: Results From the National Cancer Institute-Molecular Analysis for Therapy Choice ECOG-ACRIN Trial (EAY131) Subprotocol EAY131-B. JCO Precis Oncol. 2022;6:e2200165. [DOI] [PubMed] [PMC]

107.

Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554:189–94. [DOI] [PubMed] [PMC]

108.

Li S, Liu Q, Liu M, Liu T. Response to Pyrotinib in a Patient with Metastatic Bladder Urothelial Carcinoma Harboring HER2 V842I Mutation: A Case Report. Cancer Manag Res. 2022;14:2927–32. [DOI] [PubMed] [PMC]

109.

de Vries EGE, Rüschoff J, Lolkema M, Tabernero J, Gianni L, Voest E, et al. Phase II study (KAMELEON) of single-agent T-DM1 in patients with HER2-positive advanced urothelial bladder cancer or pancreatic cancer/cholangiocarcinoma. Cancer Med. 2023;12:12071–83. [DOI] [PubMed] [PMC]

110.

Goto K, Goto Y, Kubo T, Ninomiya K, Kim SW, Planchard D, et al. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol. 2023;41:4852–63. [DOI] [PubMed] [PMC]

111.

Yoshino T, Di Bartolomeo M, Raghav K, Masuishi T, Loupakis F, Kawakami H, et al.; DESTINY-CRC01 investigators. Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun. 2023;14:3332. [DOI] [PubMed] [PMC]

112.

Galsky MD, Del Conte G, Foti S, Yu EY, Machiels JPH, Doger B, et al. Primary analysis from DS8201-A-U105: A phase 1b, two-part, open-label study of trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing urothelial carcinoma (UC). J Clin Oncol. 2022;40:438. [DOI]

113.

Sheng X, Wang L, He Z, Shi Y, Luo H, Han W, et al. Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials. J Clin Oncol. 2024;42:1391–402. [DOI] [PubMed] [PMC]

114.

Wei Y, Zhang R, Yu C, Hong Z, Lin L, Li T, et al. Disitamab vedotin in combination with immune checkpoint inhibitors for locally and locally advanced bladder urothelial carcinoma: a two-center’s real-world study. Front Pharmacol. 2023;14:1230395. [DOI] [PubMed] [PMC]

115.

Zhu K, Chang Y, Zhao D, Guo A, Cao J, Wu C, et al. Expression of HER2 in high-grade urothelial carcinoma based on Chinese expert consensus and the clinical effects of disitamab vedotin-tislelizumab combination therapy in the treatment of advanced patients. Front Pharmacol. 2024;15:1355081. [DOI] [PubMed] [PMC]

116.

Sheng X, Zhou L, He Z, Guo H, Yan X, Li S, et al. Preliminary results of a phase Ib/II combination study of RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC) with toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2022;40:4518. [DOI]

117.

Xu H, Sheng X, Zhou L, Yan X, Li S, Chi Z, et al. A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2022;40:4519. [DOI]

118.

Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20:1124–35. [DOI] [PubMed]

119.

Bhattacharjee S, Sullivan MJ, Wynn RR, Demagall A, Hendrix AS, Sindhwani P, et al. PARP inhibitors chemopotentiate and synergize with cisplatin to inhibit bladder cancer cell survival and tumor growth. BMC Cancer. 2022;22:312. [DOI] [PubMed] [PMC]

120.

Zhang JH, Starr SL, Chamie K. Contemporary Systemic Therapies in Urothelial Carcinoma. Urology. 2023;174:150–8. [DOI] [PubMed]

121.

Gamba T, Paparo J, Panepinto O, Dionisio R, Di Maio M, Vignani F. Poly (ADP-Ribose) Polymerase Inhibitors in Patients With Urothelial Cancer. Clin Genitourin Cancer. 2023;21:509–16. [DOI] [PubMed]

122.

Grivas P, Loriot Y, Morales-Barrera R, Teo MY, Zakharia Y, Feyerabend S, et al. Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS). BMC Cancer. 2021;21:593. [DOI] [PubMed] [PMC]

123.

Sweis RF, Heiss B, Segal J, Ritterhouse L, Kadri S, Churpek JE, et al. Clinical Activity of Olaparib in Urothelial Bladder Cancer With DNA Damage Response Gene Mutations. JCO Precis Oncol. 2018;2:1–7. [DOI] [PubMed]

124.

Doroshow DB, O’Donnell PH, Hoffman-Censits JH, Gupta SV, Vaishampayan U, Heath EI, et al. Phase II Trial of Olaparib in Patients With Metastatic Urothelial Cancer Harboring DNA Damage Response Gene Alterations. JCO Precis Oncol. 2023;7:e2300095. [DOI] [PubMed]

125.

Rosenberg JE, Park SH, Kozlov V, Dao TV, Castellano D, Li JR, et al. Durvalumab Plus Olaparib in Previously Untreated, Platinum-Ineligible Patients With Metastatic Urothelial Carcinoma: A Multicenter, Randomized, Phase II Trial (BAYOU). J Clin Oncol. 2023;41:43–53. [DOI] [PubMed] [PMC]

126.

Powles T, Carroll D, Chowdhury S, Gravis G, Joly F, Carles J, et al. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nat Med. 2021;27:793–801. [DOI] [PubMed]

127.

Yap TA, Bardia A, Dvorkin M, Galsky MD, Beck JT, Wise DR, et al. Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial. JAMA Oncol. 2023;9:40–50. [DOI] [PubMed] [PMC]

128.

Coquan E, Clarisse B, Lequesne J, Brachet PE, Nevière Z, Meriaux E, et al. TALASUR trial: a single arm phase II trial assessing efficacy and safety of TALazoparib and Avelumab as maintenance therapy in platinum-Sensitive metastatic or locally advanced URothelial carcinoma. BMC Cancer. 2022;22:1213. [DOI] [PubMed] [PMC]

129.

Drakaki A, Kalebasty AR, Lee JL, Martin-Liberal J, Kim M, Shin SJ, et al. Phase Ib/II umbrella trial to evaluate the safety and efficacy of multiple 2L cancer immunotherapy (CIT) combinations in advanced/metastatic urothelial carcinoma (mUC): MORPHEUS-mUC. J Clin Oncol. 2020;38:TPS591. [DOI]

130.

Fulton B, Jones R, Powles T, Crabb S, Paul J, Birtle A, et al. ATLANTIS: a randomised multi-arm phase II biomarker-directed umbrella screening trial of maintenance targeted therapy after chemotherapy in patients with advanced or metastatic urothelial cancer. Trials. 2020;21:344. [DOI] [PubMed] [PMC]

131.

Vignani F, Tambaro R, De Giorgi U, Giannatempo P, Bimbatti D, Carella C, et al.; Meet-URO12 Investigators. Addition of Niraparib to Best Supportive Care as Maintenance Treatment in Patients with Advanced Urothelial Carcinoma Whose Disease Did Not Progress After First-line Platinum-based Chemotherapy: The Meet-URO12 Randomized Phase 2 Trial. Eur Urol. 2023;83:82–9. [DOI] [PubMed]

132.

Font A, Mellado B, Climent MA, Virizuela JA, Oudard S, Puente J, et al. Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1). Br J Cancer. 2024;130:434–41. [DOI] [PubMed] [PMC]

133.

Narayan V, Mamtani R, Keefe S, Guzzo T, Malkowicz SB, Vaughn DJ. Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer. Cancer Res Treat. 2016;48:1084–91. [DOI] [PubMed] [PMC]

134.

Miller K, Morant R, Stenzl A, Zuna I, Wirth M. A Phase II Study of the Central European Society of Anticancer-Drug Research (CESAR) Group: Results of an Open-Label Study of Gemcitabine plus Cisplatin with or without Concomitant or Sequential Gefitinib in Patients with Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium. Urol Int. 2016;96:5–13. [DOI] [PubMed]

135.

Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Tretter C, et al. Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol. 2014;32:1889–94. [DOI] [PubMed] [PMC]

136.

Balar AV, Apolo AB, Ostrovnaya I, Mironov S, Iasonos A, Trout A, et al. Phase II study of gemcitabine, carboplatin, and bevacizumab in patients with advanced unresectable or metastatic urothelial cancer. J Clin Oncol. 2013;31:724–30. [DOI] [PubMed] [PMC]

137.

Hahn NM, Stadler WM, Zon RT, Waterhouse D, Picus J, Nattam S, et al.; Hoosier Oncology Group. Phase II trial of cisplatin, gemcitabine, and bevacizumab as first-line therapy for metastatic urothelial carcinoma: Hoosier Oncology Group GU 04-75. J Clin Oncol. 2011;29:1525–30. [DOI] [PubMed]

138.

Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, et al. Randomized Phase III Trial of Gemcitabine and Cisplatin With Bevacizumab or Placebo in Patients With Advanced Urothelial Carcinoma: Results of CALGB 90601 (Alliance). J Clin Oncol. 2021;39:2486–96. [DOI] [PubMed] [PMC]

139.

Hurwitz ME, Markowski P, Yao X, Deshpande H, Patel J, Mortazavi A, et al. Multicenter Phase 2 Trial of Gemcitabine, Carboplatin, and Sorafenib in Patients With Metastatic or Unresectable Transitional-Cell Carcinoma. Clin Genitourin Cancer. 2018;16:437–44.e6. [DOI] [PubMed]

140.

Necchi A, Lo Vullo S, Raggi D, Perrone F, Giannatempo P, Calareso G, et al. Neoadjuvant sorafenib, gemcitabine, and cisplatin administration preceding cystectomy in patients with muscle-invasive urothelial bladder carcinoma: An open-label, single-arm, single-center, phase 2 study. Urol Oncol. 2018;36:8.e1–8. [DOI] [PubMed]

141.

Shah CH, Pappot H, Agerbæk M, Holmsten K, Jäderling F, Yachnin J, et al. Safety and Activity of Sorafenib in Addition to Vinflunine in Post-Platinum Metastatic Urothelial Carcinoma (Vinsor): Phase I Trial. Oncologist. 2019;24:745–e213. [DOI] [PubMed] [PMC]

142.

Galsky MD, Hahn NM, Powles T, Hellerstedt BA, Lerner SP, Gardner TA, et al. Gemcitabine, Cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer. Clin Genitourin Cancer. 2013;11:175–81. [DOI] [PubMed]

143.

Geldart T, Chester J, Casbard A, Crabb S, Elliott T, Protheroe A, et al. SUCCINCT: an open-label, single-arm, non-randomised, phase 2 trial of gemcitabine and cisplatin chemotherapy in combination with sunitinib as first-line treatment for patients with advanced urothelial carcinoma. Eur Urol. 2015;67:599–602. [DOI] [PubMed] [PMC]

144.

Apolo AB, Nadal R, Tomita Y, Davarpanah NN, Cordes LM, Steinberg SM, et al. Cabozantinib in patients with platinum-refractory metastatic urothelial carcinoma: an open-label, single-centre, phase 2 trial. Lancet Oncol. 2020;21:1099–109. [DOI] [PubMed] [PMC]

145.

Girardi DM, Niglio SA, Mortazavi A, Nadal R, Lara P, Pal SK, et al. Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy. Clin Cancer Res. 2022;28:1353–62. [DOI] [PubMed] [PMC]

146.

Marandino L, Raggi D, Calareso G, Alessi A, Colecchia M, Martini A, et al. Cabozantinib Plus Durvalumab in Patients With Advanced Urothelial Carcinoma After Platinum Chemotherapy: Safety and Preliminary Activity of the Open-Label, Single-Arm, Phase 2 ARCADIA Trial. Clin Genitourin Cancer. 2021;19:457–65. [DOI] [PubMed]

147.

Pal S, Agarwal N, Singh P, Necchi A, McGregor BA, Hauke RJ, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): Results from Cohorts 3, 4, 5 of the COSMIC-021 study. J Clin Oncol. 2022;40:4504. [DOI]

148.

Pal S, Agarwal N, Loriot Y, Suarez Rodriguez C, Singh P, Vaishampayan UN, et al. Cabozantinib in combination with atezolizumab in urothelial carcinoma previously treated with platinum-containing chemotherapy: Results from cohort 2 of the COSMIC-021 study. J Clin Oncol. 2020;38:5013. [DOI]

149.

Msaouel P, Sweis RF, Bupathi M, Heath E, Goodman OB Jr, Hoimes CJ, et al. A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma. Eur Urol Oncol. 2024;7:933–43. [DOI] [PubMed]

150.

Matsubara N, de Wit R, Balar AV, Siefker-Radtke AO, Zolnierek J, Csoszi T, et al. Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Eur Urol. 2024;85:229–38. [DOI] [PubMed]

151.

Kamoun A, de Reyniès A, Allory Y, Sjödahl G, Robertson AG, Seiler R, et al.; Bladder Cancer Molecular Taxonomy Group. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur Urol. 2020;77:420–33. [DOI] [PubMed] [PMC]

152.

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22. [DOI] [PubMed] [PMC]

153.

Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18:1483–92. [DOI] [PubMed]

154.

Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al.; KEYNOTE-045 Investigators. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376:1015–26. [DOI] [PubMed] [PMC]

155.

Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2018;391:748–57. [DOI] [PubMed]

156.

Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer. J Clin Oncol. 2016;34:3119–25. [DOI] [PubMed] [PMC]

157.

Apolo AB, Ellerton JA, Infante JR, Agrawal M, Gordon MS, Aljumaily R, et al. Avelumab as second-line therapy for metastatic, platinum-treated urothelial carcinoma in the phase Ib JAVELIN Solid Tumor study: 2-year updated efficacy and safety analysis. J Immunother Cancer. 2020;8:e001246. [DOI] [PubMed] [PMC]

158.

Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18:312–22. [DOI] [PubMed]

159.

Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, et al.; ESMO Guidelines Committee. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma. Ann Oncol. 2024;35:485–90. [DOI]

160.

Alfred Witjes J, Max Bruins H, Carrión A, Cathomas R, Compérat E, Efstathiou JA, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2023 Guidelines. Eur Urol. 2024;85:17–31. [DOI] [PubMed]

161.

Mathew Thomas V, Jo Y, Tripathi N, Roy S, Chigarira B, Narang A, et al. Treatment Patterns and Attrition With Lines of Therapy for Advanced Urothelial Carcinoma in the US. JAMA Netw Open. 2024;7:e249417. [DOI] [PubMed] [PMC]

162.

Koshkin VS. Therapy Attrition and Lessons for Future Approaches to Treatment of Advanced Urothelial Cancer. JAMA Netw Open. 2024;7:e249426. [DOI] [PubMed]

163.

Grande E, Birtle AJ, Kamat AM. Re: Thomas Powles, Begoña Pérez-Valderrama, Shilpa Gupta, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390:875–88. [DOI] [PubMed]

164.

Galsky MD, Sonpavde GP, Powles T, Claps M, Burotto M, Schenker M, et al. Characterization of complete responders to nivolumab + gemcitabine-cisplatin versus gemcitabine-cisplatin alone in patients with lymph node–only metastatic urothelial carcinoma from the CheckMate 901 trial. J Clin Oncol. 2024;42:4509. [DOI]

165.

Grimm MO, Grün CB, Niegisch G, Pichler M, Roghmann F, Schmitz-Dräger B, et al. Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2023;24:347–59. [DOI] [PubMed]

166.

Wong RL, Ferris LA, Do OA, Holt SK, Ramos JD, Crabb SJ, et al. Efficacy of Platinum Rechallenge in Metastatic Urothelial Carcinoma After Previous Platinum-Based Chemotherapy for Metastatic Disease. Oncologist. 2021;26:1026–34. [DOI] [PubMed] [PMC]