Exploration of Targeted Anti-tumor Therapy

Table 2. Ongoing clinical trials of ErbB-targeted therapy in UC

Drugs	Targets	Combination	Conditions	Phase	NCT
Afatinib	ErbB-1/2 (EGFR/ HER2)	Null	Adv UC	II	NCT02122172
Afatinib	ErbB-1/2 (EGFR/ HER2)	Null	Adv solid tumors	II	NCT02465060
Cetuximab	ErbB-1 (EGFR)	TTX-080	Cancer	I	NCT04485013
Cetuximab	ErbB-1 (EGFR)	SNK01	UC	I/II	NCT04464967
Lapatinib	ErbB-1/2 (EGFR/ HER2)	Null	UC	II/III	NCT00949455
Lapatinib	ErbB-1/2 (EGFR/ HER2)	Paclitaxel	UC	II	NCT01700010
Trastuzumab deruxtecan	ErbB-2 (HER2)	Null	UC	II	NCT04482309
Trastuzumab deruxtecan	ErbB-2 (HER2)	Nivolumab	UC	I	NCT03523572
Trastuzumab deruxtecan	ErbB-2 (HER2)	Pyrotinib	Met/Adv UC, HER2 positive	II	NCT05318339
Trastuzumab deruxtecan	ErbB-2 (HER2)	Tucatinib	Urologic neoplasms	II	NCT04579380
Trastuzumab deruxtecan	ErbB-2 (HER2)	AZD5305	UC	I/II	NCT04644068
RC48-ADC	ErbB-2 (HER2)	Null	UC \| NMIBC	II	NCT05996952
RC48-ADC	ErbB-2 (HER2)	Toripalimab	UC \| MIBC	II	NCT05297552
RC48-ADC	ErbB-2 (HER2)	Triplizumab	UC \| MIBC, HER2 positive	II	NCT05356351
RC48-ADC	ErbB-2 (HER2)	Triplizumab	UC	II	NCT05016973
RC48-ADC	ErbB-2 (HER2)	Toripalimab	UC \| MIBC, HER2 positive	II	NCT05979740
RC48-ADC	ErbB-2 (HER2)	pembrolizumab	UC	II	NCT04879329
RC48-ADC	ErbB-2 (HER2)	pembrolizumab	UC	III	NCT05911295
Trastuzumab emtansine	ErbB-2 (HER2)	Null	UC	II	NCT02675829

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Null in combination indicates that the trial is monotherapy. ErbB: erythroblastic oncogene B; EGFR: epidermal growth factor receptor; HER2: human epidermal growth factor receptor 2; MIBC: muscle-invasive bladder cancer; NMIBC: non-MIBC; UC: urothelial carcinoma; Adv: advanced, Met: metastatic, Rec: recurrent; RC48-ADC: disitamab vedotin; NCT: national clinical trial

Declarations

Author contributions

SS, LZ, and KL contributed equally to: Writing—original draft, Writing—review & editing. ML, JZ, DJ, DW, ZS, and PX: Investigation, Writing—review & editing. JY and ZZ: Conceptualization, Writing—review & editing, Supervision. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This study was supported by the Shaanxi Province Key Industry Chain Project [2022ZDLSF05-14]. The funder played no role in the study design, data collection and analysis, decision to publish, or in the preparation of the manuscript.

Copyright

References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. [DOI] [PubMed]

Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European association of urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and Carcinoma in Situ). Eur Urol. 2022;81:75–94. [DOI] [PubMed]

Burger M, Catto JW, Dalbagni G, Grossman HB, Herr H, Karakiewicz P, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63:234–41. [DOI] [PubMed]

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33. [DOI] [PubMed]

Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol. 2011;29:2432–8. [DOI] [PubMed]

Maisch P, Hwang EC, Kim K, Narayan VM, Bakker C, Kunath F, et al. Immunotherapy for advanced or metastatic urothelial carcinoma. Cochrane Database Syst Rev. 2023;10:CD013774. [DOI] [PubMed]

Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171:540–56. Erratum for: Cell. 2018;174:1033. [DOI] [PubMed] [PMC]

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

Kamoun A, de Reyniès A, Allory Y, Sjödahl G, Robertson AG, Seiler R, et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol. 2020;77:420–33. [DOI] [PubMed] [PMC]

10.

Zangouei AS, Barjasteh AH, Rahimi HR, Mojarrad M, Moghbeli M. Role of tyrosine kinases in bladder cancer progression: an overview. Cell Commun Signal. 2020;18:127. [DOI] [PubMed] [PMC]

11.

Moghbeli M, Makhdoumi Y, Soltani Delgosha M, Aarabi A, Dadkhah E, Memar B, et al. ErbB1 and ErbB3 co-over expression as a prognostic factor in gastric cancer. Biol Res. 2019;52:2. [DOI] [PubMed] [PMC]

12.

Goetz R, Mohammadi M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol. 2013;14:166–80. [DOI] [PubMed] [PMC]

13.

Klint P, Claesson-Welsh L. Signal transduction by fibroblast growth factor receptors. Front Biosci. 1999;4:D165–77. [DOI] [PubMed]

14.

Helsten T, Schwaederle M, Kurzrock R. Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications. Cancer Metastasis Rev. 2015;34:479–96. [DOI] [PubMed] [PMC]

15.

Katoh M. FGFR inhibitors: effects on cancer cells, tumor microenvironment and whole-body homeostasis (review). Int J Mol Med. 2016;38:3–15. [DOI] [PubMed] [PMC]

16.

Nassar AH, Lundgren K, Pomerantz M, Van Allen E, Harshman L, Choudhury AD, et al. Enrichment of FGFR3-TACC3 fusions in patients with bladder cancer who are young, asian, or have never smoked. JCO Precis Oncol. 2018;2:1–11. [DOI] [PubMed] [PMC]

17.

Hood FE, Royle SJ. Pulling it together: the mitotic function of TACC3. Bioarchitecture. 2011;1:105–9. [DOI] [PubMed] [PMC]

18.

Nelson KN, Meyer AN, Siari A, Campos AR, Motamedchaboki K, Donoghue DJ. Oncogenic gene fusion FGFR3-TACC3 is regulated by tyrosine phosphorylation. Mol Cancer Res. 2016;14:458–69. [DOI] [PubMed]

19.

Parker BC, Engels M, Annala M, Zhang W. Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours. J Pathol. 2014;232:4–15. [DOI] [PubMed]

20.

Parker BC, Annala MJ, Cogdell DE, Granberg KJ, Sun Y, Ji P, et al. The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma. J Clin Invest. 2013;123:855-65. [DOI] [PubMed] [PMC]

21.

Costa R, Carneiro BA, Taxter T, Tavora FA, Kalyan A, Pai SA, et al. FGFR3-TACC3 fusion in solid tumors: mini review. Oncotarget. 2016;7:55924–38. [DOI] [PubMed] [PMC]

22.

Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213:91–8. [DOI] [PubMed] [PMC]

23.

Billerey C, Chopin D, Aubriot-Lorton MH, Ricol D, Gil Diez de Medina S, Van Rhijn B, et al. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am J Pathol. 2001;158:1955–9. [DOI] [PubMed] [PMC]

24.

di Martino E, Tomlinson DC, Knowles MA. A decade of FGF receptor research in bladder cancer: past, present, and future challenges. Adv Urol. 2012;2012:429213. [DOI] [PubMed] [PMC]

25.

Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res. 2016;22:259–67. [DOI] [PubMed]

26.

Tomlinson DC, Baxter EW, Loadman PM, Hull MA, Knowles MA. FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCγ/COX-2-mediated mechanisms. PLoS One. 2012;7:e38972. [DOI] [PubMed] [PMC]

27.

Perera TPS, Jovcheva E, Mevellec L, Vialard J, De Lange D, Verhulst T, et al. Discovery and pharmacological characterization of JNJ-42756493 (Erdafitinib), a functionally selective small-molecule FGFR family inhibitor. Mol Cancer Ther. 2017;16:1010–20. [DOI] [PubMed]

28.

Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, et al. 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]

29.

Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019;381:338–48. [DOI] [PubMed]

30.

Loriot Y, Necchi A, Park SH, Huddart RA, Burgess E, Zhong B, et al. Erdafitinib compared with vinflunine or docetaxel or pembrolizumab in patients (pts) with metastatic or surgically unresectable (M/UR) urothelial carcinoma (UC) and selected fgfr gene alterations (FGFRalt): the phase III THOR study. Ann Oncol. 2018;29:viii327–8. [DOI]

31.

Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, et al. Phase 3 THOR study: results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt). J clin Oncol. 2023;41:LBA4619. [DOI]

32.

Li X, Li Y, Liu B, Chen L, Lyu F, Zhang P, et al. P4HA2-mediated HIF-1α stabilization promotes erdafitinib-resistance in FGFR3-alteration bladder cancer. Faseb J. 2023;37:e22840. [DOI] [PubMed]

33.

Facchinetti F, Hollebecque A, Braye F, Vasseur D, Pradat Y, Bahleda R, et al. Resistance to selective FGFR inhibitors in FGFR-driven urothelial cancer. Cancer Discov. 2023;13:1998–2011. [DOI] [PubMed] [PMC]

34.

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]

35.

Grünewald S, Politz O, Bender S, Héroult M, Lustig K, Thuss U, et al. Rogaratinib: a potent and selective pan-FGFR inhibitor with broad antitumor activity in FGFR-overexpressing preclinical cancer models. Int J Cancer. 2019;145:1346–57. [DOI] [PubMed] [PMC]

36.

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. 2022;41:629–39. [DOI] [PubMed] [PMC]

37.

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]

38.

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]

39.

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.

40.

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]

41.

Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, Galsky MD, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov. 2018;8:812–21. [DOI] [PubMed] [PMC]

42.

Lyou Y, Grivas P, Rosenberg JE, Hoffman-Censits J, Quinn DI, D PP, et al. Hyperphosphatemia secondary to the selective fibroblast growth factor receptor 1–3 inhibitor infigratinib (BGJ398) is associated with antitumor efficacy in fibroblast growth factor receptor 3–altered advanced/metastatic urothelial carcinoma. Eur Urol. 2020;78:916–24. [DOI] [PubMed] [PMC]

43.

Grivas P, Daneshmand S, Makarov V, Bellmunt J, Sridhar SS, Sonpavde GP, et al. Fibroblast growth factor receptor 3 (FGFR3) alterations in PROOF 302: A phase III trial of infigratinib (BGJ398) as adjuvant therapy in patients (pts) with invasive urothelial carcinoma (UC). J Clin Oncol. 2023;41:4511. [DOI]

44.

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]

45.

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]

46.

Meric-Bernstam F, Hollebecque A, Furuse J, Oh D-Y, Bridgewater JA, Shimura M, et al. Management (mgmt) of futibatinib-associated adverse events (AEs) in patients (pts) with advanced cancers: results of a pooled analysis. J Clin Oncol. 2023;41:586. [DOI]

47.

Jain RK, Kim Y, Rembisz J, Piekarz R, Synold TW, Zhang J, et al. Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs). J Clin Oncol. 2022;40:TPS595. [DOI]

48.

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;41:4504. [DOI]

49.

Rosenberg JE, Gajate P, Morales-Barrera R, Lee J-L, Necchi A, Penel N, et al. Safety and preliminary efficacy of rogaratinib in combination with atezolizumab in a phase Ib/II study (FORT-2) of first-line treatment in cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (UC) and FGFR mRNA overexpression. J Clin Oncol. 2020;38:5014. [DOI]

50.

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]

51.

Wang Z, Muthusamy V, Petrylak DP, Anderson KS. Tackling FGFR3-driven bladder cancer with a promising synergistic FGFR/HDAC targeted therapy. NPJ Precis Oncol. 2023;7:70. [DOI] [PubMed] [PMC]

52.

Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000;19:3159–67. [DOI] [PubMed] [PMC]

53.

Thomas J, Sonpavde G. Molecularly targeted therapy towards genetic alterations in advanced bladder cancer. Cancers (Basel). 2022;14:1795. [DOI] [PubMed] [PMC]

54.

Patelli G, Zeppellini A, Spina F, Righetti E, Stabile S, Amatu A, et al. The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: a systematic review and future perspectives. Cancer Treat Rev. 2022;104:102351. [DOI] [PubMed]

55.

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]

56.

Ross JS, Wang K, Al-Rohil RN, Nazeer T, Sheehan CE, Otto GA, et al. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol. 2014;27:271–80. [DOI] [PubMed]

57.

Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest. 2007;117:2051–8. [DOI] [PubMed] [PMC]

58.

Tang Y, Zhang X, Qi F, Chen M, Li Y, Liu L, et al. Afatinib inhibits proliferation and invasion and promotes apoptosis of the T24 bladder cancer cell line. Exp Ther Med. 2015;9:1851–6. [DOI] [PubMed] [PMC]

59.

Choudhury NJ, Campanile A, Antic T, Yap KL, Fitzpatrick CA, Wade JL, 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]

60.

Grivas PD, Day KC, Karatsinides A, Paul A, Shakir N, Owainati I, et al. Evaluation of the antitumor activity of dacomitinib in models of human bladder cancer. Mol Med. 2013;19:367–76. [DOI] [PubMed] [PMC]

61.

Tsai YC, Ho PY, Tzen KY, Tuan TF, Liu WL, Cheng AL, et al. Synergistic blockade of EGFR and HER2 by new-generation EGFR tyrosine kinase inhibitor enhances radiation effect in bladder cancer cells. Mol Cancer Ther. 2015;14:810–20. [DOI] [PubMed]

62.

Dominguez-Escrig JL, Kelly JD, Neal DE, King SM, Davies BR. Evaluation of the therapeutic potential of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in preclinical models of bladder cancer. Clin Cancer Res. 2004;10:4874–84. [DOI] [PubMed]

63.

Nutt JE, Lazarowicz HP, Mellon JK, Lunec J. Gefitinib (‘Iressa’, ZD1839) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces TIMP2. Br J Cancer. 2004;90:1679–85. [DOI] [PubMed] [PMC]

64.

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]

65.

Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999;5:257–65. [PubMed]

66.

Inoue K, Slaton JW, Perrotte P, Davis DW, Bruns CJ, Hicklin DJ, et al. Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma. Clin Cancer Res. 2000;6:4874–84. [PubMed]

67.

Wong YN, Litwin S, Vaughn D, Cohen S, Plimack ER, Lee J, et al. Phase II trial of cetuximab with or without paclitaxel in patients with advanced urothelial tract carcinoma. J Clin Oncol. 2012;30:3545–51. [DOI] [PMC]

68.

Hussain M, Daignault S, Agarwal N, Grivas PD, Siefker-Radtke AO, Puzanov I, et al. A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma. Cancer. 2014;120:2684–93. [DOI] [PubMed] [PMC]

69.

James ND, Liu W, Pirrie S, Kaur B, Hendron C, Ford D, et al. TUXEDO: a phase I/II trial of cetuximab with chemoradiotherapy in muscle-invasive bladder cancer. BJU Int. 2022;131:63–72. [DOI] [PubMed] [PMC]

70.

Pruthi RS, Nielsen M, Heathcote S, Wallen EM, Rathmell WK, Godley P, et al. A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy: clinical and pathological results. BJU Int. 2010;106:349–54. [DOI] [PubMed]

71.

Mohammed A, Miller MS, Lubet RA, Suen CS, Sei S, Shoemaker RH, et al. Combination of erlotinib and naproxen employing pulsatile or intermittent dosing profoundly inhibits urinary bladder cancers. Cancer Prev Res (Phila). 2020;13:273–82. [DOI] [PubMed] [PMC]

72.

Hussain MH, MacVicar GR, Petrylak DP, Dunn RL, Vaishampayan U, Lara PN Jr, et al. 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]

73.

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] [PubMed]

74.

Jiang Q, Xie MX, Zhang XC. Complete response to trastuzumab and chemotherapy in recurrent urothelial bladder carcinoma with HER2 gene amplification: a case report. World J Clin Cases. 2020;8:594–9. [DOI] [PubMed] [PMC]

75.

Wezel F, Erben P, Gaiser T, Budjan J, von Hardenberg J, Michel MS, et al. Complete and durable remission of human epidermal growth factor receptor 2-positive metastatic urothelial carcinoma following third-line treatment with trastuzumab and gemcitabine. Urol Int. 2018;100:122–5. [DOI] [PubMed]

76.

Hayashi T, Seiler R, Oo HZ, Jäger W, Moskalev I, Awrey S, et al. Targeting HER2 with T-DM1, an antibody cytotoxic drug conjugate, is effective in HER2 over expressing bladder cancer. J Urol. 2015;194:1120–31. [DOI] [PubMed]

77.

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]

78.

Meric-Bernstam F, Makker V, Oaknin A, Oh D-Y, Banerjee SN, Gonzalez Martin A, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41:LBA3000. [DOI]

79.

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]

80.

Maeda S, Sakai K, Kaji K, Iio A, Nakazawa M, Motegi T, et al. Lapatinib as first-line treatment for muscle-invasive urothelial carcinoma in dogs. Sci Rep. 2022;12:4. [DOI] [PubMed] [PMC]

81.

Gong J, Shen L, Wang W, Fang J. Safety, pharmacokinetics and efficacy of RC48-ADC in a phase I study in patients with HER2-overexpression advanced solid cancer. J Clin Oncol. 2018;36:e16059. [DOI]

82.

Sheng X, Yan X, Wang L, Shi Y, Yao X, Luo H, et al. Open-label, multicenter, phase ii study of RC48-ADC, a HER2-targeting antibody–drug conjugate, in patients with locally advanced or metastatic urothelial carcinoma. Clin Cancer Res. 2021;27:43–51. [DOI] [PubMed]

83.

Zhou L, Xu H, Li S, Yan X, Li J, Wu X, et al. Study RC48-C014: preliminary results of RC48-ADC combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma. J Clin Oncol. 2022;40:515. [DOI]

84.

Sheng X, Zhou L, Yang K, Zhang S, Xu H, Yan X, et al. Disitamab vedotin, a novel humanized anti-HER2 antibody-drug conjugate (ADC), combined with toripalimab in patients with locally advanced or metastatic urothelial carcinoma: an open-label phase 1b/2 study. J Clin Oncol. 2023;41:4566. [DOI]

85.

Xu Z, Ma J, Chen T, Yang Y. Case report: the remarkable response of pembrolizumab combined with RC48 in the third-line treatment of metastatic urothelial carcinoma. Front Immunol. 2022;13:978266. [DOI] [PubMed] [PMC]

86.

Galsky MD, Del Conte G, Foti S, Yu EY, Machiels J-PH, 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]

87.

Peng M, Huang Y, Tao T, Peng CY, Su Q, Xu W, et al. Metformin and gefitinib cooperate to inhibit bladder cancer growth via both AMPK and EGFR pathways joining at Akt and Erk. Sci Rep. 2016;6:28611. [DOI] [PubMed] [PMC]

88.

Deng J, Peng M, Wang Z, Zhou S, Xiao D, Deng J, et al. Novel application of metformin combined with targeted drugs on anticancer treatment. Cancer Sci. 2019;110:23–30. [DOI] [PubMed] [PMC]

89.

Huang Y, Zhou S, He C, Deng J, Tao T, Su Q, et al. Phenformin alone or combined with gefitinib inhibits bladder cancer via AMPK and EGFR pathways. Cancer Commun (Lond). 2018;38:50. [DOI] [PubMed] [PMC]

90.

Ghafouri S, Burkenroad A, Pantuck M, Almomani B, Stefanoudakis D, Shen J, et al. VEGF inhibition in urothelial cancer: the past, present and future. World J Urol. 2021;39:741–9. [DOI] [PubMed]

91.

Narayanan S, Srinivas S. Incorporating VEGF-targeted therapy in advanced urothelial cancer. Ther Adv Med Oncol. 2017;9:33–45. [DOI] [PubMed] [PMC]

92.

Fus Ł P, Górnicka B. Role of angiogenesis in urothelial bladder carcinoma. Cent European J Urol. 2016;69:258–63. [DOI] [PubMed] [PMC]

93.

Charlesworth PJ, Harris AL. Mechanisms of disease: angiogenesis in urologic malignancies. Nat Clin Pract Urol. 2006;3:157–69. [DOI] [PubMed]

94.

Nakanishi R, Oka N, Nakatsuji H, Koizumi T, Sakaki M, Takahashi M, et al. Effect of vascular endothelial growth factor and its receptor inhibitor on proliferation and invasion in bladder cancer. Urol Int. 2009;83:98–106. [DOI] [PubMed]

95.

Videira PA, Piteira AR, Cabral MG, Martins C, Correia M, Severino P, et al. Effects of bevacizumab on autocrine VEGF stimulation in bladder cancer cell lines. Urol Int. 2011;86:95–101. [DOI] [PubMed]

96.

Hahn NM, Stadler WM, Zon RT, Waterhouse D, Picus J, Nattam S, et al. 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]

97.

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]

98.

Vennepureddy A, Singh P, Rastogi R, Atallah JP, Terjanian T. Evolution of ramucirumab in the treatment of cancer – a review of literature. J Oncol Pharm Pract. 2017;23:525–39. [DOI] [PubMed]

99.

Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, et al. Docetaxel as monotherapy or combined with ramucirumab or icrucumab in second-line treatment for locally advanced or metastatic urothelial carcinoma: an open-label, three-arm, randomized controlled phase II trial. J Clin Oncol. 2016;34:1500–9. [DOI] [PubMed]

100.

Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): overall survival and updated results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2020;21:105–20. [DOI] [PubMed] [PMC]

101.

Flaig TW, Su LJ, McCoach C, Li Y, Raben D, Varella-Garcia M, et al. Dual epidermal growth factor receptor and vascular endothelial growth factor receptor inhibition with vandetanib sensitizes bladder cancer cells to cisplatin in a dose- and sequence-dependent manner. BJU Int. 2009;103:1729–37. [DOI] [PubMed]

102.

Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, et al. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012;30:507–12. [DOI] [PubMed] [PMC]

103.

Jones R, Crabb S, Chester J, Elliott T, Huddart R, Birtle A, et al. A randomised phase II trial of carboplatin and gemcitabine ± vandetanib in first-line treatment of patients with advanced urothelial cell cancer not suitable to receive cisplatin. BJU Int. 2020;126:292–9. [DOI] [PubMed]

104.

Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007;6:2012–21. [DOI] [PubMed]

105.

Necchi A, Mariani L, Zaffaroni N, Schwartz LH, Giannatempo P, Crippa F, et al. Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol. 2012;13:810–6. [DOI] [PubMed]

106.

Pili R, Qin R, Flynn PJ, Picus J, Millward M, Ho WM, et al. A phase II safety and efficacy study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer. Clin Genitourin Cancer. 2013;11:477–83. [DOI] [PubMed] [PMC]

107.

Gerullis H, Eimer C, Ecke TH, Georgas E, Arndt C, Otto T. Combined treatment with pazopanib and vinflunine in patients with advanced urothelial carcinoma refractory after first-line therapy. Anticancer Drugs. 2013;24:422–5. [DOI] [PubMed]

108.

Narayanan S, Lam A, Vaishampayan U, Harshman L, Fan A, Pachynski R, et al. Phase II study of pazopanib and paclitaxel in patients with refractory urothelial cancer. Clin Genitourin Cancer. 2016;14:432–7. [DOI] [PubMed] [PMC]

109.

Herbst RS, Arkenau HT, Santana-Davila R, Calvo E, Paz-Ares L, Cassier PA, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol. 2019;20:1109-23. [DOI] [PubMed]

110.

Taylor MH, Lee CH, Makker V, Rasco D, Dutcus CE, Wu J, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. J Clin Oncol. 2020;38:1154–63. [DOI] [PubMed] [PMC]

111.

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]

112.

Bellmunt J, Lalani AA, Jacobus S, Wankowicz SA, Polacek L, Takeda DY, et al. Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma. Br J Cancer. 2018;119:707–12. [DOI] [PubMed] [PMC]

113.

Porta C, Giglione P, Liguigli W, Paglino C. Dovitinib (CHIR258, TKI258): structure, development and preclinical and clinical activity. Future Oncol. 2015;11:39–50. [DOI] [PubMed]

114.

Hahn NM, Bivalacqua TJ, Ross AE, Netto GJ, Baras A, Park JC, et al. A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression: hoosier cancer research network trial HCRN 12-157. Clin Cancer Res. 2017;23:3003–11. [DOI] [PubMed] [PMC]

115.

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]

116.

Meng Z, Pei X, Gu Y, Li L, He D, Wu K. In vitro and in vivo investigations of anlotinib in bladder cancer treatment. J Clin Oncol. 2022;40:e16505. [DOI]

117.

Qu YY, Sun Z, Han W, Zou Q, Xing N, Luo H, et al. Camrelizumab plus famitinib for advanced or metastatic urothelial carcinoma after platinum-based therapy: data from a multicohort phase 2 study. J Immunother Cancer. 2022;10:e004427. [DOI] [PubMed] [PMC]

118.

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]

119.

Kikuchi E, Hayakawa N. Cabozantinib as a choice for platinum-refractory metastatic urothelial cancer. Lancet Oncol. 2020;21:1005–6. [DOI] [PubMed]

120.

Jones RJ, Hussain SA, Birtle AJ, Song YP, Enting D, Faust G, et al. A randomised, double blind, phase II clinical trial of maintenance cabozantinib following chemotherapy for metastatic urothelial carcinoma (mUC): final analysis of the ATLANTIS cabozantinib comparison. J Clin Oncol. 2022;40:LBA4505. [DOI]

121.

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]

122.

Galffy G, Lugowska I, Poddubskaya EV, Cho BC, Ahn MJ, Han JY, et al. A phase II open-label trial of avelumab plus axitinib in previously treated non-small-cell lung cancer or treatment-naïve, cisplatin-ineligible urothelial cancer. ESMO Open. 2023;8:101173. [DOI] [PMC]

123.

Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. J Clin Oncol. 2020;38:3672–84. [DOI] [PubMed] [PMC]

124.

Giannatempo P, Guadalupi V, Marandino L, Raggi D, Stellato M, Rametta A, et al. Activity of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) or non-UC variant histologies (VH) after platinum chemotherapy: interim results from the phase 2 ARCADIA trial. J Clin Oncol. 2023;41:4578. [DOI]

125.

Pal SK, 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]

126.

Kilari D, Szabo A, Tripathi A, Paul AK, Alter RS, Bylow KA, et al. A phase 2 study of cabozantinib in combination with atezolizumab as neoadjuvant treatment for muscle-invasive bladder cancer (HCRN GU18-343) ABATE study. J Clin Oncol. 2022;40:TPS4618. [DOI]

127.

Castellano DE, Duran I, Mellado B, Climent Duran MAA, Garcia del Muro X, Sala González N, et al. Phase I-II study to evaluate safety and efficacy of niraparib plus cabozantinib in patients with advanced urothelial/kidney cancer (NICARAGUA trial): preliminary data of phase I study. J Clin Oncol. 2022;40:490. [DOI]

128.

Gupta S, Ballman KV, Galsky MD, Morris MJ, Chen RC, Chan TA, et al. MAIN-CAV: phase III randomized trial of maintenance cabozantinib and avelumab versus avelumab after first-line platinum-based chemotherapy in patients with metastatic urothelial cancer (mUC) (Alliance A032001). J Clin Oncol. 2022;40:TPS4607. [DOI]

129.

Huan J, Grivas P, Birch J, Hansel DE. Emerging roles for mammalian target of rapamycin (mTOR) complexes in bladder cancer progression and therapy. Cancers (Basel). 2022;14:1555. [DOI] [PubMed] [PMC]

130.

Mayer IA, Arteaga CL. The PI3K/akt pathway as a target for cancer treatment. Annu Rev Med. 2016;67:11–28. [DOI] [PubMed]

131.

Bellmunt J, Werner L, Leow JJ, Mullane SA, Fay AP, Riester M, et al. somatic copy number abnormalities and mutations in PI3K/AKT/mTOR pathway have prognostic significance for overall survival in platinum treated locally advanced or metastatic urothelial tumors. PLoS One. 2015;10:e0124711. [DOI] [PubMed] [PMC]

132.

Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell. 2005;121:179–93. [DOI] [PubMed]

133.

Mendoza MC, Er EE, Blenis J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem Sci. 2011;36:320–8. [DOI] [PubMed] [PMC]

134.

She QB, Halilovic E, Ye Q, Zhen W, Shirasawa S, Sasazuki T, et al. 4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors. Cancer Cell. 2010;18:39–51. [DOI] [PubMed] [PMC]

135.

Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7. [DOI] [PubMed] [PMC]

136.

Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, et al. Phase I, dose-escalation study of BKM120, an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2012;30:282–90. [DOI] [PubMed]

137.

McPherson V, Reardon B, Bhayankara A, Scott SN, Boyd ME, Garcia-Grossman IR, et al. A phase 2 trial of buparlisib in patients with platinum-resistant metastatic urothelial carcinoma. Cancer. 2020;126:4532–44. [DOI] [PubMed] [PMC]

138.

Zhu S, Ma AH, Zhu Z, Adib E, Rao T, Li N, et al. Synergistic antitumor activity of pan-PI3K inhibition and immune checkpoint blockade in bladder cancer. J Immunother Cancer. 2021;9:e002917. [DOI] [PubMed] [PMC]

139.

Farrukh H, Zhu Z, Zhu S, Montgomery RB, Meeks JJ, VanderWeele DJ, et al. A phase II trial with copanlisib plus avelumab as maintenance therapy for metastatic bladder cancer after platinum-based chemotherapy. J Clin Oncol. 2023;41:TPS4610. [DOI]

140.

Chen CH, Changou CA, Hsieh TH, Lee YC, Chu CY, Hsu KC, et al. Dual inhibition of PIK3C3 and FGFR as a new therapeutic approach to treat bladder cancer. Clin Cancer Res. 2018;24:1176–89. [DOI] [PubMed]

141.

Chen CH, Liu YM, Pan SL, Liu YR, Liou JP, Yen Y. Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo. Oncotarget. 2016;7:26374–87. [DOI] [PubMed] [PMC]

142.

Juric D, Rodon J, Tabernero J, Janku F, Burris HA, Schellens JHM, et al. Phosphatidylinositol 3-kinase α–selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors: results from the first-in-human study. J Clin Oncol. 2018;36:1291–9. [DOI] [PubMed] [PMC]

143.

Marqués M, Corral S, Sánchez-Díaz M, Del Pozo N, Martínez de Villarreal J, Schweifer N, et al. tumor and stromal cell targeting with nintedanib and alpelisib overcomes intrinsic bladder cancer resistance. Mol Cancer Ther. 2023;22:616–29. [DOI] [PubMed]

144.

Borcoman E, De La Rochere P, Richer W, Vacher S, Chemlali W, Krucker C, et al. Inhibition of PI3K pathway increases immune infiltrate in muscle-invasive bladder cancer. Oncoimmunology. 2019;8:e1581556. [DOI] [PubMed] [PMC]

145.

Zeng SX, Zhu Y, Ma AH, Yu W, Zhang H, Lin TY, et al. The phosphatidylinositol 3-kinase pathway as a potential therapeutic target in bladder cancer. Clin Cancer Res. 2017;23:6580–91. [DOI] [PubMed] [PMC]

146.

De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016;539:443–7. [DOI]

147.

Hong DS, Postow M, Chmielowski B, Sullivan R, Patnaik A, Cohen EEW, et al. Eganelisib, a first-in-class PI3Kγ Inhibitor, in patients with advanced solid tumors: results of the phase 1/1b MARIO-1 trial. Clin Cancer Res. 2023;29:2210–9. [DOI] [PubMed] [PMC]

148.

Sathe A, Guerth F, Cronauer MV, Heck MM, Thalgott M, Gschwend JE, et al. Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy. Br J Cancer. 2014;111:2103–13. [DOI] [PubMed] [PMC]

149.

Dickstein RJ, Nitti G, Dinney CP, Davies BR, Kamat AM, McConkey DJ. Autophagy limits the cytotoxic effects of the AKT inhibitor AZ7328 in human bladder cancer cells. Cancer Biol Ther. 2012;13:1325–38. [DOI] [PubMed] [PMC]

150.

Peng M, Deng J, Zhou S, Xiao D, Long J, Zhang N, et al. Dual inhibition of pirarubicin-induced AKT and ERK activations by phenformin sensitively suppresses bladder cancer growth. Front Pharmacol. 2019;10:1159. [DOI] [PubMed] [PMC]

151.

Kim H, Lee SJ, Lee IK, Min SC, Sung HH, Jeong BC, et al. Synergistic effects of combination therapy with AKT and mTOR inhibitors on bladder cancer cells. Int J Mol Sci. 2020;21:2825. [DOI] [PubMed] [PMC]

152.

Isakoff SJ, Tabernero J, Molife LR, Soria JC, Cervantes A, Vogelzang NJ, et al. Antitumor activity of ipatasertib combined with chemotherapy: results from a phase Ib study in solid tumors. Ann Oncol. 2020;31:626–33. [DOI] [PubMed]

153.

Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer. 2004;100:657–66. [DOI] [PubMed]

154.

Mansure JJ, Nassim R, Chevalier S, Rocha J, Scarlata E, Kassouf W. Inhibition of mammalian target of rapamycin as a therapeutic strategy in the management of bladder cancer. Cancer Biol Ther. 2009;8:2339–47. [DOI] [PubMed]

155.

Milowsky MI, Iyer G, Regazzi AM, Al-Ahmadie H, Gerst SR, Ostrovnaya I, et al. Phase II study of everolimus in metastatic urothelial cancer. BJU Int. 2013;112:462–70. [DOI] [PubMed] [PMC]

156.

Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338:221. [DOI] [PubMed] [PMC]

157.

Seront E, Rottey S, Sautois B, Kerger J, D’Hondt LA, Verschaeve V, et al. Phase II study of everolimus in patients with locally advanced or metastatic transitional cell carcinoma of the urothelial tract: clinical activity, molecular response, and biomarkers. Ann Oncol. 2012;23:2663–70. [DOI] [PubMed]

158.

Faes S, Demartines N, Dormond O. Resistance to mTORC1 inhibitors in cancer therapy: from kinase mutations to intratumoral heterogeneity of kinase activity. Oxid Med Cell Longev. 2017;2017:1726078. [DOI] [PubMed] [PMC]

159.

Adib E, Klonowska K, Giannikou K, Do KT, Pruitt-Thompson S, Bhushan K, et al. Phase II clinical trial of everolimus in a pan-cancer cohort of patients with mTOR pathway alterations. Clin Cancer Res. 2021;27:3845–53. [DOI] [PubMed] [PMC]

160.

Pan S, Li S, Xiao M, Chen D, Li J. Significant benefit of everolimus in a patient with urothelial bladder cancer harboring a rare M1043I mutation of PIK3CA. Invest New Drugs. 2021;39:1197–9. [DOI] [PubMed]

161.

Xia W, Zhang S, Duan H, Wang C, Qian S, Shen H. The combination therapy of everolimus and anti-PD-1 improves the antitumor effect by regulating CD8⁺ T cells in bladder cancer. Med Oncol. 2022;39:37. [DOI] [PubMed]

162.

Pinto-Leite R, Arantes-Rodrigues R, Ferreira R, Palmeira C, Colaço A, Moreira da Silva V, et al. Temsirolimus improves cytotoxic efficacy of cisplatin and gemcitabine against urinary bladder cancer cell lines. Urol Oncol. 2014;32:41.e11–22. [DOI] [PubMed]

163.

Pulido M, Roubaud G, Cazeau AL, Mahammedi H, Vedrine L, Joly F, et al. Safety and efficacy of temsirolimus as second line treatment for patients with recurrent bladder cancer. BMC Cancer. 2018;18:194. [DOI] [PubMed] [PMC]

164.

Gerullis H, Eimer C, Ecke TH, Georgas E, Freitas C, Kastenholz S, et al. A phase II trial of temsirolimus in second-line metastatic urothelial cancer. Med Oncol. 2012;29:2870–6. [DOI] [PubMed]

165.

Chen Y, Zhou X. Research progress of mTOR inhibitors. Eur J Med Chem. 2020;208:112820. [DOI] [PubMed]

166.

Becker MN, Wu KJ, Marlow LA, Kreinest PA, Vonroemeling CA, Copland JA, et al. The combination of an mTORc1/TORc2 inhibitor with lapatinib is synergistic in bladder cancer in vitro. Urol Oncol. 2014;32:317–26. [DOI] [PubMed] [PMC]

167.

Hernández-Prat A, Rodriguez-Vida A, Juanpere-Rodero N, Arpi O, Menéndez S, Soria-Jiménez L, et al. Novel oral mTORC1/2 inhibitor TAK-228 has synergistic antitumor effects when combined with paclitaxel or PI3Kα inhibitor TAK-117 in preclinical bladder cancer models. Mol Cancer Res. 2019;17:1931–44. [DOI] [PubMed]

168.

Voss MH, Gordon MS, Mita M, Rini B, Makker V, Macarulla T, et al. Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer. Br J Cancer. 2020;123:1590–8. [DOI] [PubMed] [PMC]

169.

Kim JW, Milowsky MI, Hahn NM, Kwiatkowski DJ, Morgans AK, Davis NB, et al. Sapanisertib, a dual mTORC1/2 inhibitor, for TSC1- or TSC2-mutated metastatic urothelial carcinoma (mUC). J Clin Oncol. 2021;39:431. [DOI]

170.

Moon du G, Lee SE, Oh MM, Lee SC, Jeong SJ, Hong SK, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells. Int J Oncol. 2014;45:1027–35. [DOI] [PubMed] [PMC]

171.

Seront E, Rottey S, Filleul B, Glorieux P, Goeminne JC, Verschaeve V, et al. Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma. BJU Int. 2016;118:408–15. [DOI] [PubMed]

172.

Hyman DM, Tran B, Paz-Ares L, Machiels J-P, Schellens JH, Bedard PL, et al. Combined PIK3CA and fgfr inhibition with alpelisib and infigratinib in patients with PIK3CA-mutant solid tumors, with or without FGFR alterations. JCO Precis Oncol. 2019;3:1–13. [DOI]

173.

Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers (Basel). 2019;11:1618. [DOI] [PubMed] [PMC]

174.

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]

175.

Rosenberg JE, von der Maase H, Seigne JD, Mardiak J, Vaughn DJ, Moore M, et al. A phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with advanced urothelial tract transitional cell carcinoma. Cancer. 2005;103:2035–41. [DOI] [PubMed]

176.

Lee HW, Sa JK, Gualberto A, Scholz C, Sung HH, Jeong BC, et al. A phase II trial of tipifarnib for patients with previously treated, metastatic urothelial carcinoma harboring HRAS mutations. Clin Cancer Res. 2020;26:5113-9. [DOI] [PubMed]

177.

Rose A, Grandoch M, vom Dorp F, Rübben H, Rosenkranz A, Fischer JW, et al. Stimulatory effects of the multi-kinase inhibitor sorafenib on human bladder cancer cells. Br J Pharmacol. 2010;160:1690–8. [DOI] [PubMed] [PMC]

178.

Dreicer R, Li H, Stein M, DiPaola R, Eleff M, Roth BJ, et al. Phase 2 trial of sorafenib in patients with advanced urothelial cancer: a trial of the Eastern Cooperative Oncology Group. Cancer. 2009;115:4090–5. [DOI] [PubMed] [PMC]

179.

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]

180.

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]

181.

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]

182.

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]

183.

Crabb SJ, Hussain S, Soulis E, Hinsley S, Dempsey L, Trevethan A, et al. A randomized, double-blind, biomarker-selected, phase II clinical trial of maintenance poly adp-ribose polymerase inhibition with rucaparib following chemotherapy for metastatic urothelial carcinoma. J Clin Oncol. 2023;41:54–64. [DOI] [PubMed] [PMC]

184.

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]

185.

Rodriguez-Moreno JF, de Velasco G, Alvarez-Fernandez C, Collado R, Fernandez-Rodriguez R, Estevez SV, et al. 761P Impact of the combination of durvalumab (MEDI4736) plus olaparib (AZD2281) administered prior to surgery in the molecular profile of resectable urothelial bladder cancer. NEODURVARIB trial. Ann Oncol. 2020;31:S589. [DOI]

186.

Rosenberg JE, Park SH, Kozlov V, Dao TV, Castellano D, Li J-R, 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. 2022;41:43–53. [DOI] [PubMed] [PMC]

187.

Vignani F, Tambaro R, De Giorgi U, Giannatempo P, Bimbatti D, Carella C, et al. 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]

188.

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]

189.

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]

190.

Quinn DI, Tsao-Wei DD, Twardowski P, Aparicio AM, Frankel P, Chatta G, et al. Phase II study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid; SAHA) in recurrent or metastatic transitional cell carcinoma of the urothelium – an NCI-CTEP sponsored: california cancer consortium trial, NCI 6879. Invest New Drugs. 2021;39:812–20. [DOI] [PubMed]

191.

Buckley MT, Yoon J, Yee H, Chiriboga L, Liebes L, Ara G, et al. The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo. J Transl Med. 2007;5:49. [DOI] [PubMed] [PMC]

192.

Hussain MHA, Kocherginsky M, Singh P, Myint Z, Jiang DM, Wulff-Burchfield EM, et al. A pilot study of tazemetostat and pembrolizumab in advanced urothelial carcinoma (ETCTN 10183). J Clin Oncol. 2023;41:506. [DOI]

193.

Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483:570–5. [DOI] [PubMed] [PMC]

194.

Rose TL, Chism DD, Alva AS, Deal AM, Maygarden SJ, Whang YE, et al. Phase II trial of palbociclib in patients with metastatic urothelial cancer after failure of first-line chemotherapy. Br J Cancer. 2018;119:801–7. [DOI] [PubMed] [PMC]

195.

Klein FG, Granier C, Zhao Y, Pan Q, Tong Z, Gschwend JE, et al. Combination of talazoparib and palbociclib as a potent treatment strategy in bladder cancer. J Pers Med. 2021;11:340. [DOI] [PubMed] [PMC]

196.

Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8. [DOI]

197.

McGovern K, Castro A, Cavanaugh J, Sanchez-Martin M, Tchaicha J, Syed S, et al. 448 Discovery of clinical candidate IK-175, a selective orally active AHR antagonist. J Immunother Cancer. 2020;8:A272. [DOI]

198.

Aggen D, McKean M, Lakhani N, Bashir B, Hoffman-Censits J, Alhalabi O, et al. 661 Initial results from a phase 1a/b study of IK-175, an oral AHR inhibitor, as a single agent and in combination with nivolumab in patients with advanced solid tumors and urothelial carcinoma. J Immunother Cancer. 2022;10:A692. [DOI]