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The future of bladder cancer therapy: Optimizing the inhibition of the fibroblast growth factor receptor

Published:March 13, 2020DOI:https://doi.org/10.1016/j.ctrv.2020.102000

      Highlights

      • Targeted therapies in advanced/metastastic bladder cancer have significant challenges due to molecular heterogeneity.
      • FGFRs have been considered as promising drug targets for the therapy of various cancers, including advanced/metastatic bladder cancer.
      • Several inhibitors targeting FGFRs are in development.
      • Erdafitinib has been approved by FDA as a therapy for metastatic BC in patients who have progressed to platinum-based chemotherapy.

      Abstract

      Therapeutic options for metastatic bladder cancer (BC) have seen minimal evolution over the past 30 years, with platinum-based chemotherapy remaining the mainstay of standard of care for metastatic BC. Recently, five immune checkpoint inhibitors (ICIs) have been approved by the FDA as second-line therapy, and two ICIs are approved as first-line treatment in selected patients. Molecular alterations of muscle-invasive bladder cancer (MIBC) have been reported by The Cancer Genome Atlas. About 15% of patients with MIBC have molecular alterations in the fibroblast growth factor (FGF) axis. Several ongoing trials are testing novel FGF receptor (FGFR) inhibitors in patients with FGFR genomic aberrations. Recently, erdafitinib, a pan-FGFR inhibitor, was approved by the FDA in patients with metastatic BC who have progressed on platinum-based chemotherapy. We reviewed the literature over the last decade and provide a summary of current knowledge of FGF signaling, and the prognosis associated with FGFR mutations in BC. We cover the role of FGFR inhibition with non-selective and selective tyrosine kinase inhibitors as well as novel agents in metastatic BC. Efficacy and safety data including insights from mechanism-based toxicity are reported for selected populations of metastatic BC with FGFR aberrations. Current strategies to managing resistance to anti-FGFR agents is addressed, and the importance of developing reliable biomarkers as the therapeutic landscape moves towards an individualized therapeutic approach.

      Keywords

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      References

        • Ferlay J.
        • Colombet M.
        • Soerjomataram I.
        • et al.
        Estimating the global cancer incidence and mortality in 2018: GLOBOCAN source and methods.
        Int J Cancer. 2019; 144: 1941-1953
        • Ferlay J.
        • Colombet M.
        • Soerjomataram I.
        • et al.
        Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018.
        Eur J Cancer. 2018; 103: 356-387
        • Lopez-Beltran A.
        • Henriques V.
        • Montironi R.
        • Cimadamore A.
        • Raspollini M.R.
        • Cheng L.
        Variants and new entities of bladder cancer.
        Histopathology. 2019; 74: 77-96
        • Park S.
        • Rueter V.E.
        • Hansel D.E.
        Histopathology. 2019; 74: 111
        • Robertson A.G.
        • Kim J.
        • Al-Ahmadie H.
        • et al.
        Comprehensive molecular characterization of muscle-invasive bladder cancer.
        Cell. 2017; 171: 540-556e
        • The Cancer Genome Atlas Research Network
        Comprehensive molecular characterization of urothelial bladder carcinoma.
        Nature. 2014; 507: 315-322
        • Yang B.
        • Li X.
        • Lei L.
        • Chen J.
        APOBEC: From mutator to editor.
        J Genet Genomics. 2017; 44: 423-437
        • Babina I.S.
        • Tunrner N.C.
        Advanced and challenges in targeting FGFR signaling in cancer.
        Nat Rev Cancer. 2017; 17: 318-332
        • Helsten T.
        • Schwaerde M.
        • Kurzrock R.
        Fibroblast growth factor receptor signaling in hereditary and neoplastic disease: biologic and clinical implications.
        Cancer Metastasis Rev. 2015; 34: 479-496
        • Katoh M.
        FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis.
        Int J Mol Med. 2016; 38: 3-15
        • Hui Q.
        • Jin Z.
        • Li X.
        • Liu C.
        • Wang X.
        FGF family: from drug development to clinical application.
        Int J Mol Sci. 2018; 19: pii-E1875https://doi.org/10.3390/ijms19071875
        • Turner N.
        • Grose R.
        Fibroblast growth factor signaling: from development to cancer.
        Nat Rev Cancer. 2010; 2: 116-129
        • Hierro C.
        • Rodon J.
        • Tabernero J.
        Fibroblast growth factor (FGF) receptor/FGF inhibitors: novel targets and strategies for optimization of response of solid tumors.
        Semin Oncol. 2015; 42: 801-819
        • Porta R.
        • Borea R.
        • Coelho A.
        • Khan S.
        • Araújo A.
        • Reclusa P.
        • et al.
        FGFR a promising druggable target in cancer: molecular biology and new drugs.
        Crit Rev Oncol Hematol. 2017; 113: 256-267
        • Helsten T.
        • Elkin S.
        • Arthur E.
        • Tomson B.N.
        • Carter J.
        • Kurzrock R.
        The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing.
        Clin Cancer Res. 2016; 22: 259-267
        • Bertz S.
        • Eckstein M.
        • Stoehr R.
        • Weyerer V.
        • Hartmann A.
        Urothelial bladder cancer: An update on molecular pathology with clinical implications.
        Eur Urol Suppl. 2017; 12: 272-294
        • Chae Y.K.
        • Ranganath K.
        • Hammerman P.S.
        • Vaklavas C.
        • Mohindra N.
        • Kalyan A.
        • et al.
        Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical aplicactions.
        Oncotarget. 2017; 8: 16052-16074
        • Costa R.
        • Carneiro B.A.
        • Taxter T.
        • Tavora F.A.
        • Kalyan A.
        • Pai S.A.
        • et al.
        FGFR3-TACC3 fusion in solid tumors: mini review.
        Oncotarget. 2016; 7: 55924-55938
        • Sarkar S.
        • Ryan E.L.
        • Royle S.J.
        FGFR3-TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle.
        Open Biol. 2017; 7: Pii-170080https://doi.org/10.1098/rsob.170080
        • Van Rhijn B.W.
        • Vis A.N.
        • van der Kwast T.H.
        • Kirkles W.J.
        • Radvanyi F.
        • Ooms E.C.
        • et al.
        Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to patohologic grade for the prediction of clinical outcome.
        J Clin Oncol. 2003; 21: 1912-1921
        • van oers J.M.
        • Zwarthoff E.C.
        • Rehman I.
        • Azzouzi A.R.
        • Cussenot O.
        • Meuth M.
        • et al.
        FGFR3 mutations indicated better survival in invasive upper urinary tract and bladder tumors.
        Eur Urol. 2009; 55: 650-657
        • Necchi A.
        • Pal S.K.
        • Ross J.S.
        • et al.
        Comprehensive genomic profiling (CGP) of upper-tract (UTUC) and bladder (BUC) urothelial carcinoma reveals opportunities for therapeutic and biomarker development.
        J Clin Oncol. 2019; 37_15 suppl: 4581
        • Turo R.
        • Harnden P.
        • Thygesen H.
        • Fleischmann A.
        • Thalmann N.G.
        • Siler R.
        • et al.
        FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases.
        J Urol. 2015; 193: 325-330
        • Guancial E.A.
        • Wemer L.
        • Bellmunt J.
        • Bamias A.
        • Chouriri T.K.
        • Ross R.
        • et al.
        FGFR3 expression in primary and metastatic urothelial carcinoma of the bladder.
        Cancer Med. 2014; 3: 835-844
        • Necchi A.
        • Lo Vullo S.
        • Raggi D.
        • et al.
        Prognostic effect of FGFR mutations or gene fusions in patients with metastatic urothelial carcinoma receiving first-line platinum-based chemotherapy: results from a large, single-institution cohort.
        Eur Urol Focus. 2018; (Marz 7.pii: S2405-4569(18)30075-0)https://doi.org/10.1016/j.euf.2018.02.013
        • Santiago-Walker A.E.
        • Chen F.
        • Loriot Y.
        • et al.
        Predictive value of fibroblast growth factor receptor (FGFR) mutations and gene fusions on anti-PD-(L)1 treatment outcomes in patients (pts) with advanced urothelial cancer (UC).
        J Clin Oncol. 2019; 37: 419
        • Rose T.L.
        • Hayward M.C.
        • Salaza A.H.
        • et al.
        Fibroblast growth factor receptor status and response to immune checkpoint inhibition in metastatic urothelial cancer.
        J Clin Oncol. 2019; 37: 458
        • Wang L.
        • Gong Y.
        • Saci A.
        • et al.
        Fibroblast Growth Factor Receptor 3 alterations and response to PD/PD-L1 blockade in patients with metastatic urothelial cancer.
        Eur Urol. 2019; 76: 599-603
        • Milowsky M.I.
        • Dittrich D.
        • Duran I.
        • Jagdev S.
        • Millard F.E.
        • Sweeney C.J.
        • et al.
        Phase 2 trial of dovinitnib in patients with progressive FGFR3-mutated or FGFR3 wild-type advanced urothelial carcinoma.
        Eur J Cancer. 2014; 50: 3145-3152
        • Hahn N.M.
        • Bivalacqua T.J.
        • Ross A.E.
        • Netto G.J.
        • Baras A.
        • Park J.C.
        • et al.
        A phase II trial of dovitinib in BCG-unresponsive urothelial carcinoma with FGFR3 mutations or overexpression: Hossier Cancer Research Network Trial HCRN 12–157.
        Clin Cancer Res. 2017; 15: 3003-3011
        • Necchi A.
        • Mariani L.
        • Zaffaroni N.
        • Schwartz L.H.
        • 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: 810-816
        • Pili R.
        • Qin R.
        • Flynn P.J.
        • Picus J.
        • Millward M.
        • Ho W.M.
        • et al.
        A phase II safety and efficacy study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with metastatatic urohelial cancer.
        Clin Genitourin Cancer. 2013; 11: 477-483
        • Palma N.
        • Morris J.C.
        • Ali S.M.
        • Ross J.S.
        • Pal S.K.
        Exceptional response to pazopanib in a patient with urothelial carcinoma herboring FGFR3 activating mutation and amplification.
        Eur Urol. 2015; 68: 168-170
        • Roth G.J.
        • Binder R.
        • Colbatzky F.
        • et al.
        Nintedanib: from discovery to the clinic.
        J Med Chem. 2015; 58: 1053-1063
        • Mross K.
        • Stefanic M.
        • Gmehling D.
        • et al.
        Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors.
        Clin Cancer Res. 2010; 16: 311-319
        • Hussain S.A.
        • Lester J.F.
        • Jackson R.
        • et al.
        Phase II randomized placebo-controlled neoadjuvant trial of nintedanib or placebo with gemcitabine and cisplatin in locally advanced muscle invasive bladder cacner (NEO-BLADE).
        J Clin Oncol. 2020; 6_supple: 438
        • Papadopoulos K.P.
        • El-Rayes B.F.
        • Tolcher A.W.
        • et al.
        A phase 1 study of ARQ 087, an oral pan-FGFR inhibitor in patients with advanced solid tumors.
        Br J Cancer. 2017; 117: 1592-1599
        • Loriot Y.
        • Necchi A.
        • Park S.H.
        • et al.
        Erdafitinib in locally advanced or metastatic urothelial carcinoma.
        N Engl J Med. 2019; 381: 338-348
      1. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-metastatic-bladder-cancer.

        • Moreno V.
        • Loriot Y.
        • Perez Valderrama B.
        • et al.
        Does escalation results from phase Ib/II Norse study of erdafatinib + PD-1 inhibitor JNJ-63723283 in patients with metastatic or locally advanced urothelial carcinoma and selected fibroblast growth factor receptor gene alterations.
        J Clin Oncol. 2020; 38: 511
        • Nogova L.
        • Sequist L.V.
        • Perez Garcia J.M.
        • Andre F.
        • Delord J.P.
        • 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: 157-165
        • Pal S.K.
        • Rosenberg J.E.
        • Hoffman-Censits J.H.
        • Berger R.
        • Quinn D.I.
        • Galsky M.D.
        • 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: 812-821
        • Collin M.P.
        • Lobell M.
        • Hübsch W.
        • et al.
        Discovery of rogaratinib (BAY1163877): a pan-FGFR inhibitor.
        Chem Med Chem. 2018; 13: 437-445
        • Joerger M.
        • Soo R.
        • Cho B.C.
        • Navarro Mendivil A.
        • Sayehli C.
        • Richly H.
        Phase I study of pan-fibroblast growth factor receptor inhibitor BAY 1163877 with expansión cohorts for subjects based on tumor FGFR mRNS expression.
        Ann Oncol. 2016; 27: 1-36https://doi.org/10.1093/annonc/mdw435
        • Joerger M.
        • Cassier P.A.
        • Penel N.
        • Cathomas R.
        • Richly H.
        • Schostak M.
        • et al.
        Rogaratinib in patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression and effects of mutations in the FGFR signaling patways.
        J Clin Oncol. 2018; 36
        • Quinn D.I.
        • Petrylak D.
        • Bellmun J.
        • et al.
        FORT-1: Phase II/III study of ragartinib versus chemotherapy in patients with locally advanced or metastatic urothelial carcinoma selected based on FGFR1/3mRNA expression.
        J Clin Oncol. 2020; 38: 489
        • Andre F.
        • Ranson M.
        • Emma Dean
        • Varga A.
        • van der Noll R.
        • Stockman P.K.
        Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor, in patients with advanced solid tumors.
        Cancer Res. 2013; 8
        • Jones R.H.
        • Anthoney D.A.
        • Jones R.J.
        • Crabb S.J.
        • Hussain S.A.
        Birtle AJ. FIESTA: a phase Ib and pharmacokinectic trial of AZD4547 in combination with gemcitabine and cisplatin.
        J Clin Oncol. 2016; 34
        • Chae Y.K.
        • Vaklavas C.
        • Cheng H.H.
        • Hong F.
        • Harris L.
        • Mitchell E.P.
        • et al.
        Molecular analysis for therapy choice (MATCH) arm W: phase II study of AZD4547 in patients with tumors with aberrations in the FGFR pathway.
        J Clin Oncol. 2018; 36
        • Powles T.
        • Balar A.V.
        • Gravis G.
        • et al.
        An adaptative, biomarker directed platform study in metastatic urothelial cancer (BISCAY) with durvalumab in combination with targeted therapies.
        Ann Oncol. 2019; 30_suppl 5: v356-v402https://doi.org/10.1093/annonc/mdz249
        • Voss M.H.
        • Hierro C.
        • Heist R.S.
        • et al.
        A phase I, open-label, multicenter, dose-escalation study of the oral selective FGFR inhibitor Debio 1347 in patients with advanced solid tumor harboring FGFR gene alterations.
        Clin Cancer Res. 2019; 25: 2699-2707
      2. https://www.debiopharm.com/medias/press-release/item/3860-fda-grants-fast-track-designation-to-debiopharm-international-s-debio-1347-for-the-treatment-of-patients-with-unresectable-or-metastatic-tumors-with-a-specific-fgfr-gene-alteration.

        • Ochiiwa H.
        • Fujita H.
        • Itoh K.
        • Sootome H.
        • Hashimoto A.
        • Fujioka Y.
        • et al.
        TAS-120, a highly potent and selective irreversible FGFR inhibitor, is effective in tumors harboring various FGFR gene abnormalities.
        Mol Cancer Ther. 2013; 11
        • Kuboki Y.
        • Matsubara N.
        • Bando H.
        • Shitara K.
        • Yoh K.
        • Kojima T.
        First in human study of TAS-120, a highly selective covalent oral fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.
        Ann Oncol. 2018; 5
        • Liu P.C.
        • Wu L.
        • Koblish H.
        • Bowman K.
        • Zhang Y.
        • Klabe R.
        • et al.
        Preclinical characterization of the selective FGFR inhibitor INCB054828.
        Cancer Res. 2015; 15
        • Goyal L.
        • Shi L.
        • Liu L.Y.
        • et al.
        TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma.
        Cancer Discov. 2019; 9: 1064-1079
        • Saleh M.
        • Gutierrez M.
        • Subbiah V.
        • Smicth D.C.
        • Féliz L.
        • Zhen H.
        • et al.
        Preliminary results from a phase 1/2 study of INCB054828, a highly selective fibroblast growth factor receptor inhibitor, in patients with advanced malignancies.
        Mol Cancer Ther. 2018; 17
        • Necchi A.
        • Pouessel D.
        • Leibowitz-Amit R.
        • et al.
        Interim results of fight-201, a phase 2, open label, multicenter study of INCB054828 in patients (pts) with metastatic or surgically unresectable utothelial carcinoma.
        Ann Oncol. 2018; 29 (viii303-viii331/10.1093/annonc/mdy283)
        • Herbert C.
        • Lassalle G.
        • Alcouffe C.
        • Bono F.
        Approaches targeting the FGF-FGFR system: a review of the recent patent literature and associated advanced therapeutic agents.
        Pharm Pat Anal. 2014; 3: 585-612
        • Bellmunt J.
        • Pal S.K.
        • Picus J.
        • et al.
        Safety and efficacy of docetael + B-701, a selective inhibitor of FGFR3, in subjects with advanced or metastatic urothelial carcinoma.
        J Clin Oncol. 2017; 35: 4540
        • Bellmunt J.
        • Picus J.
        • Kohli M.
        • et al.
        FIERCE-21: phase 1b/study of docetaxel + B-701, a selective inhibitor of FGFR3, in relapsed or refractory metastatic urothelial carcinoma.
        J Clin Oncol. 2018; 36: 4534
        • Necchi A.
        • Castellano D.
        • Mellado B.
        • et al.
        Fierce- 21: Phase II study of vofatamab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urotehlial carcinoma.
        J Clin Oncol. 2019; 37: 409
        • Siefker-Radtke A.
        • Currie G.
        • Abella E.
        • et al.
        FIERCE 22: clinical activity of vofatamab a FGFR3 selective inhibitor in combination with pembrolizumab in WT metastatic urothelial carcinoma, preliminary analysis.
        J Clin Oncol. 2019; 37: 4511
        • Shepard H.M.
        • Philips G.L.
        • D Thanos C.
        • Feldmann M.
        Developments in therapy with monoclonal antibodies and related proteins.
        Clin Med (Lond). 2017; 17: 220-232
        • Presta M.
        • Chiodeli P.
        • Giacomini A.
        • Rusnati M.
        • Ronca R.
        Fibroblast growth factors (FGF) in cancer: FGF traps as a new therapeutic approach.
        Pharmacol Ther. 2017; 179: 171-187
        • Harding T.C.
        • Long L.
        • Palencia S.
        • et al.
        Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer.
        Sci Transl Med. 2013; 5: 178ra139
        • Tolcher A.W.
        • Papadopoulos K.P.
        • Patnaik A.
        • et al.
        A phase I, first in human study of FP-1039 (GSK3052230), a novel FGF ligand trap, in patients with advanced solid tumors.
        Ann Oncol. 2016; 27: 526-532
        • Stöhr R.
        • Schuh A.
        • Heine G.H.
        • Brandenburg V.
        FGF23 in cardiovascular disease: innocent bystander or active mediator.
        Front Endocrinol (Lausanne). 2018; 9: 351
        • Zhou X.
        • Wang X.
        Klotho: a novel biomarker for cancer.
        J Cancer Res Clin Oncol. 2015; 141: 961-969
        • Jonsson K.B.
        • Zahradnik R.
        • Larsson T.
        • et al.
        Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.
        N Engl J Med. 2003; 348: 1656-1663
        • Kay P.
        • Yang Y.C.
        • Paraoan L.
        Directional protein secretion by the retinal pigment epitelium: roles in retinal health and the development of age-related macular degeration.
        J Cell Mol Med. 2013; 17: 833-843
        • Ml Weber
        • Liang M.C.
        • Flaherty K.T.
        • Heier J.S.
        Subretinal fluid associated with MEK inhibitor use in the treatment of systemic cancer.
        JAMA Ophthalmol. 2016; 134: 855-862
        • Liu H.
        • Ai J.
        • Shen A.
        • et al.
        c-Myc alteration determines the therapeutic response to FGFR inhibitors.
        Clin Canc Res. 2017; 23: 974-984
        • Wang L.
        • Sustic T.
        • Leite de Oliveira R.
        • et al.
        A functional genetic screen identifies the phosphoinositide 3-kinase pathway as a determinant of resistance of fibroblast growth factor receptor inhibitors in FGFR mutant urothelial carcinoma.
        Eur Urol. 2017; 71: 858-862
        • Herrera-Abreu M.T.
        • Pearson A.
        • Campbell J.
        • et al.
        Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3 mutant cancer.
        Cancer Discov. 2013; 3: 1058-1071
        • Datta J.
        • Damodaran S.
        • Parks H.
        • et al.
        Akt activation mediates acquired resistance to fibroblast growth factor receptor inhibitor BGJ398.
        Mol Cancer Ther. 2017; 16: 614-624
        • Hu Y.
        • Lu H.
        • Zhang J.
        • Chen J.
        • Chai Z.
        • Zhang J.
        Essential role of AKT in tumor cells addicted to FGFR.
        Anticancer Drugs. 2014; 25: 183-188
        • Wang J.
        • Mikse O.
        • Liao R.G.
        • et al.
        Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR-3 dependent cancer cells.
        Oncogene. 2015; 34: 2167-2177
        • Mahe M.
        • Dufour F.
        • Neyret-Kahn H.
        • et al.
        An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers.
        EMBO Mol Med. 2018; (Pii e8163)https://doi.org/10.15252/emmm.201708163
        • Acquaviva J.
        • He S.
        • Zhang C.
        • et al.
        FGFR3 translocations in bladder cancer: differential sensitivity to HSP90 inhibition based on drug metabolism.
        Mol Cancer Res. 2014; 12: 1042-1054
        • Tomlinson D.C.
        • Baxter E.W.
        • Loadman P.M.
        • et al.
        FGFR1-induced epitehial mesenchymal transition through MAPK/PLCγ/COX-2-mediated mechanisms.
        PLoS One. 2012; 7: e38972
        • Yang F.
        • Zhang Y.
        • Ressier S.J.
        • et al.
        FGFR1 is essential for prostate cancer progression and metastasis.
        Cancer Res. 2013; 73: 3716-3724
        • Kim S.H.
        • Ryu H.
        • Ock C.Y.
        • et al.
        BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression.
        Int J Mol Sci. 2018; 19 (pii: E3164)https://doi.org/10.3390/ijms19103164
        • Morales-Barrera R.
        • González M.
        • Suárez C.
        • Carles J.
        Detection of circulating tumor DNA for advanced bladder cancer: where are we going?.
        Transl Androl Urol. 2018; 7: S101-S103
        • Vandekerhove G.
        • Lavoie J.M.
        • Annala M.
        • et al.
        Genomic concordance between profiling of circulating tumor DNA (ctDNA) and matched tissue in metastatic urothelial carcinoma.
        J Clin Oncol. 2019; 37: 457
        • Rosenberg J.E.
        • ÓDonnell P.H.
        • Balar A.V.
        • 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: 2592-2600
        • Tagawa S.T.T.
        • Balar A.
        • Petrylak D.P.
        • et al.
        LBA55 initial results from TROPHY-U- 01: a phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial cancer after failure of platinum-based regimens or immunotherapy.
        Ann Oncol. 2019; 30https://doi.org/10.1093/annonc/mdz394.049