Current Systemic Treatment Options in Metastatic Urothelial Carcinoma after Progression on Checkpoint Inhibition Therapy—A Systemic Review Combined with Single-Group Meta-Analysis of Three Studies Testing Enfortumab Vedotin
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Literature Search
2.2. Study Selection
2.3. Data Extraction
2.4. Statistical Methods
3. Results
3.1. Chemotherapy (CT) Alone or as Combination Therapy
3.1.1. Gemcitabine Plus Cisplatin or Carboplatin, Docetaxel, Paclitaxel, Vinflunine and Others
3.1.2. Docetaxel Plus Placebo or Ramucirumab (RAM)—An Epidermal Growth Factor Receptor (EGFR) Antibody—The RANGE Study
3.2. EV-an ADC Targeting Nectin-4
3.2.1. The EV-101, EV-201 and EV-301 Studies—Study Design
3.2.2. Study Data
3.3. Clinical Use and Outlook
3.4. Erdafitinib (Erd)—A Pan-Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor
3.4.1. The BLC2001 Study—Study Design and Results
3.4.2. Clinical Use and Outlook
3.5. Sacituzumab Govitecan (SG)—An ADC Consisting of an Immunglobulin G (IgG) Antibody Targeting Troponin-2 and the Topoisomerase-I Inhibitor SN-38
3.5.1. The IMMU-132 and the TROPHY-U-01 (IMMU-132–06) Studies—Study Design and Results
3.5.2. Clinical Use and Outlook
4. Discussion
Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADC | Antibody-drug conjugate |
AEs | Adverse events |
G3 AE | Grade 3 adverse event |
AKT | Protein kinase B |
AR | Androgen receptor |
ASCO-GU | Genitourinary Cancers Symposium of the American Society of Clinical Oncology |
BC | Bladder cancer |
NMIBC | Nonmuscle invasive bladder cancer |
MIBC | Muscle invasive bladder cancer |
BSC | Best supportive care |
CPI | Checkpoint inhibition |
CR | Complete response |
CT | Chemotherapy |
D + R/P | Docetaxel + Ramucirumab/Placebo |
DoR | Duration of response |
EAU | European Association of Urology |
ECOG | Eastern Cooperative Oncology Group |
EGFR | Epidermal Growth Factor Receptor |
EMA | European Medicines Agency |
Erd | Erdafitinib |
ESMO | European Society for Medical Oncology |
ESMO | European Society for Medical Oncology |
EV | Enfortumab vedotin |
FDA | United States Food and Drug Administration |
FGFR | Fibroblast growth factor receptor |
FU | Follow up |
GA | Genetic alterations |
HER2 | Human epidermal growth factor receptor 2 |
i.v. | Intravenously |
IgG | Immunglobulin G |
ITT | Intention to treat |
MAPK | Mitogen-activated protein kinase |
MHC | Major histocompatibility complex |
mTOR | Mechanistic Target of Rapamycin |
M-VAC | Methotrexate, Vinblastine, Adriamycin and Cisplatin |
NA | Not available |
NR | Not reached |
ORR | Objective response rate |
OS | Overall survival |
PARP | poly(ADP-ribose) polymerase |
PD | Progressive disease |
PD-(L)1 | Programmed cell death (ligand)-1 |
PFS | Progression free survival |
PR | Partial response |
PRISMA | Preferred Reporting Items for Systematic Review and meta-analysis Statement |
PSN | Peripheral sensory neuropathy |
RAM | Ramucirumab |
RECIST | Response evaluation criteria in solid tumors |
RTK | Receptor tyrosine kinases |
SG | Sacituzumab govitecan |
SRM | Selected regimen |
TCGA | The Cancer Genome Atlas |
TKI | Tyrosine kinase inhibitor |
(m)UC | (Metastatic) urothelial carcinoma |
UTI | Urinary tract infection |
VEGF | Vascular endothelial growth factor |
WBC | White blood cell |
References
- Estimated Number of New Cases in 2020, Worldwide, Both Sexes, All Ages. Available online: https://gco.iarc.fr/today/online-analysis-table?v=2020&mode=cancer&mode_population=continents&population=900&populations=900&key=asr&sex=0&cancer=39&type=0&statistic=5&prevalence=0&population_group=0&ages_group%5B%5D=0&ages_group%5B%5D=17&group_cancer=1&include_nmsc=1&include_nmsc_other=1 (accessed on 25 May 2021).
- van Osch, F.H.; Jochems, S.H.; van Schooten, F.J.; Bryan, R.T.; Zeegers, M.P. Quantified relations between exposure to tobacco smoking and bladder cancer risk: A meta-analysis of 89 observational studies. Int. J. Epidemiol. 2016, 45, 857–870. [Google Scholar] [CrossRef][Green Version]
- Brennan, P.; Bogillot, O.; Cordier, S.; Greiser, E.; Schill, W.; Vineis, P.; Lopez-Abente, G.; Tzonou, A.; Chang-Claude, J.; Bolm-Audorff, U.; et al. Cigarette smoking and bladder cancer in men: A pooled analysis of 11 case-control studies. Int. J. Cancer 2000, 86, 289–294. [Google Scholar] [CrossRef]
- Pesch, B.; Taeger, D.; Johnen, G.; Gawrych, K.; Bonberg, N.; Schwentner, C.; Wellhausser, H.; Kluckert, M.; Leng, G.; Nasterlack, M.; et al. Screening for bladder cancer with urinary tumor markers in chemical workers with exposure to aromatic amines. Int. Arch. Occup. Environ. Health 2014, 87, 715–724. [Google Scholar] [CrossRef] [PubMed]
- Burger, M.; Catto, J.W.; Dalbagni, G.; Grossman, H.B.; Herr, H.; Karakiewicz, P.; Kassouf, W.; Kiemeney, L.A.; La Vecchia, C.; Shariat, S.; et al. Epidemiology and risk factors of urothelial bladder cancer. Eur. Urol. 2013, 63, 234–241. [Google Scholar] [CrossRef] [PubMed]
- Steinmaus, C.; Ferreccio, C.; Acevedo, J.; Yuan, Y.; Liaw, J.; Duran, V.; Cuevas, S.; Garcia, J.; Meza, R.; Valdes, R.; et al. Increased lung and bladder cancer incidence in adults after in utero and early-life arsenic exposure. Cancer Epidemiol. Biomark. Prev. 2014, 23, 1529–1538. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Villanueva, C.M.; Fernandez, F.; Malats, N.; Grimalt, J.O.; Kogevinas, M. Meta-analysis of studies on individual consumption of chlorinated drinking water and bladder cancer. J. Epidemiol. Community Health 2003, 57, 166–173. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Rogers, C.G.; Palapattu, G.S.; Shariat, S.F.; Karakiewicz, P.I.; Bastian, P.J.; Lotan, Y.; Gupta, A.; Vazina, A.; Gilad, A.; Sagalowsky, A.I.; et al. Clinical outcomes following radical cystectomy for primary nontransitional cell carcinoma of the bladder compared to transitional cell carcinoma of the bladder. J. Urol. 2006, 175, 2048–2053, discussion 2053. [Google Scholar] [CrossRef]
- Ismaili, N. A rare bladder cancer—Small cell carcinoma: Review and update. Orphanet J. Rare Dis. 2011, 6, 75. [Google Scholar] [CrossRef][Green Version]
- Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014, 507, 315–322. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Kamoun, A.; de Reynies, A.; Allory, Y.; Sjodahl, G.; Robertson, A.G.; Seiler, R.; Hoadley, K.A.; Groeneveld, C.S.; Al-Ahmadie, H.; Choi, W.; et al. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer. Eur. Urol. 2020, 77, 420–433. [Google Scholar] [CrossRef]
- Robertson, A.G.; Kim, J.; Al-Ahmadie, H.; Bellmunt, J.; Guo, G.; Cherniack, A.D.; Hinoue, T.; Laird, P.W.; Hoadley, K.A.; Akbani, R.; et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell 2017, 171, 540–556.e525. [Google Scholar] [CrossRef][Green Version]
- Brierley, J.D.; Gospodarowicz, M.K.; Wittekind, C. (Eds.) TNM Classification of Malignant Tumours, 8th ed.; Wiley-Blackwell: Hoboken, NJ, USA, 2016. [Google Scholar]
- Sylvester, R.J.; van der Meijden, A.P.; Oosterlinck, W.; Witjes, J.A.; Bouffioux, C.; Denis, L.; Newling, D.W.; Kurth, K. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials. Eur. Urol. 2006, 49, 465–466, discussion 475–467. [Google Scholar] [CrossRef]
- Comperat, E.; Larre, S.; Roupret, M.; Neuzillet, Y.; Pignot, G.; Quintens, H.; Houede, N.; Roy, C.; Durand, X.; Varinot, J.; et al. Clinicopathological characteristics of urothelial bladder cancer in patients less than 40 years old. Virchows Arch. 2015, 466, 589–594. [Google Scholar] [CrossRef] [PubMed]
- EORTC Risk Tables for Predicting Recurrence and Progression in Individual Patients with Stage Ta T1 Bladder Cancer. Available online: https://www.eortc.be/tools/bladdercalculator/ (accessed on 27 May 2021).
- Thiel, T.; Ryk, C.; Renstrom-Koskela, L.; Steineck, G.; Schumacher, M.C.; Wiklund, N.P.; de Verdier, P.J. Intravesical BCG treatment causes a long-lasting reduction of recurrence and progression in patients with high-risk non-muscle-invasive bladder cancer. World J. Urol. 2019, 37, 155–163. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Porten, S.P.; Leapman, M.S.; Greene, K.L. Intravesical chemotherapy in non-muscle-invasive bladder cancer. Indian J. Urol. 2015, 31, 297–303. [Google Scholar] [CrossRef]
- Fernandez-Gomez, J.; Madero, R.; Solsona, E.; Unda, M.; Martinez-Pineiro, L.; Gonzalez, M.; Portillo, J.; Ojea, A.; Pertusa, C.; Rodriguez-Molina, J.; et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: The CUETO scoring model. J. Urol. 2009, 182, 2195–2203. [Google Scholar] [CrossRef]
- Vale, C.L. Neoadjuvant chemotherapy in invasive bladder cancer: Update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur. Urol. 2005, 48, 202–205, discussion 205–206. [Google Scholar] [CrossRef] [PubMed]
- Saginala, K.; Barsouk, A.; Aluru, J.S.; Rawla, P.; Padala, S.A.; Barsouk, A. Epidemiology of Bladder Cancer. Med. Sci. 2020, 8, 15. [Google Scholar] [CrossRef][Green Version]
- Nishio, Y.; Shirahase, T.; Shichiri, Y.; Habuchi, T.; Matsuda, T.; Nishimura, K.; Hida, S.; Okada, Y.; Yoshida, O. Experience with combination chemotherapy consisting of methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) in advanced urothelial cancer. Hinyokika Kiyo Acta Urol. Jpn. 1988, 34, 1371–1375. [Google Scholar]
- von der Maase, H.; Hansen, S.W.; Roberts, J.T.; Dogliotti, L.; Oliver, T.; Moore, M.J.; Bodrogi, I.; Albers, P.; Knuth, A.; Lippert, C.M.; et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: Results of a large, randomized, multinational, multicenter, phase III study. J. Clin. Oncol. 2000, 18, 3068–3077. [Google Scholar] [CrossRef]
- Oing, C.; Rink, M.; Oechsle, K.; Seidel, C.; von Amsberg, G.; Bokemeyer, C. Second Line Chemotherapy for Advanced and Metastatic Urothelial Carcinoma: Vinflunine and Beyond—A Comprehensive Review of the Current Literature. J. Urol. 2016, 195, 254–263. [Google Scholar] [CrossRef] [PubMed]
- Bellmunt, J.; Fougeray, R.; Rosenberg, J.E.; von der Maase, H.; Schutz, F.A.; Salhi, Y.; Culine, S.; Choueiri, T.K. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann. Oncol. 2013, 24, 1466–1472. [Google Scholar] [CrossRef]
- Bellmunt, J.; Theodore, C.; Demkov, T.; Komyakov, B.; Sengelov, L.; Daugaard, G.; Caty, A.; Carles, J.; Jagiello-Gruszfeld, A.; Karyakin, O.; et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J. Clin. Oncol. 2009, 27, 4454–4461. [Google Scholar] [CrossRef] [PubMed]
- FDA Approves New, Targeted Treatment for Bladder Cancer. Available online: https://www.prnewswire.com/news-releases/fda-approves-new-targeted-treatment-for-bladder-cancer-300271014.html (accessed on 20 February 2021).
- Powles, T.; Duran, I.; van der Heijden, M.S.; Loriot, Y.; Vogelzang, N.J.; De Giorgi, U.; Oudard, S.; Retz, M.M.; Castellano, D.; Bamias, A.; 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, 748–757. [Google Scholar] [CrossRef]
- Balar, A.V.; Galsky, M.D.; Rosenberg, J.E.; Powles, T.; Petrylak, D.P.; Bellmunt, J.; Loriot, Y.; Necchi, A.; Hoffman-Censits, J.; Perez-Gracia, J.L.; et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: A single-arm, multicentre, phase 2 trial. Lancet 2017, 389, 67–76. [Google Scholar] [CrossRef][Green Version]
- Grivas, P.; Plimack, E.R.; Balar, A.V.; Castellano, D.; O’Donnell, P.H.; Bellmunt, J.; Powles, T.; Hahn, N.M.; de Wit, R.; Bajorin, D.F.; et al. Pembrolizumab as First-line Therapy in Cisplatin-ineligible Advanced Urothelial Cancer (KEYNOTE-052): Outcomes in Older Patients by Age and Performance Status. Eur. Urol. Oncol. 2020, 3, 351–359. [Google Scholar] [CrossRef] [PubMed]
- Bellmunt, J.; de Wit, R.; Vaughn, D.J.; Fradet, Y.; Lee, J.L.; Fong, L.; Vogelzang, N.J.; Climent, M.A.; Petrylak, D.P.; Choueiri, T.K.; et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N. Engl. J. Med. 2017, 376, 1015–1026. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Vuky, J.; Balar, A.V.; Castellano, D.; O’Donnell, P.H.; Grivas, P.; Bellmunt, J.; Powles, T.; Bajorin, D.; Hahn, N.M.; Savage, M.J.; et al. Long-Term Outcomes in KEYNOTE-052: Phase II Study Investigating First-Line Pembrolizumab in Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer. J. Clin. Oncol. 2020, 38, 2658–2666. [Google Scholar] [CrossRef] [PubMed]
- Nadal, R.; Bellmunt, J. Management of metastatic bladder cancer. Cancer Treat. Rev. 2019, 76, 10–21. [Google Scholar] [CrossRef]
- The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Website. Available online: http://www.prisma-statement.org (accessed on 29 April 2021).
- Eisenhauer, E.A.; Therasse, P.; Bogaerts, J.; Schwartz, L.H.; Sargent, D.; Ford, R.; Dancey, J.; Arbuck, S.; Gwyther, S.; Mooney, M.; et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. Cancer 2009, 45, 228–247. [Google Scholar] [CrossRef] [PubMed]
- Balduzzi, S.; Rücker, G.; Schwarzer, G. How to perform a meta-analysis with R: A practical tutorial. Evid.-Based Ment. Health 2019, 2, 153–160. [Google Scholar] [CrossRef][Green Version]
- McGrath, S.; Zhao, X.; Qin, Z.Z.; Steele, R.; Benedetti, A. One-sample aggregate data meta-analysis of medians. Stat. Med. 2019, 38, 969–984. [Google Scholar] [CrossRef][Green Version]
- Combescure, C.; Foucher, Y.; Jackson, D. Meta-analysis of single-arm survival studies: A distribution-free approach for estimating summary survival curves with random effects. Stat. Med. 2014, 33, 2521–2537. [Google Scholar] [CrossRef] [PubMed]
- Common Terminology Criteria for Adverse Events (CTCAE). Available online: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm (accessed on 20 April 2021).
- Rosenberg, J.; Sridhar, S.S.; Zhang, J.; Smith, D.; Ruether, D.; Flaig, T.W.; Baranda, J.; Lang, J.; Plimack, E.R.; Sangha, R.; 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, 1041–1049. [Google Scholar] [CrossRef] [PubMed]
- Rosenberg, J.E.; O’Donnell, P.H.; Balar, A.V.; McGregor, B.A.; Heath, E.I.; Yu, E.Y.; Galsky, M.D.; Hahn, N.M.; Gartner, E.M.; Pinelli, J.M.; 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. [Google Scholar] [CrossRef]
- Powles, T.; Rosenberg, J.E.; Sonpavde, G.P.; Loriot, Y.; Duran, I.; Lee, J.L.; Matsubara, N.; Vulsteke, C.; Castellano, D.; Wu, C.; et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N. Engl. J. Med. 2021, 384, 1125–1135. [Google Scholar] [CrossRef]
- Petrylak, D.P.; de Wit, R.; Chi, K.N.; Drakaki, A.; Sternberg, C.N.; Nishiyama, H.; Castellano, D.; Hussain, S.A.; Flechon, A.; Bamias, A.; 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, 105–120. [Google Scholar] [CrossRef]
- Loriot, Y.; Necchi, A.; Park, S.H.; Garcia-Donas, J.; Huddart, R.; Burgess, E.; Fleming, M.; Rezazadeh, A.; Mellado, B.; Varlamov, S.; et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N. Engl. J. Med. 2019, 381, 338–348. [Google Scholar] [CrossRef] [PubMed]
- Ocean, A.J.; Starodub, A.N.; Bardia, A.; Vahdat, L.T.; Isakoff, S.J.; Guarino, M.; Messersmith, W.A.; Picozzi, V.J.; Mayer, I.A.; Wegener, W.A.; et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics. Cancer 2017, 123, 3843–3854. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Tagawa, S.T.; Morris Faltas, B.; Tat Lam, E.; Saylor, P.J.; Bardia, A.; Hajdenberg, J. Sacituzumab govitecan (IMMU-132) in patients with previously treated metastatic urothelial cancer (mUC): Results from a phase I/II study. J. Clin. Oncol. 2019, 37, 354. [Google Scholar] [CrossRef]
- Sideris, S.; Aoun, F.; Zanaty, M.; Martinez, N.C.; Latifyan, S.; Awada, A.; Gil, T. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol. Clin. Oncol. 2016, 4, 1063–1067. [Google Scholar] [CrossRef][Green Version]
- de Liaño Lista, A.G.; van Dijk, N.; de Rueda, G.D.; Necchi, A.; Lavaud, P.; Morales-Barrera, R.; Gordoa, T.A.; Maroto, P.; Ravaud, A.; Durán, I.; et al. Clinical outcome after progressing to frontline and second-line Anti—PD-1/PD-L1 in advanced urothelial cancer. Eur. Urol. 2020, 77, 269–276. [Google Scholar] [CrossRef] [PubMed]
- Petrylak, D.P.; de Wit, R.; Chi, K.N.; Drakaki, A.; Sternberg, C.N.; Nishiyama, H.; Castellano, D.; Hussain, S.; Flechon, A.; Bamias, A.; et al. Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): A randomised, double-blind, phase 3 trial. Lancet 2017, 390, 2266–2277. [Google Scholar] [CrossRef][Green Version]
- Drakaki, A.; Kirby, R.; Van der Heijden, M.S.; Petrylak, D.P.; Powles, T.; Chi, K.N. Docetaxel with or without ramucirumab after immune checkpoint inhibition in platinum-refractory metastatic urothelial carcinoma (mUC): Prespecified subgroup analysis from the phase 3 RANGE trial. J. Clin. Oncol. 2018, 36, 434. [Google Scholar] [CrossRef]
- Rikitake, Y.; Mandai, K.; Takai, Y. The role of nectins in different types of cell-cell adhesion. J. Cell Sci. 2012, 125, 3713–3722. [Google Scholar] [CrossRef] [PubMed][Green Version]
- FDA Grants Accelerated Approval to Enfortumab Vedotin-Ejfv for Metastatic Urothelial Cancer. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-metastatic-urothelial-cancer (accessed on 20 April 2021).
- European Medicines Agency Accepts Marketing Authorization Application for Enfortumab Vedotin. Available online: https://www.biospace.com/article/releases/european-medicines-agency-accepts-marketing-authorization-application-for-enfortumab-vedotin/ (accessed on 20 April 2021).
- FDA Grants Accelerated Approval to Erdafitinib for Metastatic Urothelial Carcinoma. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-erdafitinib-metastatic-urothelial-carcinoma (accessed on 13 March 2021).
- Highlights of Prescribing Information Balversa; Janssen Pharmaceutical Companies: Beerse, Belgium, 2019.
- A Study of Erdafitinib Compared with Vinflunine or Docetaxel or Pembrolizumab in Participants with Advanced Urothelial Cancer and Selected Fibroblast Growth Factor Receptor (FGFR) Gene Aberrations. Available online: https://clinicaltrials.gov/ct2/show/NCT03390504 (accessed on 13 March 2021).
- ESMO Virtual Congress 2020: TROPHY-U-01 Cohort 1 Final Results: A Phase 2 Study of Sacituzumab Govitecan (SG) in Metastatic Urothelial Cancer That Has Progressed after Platinum and Checkpoint Inhibitors. Available online: https://www.urotoday.com/conference-highlights/esmo-2020/bladder-cancer/124543-esmo-virtual-congress-2020-trophy-u-01-cohort-1-final-results-a-phase-2-study-of-sacituzumab-govitecan-sg-in-metastatic-urothelial-cancer-that-has-progressed-after-platinum-and-checkpoint-inhibitors.html (accessed on 20 April 2021).
- Loriot, Y.; Balar, A.V.; Petrylak, D.P. LBA24—TROPHY-U-01 cohort 1 final results: A phase II study of sacituzumab govitecan (SG) in metastatic urothelial cancer (mUC) that has progressed after platinum (PLT) and checkpoint inhibitors (CPI). Ann. Oncol. 2020, 31, S1142–S1215. [Google Scholar] [CrossRef]
- Grivas, P.; Tagawa, S.T.; Bellmunt, J. 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. [Google Scholar] [CrossRef]
- Sacituzumab Govitecan Plus EV in Metastatic UC. Available online: https://clinicaltrials.gov/ct2/show/NCT04724018 (accessed on 24 April 2021).
- FDA Approves Trodelvy®, the First Treatment for Metastatic Triple-Negative Breast Cancer Shown to Improve Progression-Free Survival and Overall Survival. Available online: https://www.gilead.com/news-and-press/press-room/press-releases/2021/4/fda-approves-trodelvy-the-first-treatment-for-metastatic-triplenegative-breast-cancer-shown-to-improve-progressionfree-survival-and-overall-surviv (accessed on 20 April 2021).
- Di Lorenzo, G.; Buonerba, C.; Bellelli, T.; Romano, C.; Montanaro, V.; Ferro, M.; Benincasa, A.; Ribera, D.; Lucarelli, G.; De Cobelli, O.; et al. Third-Line Chemotherapy for Metastatic Urothelial Cancer: A Retrospective Observational Study. Medicine 2015, 94, e2297. [Google Scholar] [CrossRef]
- Mathijssen, R.H.; van Alphen, R.J.; Verweij, J.; Loos, W.J.; Nooter, K.; Stoter, G.; Sparreboom, A. Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin. Cancer Res. 2001, 7, 2182–2194. [Google Scholar]
- Beer, T.M.; Goldman, B.; Nichols, C.R.; Petrylak, D.P.; Agarwal, M.; Ryan, C.W.; Crawford, E.D. Southwest Oncology Group phase II study of irinotecan in patients with advanced transitional cell carcinoma of the urothelium that progressed after platinum-based chemotherapy. Clin. Genitourin. Cancer 2008, 6, 36–39. [Google Scholar] [CrossRef]
- Chaudhary, U.B.; Verma, N.; Keane, T.; Gudena, V. A phase II study of gemcitabine and irinotecan in patients with locally advanced or metastatic bladder cancer. Am. J. Clin. Oncol. 2014, 37, 188–193. [Google Scholar] [CrossRef] [PubMed]
- Zaman, S.; Jadid, H.; Denson, A.C.; Gray, J.E. Targeting Trop-2 in solid tumors: Future prospects. Onco Targets Ther. 2019, 12, 1781–1790. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Iwai, T.; Sugimoto, M.; Wakita, D.; Yorozu, K.; Kurasawa, M.; Yamamoto, K. Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies. Oncotarget 2018, 9, 31411–31421. [Google Scholar] [CrossRef]
- Immunomedics Expands Collaboration with Roche Evaluating Trodelvy™ (Sacituzumab Govitecan-Hziy) in Combination with Tecentriq® (atezolizumab) into Urothelial and Non-Small Cell Lung Cancers. Available online: https://www.globenewswire.com/news-release/2020/07/13/2061470/0/en/Immunomedics-Expands-Collaboration-with-Roche-Evaluating-Trodelvy-sacituzumab-govitecan-hziy-in-Combination-with-Tecentriq-atezolizumab-into-Urothelial-and-Non-Small-Cell-Lung-Canc.html (accessed on 21 April 2021).
- Challita-Eid, P.M.; Satpayev, D.; Yang, P.; An, Z.; Morrison, K.; Shostak, Y.; Raitano, A.; Nadell, R.; Liu, W.; Lortie, D.R.; 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, 3003–3013. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Rosenberg, J.E.; Hoffman-Censits, J.; Powles, T.; van der Heijden, M.S.; Balar, A.V.; Necchi, A.; Dawson, N.; O’Donnell, P.H.; Balmanoukian, A.; Loriot, Y.; et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet 2016, 387, 1909–1920. [Google Scholar] [CrossRef][Green Version]
- Tomiyama, E.; Fujita, K.; Rodriguez Pena, M.D.C.; Taheri, D.; Banno, E.; Kato, T.; Hatano, K.; Kawashima, A.; Ujike, T.; Uemura, M.; et al. Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma. Int. J. Mol. Sci. 2020, 21, 5390. [Google Scholar] [CrossRef]
- Chu, C.; Sjöström, M.; Egusa, E.A.; Gibb, E.; Badura, M.L.; Chou, J. Heterogeneity in Nectin-4 expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin. Clin. Cancer Res. 2021, 39. [Google Scholar] [CrossRef]
- Choi, W.; Porten, S.; Kim, S.; Willis, D.; Plimack, E.R.; Hoffman-Censits, J.; Roth, B.; Cheng, T.; Tran, M.; Lee, I.L.; et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014, 25, 152–165. [Google Scholar] [CrossRef][Green Version]
- Gust, K.M.; McConkey, D.J.; Awrey, S.; Hegarty, P.K.; Qing, J.; Bondaruk, J.; Ashkenazi, A.; Czerniak, B.; Dinney, C.P.; Black, P.C. Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. Mol. Cancer Ther. 2013, 12, 1245–1254. [Google Scholar] [CrossRef][Green Version]
- Joerger, M.; Cassier, P.; Penel, N.; Cathomas, R.; Richly, H.; Schostak, M. Rogaratinib treatment of patients with advanced urothelial carcinomas prescreened for tumor FGFR mRNA expression. J. Clin. Oncol. 2018, 36, 494. [Google Scholar] [CrossRef]
- Rebouissou, S.; Bernard-Pierrot, I.; de Reynies, A.; Lepage, M.L.; Krucker, C.; Chapeaublanc, E.; Herault, A.; Kamoun, A.; Caillault, A.; Letouze, E.; et al. EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci. Transl. Med. 2014, 6, 244ra291. [Google Scholar] [CrossRef]
- Chaux, A.; Cohen, J.S.; Schultz, L.; Albadine, R.; Jadallah, S.; Murphy, K.M.; Sharma, R.; Schoenberg, M.P.; Netto, G.J. High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: A study using formalin-fixed, paraffin-embedded archival tissues. Hum. Pathol. 2012, 43, 1590–1595. [Google Scholar] [CrossRef] [PubMed][Green Version]
- van der Heijden, M.; Powles, T.; Petrylak, D.; de Wit, R.; Chi, K.; Necchi, A.; Drakaki, A. 929P—Biomarker analyses of ramucirumab in patients with platinum refractory urothelial cancer from RANGE, a global, randomized, double-blind, phase III study. Ann. Oncol. 2019, 30, 373–374. [Google Scholar] [CrossRef]
- Tabernero, J. The role of VEGF and EGFR inhibition: Implications for combining anti-VEGF and anti-EGFR agents. Mol. Cancer Res. 2007, 5, 203–220. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Dreicer, R.; Li, H.; Stein, M.; DiPaola, R.; Eleff, M.; Roth, B.J.; Wilding, G. Phase 2 trial of sorafenib in patients with advanced urothelial cancer: A trial of the Eastern Cooperative Oncology Group. Cancer 2009, 115, 4090–4095. [Google Scholar] [CrossRef]
- Necchi, A.; Mariani, L.; Zaffaroni, N.; Schwartz, L.H.; Giannatempo, P.; Crippa, F.; Morosi, C.; Lanocita, R.; Sava, T.; Ortega, C.; et al. Pazopanib in advanced and platinum-resistant urothelial cancer: An open-label, single group, phase 2 trial. Lancet Oncol. 2012, 13, 810–816. [Google Scholar] [CrossRef]
- Rosenberg, J.E.; Ballman, K.V.; Halabi, S.; Watt, C.; Hahn, O.M.; Steen, P.D. CALGB 90601 (Alliance): Randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma. J. Clin. Oncol. 2019, 37, 4503. [Google Scholar] [CrossRef]
- Choueiri, T.K.; Ross, R.W.; Jacobus, S.; Vaishampayan, U.; Yu, E.Y.; Quinn, D.I.; Hahn, N.M.; Hutson, T.E.; Sonpavde, G.; Morrissey, S.C.; 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, 507–512. [Google Scholar] [CrossRef] [PubMed]
- Jimenez, R.E.; Hussain, M.; Bianco, F.J., Jr.; Vaishampayan, U.; Tabazcka, P.; Sakr, W.A.; Pontes, J.E.; Wood, D.P., Jr.; Grignon, D.J. Her-2/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: Prognostic significance and comparative analysis in primary and metastatic tumors. Clin. Cancer Res. 2001, 7, 2440–2447. [Google Scholar] [PubMed]
- Chow, N.H.; Chan, S.H.; Tzai, T.S.; Ho, C.L.; Liu, H.S. Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin. Cancer Res. 2001, 7, 1957–1962. [Google Scholar] [PubMed]
- Fleischmann, A.; Rotzer, D.; Seiler, R.; Studer, U.E.; Thalmann, G.N. Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours. Eur. Urol. 2011, 60, 350–357. [Google Scholar] [CrossRef] [PubMed]
- Zhao, J.; Xu, W.; Zhang, Z.; Song, R.; Zeng, S.; Sun, Y.; Xu, C. Prognostic role of HER2 expression in bladder cancer: A systematic review and meta-analysis. Int. Urol. Nephrol. 2015, 47, 87–94. [Google Scholar] [CrossRef] [PubMed]
- Mejri, N.; Sellami, R.; Lamia, C.; Raoudha, D.; Hmida, N.B.; Sriha, B.; Sihem, H.; Karima, M.; Romdhane, K.B. Status of Her2 over expression in muscle invasive urothelial bladder carcinoma: Report of 21 cases. Urol. Ann. 2014, 6, 63–67. [Google Scholar] [CrossRef]
- Chen, F.; Yin, X.; Wang, Y.; Lv, Y.; Sheng, S.; Ouyang, S.; Zhong, Y. Pharmacokinetics, Tissue Distribution, and Druggability Prediction of the Natural Anticancer Active Compound Cytisine N-Isoflavones Combined with Computer Simulation. Biol. Pharm. Bull. 2020, 43, 976–984. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Mir, C.; Shariat, S.F.; van der Kwast, T.H.; Ashfaq, R.; Lotan, Y.; Evans, A.; Skeldon, S.; Hanna, S.; Vajpeyi, R.; Kuk, C.; et al. Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: A large multi-institutional study. BJU Int. 2011, 108, 24–30. [Google Scholar] [CrossRef]
- Boorjian, S.A.; Heemers, H.V.; Frank, I.; Farmer, S.A.; Schmidt, L.J.; Sebo, T.J.; Tindall, D.J. Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder. Endocr.-Relat. Cancer 2009, 16, 123–137. [Google Scholar] [CrossRef][Green Version]
- Boorjian, S.; Ugras, S.; Mongan, N.P.; Gudas, L.J.; You, X.; Tickoo, S.K.; Scherr, D.S. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology 2004, 64, 383–388. [Google Scholar] [CrossRef]
- Chen, J.; Cui, Y.; Li, P.; Liu, L.; Li, C.; Zu, X. Expression and clinical significance of androgen receptor in bladder cancer: A meta-analysis. Mol. Clin. Oncol. 2017, 7, 919–927. [Google Scholar] [CrossRef][Green Version]
- Gakis, G.; Stenzl, A. Gender-specific differences in muscle-invasive bladder cancer: The concept of sex steroid sensitivity. World J. Urol. 2013, 31, 1059–1064. [Google Scholar] [CrossRef]
- Enzalutamide in Combination with Gemcitabine and Cisplatin in Bladder Cancer. Available online: https://clinicaltrials.gov/ct2/show/NCT02300610 (accessed on 10 April 2021).
- Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. Available online: https://www.urotoday.com/recent-abstracts/urologic-oncology/bladder-cancer/117194-next-generation-sequencing-of-nonmuscle-invasive-bladder-cancer-reveals-potential-biomarkers-and-rational-therapeutic-targets.html (accessed on 24 April 2021).
- ASCO GU 2020: Rucaparib for Recurrent, Locally Advanced, or Metastatic Urothelial Carcinoma (mUC): Results from ATLAS, A Phase II Open-Label Trial. Available online: https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-bladder-cancer/119161-asco-gu-2020-rucaparib-for-recurrent-locally-advanced-or-metastatic-urothelial-carcinoma-muc-results-from-atlas-a-phase-ii-open-label-trial.html (accessed on 24 April 2021).
- A Study to Evaluate Rucaparib in Combination with Other Anticancer Agents in Patients with a Solid Tumor (SEASTAR). Available online: https://clinicaltrials.gov/ct2/show/NCT03992131 (accessed on 24 April 2021).
- Everolimus (RAD001) in Metastatic Transitional Cell Carcinoma of the Urothelium. Available online: https://clinicaltrials.gov/ct2/show/NCT00805129 (accessed on 24 April 2021).
- Sapanisertib in Treating Patients with Locally Advanced or Metastatic Bladder Cancer with TSC1 and/or TSC2 Mutations. Available online: https://clinicaltrials.gov/ct2/show/NCT03047213 (accessed on 24 April 2021).
- ASCO 2020: Study EV-103: New Randomized Cohort Testing Enfortumab Vedotin as Monotherapy or in Combination with Pembrolizumab in Locally Advanced or Metastatic Urothelial Cancer (Trial in Progress). Available online: https://www.urotoday.com/conference-highlights/asco-2020/asco-2020-bladder-cancer/121869-asco-2020-study-ev-103-new-randomized-cohort-testing-edfortumab-vedotin-as-monotherapy-or-in-combination-with-pembrolizumab-in-locally-advanced-or-metastatic-urothelial-cancer-trial-in-progress.html (accessed on 21 June 2021).
- Galsky, M.D.; Necchi, A.; Shore, N.D.; Plimack, E.R. KEYNOTE-905/EV-303: Perioperative pembrolizumab or pembrolizumab plus enfortumab vedotin (EV) and cystectomy compared to cystectomy alone in cisplatin-ineligible patients with muscle-invasive bladder cancer (MIBC). J. Clin. Oncol. 2021, 39, TPS507. [Google Scholar] [CrossRef]
- Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-eligible Muscle Invasive Bladder Cancer (MIBC). Available online: https://clinicaltrials.gov/ct2/show/NCT04700124 (accessed on 21 June 2021).
- Drakaki, A.; Kalebasty, A.R.; Lee, J.L.; Martin-Liberal, J. 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. [Google Scholar] [CrossRef]
- Robertson, A.G.; Kim, J.; Al-Ahmadie, H.; Bellmunt, J.; Guo, G.; Cherniack, A.D.; Hinoue, T.; Laird, P.W.; Hoadley, K.A.; Akbani, R.; et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell 2018, 174, 1033. [Google Scholar] [CrossRef] [PubMed][Green Version]
- EAU Guidelines. Edn. Presented at the EAU Annual Congress Milan 2021. Available online: http://uroweb.org/guidelines/compilations-of-all-guidelines/ (accessed on 21 June 2021).
Medication | CT * [42] | D ± R [43] | Erd ° [44] | EV ∆ [40,41,42] | SG ● [45,46] | ||
---|---|---|---|---|---|---|---|
D + R | D + P | ||||||
Study phase | 4 | 3 | 2 | 1, 2, 3 | 2 | ||
Number of patients (n) | 307 | 263 | 267 | 99 | 155 + 125 + 301 | 45 | |
Median age in years (Range) | 68 (30–88) | 65 (59–72) | 66 (59–72) | 68 (36–87) | 68 (24–86) | 67 (49–90) | |
Sex male, % | 75.6 | 80.9 | 80.5 | 76.8 | 75.2 | 91.1 | |
ECOG = 0, % | 40.4 | 46.0 | 46.8 | 50.5 | 35.5 | 31.0 | |
ECOG ≥ 1, % | 59.6 | 52.9 | 53.2 | 49.5 | 64.5 | 69.0 | |
Sites of metastasis | Visceral, % | 81.7 | 69.2 | 70.4 | 78.8 | 80.2 | 73.3 |
Lung, % | NA | 37.3 | 45.3 | 57.6 | 47.1 ▀ | 60.0 | |
Liver, % | 30.9 | 29.7 | 25.8 | 20.2 | 34.9 | 33.3 | |
Bone, % | NA | 21.3 | 19.9 | 21.2 | NA | NA | |
Lymph nodes only, % | 9.2 | 15.6 | 15.7 | 21.2 | 10.2 | NA | |
Prior therapies before study inclusion | CT platinum base, % | 100.0 | NA | 98 | 87.9 | 99.0 | 95.0 |
CT cisplatinum-base, % | NA | 61.2 | 70.8 | NA | 74.6 ▀ | NA | |
CT carboplatinum-base, % | NA | 36.9 | 28.8 | NA | 37.1 ▀ | NA | |
CPI, % | 100.0 | 6.5 | 10.5 | 22.2 | 92.6 | 38.0 |
Medication | CT * [42] | D ± R [43] | Erd ° [44] | EV ∆ [40,41,42] | SG [45,46] | |
---|---|---|---|---|---|---|
D + R | D + P | |||||
Number of CPI pretreated patients (n) | 296 | 17 | 28 | 22 | 74 + 125 + 288 | 17 |
ORR (%) (95% CI) | 17.9 (13.7; 22.8) | 29.4 | 7.1 | 59.0 | 42.1 (37.8; 46.5) | 23.5 |
CR (%) (95% CI) | 2.7 | 0 | 0 | NA | 8.5 (4.6; 15.1) | NA |
PR (%) (95% CI) | 15.2 | 29.4 | 7.1 | NA | 34.5 (30.4; 38.9) | NA |
SD (%) (95% CI) | 35.5 | 35.3 | 57.1 | NA | 31.3 (27.3; 35.5) | NA |
PD (%) (95% CI) | 28.0 | 17.6 | 25.0 | NA | 16.7 (13.6; 20.3) | NA |
Median DoR in months | 8.1 (5.7; 9.6) | NA | NA | NA | 7.5 ▼,π | NA |
Median PFS in months (95% CI) | 3.7 (3.5; 3.9) | NA | NA | NA | 5.9 (5.4; 6.6) ▼,▯ | NA |
Median OS in months | 9.0 (8.1; 10.7) | NA | NA | NA | 12.8, ▼,± | NA |
Medication | CT * [42] | D ± R [43] | Erd [44] | EV ● [40,41,42] | SG ▼ [45] | |
---|---|---|---|---|---|---|
D + R | D + P | |||||
Number of patients (n) | 291 | 258 | 265 | 99 | 112 + 125 + 296 | 97 |
Treatment related AE, % | 91.8 | 85.7 | 84.2 | NA | 93.8 (91.1–95.8) ▯ | 91.8 |
Treatment related ≥G3 AE, % | 49.8 | 47.7 | 40.8 | 46.0 | 52.3 (47.5–57.0) ▯ | NA |
Fitness | ||||||
Asthenia, % | NA | NA | NA | 20.2 | NA | NA |
≥G3 asthenia, % | NA | NA | NA | 7.1 | NA | NA |
Fatigue, % (95% CI) | 22.7 | 39.1 | 36.2 | 32.3 | 43.9 (29.8–58.9) | 47.4 |
≥G3 fatigue, % (95% CI) | 4.5 | 6.6 | 6.0 | 2.0 | 5.7 (3.9–8.1) | 8.2 |
Skin, hair, nail and mucosa | ||||||
Alopecia, % (95% CI) | 36.4 | 23.6 | 30.6 | 29.3 | 46.3 (42.1–50.6) | 34.0 |
≥G3 alopecia, % | 0 | 0 | 0.4 | 0 | 0 | NA |
Dry mouth, % | NA | NA | NA | 45.5 | NA | NA |
≥G3 dry mouth, % | NA | NA | NA | 0 | NA | NA |
Dry skin, % (95% CI) | NA | NA | NA | 32.3 | 21.9 (17.1–27.7) | NA |
≥G3 dry skin, % | NA | NA | NA | 0 | 0 | NA |
Hand-foot syndrome, % | NA | NA | NA | 23.2 | NA | NA |
≥G3 hand-foot syndrome, % | NA | NA | NA | 5.1 | NA | NA |
Maculopapular rash, % (95% CI) | NA | NA | NA | NA | 20.9 (15.2–27.9) | NA |
≥G3 maculopapular rash, % (95% CI) | NA | NA | NA | NA | 6.0 (4.3–8.5) | NA |
Nail dystrophy, % | NA | NA | NA | 16.2 | NA | NA |
≥G3 nail dystrophy, % | NA | NA | NA | 6.1 | NA | NA |
Pruritus, % (95% CI) | NA | NA | NA | NA | 27.6 (18.7–38.7) | NA |
≥G3 pruritus, % (95% CI) | NA | NA | NA | NA | 1.1 (0.5–2.6) | NA |
Stomatitis, % | NA | 23.3 | 9.1 | 57.6 | NA | NA |
≥G3 stomatitis, % | NA | 3.5 | 0 | 10.1 | NA | NA |
Gastrointestinal and urinary tract | ||||||
Abdominal pain, % | NA | NA | NA | NA | NA | 22.7 |
≥G3 abdominal pain, % | NA | NA | NA | NA | NA | 3.1 |
Constipation, % | NA | NA | NA | 28.3 | NA | 30.9 |
≥G3 constipation, % | NA | NA | NA | 1.0 | NA | 1.0 |
Decreased appetite/anorexia, % (95% CI) | 23.4 | 22.1 | 17.0 | 38.4 | 38.3 (29.6–47.7) | NA |
≥G3 decreased appetite/anorexia, % | 1.7 | 1.6 | 0.4 | 0 | 2.4 (1.3–4.3) | NA |
Diarrhoea, % (95% CI) | NA | 23.6 | 16.6 | 50.5 | 28.1 (24.5–32.1) | 56.7 |
≥G3 diarrhoea, % (95% CI) | NA | 3.1 | 1.1 | 4.0 | 2.9 (1.7–4.8) | 9.3 |
Dysgeusia, % (95% CI) | NA | NA | NA | 37.4 | 33.5 (23.4–45.4) | NA |
≥G3 dysgeusia, % | NA | NA | NA | 1.0 | 0 | NA |
Nausea, % (95% CI) | 21.6 | 22.1 | 14.0 | 20.2 | 32.3 (21.8–45.0) | 57.7 |
≥G3 nausea, % (95% CI) | 1.4 | 0.8 | 0.8 | 1.0 | 1.4 (0.7–3.0) | 2.1 |
UTI, % | NA | NA | NA | 16.2 | NA | NA |
≥G3 UTI, % | NA | NA | NA | 5.1 | NA | NA |
Vomiting, % | NA | NA | NA | NA | NA | 39.2 |
≥G3 vomiting, % | NA | NA | NA | NA | NA | 3.1 |
Laboratory changes | ||||||
Anemia, % | 20.3 | 11.6 | 16.2 | 20.2 | NA | 38.1 |
≥G3 anemia, % | 7.6 | 1.9 | 5.3 | 4.0 | NA | 11.3 |
Hyponatremia, % | NA | NA | NA | 12.1 | NA | NA |
≥G3 hyponatremia, % | NA | NA | NA | 11.1 | NA | NA |
Hyperphosphatemia, % | NA | NA | NA | 76.8 | NA | NA |
≥G3 hyperphosphatemia, % | NA | NA | NA | 2.0 | NA | NA |
Leucopenia, % | NA | NA | NA | NA | NA | NA |
≥G3 leucopenia, % | NA | NA | NA | NA | NA | NA |
White blood cell count decrease, % | 10.7 | 6.6 | 7.5 | NA | NA | 17.5 |
≥G3 White blood cell count decrease, % | 6.9 | 4.3 | 6.4 | NA | NA | 11.3 |
Neutrophil count decrease, % | 16.8 | 11.6 | 10.6 | NA | 10.2 (7.7–13.5) | 53.6 |
≥G3 Neutrophil count decrease, % | 13.4 | 8.9 | 10.2 | NA | 6.7 (4.7–9.5) | 33.0 |
Neutropenia, % | 8.2 | 8.5 | 4.2 | NA | NA | NA |
≥G3 Neutropenia, % | 6.2 | 6.6 | 2.3 | NA | NA | NA |
Neutropenia, febrile, % | 5.5 | 9.3 | 6.0 | NA | NA | NA |
≥G3 neutropenia, febrile, % | 5.5 | 9.3 | 6.0 | NA | NA | 6.2 |
Others | ||||||
PSN, % (95% CI) | 21.3 | NA | NA | NA | 36.1 (32.1–40.2) | NA |
≥G3 PSN, % (95% CI) | 2.1 | NA | NA | NA | 2.5 (1.4–4.3) | NA |
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Deininger, S.; Törzsök, P.; Oswald, D.; Lusuardi, L. Current Systemic Treatment Options in Metastatic Urothelial Carcinoma after Progression on Checkpoint Inhibition Therapy—A Systemic Review Combined with Single-Group Meta-Analysis of Three Studies Testing Enfortumab Vedotin. Cancers 2021, 13, 3206. https://doi.org/10.3390/cancers13133206
Deininger S, Törzsök P, Oswald D, Lusuardi L. Current Systemic Treatment Options in Metastatic Urothelial Carcinoma after Progression on Checkpoint Inhibition Therapy—A Systemic Review Combined with Single-Group Meta-Analysis of Three Studies Testing Enfortumab Vedotin. Cancers. 2021; 13(13):3206. https://doi.org/10.3390/cancers13133206
Chicago/Turabian StyleDeininger, Susanne, Peter Törzsök, David Oswald, and Lukas Lusuardi. 2021. "Current Systemic Treatment Options in Metastatic Urothelial Carcinoma after Progression on Checkpoint Inhibition Therapy—A Systemic Review Combined with Single-Group Meta-Analysis of Three Studies Testing Enfortumab Vedotin" Cancers 13, no. 13: 3206. https://doi.org/10.3390/cancers13133206