Urothelial carcinoma

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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: this page has regimens that are generic to urothelial cancer, primarily in the locally advanced and metastatic settings. 
*See the bladder cancer page for regimens specific to bladder cancer (e.g., perioperative therapy).
*See the upper tract urothelial carcinoma page for regimens specific to UTUC.
Last updated on 2024-12-02:35 regimens on this page
53 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ESMO==
*2024: Powles et al. ESMO Clinical Practice Guideline interim update on first-line therapy in advanced urothelial carcinoma EuroPMC
*2022: Powles et al. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
**2014: Bellmunt et al. Bladder cancer: ESMO Clinical Practice Guidelines EuroPMC
**2011: Bellmunt et al. Bladder cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==NCCN==
*NCCN Guidelines - Bladder Cancer
*2017: Spiess et al. Bladder Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology EuroPMC
*2009: Montie et al. Bladder cancer EuroPMC
==SITC==
*2021: Galsky et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of urothelial cancer link to PMC article EuroPMC
**2017: Kamat et al. Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma EuroPMC
=Adjuvant therapy=
==Nivolumab monotherapy==
===Regimen variant #1, q2wks===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bajorin et al. 2021 (CheckMate 274)	2016-2020 	Phase 3 (E-RT-esc)	Placebo 	Longer DFS1 (co-primary endpoint)Median DFS: 22 vs 10.9 mo(HR 0.71, 95% CI 0.58-0.86)Seems to have longer OS1 (secondary endpoint)Median OS: 69.5 vs 50.1 mo(HR 0.76, 95% CI 0.61-0.96)
1Reported efficacy is based on the 2024 update.
====Preceding treatment====
*CheckMate 274: Radical surgery
====Immunotherapy====
*Nivolumab (Opdivo) 240 mg IV over 30 minutes once on day 1
14-day cycle for up to 26 cycles (1 year)
===Regimen variant #2, q4wks===
FDA-recommended dose
Note: this is not the dose that was used in the registration study, CheckMate 274.
====Preceding treatment====
*CheckMate 274: Radical surgery
====Immunotherapy====
*Nivolumab (Opdivo) 480 mg IV once on day 1
28-day cycle for up to 13 cycles (1 year)
===References===
#CheckMate 274: Bajorin DF, Witjes JA, Gschwend JE, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Ye D, Agerbaek M, Enting D, McDermott R, Gajate P, Peer A, Milowsky MI, Nosov A, Neif Antonio J Jr, Tupikowski K, Toms L, Fischer BS, Qureshi A, Collette S, Unsal-Kacmaz K, Broughton E, Zardavas D, Koon HB, Galsky MD. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021 Jun 3;384(22):2102-2114. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02632409
##HRQoL analysis: Witjes JA, Galsky MD, Gschwend JE, Broughton E, Braverman J, Nasroulah F, Maira-Arce M, Ye X, Shi L, Guo S, Hamilton M, Bajorin DF. Health-related Quality of Life with Adjuvant Nivolumab After Radical Resection for High-risk Muscle-invasive Urothelial Carcinoma: Results from the Phase 3 CheckMate 274 Trial. Eur Urol Oncol. 2022 Oct;5(5):553-563. Epub 2022 Mar 11. link to original article link to PMC article EuroPMC
##Update: Galsky MD, Witjes JA, Gschwend JE, Milowsky MI, Schenker M, Valderrama BP, Tomita Y, Bamias A, Lebret T, Shariat SF, Park SH, Agerbaek M, Jha G, Stenner F, Ye D, Giudici F, Dutta S, Askelson M, Nasroulah F, Zhang J, Brophy L, Bajorin DF. Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274. J Clin Oncol. 2025 Jan;43(1):15-21. Epub 2024 Oct 11. link to original article EuroPMC
#VOLGA: NCT04960709
==Pembrolizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Apolo et al. 2024 (AMBASSADOR)	2017-09-21 to 2021-08-24	Phase 3 (E-esc)	Observation	Longer DFS (co-primary endpoint)Median DFS: 29.6 vs 14.2 mo(HR 0.73, 95% CI 0.59-0.90)
====Preceding treatment====
*Radical surgery
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 18 cycles (1 year)
===References===
# AMBASSADOR: Apolo AB, Ballman KV, Sonpavde G, Berg S, Kim WY, Parikh R, Teo MY, Sweis RF, Geynisman DM, Grivas P, Chatta G, Reichert ZR, Kim JW, Bilen MA, McGregor B, Singh P, Tripathi A, Cole S, Simon N, Niglio S, Ley L, Cordes L, Srinivas S, Huang J, Odegaard M, Watt C, Petrylak D, Hoffman-Censits J, Wen Y, Hahn O, Mitchell C, Tan A, Streicher H, Sharon E, Moon H, Woods M, Halabi S, Perez Burbano G, Morris MJ, Rosenberg JE. Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2025 Jan 2;392(1):45-55. Epub 2024 Sep 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03244384
=Locally advanced or metastatic disease, first-line, platinum-ineligible=
==Gemcitabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Heinzelbecker et al. 2023 (AUO-AB 22/00)	2000-07 to 2008-12 	Phase 3 (C)	Gemcitabine; adjuvant	Did not meet primary endpoint of OS
====Chemotherapy====
*Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
===References===
#AUO-AB 22/00: Heinzelbecker J, Spieler N, Kuehn M, Fischer C, Volkmer B, von Rundstedt F, Albers P, Becht E, Bannowsky A, Weber HM, Hofmann R, Müller M, Langbein S, Steiner G, Retz M, Kamradt J, Wagenpfeil G, Wellek S, Lehmann J, Stoeckle M. Adjuvant vs progression-triggered treatment with gemcitabine in platinum-ineligible high-risk bladder cancer patients: Long-term follow-up of a randomized phase 3 trial. Urol Oncol. 2023 Aug;41(8):356.e19-356.e30. Epub 2023 May 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00146276
==Pembrolizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Balar et al. 2017 (KEYNOTE-052) 	2015-2016 	Phase 2 (RT)	 	ORR: 24% (95% CI 20-29)
Necchi et al. 2024 (ECHO-307) 	2017-12-04 to 2018-05-02	Phase 3 (C) 	Epacadostat & Pembrolizumab	Did not meet primary endpoint of ORRORR: 24.5% vs 31.8%
Matsubara et al. 2023 (LEAP-011)	2019-06-25 to 2021-07-21	Phase 3 (C) 	Lenvatinib & Pembrolizumab 	Did not meet co-primary endpoint of PFSMedian PFS: 4 vs 4.5 mo(HR 1.11, 95% CI 0.88-1.39)Did not meet co-primary endpoint of OSMedian OS: 12.9 vs 11.8 mo(HR 0.88, 95% CI 0.68-1.15)
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
#KEYNOTE-052: Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, Plimack ER, Hahn NM, de Wit R, Pang L, Savage MJ, Perini RF, Keefe SM, Bajorin D, Bellmunt J. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017 Nov;18(11):1483-1492. Epub 2017 Sep 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02335424
##Update: Vuky J, Balar AV, Castellano D, O'Donnell PH, Grivas P, Bellmunt J, Powles T, Bajorin D, Hahn NM, Savage MJ, Fang X, Godwin JL, Frenkl TL, Homet Moreno B, de Wit R, Plimack ER. 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 Aug 10;38(23):2658-2666. Epub 2020 Jun 17. link to original article EuroPMC
##Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article EuroPMC
#ECHO-307: Necchi A, Van der Heijden MS, Trukhin D, Peer A, Gurney H, Alekseev BY, Parnis FX, Leibowitz R, De Santis M, Grivas P, Clark J, Munteanu M, Kataria R, Jia C, Balar AV, de Wit R. Pembrolizumab plus either epacadostat or placebo for cisplatin-ineligible urothelial carcinoma: results from the ECHO-307/KEYNOTE-672 study. BMC Cancer. 2024 Jul 25;23(Suppl 1):1252. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03361865
#LEAP-011: Matsubara N, de Wit R, Balar AV, Siefker-Radtke AO, Zolnierek J, Csoszi T, Shin SJ, Park SH, Atduev V, Gumus M, Su YL, Karaca SB, Cutuli HJ, Sendur MAN, Shen L, O'Hara K, Okpara CE, Franco S, Moreno BH, Grivas P, Loriot Y. 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 Mar;85(3):229-238. Epub 2023 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03898180
=Locally advanced or metastatic disease, first-line, platinum-eligible=
==Carboplatin & Gemcitabine (GCb)==
GCb: Gemcitabine & Carboplatin
===Regimen variant #1, AUC 4.5/1000 x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Powles et al. 2020 (DANUBE)	2015-2017 	Phase 3 (C)	1. Durvalumab 	Did not meet co-primary endpoint of OS 	More toxic
Powles et al. 2020 (DANUBE)	2015-2017 	Phase 3 (C)	2. Durvalumab & Tremelimumab 	Might have shorter OS (co-primary endpoint)Median OS: 12.1 vs 15.1 mo(HR 1.18, 95% CI 0.98-1.39) 	Not more toxic
Powles et al. 2024 (EV-302)	2020-2023 	Phase 3 (C)	Enfortumab vedotin & Pembrolizumab	Shorter PFSMedian PFS: 6.3 vs 12.5 mo(HR 2.22, 95% CI 1.85-2.63)Shorter OSMedian OS: 16.1 vs 31.5 mo(HR 2.13, 95% CI 1.72-2.63)	
An et al. 2024 	2019-02 to 2021-06 	Phase 3 (C)	Gemcitabine & nab-Paclitaxel (GA) 	Did not meet primary endpoint of PFSMedian PFS: 5.9 vs 6.7 mo 	
Note: this was the lower bound of AUC specified by DANUBE & EV-302. An et al. 2024 closed early for slow accrual, being especially impacted by the COVID-19 pandemic.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 4.5 IV over 60 minutes once on day 1, given second
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8, given first
21-day cycle for up to 6 cycles
===Regimen variant #2, AUC 4.5/1000, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
De Santis et al. 2009 (EORTC 30986)	2001-2005 	Randomized Phase 2/3 (E-de-esc)	M-CAVI 	Did not meet primary endpoint of ORR1ORR: 30.3% vs 41.2%	Lower toxicity than M-CAVI
Galsky et al. 2020 (IMvigor130) 	2016-2018 	Phase 3 (C) 	1. Atezolizumab 	Did not meet co-primary endpoint of OS 	
Galsky et al. 2020 (IMvigor130) 	2016-2018 	Phase 3 (C) 	2a. GCb & Atezolizumab2b. GC & Atezolizumab	Might have shorter OS2 	
1Reported efficacy for EORTC 30986 is based on the 2011 update.
2Reported efficacy for IMvigor130 is based on the 2023 update.
Note: Patients in EORTC 30986 who achieved complete response were given two additional cycles of treatment.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 4.5 IV over 60 minutes once on day 1, given second
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8, given first
21-day cycles
===Regimen variant #3, AUC 5/1000 x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Carles et al. 2000 	1997-1998 	Phase 2, fewer than 20 pts	 	
Powles et al. 2020 (DANUBE) 	2015-2017 	Phase 3 (C) 	1. Durvalumab 	Did not meet co-primary endpoint of OS
Powles et al. 2020 (DANUBE) 	2015-2017 	Phase 3 (C) 	2. Durvalumab & Tremelimumab 	Might have shorter OS (co-primary endpoint)Median OS: 12.1 vs 15.1 mo(HR 1.18, 95% CI 0.98-1.39)
Powles et al. 2021 (KEYNOTE-361)	2016-2018 	Phase 3 (C) 	1a. GC & Pembrolizumab1b. GCb & Pembrolizumab	Might have shorter OS (co-primary endpoint)Median OS: 14.3 vs 17 mo(HR 1.16, 95% CI 0.98-1.39)Might have shorter PFS1 (co-primary endpoint)Median PFS: 7.1 vs 8.3 mo(HR 1.28, 95% CI 1.08-1.54)
Powles et al. 2021 (KEYNOTE-361)	2016-2018 	Phase 3 (C) 	2. Pembrolizumab 	Not reported
Powles et al. 2024 (EV-302) 	2020-2023 	Phase 3 (C) 	Enfortumab vedotin & Pembrolizumab 	Shorter PFSMedian PFS: 6.3 vs 12.5 mo(HR 2.22, 95% CI 1.85-2.63)Shorter OSMedian OS: 16.1 vs 31.5 mo(HR 2.13, 95% CI 1.72-2.63)
1Reported efficacy did not meet the prespecified boundary for statistical significance.
Note: this was the upper bound of AUC specified by DANUBE & EV-302.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 6 cycles
===Regimen variant #4, AUC 5/1250===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy	Comparative Toxicity
Dogliotti et al. 2006	2000-2002 	Randomized Phase 2 (E-switch-ic)	Cisplatin & Gemcitabine	 	Did not meet primary endpoint of reduced toxicity
ORR for this arm: Intention to treat: 40% (95% CI NR)Evaluable patients only: 56%(95% CI: 40–72)
ORR for control arm: Intention to treat: 49% (95% CI NR)Evaluable patients only: 66%(95% CI: 49–80)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV over 30 to 60 minutes once on day 2
*Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
21-day cycle for up to 6 cycles
===References===
#Carles J, Nogué M, Domènech M, Pérez C, Saigí E, Villadiego K, Guasch I, Ibeas R. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000 Jun;59(1):24-7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EORTC 30986: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Skoneczna I, Marreaud S, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol. 2009 Nov 20;27(33):5634-9. Epub 2009 Sep 28. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00111787
##Update: De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012 Jan 10;30(2):191-9. Epub 2011 Dec 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
#IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02807636
##Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article EuroPMC
#DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. link to original article EuroPMC NCT02516241
#KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02853305
#EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04223856
#An X, Xue C, Chen M, Ni M, Ma H, Tian L, Huang R, Li X, Ye Y, Qin T, Dong P, Li Z, Peng J, Yao K, Zhou F, Liu Z, Shi Y. Gemcitabine/nab-paclitaxel vs gemcitabine/carboplatin for advanced urothelial carcinoma. BJU Int. 2024 Jul;134(1):63-71. Epub 2024 Feb 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR1900022615
#NILE: NCT03682068
#RC48-C016: NCT05302284
==Carboplatin & Gemcitabine (GCb) & Pembrolizumab==
GCb & Pembrolizumab: Gemcitabine, Carboplatin, Pembrolizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Powles et al. 2021 (KEYNOTE-361)	2016-2018 	Phase 3 (E-RT-esc)	1a. GC1b. GCb 	Might have longer OS (co-primary endpoint)Median OS: 17 vs 14.3 mo(HR 0.86, 95% CI 0.72-1.02)Might have longer PFS1 (co-primary endpoint)Median PFS: 8.3 vs 7.1 mo(HR 0.78, 95% CI 0.65-0.93)
Powles et al. 2021 (KEYNOTE-361)	2016-2018 	Phase 3 (E-RT-esc)	2. Pembrolizumab	Not reported
1Reported efficacy did not meet the prespecified boundary for statistical significance.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 up to 6: AUC 5 IV once on day 1
*Gemcitabine (Gemzar) as follows:
**Cycles 1 up to 6: 1000 mg/m2 IV once per day on days 1 & 8
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===References===
#KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02853305
==Carboplatin & Paclitaxel (CP)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Vaughn et al. 2002 (ECOG E2896) 	1996-1999 	Phase 2 	 	ORR: 24% (95% CI 12-42)
Dreicer et al. 2004 (ECOG E4897)	1998-2001 	Phase 3 (E-de-esc)	MVAC 	Did not meet primary endpoint of OS
Note: ECOG E4897 was closed early due to poor accrual.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
===References===
#ECOG E2896: Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G. Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer. 2002 Sep 1;95(5):1022-7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#ECOG E4897: Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003376
==Cisplatin & Gemcitabine (GC)==
GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)
===Regimen variant #1, 70/2000; q3wk x 6===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rosenberg et al. 2021 (CALGB 90601) 	2009-2014 	Phase 3 (C)	GC & Bevacizumab 	Might have shorter OSMedian OS: 14.3 vs 14.5 mo(HR 1.15, 95% CI 0.95-1.39)
Powles et al. 2020 (DANUBE) 	2015-2017 	Phase 3 (C)	1. Durvalumab 	Did not meet co-primary endpoint of OS
Powles et al. 2020 (DANUBE) 	2015-2017 	Phase 3 (C)	2. Durvalumab & Tremelimumab 	Might have shorter OS (co-primary endpoint)Median OS: 12.1 vs 15.1 mo(HR 1.18, 95% CI 0.98-1.39)
Powles et al. 2021 (KEYNOTE-361) 	2016-2018 	Phase 3 (C)	1a. GC & Pembrolizumab1b. GCb & Pembrolizumab	Might have shorter OS (co-primary endpoint)Median OS: 14.3 vs 17 mo(HR 1.16, 95% CI 0.98-1.39)Might have shorter PFS1 (co-primary endpoint)Median PFS: 7.1 vs 8.3 mo(HR 1.28, 95% CI 1.08-1.54)
Powles et al. 2021 (KEYNOTE-361) 	2016-2018 	Phase 3 (C)	2. Pembrolizumab 	Not reported
van der Heijden et al. 2023 (CheckMate 901 part 1)	2018-01-30 to 2022-09-28	Phase 3 (C)	GC & Nivolumab 	Seems to have shorter OS (co-primary endpoint)
Powles et al. 2024 (EV-302) 	2020-2023 	Phase 3 (C)	Enfortumab vedotin & Pembrolizumab 	Shorter PFSMedian PFS: 6.3 vs 12.5 mo(HR 2.22, 95% CI 1.85-2.63)Shorter OSMedian OS: 16.1 vs 31.5 mo(HR 2.13, 95% CI 1.72-2.63)
1Reported efficacy did not meet the prespecified boundary for statistical significance.
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV over 30 to 60 minutes once on day 1
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
====Supportive therapy====
*2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
21-day cycle for 6 cycles
===Regimen variant #2, 70/2000; q3wk, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Soto Parra et al. 2002 	1998-2000 	Randomized Phase 2, fewer than 20 pts in this subgroup (E-esc)	Cisplatin & Gemcitabine; q4wk 	Not reported
Galsky et al. 2020 (IMvigor130)	2016-2018 	Phase 3 (C) 	1. Atezolizumab 	Did not meet co-primary endpoint of OS
Galsky et al. 2020 (IMvigor130)	2016-2018 	Phase 3 (C) 	2a. GCb & Atezolizumab2b. GC & Atezolizumab	Might have shorter OS1
1Reported efficacy for IMvigor130 is based on the 2023 update.
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV over 30 to 60 minutes once on day 1 or 2
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
====Supportive therapy====
*2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
21-day cycles
===Regimen variant #3, 70/2500; q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Dogliotti et al. 2006 	2000-2002 	Randomized Phase 2 (C)	Carboplatin & Gemcitabine 	 	Did not meet primary endpoint of reduced toxicity
Powles et al. 2020 (DANUBE)	2015-2017 	Phase 3 (C) 	1. Durvalumab 	Did not meet co-primary endpoint of OS 	More toxic
Powles et al. 2020 (DANUBE)	2015-2017 	Phase 3 (C) 	2. Durvalumab & Tremelimumab	Might have shorter OS (co-primary endpoint)Median OS: 12.1 vs 15.1 mo(HR 1.18, 95% CI 0.98-1.39)	Not more toxic
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV once on day 1 or 2
*Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
21-day cycle for up to 6 cycles
===Regimen variant #4, 70/3000; q4wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
von der Maase et al. 2000 	1996-1998 	Phase 3 (E-de-esc) 	MVAC 	Did not meet primary endpoint of OS
Soto Parra et al. 2002 	1998-2000 	Randomized Phase 2, fewer than 20 pts in this subgroup (E-de-esc)	Cisplatin & Gemcitabine; q3wk	Not reported
Bellmunt et al. 2012 (EORTC 30987)	2001-2004 	Phase 3 (C) 	PCG 	Might have shorter OSMedian OS: 12.7 vs 15.8 mo(HR 1.18, 95% CI 0.98-1.39)
Sternberg et al. 2013 (CILAB) 	2008-2010 	Phase 3 (C) 	Cisplatin & Larotaxel 	Did not meet primary endpoint of OS
Powles et al. 2020 (DANUBE) 	2015-2017 	Phase 3 (C) 	1. Durvalumab 	Did not meet co-primary endpoint of OS
Powles et al. 2020 (DANUBE) 	2015-2017 	Phase 3 (C) 	2. Durvalumab & Tremelimumab 	Might have shorter OS (co-primary endpoint)Median OS: 12.1 vs 15.1 mo(HR 1.18, 95% CI 0.98-1.39)
Note: Only a minority of patients in Soto Parra et al. 2002 had bladder cancer. The majority of patients had non-small cell lung cancer.
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV over 30 to 60 minutes once on day 2
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 to 60 minutes once per day on days 1, 8, 15
====Supportive therapy====
*Per Soto Parra et al. 2002:
*2 liters of fluid and "appropriate antiemetic therapy" given with cisplatin
*"blood-product transfusion and the administration of antibiotics, antiemetics and analgesics, as appropriate"
28-day cycle for up to 6 cycles
===References===
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. 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 Sep;18(17):3068-77. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article EuroPMC
#Soto Parra H, Cavina R, Latteri F, Sala A, Dambrosio M, Antonelli G, Morenghi E, Alloisio M, Ravasi G, Santoro A. Three-week versus four-week schedule of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol. 2002 Jul;13(7):1080-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007 Jul;52(1):134-41. Epub 2006 Dec 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00022191
#CILAB: Sternberg CN, Skoneczna IA, Castellano D, Theodore C, Blais N, Voog E, Bellmunt J, Peters F, Le-Guennec S, Cerbone L, Risse ML, Machiels JP. Larotaxel with cisplatin in the first-line treatment of locally advanced/metastatic urothelial tract or bladder cancer: a randomized, active-controlled, phase III trial (CILAB). Oncology. 2013;85(4):208-15. Epub 2013 Sep 24. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00625664
#IMvigor130: Galsky MD, Arranz Arija JÁ, Bamias A, Davis ID, De Santis M, Kikuchi E, Garcia-Del-Muro X, De Giorgi U, Mencinger M, Izumi K, Panni S, Gumus M, Özgüroğlu M, Kalebasty AR, Park SH, Alekseev B, Schutz FA, Li JR, Ye D, Vogelzang NJ, Bernhard S, Tayama D, Mariathasan S, Mecke A, Thåström A, Grande E; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02807636
##Update: Grande E, Arranz JÁ, De Santis M, Bamias A, Kikuchi E, Del Muro XG, Park SH, De Giorgi U, Alekseev B, Mencinger M, Izumi K, Schutz FA, Puente J, Li JR, O'Donnell PH, Kalebasty AR, Ye D, Mariathasan S, Bene-Tchaleu F, Bernhard S, Lee C, Davis ID, Galsky MD. Atezolizumab plus chemotherapy versus placebo plus chemotherapy in untreated locally advanced or metastatic urothelial carcinoma (IMvigor130): final overall survival analysis results from a randomised, controlled, phase 3 study. Lancet Oncol. 2024 Jan;25(1):29-45. Epub 2023 Dec 12. link to original article EuroPMC
#DANUBE: Powles T, van der Heijden MS, Castellano D, Galsky MD, Loriot Y, Petrylak DP, Ogawa O, Park SH, Lee JL, De Giorgi U, Bögemann M, Bamias A, Eigl BJ, Gurney H, Mukherjee SD, Fradet Y, Skoneczna I, Tsiatas M, Novikov A, Suárez C, Fay AP, Duran I, Necchi A, Wildsmith S, He P, Angra N, Gupta AK, Levin W, Bellmunt J; DANUBE study investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1574-1588. Epub 2020 Sep 21. link to original article EuroPMC NCT02516241
#KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02853305
#CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. 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 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00942331
#CheckMate 901 part 1: van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03036098
#EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04223856
#NILE: NCT03682068
#RC48-C016: NCT05302284
==Cisplatin & Gemcitabine (GC) & Bevacizumab==
GCB: Gemcitabine, Cisplatin, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rosenberg et al. 2021 (CALGB 90601)	2009-2014 	Phase 3 (E-esc)	GC 	Might have longer OS (primary endpoint)Median OS: 14.5 vs 14.3 mo(HR 0.87, 95% CI 0.72-1.05)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 70 mg/m2 IV over 30 to 60 minutes once on day 1 or 2
*Gemcitabine (Gemzar) as follows:
**Cycles 1 to 6: 1000 mg/m2 IV once per day on days 1 & 8
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
#CALGB 90601: Rosenberg JE, Ballman KA, Halabi S, Atherton PJ, Mortazavi A, Sweeney C, Stadler WM, Teply BA, Picus J, Tagawa ST, Katragadda S, Vaena D, Misleh J, Hoimes C, Plimack ER, Flaig TW, Dreicer R, Bajorin D, Hahn O, Small EJ, Morris MJ. 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 Aug 1;39(22):2486-2496. Epub 2021 May 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00942331
==Cisplatin & Gemcitabine (GC) & Nivolumab==
GC & Nivolumab: Gemcitabine, Cisplatin, Nivolumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
van der Heijden et al. 2023 (CheckMate 901 part 1)	2018-01-30 to 2022-09-28	Phase 3 (E-RT-esc)	GC x 6 	Seems to have longer OS (co-primary endpoint)Median OS: 21.7 vs 18.9 mo(HR 0.78, 95% CI 0.63-0.96)Longer PFS (co-primary endpoint)Median PFS: 7.9 vs 7.6 mo(HR 0.72, 95% CI 0.59-0.88)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 70 mg/m2 IV once on day 1
*Gemcitabine (Gemzar) as follows:
**Cycles 1 to 6: 1000 mg/m2 IV once per day on days 1 & 8
====Immunotherapy====
*Nivolumab (Opdivo) as follows:
**Cycles 1 to 6: 360 mg IV once on day 1
**Cycle 7 up to 28: 480 mg IV once on day 1
21-day cycle for 6 cycles, then 28-day cycle for up to 22 cycles (2 years)
===References===
#CheckMate 901 part 1: van der Heijden MS, Sonpavde G, Powles T, Necchi A, Burotto M, Schenker M, Sade JP, Bamias A, Beuzeboc P, Bedke J, Oldenburg J, Chatta G, Ürün Y, Ye D, He Z, Valderrama BP, Ku JH, Tomita Y, Filian J, Wang L, Purcea D, Patel MY, Nasroulah F, Galsky MD; CheckMate 901 Trial Investigators. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789. Epub 2023 Oct 22. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03036098
==Cisplatin & Gemcitabine (GC) & Pembrolizumab==
GC & Pembrolizumab: Gemcitabine, Cisplatin, Pembrolizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Powles et al. 2021 (KEYNOTE-361)	2016-2018 	Phase 3 (E-RT-esc)	1a. GC1b. GCb 	Might have longer OS (co-primary endpoint)Median OS: 17 vs 14.3 mo(HR 0.86, 95% CI 0.72-1.02)Might have longer PFS1 (co-primary endpoint)Median PFS: 8.3 vs 7.1 mo(HR 0.78, 95% CI 0.65-0.93)
Powles et al. 2021 (KEYNOTE-361)	2016-2018 	Phase 3 (E-RT-esc)	2. Pembrolizumab	Not reported
1Reported efficacy did not meet the prespecified boundary for statistical significance.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 up to 6: 70 mg/m2 IV once on day 1
*Gemcitabine (Gemzar) as follows:
**Cycles 1 up to 6: 1000 mg/m2 IV once per day on days 1 & 8
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
#KEYNOTE-361: Powles T, Csőszi T, Özgüroğlu M, Matsubara N, Géczi L, Cheng SY, Fradet Y, Oudard S, Vulsteke C, Morales Barrera R, Fléchon A, Gunduz S, Loriot Y, Rodriguez-Vida A, Mamtani R, Yu EY, Nam K, Imai K, Homet Moreno B, Alva A; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jul;22(7):931-945. Epub 2021 May 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02853305
==Enfortumab vedotin & Pembrolizumab==
===Regimen variant #1, q3wk pembrolizumab===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Powles et al. 2024 (EV-302)	2020-2023 	Phase 3 (E-RT-switch-ooc)	1a. GC1b. GCb	Longer OS (co-primary endpoint)Median OS: 31.5 vs 16.1 mo(HR 0.47, 95% CI 0.38-0.58)Longer PFS (co-primary endpoint)Median PFS: 12.5 vs 6.3 mo(HR 0.45, 95% CI 0.38-0.54)
====Antibody-drug conjugate therapy====
*Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1 & 8
====Immunotherapy====
*Pembrolizumab (Keytruda) as follows:
**Cycles 1 to 35: 200 mg IV once on day 1
21-day cycles
===Regimen variant #2, q6wk pembrolizumab===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Powles et al. 2024 (EV-302)	2020-2023 	Phase 3 (E-RT-switch-ooc)	1a. GC1b. GCb	Longer OS (co-primary endpoint)Median OS: 31.5 vs 16.1 mo(HR 0.47, 95% CI 0.38-0.58)Longer PFS (co-primary endpoint)Median PFS: 12.5 vs 6.3 mo(HR 0.45, 95% CI 0.38-0.54)
Note: Dosing is as described in the FDA approval announcement; this dosing was not reported in Powles et al. 2024.
====Antibody-drug conjugate therapy====
*Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 22, 29
====Immunotherapy====
*Pembrolizumab (Keytruda) as follows:
**Cycles 1 to 17: 200 mg IV once on day 1
42-day cycles
===References===
#EV-302: Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, Iyer G, Vulsteke C, Park SH, Shin SJ, Castellano D, Fornarini G, Li JR, Gümüş M, Mar N, Loriot Y, Fléchon A, Duran I, Drakaki A, Narayanan S, Yu X, Gorla S, Homet Moreno B, van der Heijden MS; EV-302 Trial Investigators. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10):875-888. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04223856
==Gemcitabine & Paclitaxel==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence	Efficacy
Calabrò et al. 2009	2003-2005 	Phase 2 	ORR: 37%
====Chemotherapy====
*Gemcitabine (Gemzar) 2500 mg/m2 IV over 30 minutes once on day 1, given second
*Paclitaxel (Taxol) 150 mg/m2 IV over 3 hours once on day 1, given first
14-day cycle for 6 to 12 cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence	Efficacy
Meluch et al. 2001	1997-1999 	Phase 2 	ORR: 54% (95% CI 40-67)
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
*Paclitaxel (Taxol) 200 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Calabrò F, Lorusso V, Rosati G, Manzione L, Frassineti L, Sava T, Di Paula ED, Alonso S, Sternberg CN. Gemcitabine and paclitaxel every 2 weeks in patients with previously untreated urothelial carcinoma. Cancer. 2009 Jun 15;115(12):2652-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==MVAC==
MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin
===Regimen variant #1, standard===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Loehrer et al. 1992 (ECOG E5886) 	1984-1989 	Phase 3 (E-esc) 	Cisplatin 	Longer OS
Logothetis et al. 1990 	1985-1989 	Phase 3 (E-switch-ic)	CISCA 	Longer OS
Siefker-Radtke et al. 2002 	1992-1999 	Phase 3 (C) 	FAP 	Did not meet primary endpoint of OS50%
Sternberg et al. 2001 (EORTC 30924)	1993-1998 	Phase 3 (C) 	Dose-dense MVAC	Seems to have shorter OS1Median OS: 14.9 vs 15.1 mo(HR 1.32, 95% CI 1.01-1.72)
von der Maase et al. 2000 	1996-1998 	Phase 3 (C) 	GC 	Did not meet primary endpoint of OS
Dreicer et al. 2004 (ECOG E4897) 	1998-2001 	Phase 3 (C) 	CP 	Did not meet primary endpoint of OS
1Reported efficacy for EORTC 30924 is based on the 2005 update.
====Chemotherapy====
*Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
*Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
*Cisplatin (Platinol) 70 mg/m2 IV once over 120 minutes on day 1 or 2
28-day cycles (number of cycles and criteria to continue therapy varies depending on reference)
===Regimen variant #2, with G-CSF support===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bamias et al. 2003	1997-2002 	Phase 3 (C)	Cisplatin & Docetaxel	Longer OS (primary endpoint)Median OS: 14.2 vs 9.3 mo(HR 0.66, 95% CI 0.48-0.90)
====Chemotherapy====
*Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
*Vinblastine (Velban) 3 mg/m2 IV once per day on days 1, 15, 22
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
*Cisplatin (Platinol) 70 mg/m2 IV over 60 minutes once on day 1
====Supportive therapy====
*Filgrastim (Neupogen) (dose not specified) SC once per day on days 7, 8, 9, 25, 26
28-day cycles
===References===
#Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, Kilbourn RG. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol. 1990 Jun;8(6):1050-5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#ECOG E5886: Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, Raghavan D, Stuart-Harris R, Sarosdy MF, Lowe BA, Blumenstein B, Trump D. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1992 Jul;10(7):1066-73. Erratum in: J Clin Oncol 1993 Feb;11(2):384. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, Loehrer PJ Sr, Trump D. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol. 1997 Jul;15(7):2564-9. link to original article EuroPMC
#von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, Bodrogi I, Albers P, Knuth A, Lippert CM, Kerbrat P, Sanchez Rovira P, Wersall P, Cleall SP, Roychowdhury DF, Tomlin I, Visseren-Grul CM, Conte PF. 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 Sep;18(17):3068-77. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005 Jul 20;23(21):4602-8. link to original article EuroPMC
#EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; EORTC Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002 Mar 1;20(5):1361-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Bamias A, Aravantinos G, Deliveliotis C, Bafaloukos D, Kalofonos C, Xiros N, Zervas A, Mitropoulos D, Samantas E, Pectasides D, Papakostas P, Gika D, Kourousis C, Koutras A, Papadimitriou C, Bamias C, Kosmidis P, Dimopoulos MA; Hellenic Cooperative Oncology Group. Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jan 15;22(2):220-8. Epub 2003 Dec 9. Erratum in: J Clin Oncol. 2004 May 1;22(9):1771. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#ECOG E4897: Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G; ECOG. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004 Apr 15;100(8):1639-45. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003376
==MVAC, dose-dense==
ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin, Cisplatin
===Regimen variant #1, limited duration===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bamias et al. 2012 (HE 16/03)	2003-2008 	Phase 3 (C)	DD-GC 	Did not meet primary endpoint of OSMedian OS: 19 vs 18 mo
====Chemotherapy====
*Methotrexate (MTX) 30 mg/m2 IV once on day 1
*Vinblastine (Velban) 3 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
*Cisplatin (Platinol) 70 mg/m2 IV once on day 1
====Supportive therapy====
*G-CSF (type/route/schedule not specified) on days 5 to 9
14-day cycle for 6 to 12 cycles
===Regimen variant #2, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Sternberg et al. 2001 (EORTC 30924)	1993-1998 	Phase 3 (E-esc)	MVAC 	Seems to have longer OS1 (primary endpoint)Median OS: 15.1 vs 14.9 mo(HR 0.76, 95% CI 0.58-0.99)
1Reported efficacy is based on the 2005 update.
Note: In contrast to Sternberg et al. 2001, Sternberg et al. 2006 specified 15-day cycles. ORR for this arm of EORTC 30924 was 62% (95% CI 54-70) versus 50% (95% CI 42-59) in the control arm.
====Chemotherapy====
*Methotrexate (MTX) 30 mg/m2 IV once on day 1
*Vinblastine (Velban) 3 mg/m2 IV once on day 2
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
*Cisplatin (Platinol) 70 mg/m2 IV once on day 2
====Supportive therapy====
*G-CSF (type not specified) 240 mcg/m2 SC once per day on days 4 to 10 (additional use up to a total of 14 consecutive days if needed), injected at alternating sites, discontinued if ANC greater than 30,000/μL.
**In contrast to Sternberg et al. 2001, Sternberg et al. 2006 said G-CSF was given on days 3 to 7.
14-day cycles
===References===
#EORTC 30924: Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, Witjes F, Spina M, van Groeningen CJ, de Balincourt C, Collette L; EORTC Genitourinary Tract Cancer Cooperative Group. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organisation for Research and Treatment of Cancer Protocol no 30924. J Clin Oncol. 2001 May 15;19(10):2638-46. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L; EORTC Genito-Urinary Cancer Group. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006 Jan;42(1):50-4. Epub 2005 Dec 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#HE 16/03: Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, Xanthakis I, Tsiatas M, Koutoulidis V, Constantinidis C, Hatzimouratidis C, Samantas E, Visvikis A, Chrisophos M, Stravodimos K, Deliveliotis C, Eleftheraki A, Pectasides D, Fountzilas G, Dimopoulos MA; Hellenic Cooperative Oncology Group. Prospective, open-label, randomized, phase III study of two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol. 2013 Apr;24(4):1011-7. Epub 2012 Nov 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ACTRN12610000845033
==PGC==
PGC: Paclitaxel, Gemcitabine, Cisplatin
PCG: Paclitaxel, Cisplatin, Gemcitabine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bellmunt et al. 2012 (EORTC 30987)	2001-2004 	Phase 3 (E-esc)	Cisplatin & Gemcitabine	Might have longer OS (primary endpoint)Median OS: 15.8 vs 12.7 mo(HR 0.85, 95% CI 0.72-1.02)
Note: ORR for this arm of EORTC 30987 was 56% vs 44% in the control arm.
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV once on day 1
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8, given first
21-day cycle for up to 6 cycles
===References===
#EORTC 30987: Bellmunt J, von der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G, Boehle A, Chevreau C, Paz-Ares L, Laufman LR, Winquist E, Raghavan D, Marreaud S, Collette S, Sylvester R, de Wit R. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup study 30987. J Clin Oncol. 2012 Apr 1;30(10):1107-13. Epub 2012 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00022191
=Locally advanced or metastatic disease, maintenance after platinum chemotherapy=
==Avelumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Powles et al. 2020 (JAVELIN Bladder 100)	2016-2019 	Phase 3 (E-RT-esc)	Best supportive care	Longer OS1 (primary endpoint)Median OS: 23.8 vs 15 mo(HR 0.76, 95% CI 0.63-0.91)	More toxic
1Reported efficacy is based on the 2023 update.
====Preceding treatment====
*First-line GC x 4 to 6 or GCb x 4 to 6
====Immunotherapy====
*Avelumab (Bavencio) 10 mg/kg IV over 60 minutes once per day on days 1 & 15
====Supportive therapy====
Premedication with a histamine H1 receptor (H1) blocker and acetaminophen approximately 30 to 60 minutes prior to each dose of avelumab for the first 4 doses; for example:
*Diphenhydramine (Benadryl) 25 to 50 mg IV or PO equivalent
*Acetaminophen (Tylenol) 500 to 650 mg IV or PO equivalent
28-day cycles
===References===
#JAVELIN Bladder 100: Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulović S, Demey W, Ullén A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. Epub 2020 Sep 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02603432
##PRO analysis: Grivas P, Kopyltsov E, Su PJ, Parnis FX, Park SH, Yamamoto Y, Fong PC, Tournigand C, Climent Duran MA, Bamias A, Caserta C, Chang J, Cislo P, di Pietro A, Wang J, Powles T. Patient-reported Outcomes from JAVELIN Bladder 100: Avelumab First-line Maintenance Plus Best Supportive Care Versus Best Supportive Care Alone for Advanced Urothelial Carcinoma. Eur Urol. 2023 Apr;83(4):320-328. Epub 2022 May 30. link to original article EuroPMC
##Update: Powles T, Park SH, Caserta C, Valderrama BP, Gurney H, Ullén A, Loriot Y, Sridhar SS, Sternberg CN, Bellmunt J, Aragon-Ching JB, Wang J, Huang B, Laliberte RJ, di Pietro A, Grivas P. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023 Jul 1;41(19):3486-3492. Epub 2023 Apr 18. link to original article link to PMC article EuroPMC
#MAIN-CAV: NCT05092958
==Pembrolizumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Galsky et al. 2020 (HCRN GU14-182)	2015-2018 	Randomized Phase 2 (E-esc)	Placebo 	Seems to have longer PFS (primary endpoint)Median PFS: 5.4 vs 3 mo(HR 0.65, 95% CI 0.43-0.97)	More toxic
====Preceding treatment====
*First-line platinum-based combination chemotherapy for up to 8 cycles, without progression of disease
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
#HCRN GU14-182: Galsky MD, Mortazavi A, Milowsky MI, George S, Gupta S, Fleming MT, Dang LH, Geynisman DM, Walling R, Alter RS, Kassar M, Wang J, Gupta S, Davis N, Picus J, Philips G, Quinn DI, Haines GK 3rd, Hahn NM, Zhao Q, Yu M, Pal SK. Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer. J Clin Oncol. 2020 Jun 1;38(16):1797-1806. Epub 2020 Apr 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02500121
=Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy=
==Avelumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Apolo et al. 2017 (JAVELIN Solid Tumor)	2014-2016 	Phase 1b (RT)	ORR: 17% (95% CI 11-24)1
1Reported efficacy is based on the 2017 update.
====Immunotherapy====
*Avelumab (Bavencio) 10 mg/kg IV over 60 minutes once on day 1
====Supportive therapy====
Per Apolo et al. 2017:
*"All patients were premedicated with an antihistamine and acetaminophen (doses and routes not given)
*The avelumab package insert suggests "Premedicate with acetaminophen and an antihistamine for the first 4 infusions and subsequently as needed."
14-day cycles
===References===
#JAVELIN Solid Tumor: Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, Safran H, Stinchcombe TE, Srdanov M, Gelb AB, Schlichting M, Chin K, Gulley JL. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from a multicenter, phase Ib study. J Clin Oncol. 2017 Jul 1;35(19):2117-2124. Epub 2017 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01772004
##Update: Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, Britten CD, Dirix L, Lee KW, Taylor M, Schöffski P, Wang D, Ravaud A, Gelb AB, Xiong J, Rosen G, Gulley JL, Apolo AB. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018 Jan;19(1):51-64. Epub 2017 Dec 5. Erratum in: Lancet Oncol. 2018 Jul;19(7):e335. link to original article link to PMC article EuroPMC
==Docetaxel monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
McCaffrey et al. 1997 	1993-1995 	Phase 2 	 	
Choueiri et al. 2011 (DFCI 06-116)	2007-2010 	Phase 3 (C) 	Docetaxel & Vandetanib 	Did not meet primary endpoint of PFSMedian PFS: 1.58 vs 2.56 mo(HR 0.98, 95% CI 0.67-1.45)
Petrylak et al. 2016 (JCDC) 	2011-2014 	Randomized Phase 2 (C)	1. Docetaxel & Icrucumab 	Did not meet primary endpoint of PFS
Petrylak et al. 2016 (JCDC) 	2011-2014 	Randomized Phase 2 (C)	2. Docetaxel & Ramucirumab	Shorter PFS (primary endpoint)Median PFS: 2.8 vs 5.4 mo(sHR 2.56, 95% CI 1.56-4.26)
Bellmunt et al. 2017 (KEYNOTE-045)	2014-11-05 to 2015-11-13 	Phase 3 (C) 	Pembrolizumab 	Shorter OSMedian OS: 7 vs 10 mo(HR 1.37, 95% CI 1.10-1.69)
Powles et al. 2017 (IMvigor211) 	2015-01-13 to 2016-02-15 	Phase 3 (C) 	Atezolizumab 	Shorter OS1 (primary endpoint)OS30: 10% vs 18%(HR 1.22, 95% CI 1.06-1.41)
Petrylak et al. 2017 (RANGE) 	2015-2017 	Phase 3 (C) 	Docetaxel & Ramucirumab 	Shorter PFS2 (primary endpoint)Median PFS: 2.8 vs 4.1 mo(HR 1.43, 95% CI 1.18-1.75)
Powles et al. 2021 (EV-301) 	2018-2020 	Phase 3 (C) 	Enfortumab vedotin 	Shorter OS3Median OS: 8.94 vs 12.91 mo(HR 1.43, 95% CI 1.18-1.72)
Loriot et al. 2023 (THOR cohort 1)	2018-08-06 to not reported	Phase 3 (C) 	Erdafitinib 	Shorter OSMedian OS: 7.8 vs 12.1 mo(HR 1.56, 95% CI 1.14-2.13)
1Reported efficacy for IMvigor211 is based on the 2021 update.
2Reported efficacy for RANGE is based on the 2019 update.
3Reported efficacy for EV-301 is based on the 2023 update.
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.
====Biomarker eligibility criteria====
*THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations
====Prior treatment criteria====
*KEYNOTE-045: Exposure to platinum-based chemotherapy
*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
*THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
#McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7. link to original article EuroPMC
#DFCI 06-116: Choueiri TK, Ross RW, Jacobus S, Vaishampayan U, Yu EY, Quinn DI, Hahn NM, Hutson TE, Sonpavde G, Morrissey SC, Buckle GC, Kim WY, Petrylak DP, Ryan CW, Eisenberger MA, Mortazavi A, Bubley GJ, Taplin ME, Rosenberg JE, Kantoff PW. Double-blind, randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic urothelial cancer. J Clin Oncol. 2012 Feb 10;30(5):507-12. Epub 2011 Dec 19. link to original article link to PMC article EuroPMC NCT00880334
#JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. 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 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01282463
#KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02256436
##HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article EuroPMC
##Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article EuroPMC
##Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article EuroPMC
#RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. 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 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02426125
##Update: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. 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 Jan;21(1):105-120. Epub 2019 Nov 18. link to original article link to PMC article EuroPMC
##HRQoL analysis: Necchi A, Nishiyama H, Matsubara N, Lee JL, Petrylak DP, de Wit R, Drakaki A, Liepa AM, Mao H, Bell-McGuinn K, Powles T. Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE). BMC Urol. 2020 Nov 7;20(1):181. link to original article link to PMC article EuroPMC
#IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. 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 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02302807
##Update: van der Heijden MS, Loriot Y, Durán I, Ravaud A, Retz M, Vogelzang NJ, Nelson B, Wang J, Shen X, Powles T. Atezolizumab Versus Chemotherapy in Patients with Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: A Long-term Overall Survival and Safety Update from the Phase 3 IMvigor211 Clinical Trial. Eur Urol. 2021 Jul;80(1):7-11. Epub 2021 Apr 23. link to original article EuroPMC
#EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03474107
##Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article EuroPMC
##HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article EuroPMC
#THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03390504
#SWOG S1937: NCT04579224
#TROPiCS-04: NCT04527991
==Docetaxel & Ramucirumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Petrylak et al. 2016 (JCDC) 	2011-2014 	Randomized Phase 2 (E-esc)	1. Docetaxel 	Longer PFS (primary endpoint)Median PFS: 5.4 vs 2.8 mo(sHR 0.39, 95% CI 0.235-0.64)
Petrylak et al. 2016 (JCDC) 	2011-2014 	Randomized Phase 2 (E-esc)	2. Docetaxel & Icrucumab	Not reported
Petrylak et al. 2017 (RANGE)	2015-2017 	Phase 3 (E-esc) 	Docetaxel 	Longer PFS1 (primary endpoint)Median PFS: 4.1 vs 2.8 mo(HR 0.70, 95% CI 0.57-0.85)
1Reported efficacy for RANGE is based on the 2019 update.
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====Targeted therapy====
*Ramucirumab (Cyramza) 10 mg/kg IV once on day 1
21-day cycles
===References===
#JCDC: Petrylak DP, Tagawa ST, Kohli M, Eisen A, Canil C, Sridhar SS, Spira A, Yu EY, Burke JM, Shaffer D, Pan CX, Kim JJ, Aragon-Ching JB, Quinn DI, Vogelzang NJ, Tang S, Zhang H, Cavanaugh CT, Gao L, Kauh JS, Walgren RA, Chi KN. 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 May 1;34(13):1500-9. Epub 2016 Feb 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01282463
#RANGE: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain S, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Hegemann M, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Del Muro XG, Rodriguez-Vida A, Cicin I, Harputluoglu H, Widau RC, Liepa AM, Walgren RA, Hamid O, Zimmermann AH, Bell-McGuinn KM, Powles T; RANGE study investigators. 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 Nov 18;390(10109):2266-2277. Epub 2017 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02426125
##Update: Petrylak DP, de Wit R, Chi KN, Drakaki A, Sternberg CN, Nishiyama H, Castellano D, Hussain SA, Fléchon A, Bamias A, Yu EY, van der Heijden MS, Matsubara N, Alekseev B, Necchi A, Géczi L, Ou YC, Coskun HS, Su WP, Bedke J, Gakis G, Percent IJ, Lee JL, Tucci M, Semenov A, Laestadius F, Peer A, Tortora G, Safina S, Garcia Del Muro X, Rodriguez-Vida A, Cicin I, Harputluoglu H, Tagawa ST, Vaishampayan U, Aragon-Ching JB, Hamid O, Liepa AM, Wijayawardana S, Russo F, Walgren RA, Zimmermann AH, Hozak RR, Bell-McGuinn KM, Powles T; RANGE study investigators. 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 Jan;21(1):105-120. Epub 2019 Nov 18. link to original article link to PMC article EuroPMC
##HRQoL analysis: Necchi A, Nishiyama H, Matsubara N, Lee JL, Petrylak DP, de Wit R, Drakaki A, Liepa AM, Mao H, Bell-McGuinn K, Powles T. Health-related quality of life in the randomized phase 3 study of ramucirumab plus docetaxel versus placebo plus docetaxel in platinum-refractory advanced urothelial carcinoma (RANGE). BMC Urol. 2020 Nov 7;20(1):181. link to original article link to PMC article EuroPMC
==Enfortumab vedotin & Pembrolizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Hoimes et al. 2022 (EV-103)	2017-2020 	Phase 1b/2 (RT)	ORR: 73.3%CR: 15.6%
====Antibody-drug conjugate therapy====
*Enfortumab vedotin (Padcev) 1.25 mg/kg IV once per day on days 1 & 8
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycles
===References===
#EV-103: Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, Merchan JR, McKay RR, Petrylak DP, Sasse C, Moreno BH, Yu Y, Carret AS, Rosenberg JE. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023 Jan 1;41(1):22-31. Epub 2022 Aug 30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03288545
==Erdafitinib monotherapy==
===Regimen variant #1===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Efficacy
Loriot et al. 2019 (BLC2001)	2015-2018 	Phase 2 (RT)	ORR: 40%, 95% CI 31-50
====Biomarker eligibility criteria====
*Alterations: FGFR3 mutation, FGFR2 fusion, or FGFR3 fusion
====Targeted therapy====
*Erdafitinib (Balversa) as follows:
**Cycle 1: 8 mg PO once per day on days 1 to 21, then 9 mg PO once per day on days 22 to 28 if serum phosphorus level and tolerability are acceptable
**Cycle 2 onwards: 9 mg PO once per day on days 1 to 28
28-day cycles
===Regimen variant #2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Loriot et al. 2023 (THOR cohort 1)	2018-08-06 to not reported	Phase 3 (E-RT-switch-ooc)	1a. Docetaxel1b. Vinflunine	Longer OS (primary endpoint)Median OS: 12.1 vs 7.8 mo(HR 0.64, 95% CI 0.47-0.88)
Note: The details of pharmacodynamic guidance were not described in the manuscript.
====Biomarker eligibility criteria====
*Susceptible FGFR2 or FGFR3 alterations
====Prior treatment criteria====
*Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
====Targeted therapy====
*Erdafitinib (Balversa) as follows:
**Cycle 1: 8 mg PO once per day on days 1 to 13, then 9 mg PO once per day on days 14 to 21, guided by pharmacodynamics
**Cycle 2 onwards: 9 mg PO once per day on days 1 to 21
21-day cycles
===References===
#BLC2001: Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, Fleming M, Rezazadeh A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Zhong B, Stuyckens K, Santiago-Walker A, De Porre P, O'Hagan A, Avadhani A, Siefker-Radtke AO; BLC2001 Study Group. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med. 2019 Jul 25;381(4):338-348. link to original article EuroPMC NCT02365597
##Update: Siefker-Radtke AO, Necchi A, Park SH, García-Donas J, Huddart RA, Burgess EF, Fleming MT, Rezazadeh Kalebasty A, Mellado B, Varlamov S, Joshi M, Duran I, Tagawa ST, Zakharia Y, Akapame S, Santiago-Walker AE, Monga M, O'Hagan A, Loriot Y; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. Lancet Oncol. 2022 Feb;23(2):248-258. Epub 2022 Jan 11. link to original article EuroPMC
#THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03390504
#THOR cohort 2: Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03390504
==Gemcitabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Lorusso et al. 1998	1993-01 to 1995-01 	Phase 2
====Chemotherapy====
*Gemcitabine (Gemzar) 1200 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycle for 8 cycles
===References===
# Lorusso V, Pollera CF, Antimi M, Luporini G, Gridelli C, Frassineti GL, Oliva C, Pacini M, De Lena M; Italian Co-operative Group on Bladder Cancer. A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Eur J Cancer. 1998 Jul;34(8):1208-12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Gemcitabine & Paclitaxel==
GP: Gemcitabine & Paclitaxel
===Regimen variant #1, gemcitabine 2 out of 3 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Albers et al. 2010 (AUO AB 20/99)	2001-2005 	Phase 3 (C)	GP; prolonged	Did not meet primary endpoint of OS
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
===Regimen variant #2, weekly gemcitabine===
Study 	Dates of enrollment	Evidence 	Efficacy
Meluch et al. 2001	1997-1999 	Phase 2, fewer than 20 pts in this subgroup	ORR: 47%
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
*Paclitaxel (Taxol) 200 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
#Meluch AA, Greco FA, Burris HA 3rd, O'Rourke T, Ortega G, Steis RG, Morrissey LH, Johnson V, Hainsworth JD. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol. 2001 Jun 15;19(12):3018-24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#AUO AB 20/99: Albers P, Park SI, Niegisch G, Fechner G, Steiner U, Lehmann J, Heimbach D, Heidenreich A, Fimmers R, Siener R; AUO Bladder Cancer Group. Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]. Ann Oncol. 2011 Feb;22(2):288-94. Epub 2010 Aug 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==MVAC==
MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Han et al. 2008	2002-2006 	Phase 2 	ORR: 30%
====Chemotherapy====
*Methotrexate (MTX) 30 mg/m2 IV once per day on days 1, 15, 22
*Vinblastine (Velban) 3 mg/m2 IV once per day on days 2, 15, 22
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 2
*Cisplatin (Platinol) 70 mg/m2 IV once on day 2
28-day cycles
===References===
#Han KS, Joung JY, Kim TS, Jeong IG, Seo HK, Chung J, Lee KH. Methotrexate, vinblastine, doxorubicin and cisplatin combination regimen as salvage chemotherapy for patients with advanced or metastatic transitional cell carcinoma after failure of gemcitabine and cisplatin chemotherapy. Br J Cancer. 2008 Jan 15;98(1):86-90. Epub 2007 Dec 18. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Nivolumab monotherapy==
===Regimen variant #1, weight-based===
Study 	Dates of enrollment	Evidence 	Efficacy
Sharma et al. 2017 (CheckMate 275)	2015 	Phase 2 (RT)	19.6% overallPD-L1 expression at least 5%: 28.4%PD-L1 expression at least 1%: 23.8%PD-L1 expression less than 1%: 16.1%
Note: this is the dosing used in the study but is not the FDA-recommended dose.
====Prior treatment criteria====
*At least one platinum-based therapy, with progression
====Immunotherapy====
*Nivolumab (Opdivo) 3 mg/kg IV once on day 1
14-day cycles
===Regimen variant #2, flat dosing===
FDA-recommended dose
====Immunotherapy====
*Nivolumab (Opdivo) 240 IV over 60 minutes once on day 1
14-day cycles
===References===
#CheckMate 275: Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JÁ, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017 Mar;18(3):312-322. Epub 2017 Jan 25. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02387996
##Update: Galsky MD, Saci A, Szabo PM, Han GC, Grossfeld G, Collette S, Siefker-Radtke A, Necchi A, Sharma P. Nivolumab in Patients with Advanced Platinum-resistant Urothelial Carcinoma: Efficacy, Safety, and Biomarker Analyses with Extended Follow-up from CheckMate 275. Clin Cancer Res. 2020 Oct 1;26(19):5120-5128. Epub 2020 Jun 12. link to original article link to PMC article EuroPMC
==nab-Paclitaxel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Ko et al. 2013 (ABX207-GU07CA)	2008-2010 	Phase 2 	ORR: 28% (95% CI 17-44)
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
21-day cycles
====Dose and schedule modifications====
*"Two dose reductions were permitted, to 240 mg/m2 and then to 180 mg/m2. When further dose reductions were required, study treatment was discontinued. Patients with febrile neutropenia, or delay of cycle because of persistent neutropenia, ANC of less than 500/μL for 1 week, or grade 3 or 4 thrombocytopenia required dose reductions. When sensory neuropathy of grade 2 or higher occurred, study drug was withheld until resolution to grade 2 or better, then reinstituted at the next lower dose. When mucositis or diarrhea of grade 3 or higher occurred, study drug was withheld until resolution to grade 1 or better, then reinstituted at the next lower dose. Patients with mucositis or diarrhea of grade 4 were removed from the trial."
===References===
#ABX207-GU07CA: Ko YJ, Canil CM, Mukherjee SD, Winquist E, Elser C, Eisen A, Reaume MN, Zhang L, Sridhar SS. Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study. Lancet Oncol. 2013 Jul;14(8):769-76. Epub 2013 May 22. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00683059
==Paclitaxel monotherapy==
===Regimen variant #1, q3wks===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045)	2014-11-05 to 2015-11-13	Phase 3 (C)	Pembrolizumab 	Shorter OSMedian OS: 7 vs 10 mo(HR 1.37, 95% CI 1.10-1.69)
Powles et al. 2017 (IMvigor211) 	2015-01-13 to 2016-02-15	Phase 3 (C)	Atezolizumab 	Shorter OS1 (primary endpoint)OS30: 10% vs 18%(HR 1.22, 95% CI 1.06-1.41)
Powles et al. 2021 (EV-301) 	2018-2020 	Phase 3 (C)	Enfortumab vedotin	Shorter OS2Median OS: 8.94 vs 12.91 mo(HR 1.43, 95% CI 1.18-1.72)
1Reported efficacy for IMvigor211 is based on the 2021 update.
2Reported efficacy for EV-301 is based on the 2023 update.
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm. IMvigor211 allowed up to 2 prior lines of platinum-containing chemotherapy.
====Prior treatment criteria====
*KEYNOTE-045: Exposure to platinum-based chemotherapy
*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycles
===Regimen variant #2, 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence	Efficacy
Vaughn et al. 2002	Not reported 	Phase 2 	ORR: 10% (95% CI 0-20)
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
28-day cycles
===Regimen variant #3, weekly===
Study 	Dates of enrollment	Evidence
Sideris et al. 2016	2004-2014 	Retrospective
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
21-day cycles
===References===
#Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#Retrospective: Sideris S, Aoun F, Zanaty M, Martinez NC, 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 Jun;4(6):1063-1067. Epub 2016 Mar 17. link to original article link to PMC article EuroPMC
#KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02256436
##HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article EuroPMC
##Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article EuroPMC
##Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article EuroPMC
#IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. 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 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02302807
##Update: van der Heijden MS, Loriot Y, Durán I, Ravaud A, Retz M, Vogelzang NJ, Nelson B, Wang J, Shen X, Powles T. Atezolizumab Versus Chemotherapy in Patients with Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: A Long-term Overall Survival and Safety Update from the Phase 3 IMvigor211 Clinical Trial. Eur Urol. 2021 Jul;80(1):7-11. Epub 2021 Apr 23. link to original article EuroPMC
#EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03474107
##Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article EuroPMC
##HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article EuroPMC
#TROPiCS-04: NCT04527991
==Pembrolizumab monotherapy==
===Regimen variant #1, limited duration===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Cicin et al. 2024 (ECHO-303)	2017-12-22 to 2018-05-02	Phase 3 (C)	Epacadostat & Pembrolizumab	Did not meet primary endpoint of ORRORR: 11.9% vs 26.2%
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===Regimen variant #2, indefinite===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bellmunt et al. 2017 (KEYNOTE-045) 	2014-11-05 to 2015-11-13 	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. Docetaxel1b. Paclitaxel1c. Vinflunine	Longer OS (co-primary endpoint)Median OS: 10 vs 7 mo (HR 0.73, 95% CI 0.59-0.91)
Siefker-Radtke et al. 2023 (THOR cohort 2)	2018-04-26 to not reported	Phase 3 (C) 	Erdafitinib 	Did not meet primary endpoint of OS
====Biomarker eligibility criteria====
*THOR cohort 2: Susceptible FGFR2 or FGFR3 alterations
====Eligibility criteria====
*KEYNOTE-045: For the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) at least 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.
====Prior treatment criteria====
*KEYNOTE-045: Exposure to platinum-based chemotherapy
*THOR cohort 2: Exposure to one prior treatment that did NOT include an anti-PD-1 antibody or anti-PD-L1 antibody (anti-PD-(L)1-naive).
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1
21-day cycles
===References===
#KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02256436
##HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article EuroPMC
##Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article EuroPMC
##Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article EuroPMC
#THOR cohort 2: Siefker-Radtke AO, Matsubara N, Park SH, Huddart RA, Burgess EF, Özgüroğlu M, Valderrama BP, Laguerre B, Basso U, Triantos S, Akapame S, Kean Y, Deprince K, Mukhopadhyay S, Loriot Y; THOR cohort 2 investigators. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2024 Jan;35(1):107-117. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03390504
#ECHO-303: Cicin I, Plimack ER, Gurney H, Leibowitz R, Alekseev BY, Parnis FX, Peer A, Necchi A, Bellmunt J, Nishiyama H, Clark J, Munteanu M, Kataria R, Jia C, Powles T, Sternberg CN. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study. BMC Cancer. 2024 Jul 25;23(Suppl 1):1256. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03374488
==Pemetrexed monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Sweeney et al. 2006	2001-2004 	Phase 2 	ORR: 28% (95% CI 16-43)
====Chemotherapy====
*Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
21-day cycles
===References===
#Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol. 2006 Jul 20;24(21):3451-7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==Tislelizumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Awaiting publication (RATIONALE-204)	2017 to not reported	Phase 2
====Immunotherapy====
*Tislelizumab (Baizean) 200 mg IV once on day 1
21-day cycles
===References===
# RATIONALE-204: NCT04004221
==Toripalimab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Awaiting publication (Junshi-JS001-009)	2017 to not reported	Phase 2
====Immunotherapy====
*Toripalimab (Loqtorzi) 3 mg/kg IV once on day 1
14-day cycles
===References===
#Junshi-JS001-009: dosing details on CT.gov have been reviewed by our editors NCT03113266
==Vinflunine monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bellmunt et al. 2009 (CA183004) 	2003-2006 	Phase 3 (E-esc)	Best supportive care	Longer OS1 (primary endpoint)Median OS: 6.9 vs 4.6 mo(aHR 0.72, 95% CI 0.57-0.91)
Bellmunt et al. 2017 (KEYNOTE-045)	2014-11-05 to 2015-11-13 	Phase 3 (C) 	Pembrolizumab 	Shorter OSMedian OS: 7 vs 10 mo(HR 1.37, 95% CI 1.10-1.69)
Powles et al. 2017 (IMvigor211) 	2015-01-13 to 2016-02-15 	Phase 3 (C) 	Atezolizumab 	Shorter OS2 (primary endpoint)OS30: 10% vs 18%(HR 1.22, 95% CI 1.06-1.41)
Powles et al. 2021 (EV-301) 	2018-2020 	Phase 3 (C) 	Enfortumab vedotin 	Shorter OS3Median OS: 8.94 vs 12.91 mo(HR 1.43, 95% CI 1.18-1.72)
Loriot et al. 2023 (THOR cohort 1)	2018-08-06 to not reported	Phase 3 (C) 	Erdafitinib 	Shorter OSMedian OS: 7.8 vs 12.1 mo(HR 1.56, 95% CI 1.14-2.13)
1Reported efficacy for CA183004 is based on the 2013 update.
2Reported efficacy for IMvigor211 is based on the 2021 update.
3Reported efficacy for EV-301 is based on the 2023 update.
====Biomarker eligibility criteria====
*THOR cohort 1: Susceptible FGFR2 or FGFR3 alterations
====Prior treatment criteria====
*KEYNOTE-045: Exposure to platinum-based chemotherapy
*EV-301: Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
*THOR cohort 1: Exposure to one or two previous treatments that included an anti-PD-1 antibody or anti-PD-L1 antibody.
====Chemotherapy====
*Vinflunine (Javlor) 320 mg/m2 IV over 20 minutes once on day 1
21-day cycles
===References===
#CA183004: Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, Caty A, Carles J, Jagiello-Gruszfeld A, Karyakin O, Delgado FM, Hurteloup P, Winquist E, Morsli N, Salhi Y, Culine S, von der Maase H. 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 Sep 20;27(27):4454-61. Epub 2009 Aug 17. Erratum in: J Clin Oncol. 2010 Jan 1;28(1):182. Winquist, Eric [added]. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00315237
##Update: Bellmunt J, Fougeray R, Rosenberg JE, von der Maase H, Schutz FA, Salhi Y, Culine S, Choueiri TK. 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 Jun;24(6):1466-72. Epub 2013 Feb 17. link to original article EuroPMC
#KEYNOTE-045: Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017 Mar 16;376(11):1015-1026. Epub 2017 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02256436
##HRQoL analysis: Vaughn DJ, Bellmunt J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Li H, Perini RF, Bajorin DF, de Wit R. Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. J Clin Oncol. 2018 Jun 1;36(16):1579-1587. Epub 2018 Mar 28. link to original article EuroPMC
##Update: Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Nam K, Frenkl TL, Perini RF, de Wit R, Bajorin DF. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of > 2 years of follow-up. Ann Oncol. 2019 Jun 1;30(6):970-976. Epub 2019 May 3. link to original article link to PMC article EuroPMC
##Pooled update: Balar AV, Castellano DE, Grivas P, Vaughn DJ, Powles T, Vuky J, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Necchi A, Petrylak DP, Plimack ER, Xu JZ, Imai K, Moreno BH, Bellmunt J, de Wit R, O'Donnell PH. Efficacy and safety of pembrolizumab in metastatic urothelial carcinoma: results from KEYNOTE-045 and KEYNOTE-052 after up to 5 years of follow-up. Ann Oncol. 2023 Mar;34(3):289-299. Epub 2022 Dec 6. link to original article EuroPMC
#IMvigor211: Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, Oudard S, Retz MM, Castellano D, Bamias A, Fléchon A, Gravis G, Hussain S, Takano T, Leng N, Kadel EE 3rd, Banchereau R, Hegde PS, Mariathasan S, Cui N, Shen X, Derleth CL, Green MC, Ravaud A. 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 Feb 24;391(10122):748-757. Epub 2017 Dec 18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02302807
##Update: van der Heijden MS, Loriot Y, Durán I, Ravaud A, Retz M, Vogelzang NJ, Nelson B, Wang J, Shen X, Powles T. Atezolizumab Versus Chemotherapy in Patients with Platinum-treated Locally Advanced or Metastatic Urothelial Carcinoma: A Long-term Overall Survival and Safety Update from the Phase 3 IMvigor211 Clinical Trial. Eur Urol. 2021 Jul;80(1):7-11. Epub 2021 Apr 23. link to original article EuroPMC
#EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03474107
##Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article EuroPMC
##HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article EuroPMC
#THOR cohort 1: Loriot Y, Matsubara N, Park SH, Huddart RA, Burgess EF, Houede N, Banek S, Guadalupi V, Ku JH, Valderrama BP, Tran B, Triantos S, Kean Y, Akapame S, Deprince K, Mukhopadhyay S, Stone NL, Siefker-Radtke AO; THOR Cohort 1 Investigators. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971. Epub 2023 Oct 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03390504
#TROPiCS-04: NCT04527991
=Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy and/or immune checkpoint inhibitor=
==Enfortumab vedotin monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rosenberg et al. 2018 (EV-201)	2017-10-08 to 2018-07-02	Phase 2 (RT) 	 	ORR: 44% (95% CI 35.2-53.2)
Powles et al. 2021 (EV-301) 	2018-2020 	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. Docetaxel1b. Paclitaxel1c. Vinflunine	Longer OS1 (primary endpoint)Median OS: 12.91 vs 8.94 mo(HR 0.70, 95% CI 0.58-0.85)
1Reported efficacy for EV-301 is based on the 2023 update.
Note: ORR in this arm of EV-301 (ITT) was 40.6% vs 17.9 % in the control arm (ITT).
====Prior treatment criteria====
*Exposure to platinum-containing chemotherapy and a PD-1/L1 inhibitor, with progression
====Antibody-drug conjugate therapy====
*Enfortumab vedotin (Padcev) 1.25 mg/kg (maximum dose of 125 mg) IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
===References===
#EV-201: Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, Hahn NM, Gartner EM, Pinelli JM, Liang SY, Melhem-Bertrandt A, Petrylak DP. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019 Oct 10;37(29): 2592-2600. Epub 2019 Jul 29. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03219333
##Update: Yu EY, Petrylak DP, O'Donnell PH, Lee JL, van der Heijden MS, Loriot Y, Stein MN, Necchi A, Kojima T, Harrison MR, Hoon Park S, Quinn DI, Heath EI, Rosenberg JE, Steinberg J, Liang SY, Trowbridge J, Campbell M, McGregor B, Balar AV. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV-201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):872-882. Epub 2021 May 12. Erratum in: Lancet Oncol. 2021 Jun;22(6):e239. link to original article EuroPMC
#EV-301: Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. Epub 2021 Feb 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03474107
##Update: Rosenberg JE, Powles T, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Mamtani R, Wu C, Matsangou M, Campbell M, Petrylak DP. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Ann Oncol. 2023 Nov;34(11):1047-1054. Epub 2023 Sep 9. link to original article EuroPMC
##HRQoL analysis: Rosenberg JE, Mamtani R, Sonpavde GP, Loriot Y, Duran I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Sridhar SS, Pappot H, Gurney H, Bedke J, van der Heijden MS, Galli L, Keam B, Masumori N, Meran J, O'Donnell PH, Park SH, Grande E, Sengeløv L, Uemura H, Skaltsa K, Campbell M, Matsangou M, Wu C, Hepp Z, McKay C, Powles T, Petrylak DP. Health-related Quality of Life in Patients with Previously Treated Advanced Urothelial Carcinoma from EV-301: A Phase 3 Trial of Enfortumab Vedotin Versus Chemotherapy. Eur Urol. 2024 Jun;85(6):574-585. Epub 2024 Feb 28. link to original article EuroPMC
==Sacituzumab govitecan monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Efficacy
Tagawa et al. 2021 (TROPHY-U-01)	2018-2019 	Phase 2 (RT)	ORR: 27% (95% CI 19.5-37)
====Prior treatment criteria====
*Exposure to platinum-based therapy and checkpoint inhibitor, with progression
====Antibody-drug conjugate therapy====
*Sacituzumab govitecan (Trodelvy) 10 mg/kg IV once per day on days 1 & 8
21-day cycles
===References===
#TROPHY-U-01: Tagawa ST, Balar AV, Petrylak DP, Kalebasty AR, Loriot Y, Fléchon A, Jain RK, Agarwal N, Bupathi M, Barthelemy P, Beuzeboc P, Palmbos P, Kyriakopoulos CE, Pouessel D, Sternberg CN, Hong Q, Goswami T, Itri LM, Grivas P. TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485. Epub 2021 Apr 30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03547973
##Update: Loriot Y, Petrylak DP, Rezazadeh Kalebasty A, Fléchon A, Jain RK, Gupta S, Bupathi M, Beuzeboc P, Palmbos P, Balar AV, Kyriakopoulos CE, Pouessel D, Sternberg CN, Tonelli J, Sierecki M, Zhou H, Grivas P, Barthélémy P, Tagawa ST. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol. 2024 Apr;35(4):392-401. Epub 2024 Jan 18. link to original article EuroPMC
#TROPiCs-04: NCT04527991
Category:Urothelial carcinoma regimens
Category:Disease-specific pages
Category:Genitourinary cancers