Urothelial carcinoma

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Michael J. Glover, MD
Stanford University
Palo Alto, CA, USA
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Ali Raza Khaki, MD
Stanford University
Palo Alto, CA, USA
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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 recently been renamed from "Bladder cancer" to "Urothelial carcinoma" to reflect the fact that most regimens here are generic to urothelial cancer. For now, the page also has adjuvant and perioperative regimens specific to bladder cancer, but these will be moved to a dedicated bladder cancer page soon.

Last updated on 2024-09-06:
35 regimens on this page
52 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


NCCN


SITC


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 Superior DFS (co-primary endpoint)
Median DFS: 20.8 vs 10.8 mo
(HR 0.70, 98.22% CI 0.55-0.90)

Preceding treatment

Immunotherapy

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

Immunotherapy

28-day cycle for up to 13 cycles (1 year)

References

  1. 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 PubMed NCT02632409
    1. 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 PubMed
  2. VOLGA: NCT04960709


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

21-day cycle for up to 6 cycles

References

  1. 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 PubMed NCT00146276


Pembrolizumab monotherapy

Regimen variant #1, limited duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Necchi et al. 2024 (ECHO-307) 2017-12-04 to 2018-05-02 Phase 3 (C) Epacadostat & Pembrolizumab Did not meet primary endpoint of ORR
ORR: 24.5% vs 31.8%

Immunotherapy

21-day cycle for up to 35 cycles


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Efficacy
Balar et al. 2017 (KEYNOTE-052) 2015-2016 Phase 2 (RT) ORR: 24% (95% CI 20-29)

Immunotherapy

21-day cycles

References

  1. 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 abstract have been reviewed by our editors PubMed NCT02335424
    1. 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 PubMed
    2. 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 PubMed
  2. 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 PubMed NCT03361865
  3. LEAP-011: 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
2. Durvalumab & Tremelimumab Might have inferior OS Not more toxic
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (C) Enfortumab vedotin & Pembrolizumab Inferior PFS/OS
An et al. 2024 2019-02 to 2021-06 Phase 3 (C) Gemcitabine & nab-Paclitaxel (GA) Did not meet primary endpoint of PFS
Median 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

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 ORR1
ORR: 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
2a. GCb & Atezolizumab
2b. GC & Atezolizumab 		Might have inferior 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

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
2. Durvalumab & Tremelimumab Might have inferior OS
Powles et al. 2021 (KEYNOTE-361) 2016-2018 Phase 3 (C) 1a. GC & Pembrolizumab
1b. GCb & Pembrolizumab 		Might have inferior OS
2. Pembrolizumab Not reported
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (C) Enfortumab vedotin & Pembrolizumab Inferior PFS/OS

Note: this was the upper bound of AUC specified by DANUBE & EV-302.

Chemotherapy

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

21-day cycle for up to 6 cycles

References

  1. 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 PubMed
  2. 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 PubMed
  3. 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 PubMed NCT00111787
    1. 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 PubMed
  4. 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 PubMed NCT02807636
    1. 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 PubMed
  5. 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 PubMed NCT02516241
  6. 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 PubMed NCT02853305
  7. 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 PubMed NCT04223856
  8. 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 PubMed ChiCTR1900022615
  9. NILE: NCT03682068
  10. 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. GC
1b. GCb 		Might have superior OS (co-primary endpoint)
Median OS: 17 vs 14.3 mo
(HR 0.86, 95% CI 0.72-1.02)

Might have superior PFS1 (co-primary endpoint)
Median PFS: 8.3 vs 7.1 mo
(HR 0.78, 95% CI 0.65-0.3)
2. Pembrolizumab Not reported

1Reported efficacy did not meet the prespecified boundary for statistical significance.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles

References

  1. 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 PubMed 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

21-day cycle for up to 6 cycles

References

  1. 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 PubMed
  2. 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 PubMed NCT00003376


Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin
GP: Gemcitabine & Platinol (Cisplatin)

AIM pathway regimen 2022-08-01

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 inferior OS
Powles et al. 2020 (DANUBE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet co-primary endpoint of OS
2. Durvalumab & Tremelimumab Might have inferior OS
Powles et al. 2021 (KEYNOTE-361) 2016-2018 Phase 3 (C) 1a. GC & Pembrolizumab
1b. GCb & Pembrolizumab 		Might have inferior OS
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 inferior OS (co-primary endpoint)
Powles et al. 2024 (EV-302) 2020-2023 Phase 3 (C) Enfortumab vedotin & Pembrolizumab Inferior PFS/OS

Chemotherapy

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
2a. GCb & Atezolizumab
2b. GC & Atezolizumab 		Might have inferior OS1

1Reported efficacy for IMvigor130 is based on the 2023 update.

Chemotherapy

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
2. Durvalumab & Tremelimumab Might have inferior OS Not more toxic

Chemotherapy

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 inferior OS
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
2. Durvalumab & Tremelimumab Might have inferior OS

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

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

  1. 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 PubMed
    1. 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 PubMed
  2. 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 PubMed
  3. 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 PubMed
  4. 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 PubMed NCT00022191
  5. 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 PubMed NCT00625664
  6. 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 PubMed NCT02807636
    1. 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 PubMed
  7. 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 PubMed NCT02516241
  8. 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 PubMed NCT02853305
  9. 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 PubMed NCT00942331
  10. 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 PubMed NCT03036098
  11. 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 PubMed NCT04223856
  12. NILE: NCT03682068
  13. 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 superior OS (primary endpoint)
Median OS: 14.5 vs 14.3 mo
(HR 0.87, 95% CI 0.72-1.05)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. 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 PubMed 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 superior OS (co-primary endpoint)
Median OS: 21.7 vs 18.9 mo
(HR 0.78, 95% CI 0.63-0.96)

Superior PFS (co-primary endpoint)
Median PFS: 7.9 vs 7.6 mo
(HR 0.72, 95% CI 0.59-0.88)

Chemotherapy

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

  1. 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 PubMed 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. GC
1b. GCb 		Might have superior OS (co-primary endpoint)
Median OS: 17 vs 14.3 mo
(HR 0.86, 95% CI 0.72-1.02)

Might have superior PFS1 (co-primary endpoint)
Median PFS: 8.3 vs 7.1 mo
(HR 0.78, 95% CI 0.65-0.3)
2. Pembrolizumab Not reported

1Reported efficacy did not meet the prespecified boundary for statistical significance.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. 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 PubMed 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. GC
1b. GCb 		Superior OS (co-primary endpoint)
Median OS: 31.5 vs 16.1 mo
(HR 0.47, 95% CI 0.38-0.58)

Superior 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

Immunotherapy

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. GC
1b. GCb 		Superior OS (co-primary endpoint)
Median OS: 31.5 vs 16.1 mo
(HR 0.47, 95% CI 0.38-0.58)

Superior 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

Immunotherapy

42-day cycles

References

  1. 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 PubMed NCT04223856


Gemcitabine & Paclitaxel

Regimen variant #1

Study Dates of enrollment Evidence Efficacy
Calabrò et al. 2009 2003-2005 Phase 2 ORR: 37%

Chemotherapy

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

21-day cycles

References

  1. 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 PubMed
  2. 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 PubMed


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 Superior OS
Logothetis et al. 1990 1985-1989 Phase 3 (E-switch-ic) CISCA Superior 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 inferior OS1
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

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 Seems to have superior OS

Chemotherapy

Supportive therapy

28-day cycles

References

  1. 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 PubMed
  2. 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 PubMed
    1. 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 PubMed
  3. 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 PubMed
    1. 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 PubMed
  4. 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 PubMed
    1. 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 PubMed
  5. 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 PubMed
  6. 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 PubMed
  7. 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 PubMed NCT00003376


MVAC, dose-dense

ddMVAC: dose-dense Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sternberg et al. 2001 (EORTC 30924) 1993-1998 Phase 3 (E-esc) MVAC Seems to have superior OS1
Bamias et al. 2012 (HE 16/03) 2003-2008 Phase 3 (C) DD-GC Did not meet primary endpoint of OS

1Reported efficacy for EORTC 30924 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

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

  1. 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 PubMed
    1. 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 PubMed
  2. 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 abstract have been reviewed by our editors PubMed 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 superior 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

21-day cycle for up to 6 cycles

References

  1. 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 PubMed 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 Superior 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

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:

28-day cycles

References

  1. 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 PubMed NCT02603432
    1. 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 PubMed
    2. 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 PubMed
  2. 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 superior PFS (primary endpoint)
Median PFS: 5.4 vs 3 mo
(HR 0.65, 95% CI 0.43-0.97) 		More toxic

Preceding treatment

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. 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 PubMed 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

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

  1. 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 PubMed NCT01772004
    1. 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 PubMed


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 PFS
Petrylak et al. 2016 (JCDC) 2011-2014 Randomized Phase 2 (C) 1. Docetaxel & Icrucumab Did not meet primary endpoint of PFS
2. Docetaxel & Ramucirumab Inferior PFS
Bellmunt et al. 2017 (KEYNOTE-045) 2014-11-05 to 2015-11-13 Phase 3 (C) Pembrolizumab Inferior OS
Powles et al. 2017 (IMvigor211) 2015-01-13 to 2016-02-15 Phase 3 (C) Atezolizumab Did not meet primary endpoint of OS
Petrylak et al. 2017 (RANGE) 2015-2017 Phase 3 (C) Docetaxel & Ramucirumab Inferior PFS1
Powles et al. 2021 (EV-301) 2018-2020 Phase 3 (C) Enfortumab vedotin Inferior OS
Loriot et al. 2023 (THOR cohort 1) 2018-08-06 to not reported Phase 3 (C) Erdafitinib Inferior OS

1Reported efficacy for RANGE is based on the 2019 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

21-day cycles

References

  1. 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 PubMed
  2. 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 PubMed NCT00880334
  3. 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 PubMed NCT01282463
  4. 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 PubMed NCT02256436
    1. 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 PubMed
    2. 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 PubMed
    3. 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 PubMed
  5. 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 PubMed NCT02426125
    1. 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 PubMed
  6. 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 PubMed NCT02302807
  7. 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 PubMed NCT03474107
    1. 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 PubMed
    2. 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 PubMed
  8. 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 PubMed NCT03390504
  9. SWOG S1937: NCT04579224
  10. 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 Superior PFS (primary endpoint)
Median PFS: 5.4 vs 2.8 mo
(sHR 0.39, 95% CI 0.235-0.64)
2. Docetaxel & Icrucumab Not reported
Petrylak et al. 2017 (RANGE) 2015-2017 Phase 3 (E-esc) Docetaxel Superior PFS1 (primary endpoint)
(HR 0.70, 95% CI 0.57-0.85)

1Reported efficacy for RANGE is based on the 2019 update.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. 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 PubMed NCT01282463
  2. 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 PubMed NCT02426125
    1. 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 PubMed


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

Immunotherapy

21-day cycles

References

  1. 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 PubMed 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. Docetaxel
1b. Vinflunine 		Superior 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

  1. 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 PubMed NCT02365597
    1. 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 PubMed
  2. 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 PubMed NCT03390504
  3. 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 PubMed NCT03390504


Gemcitabine monotherapy

AIM pathway regimen 2022-08-01

Regimen

Study Dates of enrollment Evidence
Lorusso et al. 1998 1993-01 to 1995-01 Phase 2

Chemotherapy

28-day cycle for 8 cycles

References

  1. 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 PubMed


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

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

21-day cycles

References

  1. 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 PubMed
  2. 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 PubMed


MVAC

MVAC: Methotrexate, Vinblastine, Adriamycin, Cisplatin

Regimen

Study Dates of enrollment Evidence Efficacy
Han et al. 2008 2002-2006 Phase 2 ORR: 30%

Chemotherapy

28-day cycles

References

  1. 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 PubMed


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% overall
PD-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

Immunotherapy

14-day cycles


Regimen variant #2, flat dosing

FDA-recommended dose

Immunotherapy

14-day cycles

References

  1. 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 PubMed NCT02387996
    1. 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 PubMed


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

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

  1. 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 PubMed NCT00683059


Paclitaxel monotherapy

AIM pathway regimen 2022-08-01

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 Inferior OS
Powles et al. 2017 (IMvigor211) 2015-01-13 to 2016-02-15 Phase 3 (C) Atezolizumab Did not meet primary endpoint of OS
Powles et al. 2021 (EV-301) 2018-2020 Phase 3 (C) Enfortumab vedotin Inferior OS

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

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

28-day cycles


Regimen variant #3, weekly

Study Dates of enrollment Evidence
Sideris et al. 2016 2004-2014 Retrospective

Chemotherapy

21-day cycles

References

  1. 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 PubMed
  2. 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 PubMed
  3. 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 PubMed NCT02256436
    1. 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 PubMed
    2. 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 PubMed
    3. 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 PubMed
  4. 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 PubMed NCT02302807
  5. 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 PubMed NCT03474107
    1. 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 PubMed
    2. 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 PubMed
  6. TROPiCS-04: NCT04527991


Pembrolizumab monotherapy

AIM pathway regimen 2022-08-01

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 ORR
ORR: 11.9% vs 26.2%

Immunotherapy

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. Docetaxel
1b. Paclitaxel
1c. Vinflunine 		Superior 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

21-day cycles

References

  1. 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 PubMed NCT02256436
    1. 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 PubMed
    2. 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 PubMed
    3. 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 PubMed
  2. 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 PubMed NCT03390504
  3. 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 PubMed 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

21-day cycles

References

  1. 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 PubMed


Tislelizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Awaiting publication (RATIONALE-204) 2017 to not reported Phase 2

Immunotherapy

21-day cycles

References

  1. RATIONALE-204: NCT04004221


Toripalimab monotherapy

Regimen

Study Dates of enrollment Evidence
Awaiting publication (Junshi-JS001-009) 2017 to not reported Phase 2

Immunotherapy

14-day cycles

References

  1. 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 Superior 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 Inferior OS
Powles et al. 2017 (IMvigor211) 2015-01-13 to 2016-02-15 Phase 3 (C) Atezolizumab Did not meet primary endpoint of OS
Median OS: 10.6 vs 11.1 mo
(HR 1.15, 95% CI 0.83-1.59)
Powles et al. 2021 (EV-301) 2018-2020 Phase 3 (C) Enfortumab vedotin Inferior OS
Loriot et al. 2023 (THOR cohort 1) 2018-08-06 to not reported Phase 3 (C) Erdafitinib Inferior OS

1Reported efficacy for CA183004 is based on the 2013 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

21-day cycles

References

  1. 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 PubMed NCT00315237
    1. 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 PubMed
  2. 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 PubMed NCT02256436
    1. 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 PubMed
    2. 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 PubMed
    3. 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 PubMed
  3. 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 PubMed NCT02302807
  4. 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 PubMed NCT03474107
    1. 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 PubMed
    2. 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 PubMed
  5. 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 PubMed NCT03390504
  6. TROPiCS-04: NCT04527991


Locally advanced or metastatic disease, refractory/intolerant to platinum chemotherapy and/or immune checkpoint inhibitor

Enfortumab vedotin monotherapy

AIM pathway regimen 2022-08-01

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. Docetaxel
1b. Paclitaxel
1c. Vinflunine 		Superior 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

28-day cycles

References

  1. 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 PubMed NCT03219333
    1. 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 PubMed
  2. 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 PubMed NCT03474107
    1. 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 PubMed
    2. 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 PubMed


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

21-day cycles

References

  1. 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 PubMed NCT03547973
    1. 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 PubMed
  2. TROPiCs-04: NCT04527991


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