eUpdate: Bladder Cancer Treatment Recommendations

eUpdate – Bladder Cancer Treatment Recommendations

Published: 22 August 2019. Authors: ESMO Guidelines Committee

Clinical Practice Guidelines

This eUpdate refers to the Bladder cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Bellmunt Orsola JA, Leow JJ, Wiegel T et al. Ann Oncol 2014; 25 (Suppl 3): iii40–iii48.



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The ESMO Guidelines Committee would like to thank the following expert group, who drafted and reviewed the eUpdate before it was approved by the ESMO Guidelines Committee: Thomas Powles, Begona Perez-Valderrama, Maria De Santis, Robert Huddart, Yohann Loriot, Andrea Necchi, Alain Ravaud, Michiel Van Der Heijden and Joaquim Bellmunt.


Management of advanced and metastatic disease, Immune checkpoint inhibitors and targeted therapy

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Immune checkpoint inhibition in platinum-refractory disease

Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors are recommended for treatment of platinum-refractory urothelial cancer (UC). Pembrolizumab is the only agent with statistically significant randomised phase III data for overall survival (OS) in platinum-refractory UC. It is therefore the only agent with a level [I, A] recommendation (KEYNOTE-045) [1]. IMvigor211 compared the efficacy of atezolizumab with chemotherapy (ChT) in a PD-L1 biomarker-positive (SP142 antibody) subset of patients [2]. Statistically significant results were not achieved in the biomarker positive subgroup, resulting in a negative trial. Subsequent analysis showed clinically meaningful activity for atezolizumab in unselected patients, but due to the trial design, statistical significance could not be drawn from these data. Consistent OS signals have been seen with atezolizumab across phase I–IV trials [2–4]. Therefore, its use can be supported with level [II, B] evidence. Use of nivolumab, avelumab and durvalumab is supported by single-arm phase Ib/II trials [5–7]. These agents can be used in UC, although these data are less robust than pembrolizumab and to some extent atezolizumab, giving them level [III, B] recommendations. Neither avelumab nor durvalumab has received European Medicines Agency (EMA) approval in this setting. Biomarkers should not be used to select patients for therapy in platinum-refractory UC.


  • Pembrolizumab should be considered in patients with platinum-refractory urothelial cancer, as it improves OS [I, A]. The therapeutic use of other immune checkpoint inhibitors that are EMA-approved can be considered, supported with lower level evidence: atezolizumab [II, B]; nivolumab [III, B].

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Cisplatin-ineligible front-line PD-L1 biomarker-positive disease

Carboplatin-based ChT, pembrolizumab or atezolizumab are all reasonable choices for patients who are PD-L1-positive and who are not eligible for cisplatin-based ChT [8, 9]. Recent recommendations from the European Medicine Agencies (EMA) and the United States Food and Drug Administration (FDA) have limited the use of the immune checkpoint inhibitors to the biomarker-positive tumours [pembrolizumab: 22C3, combined positive score (CPS) >10 and atezolizumab: SP142, PD-L1 expression > 5%] in this setting. This change in recommendation comes from blinded data of ongoing randomised trials. Pembrolizumab and atezolizumab should only be used in patients who are PD-L1-positive [III, B]. The blinded data are not in the public domain; therefore, detailed recommendations are challenging.


  • Pembrolizumab or atezolizumab is a reasonable therapeutic choice for front-line patients with PD-L1-positive advanced UC who are not eligible for cisplatin-based ChT [III, B].

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Erdafitinib and enfortumab vedotin in platinum-refractory UC

Erdafitinib [a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor] has been tested in a phase II trial (n=99) in ChT-refractory UC patients with FGFR DNA alterations (FGFR2 or FGFR3). Response rates (RRs) were 40% with median progression-free survival (mPFS) and OS of 5.5 months [95% confidence interval (CI) 4.2–6.0] and 13.8 months [95% CI 9.8–not available (NA)], respectively [10].  Hyperphosphatemia is thought to be a surrogate for efficacy and early-dose titration is recommend based on this. Erdafitinib has level [III, B] evidence of activity in pretreated patients with FGFR alterations.

Phase II data has been reported on enfortumab vedotin (EV) in UC patients refractory to platinum-based ChT and immune checkpoint inhibitors. Confirmed RR were 44% (95% CI 35–53%). mPFS and OS were 5.8 months (95% CI 4.9–7.5) and 11.7 months (95% CI 9.1–NA), respectively [11]. The phase I EV-101 trial with EV included 112 patients with platinum-refractory disease, and 79% had also received prior immune checkpoint inhibitors. Confirmed overall response rate (ORR) was 42%. [12]. EV has level [III, B] evidence of activity in this setting and can be considered in this population, despite the lack of regulatory approval.


  • Erdafitinib can be considered in pretreated patients with advanced UC bearing FGFR2/3 alterations [III, B]. EV can be considered in UC patients refractory to platinum ChT and immune checkpoint inhibitors, if available [III, B].


Table. Summary of recommendations for immune and targeted therapy

  First-line cisplatin-ineligible, PD-L1 positive Platinum-refractory Platinum- and ICI-refractory
Pembrolizumab [1, 8] [III, B] [I, A]  
Atezolizumab [2–4, 9] [III, B] [II, B]  
Nivolumab [7]   [III, B]  
Avelumab [6]   [III, C]*  
Durvalumab [5]   [III, C]*  
Enfortumab vedotin [11, 12]     [III, B]*
Erdafitinib [10]   [III, B]* [III, B]*

*Not EMA-approved as of 22 August 2019.
Levels of evidence and grades of recommendation are presented according to the grading system used for all ESMO Clinical Practice Guidelines (adapted from the Infectious Diseases Society of America - United States Public Health Service Grading System); see Table 3 in the original text. 

EMA, European Medicines Agency; ICI, immune checkpoint inhibitor; PD-L1, programmed death-ligand 1.


  1. Bellmunt J, de Wit R, Vaughn DJ et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376(11):1015–1026.
  2. Powles T, Durán I, van der Heijden MS et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018; 391(10122): 748–757.
  3. Rosenberg JE, Hoffman-Censits J, Powles T et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016; 387(10031): 1909–1920.
  4. Sternberg CN, Loriot Y, James N et al. Primary results from SAUL, a multinational single-arm safety study of atezolizumab therapy for locally advanced or metastatic urothelial or nonurothelial carcinoma of the urinary tract. Eur Urol 2019; 76(1): 73–81.
  5. Powles T, O’Donnell PH, Massard C et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 2017; 3(9): e172411.
  6. Patel MR, Ellerton J, Infante JR et al. 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; 19(1): 51–64.
  7. Sharma P, Retz M, Siefker-Radtke A et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017; 18(3): 312–322.
  8. Balar AV, Castellano D, O’Donnell PH et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicenter, single-arm, phase 2 study. Lancet Oncol 2017; 18(11): 1483–1492.
  9. Balar AV, Galsky MD, Rosenberg JE et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389(10064): 67–76.
  10. Loriot Y, Necchi A, Park SH et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019; 381(4): 338–348.
  11. Petrylak DP, Balar AV, O'Donnell PH et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol 2019; 37(suppl): abstr LBA4505.
  12. Rosenberg JE, Sridhar SS, Zhang J et al. Mature results from EV-101: A phase I study of enfortumab vedotin in patients with metastatic urothelial cancer (mUC). J Clin Oncol 2019; 37(suppl 7S); abstr 377.