The role of modern immunotherapy in metastatic urothelial cancer: mini review

Abstract

The approval of immune checkpoint inhibitors (ICIs) has changed the treatment landscape in many aspects of urothelial cancer (UC), in both non-muscle-invasive bladder cancer and muscle-invasive bladder cancer and has introduced the concept of long-term remission for some patients in the metastatic setting. Front-line chemotherapy remains superior at achieving initial control of disease compared to front-line immune therapy. However, long-term durable responses are limited by chemotherapy resistance. The maintenance approach, sequencing chemotherapy with ICIs, could be considered a best of both worlds approach, achieving initial control with chemotherapy, which is maintained in some individuals with avelumab. However, outcomes for patients with metastatic UC remain poor. There are three steps to improving outcomes for these patients; the first is to develop better drugs and combinations of therapies, the second is the development of novel biomarkers and techniques to better select patients for treatment, and the third area of development is to give the drugs in the most optimal setting.

Keywords

Metastatic urothelial cancer / bladder cancer / immune therapy / immune checkpoint inhibitors / biomarkers

References

[1] Flaig TW,Agarwal N.Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology.J Natl Compr Canc Netw2020;18:329-54

[2] Stenehjem DD,Nkrumah MA.PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer.Onco Targets Ther2018;11:5973-89 PMCID:PMC6157986

[3] Powles T,Comperat E.Electronic address: [e-mail]. bladder cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up.Ann Oncol2022;33:244-58

[4] Balar AV,Kulkarni GS.Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study.Lancet Oncol2021;22:919-30

[5] Bajorin DF,Gschwend JE.Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma.N Engl J Med2021;384:2102-14 PMCID:PMC8215888

[6] Kim YR,You D.Gemcitabine plus split-dose cisplatin could be a promising alternative to gemcitabine plus carboplatin for cisplatin-unfit patients with advanced urothelial carcinoma.Cancer Chemother Pharmacol2015;76:141-53

[7] Sonpavde GP,Lo Vullo S.Impact of the number of cycles of platinum based first line chemotherapy for advanced urothelial carcinoma.J Urol2018;200:1207-14 PMCID:PMC6814293

[8] von der Maase H,Roberts JT.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 Oncol2000;18:3068-77

[9] von der Maase H,Roberts JT.Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer.JCO2005;23:4602-8

[10] Dogliotti L,Siena S.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 Urol2007;52:134-41

[11] De Santis M,Mead G.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 Oncol2012;30:191-9 PMCID:PMC3255563

[12] Powles T,Fine GD.MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer.Nature2014;515:558-62

[13] Plimack ER,Gupta S.Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study.Lancet Oncol2017;18:212-20

[14] Petrylak DP,Bellmunt J.Atezolizumab (MPDL3280A) monotherapy for patients with metastatic urothelial cancer: long-term outcomes from a phase 1 study.JAMA Oncol2018;4:537-44 PMCID:PMC5885219

[15] Rosenberg JE,Powles T.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.Lancet2016;387:1909-20 PMCID:PMC5480242

[16] Apolo AB,Balmanoukian A.Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study.J Clin Oncol2017;35:2117-24 PMCID:PMC5493051

[17] Patel MR,Infante JR.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 Oncol2018;19:51-64 PMCID:PMC7984727

[18] Massard C,Sharma S.Safety and efficacy of durvalumab (MEDI4736), an anti-programmed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder cancer.J Clin Oncol2016;34:3119-25 PMCID:PMC5569690

[19] Powles T,Massard C.Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study.JAMA Oncol2017;3:e172411 PMCID:PMC5824288

[20] Sharma P,Bono P.Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial.Lancet Oncol2016;17:1590-8 PMCID:PMC5648054

[21] Sharma P,Siefker-radtke A.Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial.Lancet Oncol2017;18:312-22

[22] Bellmunt J,Demkov T.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 Oncol2009;27:4454-61

[23] Sonpavde G,Choueiri TK.Single-agent taxane versus taxane-containing combination chemotherapy as salvage therapy for advanced urothelial carcinoma.Eur Urol2016;69:634-41

[24] Bellmunt J,Vaughn DJ.Pembrolizumab as second-line therapy for advanced urothelial carcinoma.N Engl J Med2017;376:1015-26 PMCID:PMC5635424

[25] Powles T,van der Heijden MS.Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial.Lancet2018;391:748-57

[26] Powles T,Castellano D.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 Oncol2020;21:1574-88

[27] Powles T,Özgüroğlu M.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 Oncol2021;22:931-45

[28] Galsky MD,Bamias A.Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.Lancet2020;395:1547-57

[29] Powles T,Voog E.Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma.N Engl J Med2020;383:1218-30

[30] Szabados B,Jackson-Spence F,Powles T.Immune checkpoint inhibitors in front-line therapy for urothelial cancer.Eur Urol Oncol2021;4:943-7

[31] Friedlander TW,Bilen MA.Study EV-103: update on durability results and long term outcome of enfortumab vedotin + pembrolizumab in first line locally advanced or metastatic urothelial carcinoma (la/mUC).JCO2021;39:4528-4528

[32] Sharma P,de Braud F.Nivolumab alone and with ipilimumab in previously treated metastatic urothelial carcinoma: checkmate 032 nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg expansion cohort results.J Clin Oncol2019;37:1608-16 PMCID:PMC6879315

[33] Sadeghi S.Phase II trial of Pembrolizumab (P) in combination with sEphB4-HSA (B4) in previously treated metastatic urothelial carcinoma (mUC). In presented at european society for medical oncology (esmo) annual congress; 2021 September 16-21; Barcelona, Spain.

[34] Loriot Y,Park SH.Erdafitinib in locally advanced or metastatic urothelial carcinoma.N Engl J Med2019;381:338-48

[35] Powles T,Chowdhury S.An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer.Nat Med2021;27:793-801

[36] Powles T,Sonpavde GP.Enfortumab vedotin in previously treated advanced urothelial carcinoma.N Engl J Med2021;384:1125-35 PMCID:PMC8450892

[37] Tagawa ST,Petrylak DP.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 Oncol2021;39:2474-85 PMCID:PMC8315301

[38] Bellmunt J,Gschwend JE.Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial.Lancet Oncol2021;22:525-37 PMCID:PMC8495594

[39] Powles T,Davarpanah N.ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.Nature2021;595:432-7

[40] Queiroz MM,Gongora ABL.Emerging biomarkers in metastatic urothelial carcinoma: tumour mutational burden, PD-L1 expression and APOBEC polypeptide-like signature in a patient with complete response to anti-programmed cell death protein-1 inhibitor.Ecancermedicalscience2021;15:1306 PMCID:PMC8580725

[41] Balar AV,Rosenberg JE.Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.Lancet2017;389:67-76 PMCID:PMC5568632

[42] Sheng X,Wang L.Open-label, multicenter, phase II study of RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with locally advanced or metastatic urothelial carcinoma.Clin Cancer Res2021;27:43-51