PURPOSE OF REVIEW: This review provides an overview of currently ongoing clinical trials evaluating the combination of immune checkpoint inhibitors (CPI) with other therapies in locally advanced or metastatic urothelial cancer and the rationale for this combination approach. We discuss the preliminary results from early data presented at recent meetings regarding the efficacy and safety of novel combination therapies including a CPI for metastatic urothelial cancer. RECENT FINDINGS: CPI emerged as novel first-line or second-line treatment options in advanced and metastatic urothelial cancer (mUC). Although the response rates and their sustainability are promising, it is far from a home run. Combination therapies have already shown improved efficacy in several other tumor entities. SUMMARY: Numerous clinical trials currently investigate combinations of CPI with other CPI, previously established systemic chemotherapy, targeted therapies, vaccines, or accompanied with radiotherapy. Preliminary data shows promising results. These results suggest that targeting pathways of immune response combined with established or novel oncological therapies may lead to a synergistic antitumor effect.

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology University of Jordan Amman Jordan

Department of Urology University of Texas Southwestern Dallas Texas USA

Department of Urology Weill Cornell Medical College New York New York

European Association of Urology Research Foundation Arnhem Netherlands

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

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Roupret M, Babjuk M, Comperat E, et al. European Association of Urology Guidelines on upper urinary tract urothelial carcinoma: 2017 update. Eur Urol 2018; 73:111–122.

Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on nonmuscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 update. Eur Urol 2019; 76:639–657.

Moschini M, Shariat SF, Roupret M, et al. Impact of primary tumor location on survival from the European Organization for the Research and Treatment of Cancer Advanced Urothelial Cancer Studies. J Urol 2018; 199:1149–1157.

von der Maase H, Sengelov L, Roberts JT, et al. 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; 23:4602–4608.

De Santis M, Bellmunt J, Mead G, et al. 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; 30:191–199.

Fradet Y, Bellmunt J, Vaughn DJ, et al. 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; 30:970–976.

Bellmunt J, Fougeray R, Rosenberg JE, et al. Long-term survival results of a randomized phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann Oncol 2013; 24:1466–1472.

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 multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18:1483–1492.

Balar AV, Galsky MD, Rosenberg JE, et al. IMvigor210 Study GroupAtezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017; 389:67–76.

Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376:1015–1026.

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; 19:51–64.

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:e172411.

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; 387:1909–1920.

Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multiarm, phase 1/2 trial. Lancet Oncol 2016; 17:1590–1598.

Sharma P, Siefker-Radtke A, de Braud F, et al. 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 Oncol 2019; 37:1608–1616.

D’Errico G, Machado HL, Sainz B Jr. A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet. Clin Transl Med 2017; 6:3.

Powles T, Galsky MD, Castellano D, et al. A phase 3 study of first-line durvalumab (MEDI4736) ± tremelimumab versus standard of care (SoC) chemotherapy (CT) in patients (pts) with unresectable stage IV urothelial bladder cancer (UBC): DANUBE. J Clin Oncol 2016; 34: (15_Suppl): TPS4574-TPS.

Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369:122–133.

Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 2019; 381:2020–2031.

Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378:1277–1290.

Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clin Cancer Res 2011; 17:6958–6962.

Galsky MD, Powles T, Li S, et al. A phase 3, open-label, randomized study of nivolumab plus ipilimumab or standard of care (SOC) versus SOC alone in patients (pts) with previously untreated unresectable or metastatic urothelial carcinoma (mUC; CheckMate 901). J Clin Oncol 2018; 36: (6 Suppl): TPS539-TPS.

Powles T, Gschwend JE, Loriot Y, et al. Phase 3 KEYNOTE-361 trial: pembrolizumab (pembro) with or without chemotherapy versus chemotherapy alone in advanced urothelial cancer. J Clin Oncol 2017; 35: (15 Suppl): TPS4590-TPS.

Grande E, Galsky M, Arranz Arija JA, et al. LBA14_PRIMvigor130: efficacy and safety from a phase III study of atezolizumab (atezo) as monotherapy or combined with platinum-based chemotherapy (PBC) vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC). Ann Oncol 2019; 30: (Suppl 5):

Grande E. ESMO 2019: IMvigor130: efficacy and safety from a phase 3 study of atezolizumab as monotherapy or combined with platinum-based chemotherapy vs placebo + PBC in previously untreated locally advanced or metastatic urothelial carcinoma. Annals of Oncology 2019; 30: (suppl_5): v851–v934.

Galsky MD, Wang H, Hahn NM, et al. Phase 2 trial of gemcitabine, cisplatin, plus ipilimumab in patients with metastatic urothelial cancer and impact of DNA damage response gene mutations on outcomes. Eur Urol 2018; 73:751–759.

Galsky MD, Necchi A, Sridhar SS, et al. A phase III, randomized, open-label, multicenter, global study of first-line (1L) durvalumab in combination with standard of care (SoC) chemotherapy and durvalumab in combination with tremelimumab and soc chemotherapy versus soc chemotherapy alone in patients with unresectable locally advanced or metastatic urothelial cancer (UC). J Clin Oncol 2019; 37: (7 Suppl): TPS499-TPS.

Vida AR, Mellado B, Muro XGd, et al. Phase II randomized study of first line avelumab with carboplatin-gemcitabine versus carboplatin-gemcitabine alone in patients with metastatic urothelial carcinoma ineligible for cisplatin-based therapy. J Clin Oncol 2018; 36: (15 Suppl): TPS4591-TPS.

Abraxane with anti-PD1/PDL1 in patients with advanced urothelial cancer. Available at: https://ClinicalTrials.gov/show/NCT03240016. [Accessed 6 January 2020]

Pembrolizumab and nab paclitaxel in patients with metastatic urothelial carcinoma. Available at: https://ClinicalTrials.gov/show/NCT03464734. [Accessed 6 January 2020]

Paclitaxel and pembrolizumab in treating patients with refractory metastatic urothelial cancer. Available at: https://ClinicalTrials.gov/show/NCT02581982. [Accessed 6 January 2020]

Trial of atezolizumab plus chemotherapy after progression on PD-1 or PD-L1 in cisplatin-ineligible patients with advanced urothelial carcinoma. Available at: https://ClinicalTrials.gov/show/NCT03737123. [Accessed 6 January 2020]

Casadei C, Dizman N, Schepisi G, et al. Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors. Ther Adv Med Oncol 2019; 11: 1758835919890285.

Kamoun A, de Reynies A, Allory Y, et al. A Consensus molecular classification of muscle-invasive bladder cancer. Eur Urol 2019; pii: S0302-2838(19)30695-5. doi: 10.1016/j.eururo.2019.09.006. [Epub ahead of print]. DOI

Wang L, Gong Y, Saci A, et al. Fibroblast growth factor receptor 3 alterations and response to PD-1/PD-L1 blockade in patients with metastatic urothelial cancer. Eur urol 2019; 76:599–603.

Cheng T, Roth B, Choi W, et al. Fibroblast growth factor receptors-1 and -3 play distinct roles in the regulation of bladder cancer growth and metastasis: implications for therapeutic targeting. PLoS One 2013; 8:e57284.

Gust KM, McConkey DJ, Awrey S, et al. Fibroblast growth factor receptor 3 is a rational therapeutic target in bladder cancer. Mol Cancer Ther 2013; 12:1245–1254.

Tan HY, Wang N, Lam W, et al. Targeting tumour microenvironment by tyrosine kinase inhibitor. Mol Cancer 2018; 17:43.

Yates A, Akanni W, Amode MR, et al. Ensembl 2016. Nucleic Acids Res 2016; 44 (D1):D710–D716.

Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. New Engl J Med 2019; 381:338–348.

A study to evaluate safety, efficacy, pharmacokinetics, and pharmacodynamics of Erdafitinib Plus JNJ-63723283 (Cetrelimab), an anti-PD-1 monoclonal antibody, in participants with metastatic or locally advanced urothelial cancer with selected FGFR Gene alterations. Available at: https://ClinicalTrials.gov/show/NCT03473743. [Accessed 6 January 2020]

Derazantinib and atezolizumab in patients with urothelial cancer. Available at: https://ClinicalTrials.gov/show/NCT04045613. [Accessed 6 January 2020]

Pemigatinib + pembrolizumab vs pemigatinib alone vs standard of care for urothelial carcinoma (FIGHT-205). Available at: https://ClinicalTrials.gov/show/NCT04003610. [Accessed 6 January 2020]

Phase 1b/2 study of rogaratinib (BAY1163877) in combination with atezolizumab in urothelial carcinoma. Available at: https://ClinicalTrials.gov/show/NCT03473756. [Accessed 6 January 2020]

A study of B-701 in combination with pembrolizumab in treatment of locally advanced or metastatic urothelial cell carcinoma. Available at: https://ClinicalTrials.gov/show/NCT03123055. [Accessed 6 January 2020]

Phase 1b/2 trial of lenvatinib (E7080) plus pembrolizumab in subjects with selected solid tumors. Available at: https://ClinicalTrials.gov/show/NCT02501096. [Accessed 6 January 2020]

Study of first-line pembrolizumab (MK-3475) with lenvatinib (MK-7902/E7080) in urothelial carcinoma cisplatin-ineligible participants whose tumors express programmed cell death-ligand 1 and in participants ineligible for platinum-containing chemotherapy (MK-7902-011/E7080-G000-317/LEAP-011). Available at: https://ClinicalTrials.gov/show/NCT03898180. [Accessed 6 January 2020]

Study of sitravatinib and nivolumab in urothelial carcinoma. Available at: https://ClinicalTrials.gov/show/NCT03606174. [Accessed 6 January 2020]

Cabozantinib S-malate and nivolumab with or without ipilimumab in treating patients with metastatic genitourinary tumors. Available at: https://ClinicalTrials.gov/show/NCT02496208. [Accessed 6 January 2020]

Atezolizumab with bevacizumab in previously untreated metastatic/unresectable urothelial cancer. Available at: https://ClinicalTrials.gov/show/NCT03272217. [Accessed 6 January 2020]

A study of enfortumab vedotin alone or with other therapies for treatment of urothelial cancer. Available at: https://ClinicalTrials.gov/show/NCT03288545. [Accessed 6 January 2020]

A study of durvalumab alone and durvalumab+olaparib in advanced, platinum-ineligible bladder cancer (BAYOU). Available at: https://ClinicalTrials.gov/show/NCT03459846. [Accessed 6 January 2020]

A multicenter, open label, phase II basket trial exploring the efficacy and safety of the combination of rucaparib (PARP inhibitor) and atezolizumab (anti-PD-L1 antibody) in patients with DNA repair-deficient or platinum-sensitive solid tumors. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-001744-62/FR. [Accessed 6 January 2020]

CV301 combined with PD-1/L1 blockade in patients with locally advanced or metastatic urothelial bladder cancer. Available at: https://ClinicalTrials.gov/show/NCT03628716. [Accessed 6 January 2020]

Open-label, randomised, multi-drug, biomarker-directed, phase Ib study in Pts w/muscle invasive bladder cancer. Available at: https://ClinicalTrials.gov/show/NCT02546661. [Accessed 6 January 2020]

A study evaluating the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with locally advanced or metastatic urothelial carcinoma after failure with platinum-containing chemotherapy Available at: https://ClinicalTrials.gov/show/NCT03869190. [Accessed 6 January 2020]

A dose escalation and cohort expansion study of NKTR-214 in combination with nivolumab and other anti-cancer therapies in patients with select advanced solid tumors (PIVOT-02). Available at: https://ClinicalTrials.gov/show/NCT02983045. [Accessed 6 January 2020]

A single-arm study of bempegaldesleukin (NKTR-214) plus nivolumab in cisplatin ineligible patients who have locally advanced or metastatic urothelial cancer. Available at: https://ClinicalTrials.gov/show/NCT03785925. [Accessed 6 January 2020]

A study of a CD122-biased cytokine (NKTR-214) in combination with anti-PD-1 (pembrolizumab) in patients with select advanced or metastatic solid tumors.

Study to evaluate the efficacy/safety of IPI-549 in combination with nivolumab in patients with advanced urothelial carcinoma (MARIO-275). Available at: https://ClinicalTrials.gov/show/NCT03980041. [Accessed 6 January 2020]

Avelumab in combination with AVB-S6-500 in patients with advanced urothelial carcinoma. Available at: https://ClinicalTrials.gov/show/NCT04004442. [Accessed 6 January 2020]

Sonidegib and pembrolizumab in treating patients with advanced solid tumors. Available at: https://ClinicalTrials.gov/show/NCT04007744. [Accessed 6 January 2020]

Siefker-Radtke AO, Currie G, Abella E, et al. FIERCE-22: clinical activity of vofatamab (V) a FGFR3 selective inhibitor in combination with pembrolizumab (P) in WT metastatic urothelial carcinoma, preliminary analysis. J Clin Oncol 2019; 37: (15 Suppl): 4511.

Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti and pro-angiogenic therapies. Genes Cancer 2011; 2:1097–1105.

Apolo AB, Parnes HL, Francis DC, et al. A phase II study of cabozantinib in patients (pts) with relapsed or refractory metastatic urothelial carcinoma (mUC). J Clin Oncol 2016; 34: (15 Suppl): 4534.

Vogelzang NJ, Encarnacion CA, Cohn AL, et al. Phase Ib/II trial of lenvatinib plus pembrolizumab in urothelial cancer. J Clin Oncol 2019; 37: (8 Suppl): 11.

Doshi GK, Vogelzang NJ, Richards DA, et al. Phase II study of sitravatinib in combination with nivolumab in patients with advanced or metastatic urothelial carcinoma (UC) after checkpoint inhibitor therapy (CIT). J Clin Oncol 2019; 37: (7 Suppl): TPS498-TPS.

Vlachostergios PJ, Jakubowski CD, Niaz MJ, et al. Antibody-drug conjugates in bladder cancer. Bladder Cancer 2018; 4:247–259.

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: (18 Suppl): 4505.

Hoimes CJ. ESMO 2019: EV-103 enfortumab vedotin plus pembrolizumab for urothelial carcinoma.

Morales J, Li L, Fattah FJ, et al. Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit Rev Eukaryot Gene Expr 2014; 24:15–28.

Boussios S, Karihtala P, Moschetta M, et al. Combined strategies with poly (ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer: a literature review. Diagnostics (Basel) 2019; 9:87.

Virtanen V, Paunu K, Ahlskog JK, et al. PARP inhibitors in prostate cancer-the preclinical rationale and current clinical development. Genes 2019; 10: pii: E565.

Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-associated immunosuppression. Clin Cancer Res 2017; 23:3711–3720.

Gatti-Mays ME, Strauss J, Donahue RN, et al. A phase I dose-escalation trial of BN-CV301, a recombinant poxviral vaccine targeting MUC1 and CEA with costimulatory molecules. Clin Cancer Res 2019; 25:4933–4944.

Nordic B. Bavarian nordic updates on phase 2 study of CV301 in bladder cancer Copenhagen2019 [October 18, 2019]. Available at: http://www.bavarian-nordic.com/investor/news/news.aspx?news=5773. [Accessed 6 January 2020]

Powles T, Balar A, Gravis G, et al. 902OAn adaptive, biomarker directed platform study in metastatic urothelial cancer (BISCAY) with durvalumab in combination with targeted therapies. Ann Oncol 2019; 30: (Suppl 5): v356–v402.

Bentebibel SE, Hurwitz ME, Bernatchez C, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rbetagamma-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019; 9:711–721.

Charych DH, Hoch U, Langowski JL, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res 2016; 22:680–690.

Siefker-Radtke AO, Fishman MN, Balar AV, et al. NKTR-214 + nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): updated results from PIVOT-02. J Clin Oncol 2019; 37: (7 Suppl): 388.

Zheng Y, Fang YC, Li J. PD-L1 expression levels on tumor cells affect their immunosuppressive activity. Oncol Lett 2019; 18:5399–5407.

Guo Z, Li Y, Zhang D, Ma J. Axl inhibition induces the antitumor immune response which can be further potentiated by PD-1 blockade in the mouse cancer models. Oncotarget 2017; 8:89761–89774.

Solanki AA, Bossi A, Efstathiou JA, et al. Combining immunotherapy with radiotherapy for the treatment of genitourinary malignancies. Eur Urol Oncol 2019; 2:79–87.

Ko EC, Formenti SC. Radiotherapy and checkpoint inhibitors: a winning new combination? Ther Adv Med Oncol 2018; 10: 1758835918768240.

Rodriguez-Vida A, Perez-Gracia JL, Bellmunt J. Immunotherapy combinations and sequences in urothelial cancer: facts and hopes. Clin Cancer Res 2018; 24:6115–6124.

Anti-PD(L)1 and SBRT in the treatment of advanced, platinum-refractory urothelial carcinoma. Available at: https://ClinicalTrials.gov/show/NCT03287050. [Accessed 6 January 2020]

A phase II randomized trial of immunotherapy plus radiotherapy in metastatic genitourinary cancers. Available at: https://ClinicalTrials.gov/show/NCT03115801. [Accessed 6 January 2020]

Pembrolizumab in muscle invasive/metastatic bladder cancer. Available at: https://ClinicalTrials.gov/show/NCT02560636. [Accessed 6 January 2020]

Tree AC, Jones K, Hafeez S, et al. Dose-limiting urinary toxicity with pembrolizumab combined with weekly hypofractionated radiation therapy in bladder cancer. Int J Radiat Oncol Biol Phys 2018; 101:1168–1171.