Investig Clin Urol.  2018 Sep;59(5):285-296. 10.4111/icu.2018.59.5.285.

Immune checkpoint inhibitors for urothelial carcinoma

• Kim HS
• Seo HK

• KMID: 2419411
• DOI: http://doi.org/10.4111/icu.2018.59.5.285

Abstract

Urothelial carcinoma (UC), originating in the bladder or upper urinary tract, is the most common histological type of cancer. Currently, platinum-based cytotoxic chemotherapy is the standard treatment for metastatic UC (mUC) and the preferred treatment option in the perioperative (neoadjuvant and/or adjuvant) setting of muscle invasive bladder cancer (MIBC). In addition, intravesical bacillus Calmette-Guerin immunotherapy or chemotherapy is applied as the adjuvant therapeutic option in non-muscle invasive bladder cancer (NMIBC) after transurethral resection, to prevent recurrence and progression. In recent years, with an increased understanding of cancer immunobiology, systemic immunotherapies targeting immune checkpoint inhibition has been explored and clinically used in the area of UC. The programmed cell death 1 receptor (PD-1) and its ligand (PD-L1) are important negative regulators of immune activity, preventing the destruction of normal tissues and autoimmunity. To date, five immune checkpoint inhibitors blocking PD-1 (pembrolizumab, nivolumab) or PD-L1 (atezolizumab, durvalumab, and avelumab) have been approved by the United States Food and Drug Administration (US-FDA) for first- or second-line use in mUC, based on durable therapeutic response and manageable safety profiles observed in relevant clinical trials. In addition, the clinical use of several immune checkpoint inhibitors is currently being tested for MIBC and NMIBC. In this article, we review the current and ongoing clinical trials, regarding immune checkpoint inhibitors, being conducted in various clinical settings of UC, including mUC, MIBC, and NMIBC.

Keyword

Immunotherapy; PD-1 inhibitor; PD-L1 inhibitor; Urinary bladder neoplasms

MeSH Terms

Autoimmunity
Bacillus
Drug Therapy
Immunotherapy
Programmed Cell Death 1 Receptor
Recurrence
United States Food and Drug Administration
Urinary Bladder
Urinary Bladder Neoplasms
Urinary Tract
Programmed Cell Death 1 Receptor

Reference

1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013; 49:1374–1403. PMID: 23485231.

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; 66:7–30. PMID: 26742998.

3. Jung KW, Won YJ, Kong HJ, Lee ES. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2015. Cancer Res Treat. 2018; 50:303–316. PMID: 29566481.

4. Clark PE, Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK, et al. NCCN guidelines insights: bladder cancer, version 2.2016. J Natl Compr Canc Netw. 2016; 14:1213–1224. PMID: 27697976.

5. Alfred Witjes J, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM, et al. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2017; 71:462–475. PMID: 27375033.

6. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, 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. PMID: 22162575.

7. Galsky MD, Pal SK, Lin SW, Ogale S, Zivkovic M, Simpson J, et al. Real-world effectiveness of chemotherapy in elderly patients with metastatic bladder cancer in the United States. Bladder Cancer. 2018; 4:227–238. PMID: 29732393.

8. Niegisch G, Gerullis H, Lin SW, Pavlova J, Gondos A, Rudolph A, et al. A real-world data study to evaluate treatment patterns, clinical characteristics and survival outcomes for first- and second-line treatment in locally advanced and metastatic urothelial cancer patients in Germany. J Cancer. 2018; 9:1337–1348. PMID: 29721042.

9. Lichtenegger FS, Rothe M, Schnorfeil FM, Deiser K, Krupka C, Augsberger C, et al. Targeting LAG-3 and PD-1 to enhance T cell activation by antigen-presenting cells. Front Immunol. 2018; 9:385. PMID: 29535740.

10. Baksh K, Weber J. Immune checkpoint protein inhibition for cancer: preclinical justification for CTLA-4 and PD-1 blockade and new combinations. Semin Oncol. 2015; 42:363–377. PMID: 25965355.

11. Marin-Acevedo JA, Soyano AE, Dholaria B, Knutson KL, Lou Y. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018; 11:8. PMID: 29329556.

12. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015; 161:205–214. PMID: 25860605.

13. Efremova M, Finotello F, Rieder D, Trajanoski Z. Neoantigens generated by individual mutations and their role in cancer immunity and immunotherapy. Front Immunol. 2017; 8:1679. PMID: 29234329.

14. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013; 500:415–421. PMID: 23945592.

15. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348:124–128. PMID: 25765070.

16. Kates M, Sopko NA, Matsui H, Drake CG, Hahn NM, Bivalacqua TJ. Immune checkpoint inhibitors: a new frontier in bladder cancer. World J Urol. 2016; 34:49–55. PMID: 26487055.

17. Kim J. Immune checkpoint blockade therapy for bladder cancer treatment. Investig Clin Urol. 2016; 57(Suppl 1):S98–S105.

18. Chism DD. Urothelial carcinoma of the bladder and the rise of immunotherapy. J Natl Compr Canc Netw. 2017; 15:1277–1284. PMID: 28982752.

19. Donin NM, Lenis AT, Holden S, Drakaki A, Pantuck A, Belldegrun A, et al. Immunotherapy for the treatment of urothelial carcinoma. J Urol. 2017; 197:14–22. PMID: 27460757.

20. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, 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. PMID: 26952546.

21. Perez-Gracia JL, Loriot Y, Rosenberg JE, Powles T, Necchi A, Hussain SA, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: outcomes by prior number of regimens. Eur Urol. 2018; 73:462–468.

22. Inman BA, Longo TA, Ramalingam S, Harrison MR. Atezolizumab: a PD-L1-blocking antibody for bladder cancer. Clin Cancer Res. 2017; 23:1886–1890. PMID: 27903674.

23. Powles T, Durán I, van der Heijden MS, Loriot Y, Vogelzang NJ, De Giorgi U, 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; 391:748–757. PMID: 29268948.

24. Necchi A, Joseph RW, Loriot Y, Hoffman-Censits J, Perez-Gracia JL, Petrylak DP, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: postprogression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017; 28:3044–3050. PMID: 28950298.

25. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017; 376:1015–1026. PMID: 28212060.

26. Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017; 18:312–322. PMID: 28131785.

27. Powles T, O'Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, 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. PMID: 28817753.

28. Patel MR, Ellerton J, Infante JR, Agrawal M, Gordon M, Aljumaily R, 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. PMID: 29217288.

29. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, 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; 389:67–76. PMID: 27939400.

30. Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, 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. PMID: 28967485.

31. Lara P, Beckett L, Li Y, Parikh M, Robles D, Aujla P, et al. Combination checkpoint immunotherapy and cytotoxic chemotherapy: pembrolizumab (pembro) plus either docetaxel or gemcitabine in patients with advanced or metastatic urothelial cancer. J Clin Oncol. 2017; 35:398.

32. Galsky MD, Wang H, Hahn NM, Twardowski P, Pal SK, Albany C, 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. PMID: 29248319.

33. US National Library of Medicine. Study of atezolizumab as monotherapy and in combination with platinum-based chemotherapy in participants with untreated locally advanced or metastatic urothelial carcinoma (IMvigor130) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02807636.

34. Powles T, Gschwend JE, Loriot Y, Bellmunt J, Geczi L, Vulsteke C, 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:TPS4590-TPS.

35. Galsky MD, Powles T, Li S, Hennicken D, Sonpavde G. 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:TPS539-TPS.

36. Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Dvorak HF, et al. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol. 1993; 143:1255–1262. PMID: 8238242.

37. Lamy A, Gobet F, Laurent M, Blanchard F, Varin C, Moulin C, et al. Molecular profiling of bladder tumors based on the detection of FGFR3 and TP53 mutations. J Urol. 2006; 176:2686–2689. PMID: 17085196.

38. US National Library of Medicine. Open-label, randomised, multi-drug, biomarker-directed, phase 1b study in pts w/muscle invasive bladder cancer (BISCAY) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02546661.

39. US National Library of Medicine. A study of ramucirumab plus pembrolizumab in participants with gastric or GEJ adenocarcinoma, NSCLC, transitional cell carcinoma of the urothelium, or biliary tract cancer [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02443324.

40. US National Library of Medicine. A study of nivolumab by itself or nivolumab combined with ipilimumab in patients with advanced or metastatic solid tumors [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT01928394.

41. Powles T, Galsky MD, Castellano D, Heijden MSVD, Petrylak DP, Armstrong J, 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:TPS4574-TPS.

42. US National Library of Medicine. Safety and efficacy of MBG453 as single agent and in combination with PDR001 in patients with advanced malignancies [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02608268.

43. Ascierto PA, Bono P, Bhatia S, Melero I, Nyakas MS, Svane IM, et al. LBA18Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations. Ann Oncol. 2017; 28:mdx440.011-mdx440.011.

44. Infante J, Ahlers CM, Hodi FS, Postel-Vinay S, Schellens JH, Heymach JV, et al. Abstract CT027: A phase I, open-label study of GSK3174998 administered alone and in combination with pembrolizumab in patients (pts) with selected advanced solid tumors (ENGAGE-1). Cancer Res. 2016; 76:CT027-CT.

45. Pedersen AW, Kopp KL, Andersen MH, Zocca MB. Immunoregulatory antigens-novel targets for cancer immunotherapy. Chin Clin Oncol. 2018; 7:19. PMID: 29764164.

46. Cekic C, Day YJ, Sag D, Linden J. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res. 2014; 74:7250–7259. PMID: 25377469.

47. McCaffery I, Laport G, Hotson A, Willingham S, Patnaik A, Beeram M, et al. Biomarker and clinical activity of CPI-444, a novel small molecule inhibitor of A2A receptor (A2AR), in a Ph1b study in advanced cancers. Ann Oncol. 2016; 27(Suppl 6):vi114–vi135.

48. Smith DC, Gajewski T, Hamid O, Wasser JS, Olszanski AJ, Patel SP, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol. 2017; 35:4503.

49. US National Library of Medicine. A study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02318277.

50. US National Library of Medicine. Phase 1/1b study to evaluate the safety and tolerability of CPI-444 alone and in combination with atezolizumab in advanced cancers [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02655822.

51. Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. 2017; 71:447–461. PMID: 27324428.

52. US National Library of Medicine. A study of atezolizumab versus observation as adjuvant therapy in participants with highrisk muscle-invasive urothelial carcinoma (UC) after surgical resection (IMvigor010) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02450331.

53. US National Library of Medicine. An investigational immunotherapy study of nivolumab, compared to placebo, in patients with bladder or upper urinary tract cancer, following surgery to remove the cancer (CheckMate 274) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02632409.

54. US National Library of Medicine. Pembrolizumab in treating patients with locally advanced bladder cancer [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT03244384.

55. US National Library of Medicine. Neo-adjuvant bladder urothelial carcinoma combination-immunotherapy (NABUCCO) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT03387761.

56. US National Library of Medicine. Neoadjuvant nivolumab with and without urelumab in patients with cisplatin-ineligible muscle-invasive urothelial carcinoma of the bladder [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02845323.

57. US National Library of Medicine. Neoadjuvant pembrolizumab for muscle-invasive urothelial bladder carcinoma [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02736266.

58. US National Library of Medicine. Neoadjuvant pembrolizumab in combination with gemcitabine therapy in cis-eligible/ineligible UC subjects [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02365766.

59. US National Library of Medicine. Preoperative MPDL3280A in transitional cell carcinoma of the bladder (ABACUS) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02662309.

60. US National Library of Medicine. Pembrolizumab in intermediate risk recurrent non-muscle invasive bladder cancer (NMIBC) (PemBla) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT03167151.

61. US National Library of Medicine. Pembrolizumab and BCG solution in treating patients with recurrent non-muscleinvasive bladder cancer [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02808143.

62. US National Library of Medicine. Study of pembrolizumab (MK-3475) in participants with high risk non-muscle invasive bladder cancer (MK-3475-057/KEYNOTE-057) [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02625961.

63. US National Library of Medicine. Atezolizumab in treating patients with recurrent BCG-unresponsive non-muscle invasive bladder cancer [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02844816.

64. US National Library of Medicine. Safety and pharmacology study of atezolizumab alone and in combination with bacille calmette-guérin (BCG) in high-risk non-muscle-invasive bladder cancer (NMIBC) participants [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02792192.

65. US National Library of Medicine. Phase 2 durvalumab (Medi4736) for bacillus calmette-guérin (BCG) refactory urothelial carcinoma in situ of the bladder [Internet]. cited 2018 Jun 7. Available from: https://clinicaltrials.gov/ct2/show/NCT02901548.

66. Massard C, Gordon MS, Sharma S, Rafii S, Wainberg ZA, Luke J, et al. 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 Oncol. 2016; 34:3119–3125. PMID: 27269937.

67. Aggen DH, Drake CG. Biomarkers for immunotherapy in bladder cancer: a moving target. J Immunother Cancer. 2017; 5:94. PMID: 29157296.

68. Drake CG, Bivalacqua TJ, Hahn NM. Programmed cell death ligand-1 blockade in urothelial bladder cancer: to select or not to select. J Clin Oncol. 2016; 34:3115–3116. PMID: 27458310.

69. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373:1803–1813. PMID: 26406148.

70. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014; 25:152–165. PMID: 24525232.

71. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014; 507:315–322. PMID: 24476821.

72. Sweis RF, Spranger S, Bao R, Paner GP, Stadler WM, Steinberg G, et al. Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol Res. 2016; 4:563–568. PMID: 27197067.

73. Gajewski TF. The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin Oncol. 2015; 42:663–671. PMID: 26320069.