Emerging Role of Immunotherapy in Advanced Urothelial Carcinoma
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Purpose of Review
Advanced urothelial carcinoma (aUC) has long been treated preferably with cisplatin-based chemotherapy, but many patients are cisplatin-ineligible whereas for those who progress on a platinum-based regimen treatment options are limited. We review key recent data regarding immune checkpoint inhibitors that are changing this treatment landscape.
Since May 2016, five different agents targeting the PD-1/PD-L1 pathway (atezolizumab, pembrolizumab, nivolumab, avelumab, durvalumab) have received FDA approval for the treatment of aUC in the platinum-refractory setting, while pembrolizumab and atezolizumab are FDA-approved for cisplatin-ineligible patients in the first-line setting. Clinical outcomes and safety profiles of these agents appear relatively comparable across separate trials; however, only pembrolizumab is supported by level I evidence from a large randomized phase III trial showing overall survival benefit over conventional cytotoxic salvage chemotherapy in the platinum-refractory setting.
Pembrolizumab has the highest level of evidence in platinum-refractory aUC, whereas pembrolizumab and atezolizumab have comparable level of evidence in the frontline setting in cisplatin-ineligible patients. Ongoing research is evaluating novel agents, various rational combinations, and sequences, as well as predictive and prognostic biomarkers.
KeywordsMetastatic bladder cancer Advanced urothelial carcinoma Immunotherapy Immune checkpoint inhibitors PD-1 PD-L1 Cisplatin-ineligible Platinum-refractory Atezolizumab Pembrolizumab Avelumab Nivolumab Durvalumab Biomarkers clinical trials
Compliance with Ethical Standards
Conflict of Interest
Vadim S. Koshkin declares that he has no conflict of interest.
Petros Grivas has received compensation from Genentech, Dendreon, Bayer, Merck, Bristol-Myers Squibb, Exelixis, AstraZeneca, Biocept, Clovis Oncology, and EMD Serono for service as a consultant; participated in educational, unbranded, not product-related speaker’s program (after providing direct input for slides content) for Genentech and Bristol-Myers Squibb; and received support for conduction of clinical trials (to Cleveland Clinic Foundation) from Genentech, Bayer, Merck, Mirati, Oncogenex, Pfizer, Bristol-Myers Squibb, and AstraZeneca.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 1.Cancer of the Urinary Bladder - Cancer Stat Facts. Available at: https://seer.cancer.gov/statfacts/html/urinb.html. Accessed: 15th November 2017.
- 4.Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005;48:202–5; discussion 205-206.CrossRefGoogle Scholar
- 5.von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, 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 Off J Am Soc Clin Oncol. 2005;23:4602–8.CrossRefGoogle Scholar
- 9.Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom A, et al. 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 Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19:2638–46.CrossRefGoogle Scholar
- 11.von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. 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 Off J Am Soc Clin Oncol. 2000;18:3068–77.CrossRefGoogle Scholar
- 12.Bamias A, Dafni U, Karadimou A, Timotheadou E, Aravantinos G, Psyrri A, et al. 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;24:1011–7.CrossRefPubMedGoogle Scholar
- 14.De Santis M, et al. 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 Off J Am Soc Clin Oncol. 2009;27:5634–9.CrossRefGoogle Scholar
- 15.De Santis M, 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 Off J Am Soc Clin Oncol. 2012;30:191–9.CrossRefGoogle Scholar
- 21.Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. 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 Off J Am Soc Clin Oncol. 2009;27:4454–61.CrossRefGoogle Scholar
- 23.Brown JA, et al. Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol Baltim Md. 2003;1950(170):1257–66.Google Scholar
- 26.• Rosenberg JE, 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;387:1909–20. Summarizes the results of Cohort 2 in IMvigor 210, a phase II trial of atezolizumab in platinum-refractory aUC. This trial led to the first approval of an immunotherapy agent (atezolizumab) in platinum-refractory aUC. CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Press Announcements - FDA approves new, targeted treatment for bladder cancer. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm501762.htm. Accessed: 18th November 2017.
- 31.Roche provides update on phase III study of TECENTRIQ® (atezolizumab) in people with previously treated advanced bladder cancer. Available at: http://www.roche.com/media/store/releases/med-cor-2017-05-10.htm. Accessed: 18th November 2017.
- 32.Powles, 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. 2017.Google Scholar
- 34.•• Bellmunt J, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015–26. Summarizes the results of a landmark phase III trial (KEYNOTE-045) showing an overall survival advantage of pembrolizumab compared to chemotherapy in platinum-refractory aUC. This trial established pembrolizumab as the current standard of care in platinum-refractory aUC. CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Research, C. for D. E and. approved drugs—pembrolizumab (Keytruda): advanced or metastatic urothelial carcinoma. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm559300.htm. Accessed: 18th November 2017.
- 38.Research, C. for D. E. and approved drugs - Nivolumab for Treatment of Urothelial Carcinoma. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm539646.htm. Accessed: 18th November 2017.
- 39.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 Off J Am Soc Clin Oncol. 2016;34:3119–25.CrossRefGoogle Scholar
- 40.• Hahn NM, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC). J Clin Oncol. 2017;35:4525. Abstract with the most updated results of the trial of durvalumab in platinum-refractory aUC. The Massard et al. reference above describes in manuscript form an earlier analysis of the same trial. Google Scholar
- 41.Research, C. for D. E. and approved drugs—durvalumab (Imfinzi). Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555930.htm. Accessed: 18th November 2017.
- 44.Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, et al. 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 Off J Am Soc Clin Oncol. 2017;35:2117–24.CrossRefGoogle Scholar
- 46.• Apolo AB, et al. Updated efficacy and safety of avelumab in metastatic urothelial carcinoma (mUC): pooled analysis from 2 cohorts of the phase 1b Javelin solid tumor study. J Clin Oncol. 2017;35:4528. Abstract describing the most updated results of the phase Ib trial of avelumab in platinum-refractory aUC patients. CrossRefGoogle Scholar
- 47.Research, C. for D. E. and. Approved drugs—FDA grants accelerated approval to avelumab for urothelial carcinoma. Available at: https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm557162.htm. Accessed: 18th November 2017.
- 48.• Balar AV, 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; https://doi.org/10.1016/S1470-2045(17)30616-2. Summarizes the results of KEYNOTE-052, a phase II study of pembrolizumab in cisplatin-ineligible aUC.
- 49.O’Donnell PH, Grivas P, Balar AV, Bellmunt J. Biomarker findings and mature clinical results from KEYNOTE-052: first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC). ASCO; 2017.Google Scholar
- 50.Powles T, 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.Google Scholar
- 51.• Balar AV, 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. Summarizes the results of Cohort 1 in IMvigor 210, a phase II trial of atezolizumab in cisplatin-ineligible patients. CrossRefPubMedGoogle Scholar
- 52.FDA grants Roche’s TECENTRIQ® (atezolizumab) accelerated approval as initial treatment for certain people with advanced bladder cancer. Available at: http://www.roche.com/media/store/releases/med-cor-2017-04-18.htm. Accessed: 19th November 2017.
- 53.Szabados B, Van Der Heijden MS, Gomez De Liano Lista A, Tang YZ, Powles T. Responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy. J Clin Oncol. 2017;35:–e16004.Google Scholar
- 54.Sharma P, Callahan MK, Calvo E. Efficacy and safety of nivolumab plus ipilimumab in previously treated metastatic urothelial carcinoma: first results from the phase I/II CheckMate 032 study. In: 2016 SITC Annual Meeting; 2016.Google Scholar
- 55.Smith DC, 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.Google Scholar
- 57.Iyer G, et al. Mismatch repair (MMR) detection in urothelial carcinoma (UC) and correlation with immune checkpoint blockade (ICB) response. J Clin Oncol. 2017;35(15_suppl):4511.Google Scholar
- 58.Teo M, et al. DNA damage repair and response (DDR) gene alterations (alt) and response to PD1/PDs1 blockade in platinum-treated metastatic urothelial carcinoma (mUC). J Clin Oncol. 2017;35:4509.Google Scholar
- 61.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. 2017.Google Scholar
- 62.Funt S, et al. Correlation of peripheral and intratumoral T-cell receptor (TCR) clonality with clinical outcomes in patients with metastatic urothelial cancer (mUC) treated with atezolizumab. J Clin Oncol. 2016;34(15_suppl):3005.Google Scholar