PD-1/PD-L1 Immune Checkpoint Inhibitors after Platinum-based Chemotherapy in Metastatic or Locally Advanced Urothelial Bladder Carcinoma: A Systematic Review and Meta-analysis
PD-1/PD-L1 Immune Checkpoint Inhibitors in Locally Advanced or Metastatic Urothelial Carcinoma
Keywords:advanced urothelial carcinoma, metastatic urothelial carcinoma, PD-1/PD-L1 inhibitors
Objective: This study aimed to assess the effect of anti-programmed cell death-1/programmed cell death-ligand-1 (PD-1/PD-L1) agents compared with second-line therapy in patients with metastatic or locally advanced urothelial bladder carcinoma following previous platinum-containing chemotherapy.
Material and Methods: We systematically searched three electronic databases. The protocol of the study was registered in Prospero (CRD42019142494). Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the certainty of evidence (CoE) was estimated.
Results: The search results initially found 8168 publications. For qualitative synthesis, two publications were included. Pooled results indicated that patients treated with anti-PD-1/PD-L1 agents had significantly prolonged overall survival (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.7-0.9; I2 21.0%; moderate CoE). According to positive PD-L1 expression, PD-1/PD-L1 inhibitors had significantly more survival than chemotherapy (HR 0.75; 95% CI 0.5-0.9, I2 57.0%, low CoE). Furthermore, there was no significant difference in adverse events (AE) between the anti-PD-1/PDL1 agents and second-line chemotherapy (risk ratio 0.68; 95% CI 0.3-1.4; I2 97.0%, low CoE).
Conclusion: The present meta-analysis and systematic review provide strong evidence that anti-PD-1/PD-L1 agents could improve overall survival and have similar results in AEs compared with second-line chemotherapy. Further studies will confirm the power of immunotherapy for the treatment of metastatic or locally advanced urothelial bladder carcinoma.
Miyazaki J, Nishiyama H. Epidemiology of urothelial carcinoma. Int J Urol 2017;24:730–4.
Cancer Research UK. Bladder cancer incidence statistics. [homepage on the Internet]. London: Cancer Research UK [cited 2019 Oct 3]. Available from: http://www.cancerresearchuk. org/cancerinfo/cancerstats/types/bladder/incidence/
Tanaka MF, Sonpavde G. Diagnosis and management of urothelial carcinoma of the bladder. Postgrad Med 2011; 123:43-55.
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, 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.
Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with metotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992;10:1066.
Wu Y, Chen W, Xu ZP, Gu W. PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition. Front Immunol 2019;10:2022.
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, multicenter, phase 2 trial. Lancet 2016;387:1909-20.
Powles T, O’Donnell PH, Massard C, Arkenau HT, Friedlander TW, Hoimes CJ, et al. Efficacy and safety of Dur valumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study. JAMA Oncol 2017;3:e172411.
Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, et al. Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEY NOTE-012): a non-randomized, open-label, phase 1B study. Lancet Oncol 2017;18:212–20.
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, multicenter, phase 2 trial. Lancet 2017;389:67–76.
Sharma P, Callahan MK, Bono P, Kim J, Spiliopoulou P, Calvo E, et al. Nivolumab monotherapy in recurrent meta static urothelial carcinoma (CheckMate 032): a multicenter, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol 2016;17:1590–8.
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 multicenter, single-arm, phase 2 trial. Lancet Oncol 2017;18:312–22.
Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992;10:1066.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 2009;151:W65eW94.
Mourad Ouzzani, Hossam Hammady, Zbys Fedorowicz, El magarmid A. Rayyan — a web and mobile app for systematic reviews. Systematic Reviews 2016;5:210.
Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for as sessing risk of bias in randomized trials. BMJ 2011;343:d5928.
Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into metaanalysis. Trials 2007;8:16.
Zhang Y, Akl EA, Schünemann HJ. Using systematic reviews in guideline development: the GRADE approach. Res Synth Methods 2018; doi: 10.1002/jrsm.1313.
Schünemann H, Brożek J, Guyatt G, Oxman A. GRADE handbook for grading quality of evidence and strength of recommendations. [monograph on the Internet] Burlington: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group; 2013. [cited 2008 Sep 26] Available from: http://www.guidelinedevelopment. org/handbook/
GRADEpro. GDT: GRADEpro Guideline Development Tool. [monograph on the Internet]. Burlington: The Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group; 2019. [cited 2008 Sep 26]. Available from: http://www.gradepro.org
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;376:1015–26.
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 multicenter, open-label, phase 3 randomized controlled trial. Lancet 2018; 391:748-57.
Fan Z, Liang Y, Yang X, et al. A meta-analysis of the efficacy and safety of PD-1/PD-L1 immune checkpoint in hibitors as treatments for metastatic bladder cancer. Onco Targets Ther 2019;12:1791–801.
Rizzo A, Mollica V, Massari F. Expression of programmed cell death ligand 1 as a predictive biomarker in metastatic urothelial carcinoma patients treated with first-line Immune checkpoint inhibitors versus chemotherapy: a systematic review and metaanalysis. Eur Urol Focus 2021;S2405- 4569:00004-3.
Sui H, Ma N, Wang Y, Li B, Cui L, Luo L, et al. Anti-PD-1/ PD-L1 therapy for non-small-cell lung cancer: toward personalized medicine and combination strategies. J Immunol Res 2018;2018:6984948.
Scheel AH, Schäfer SC. Current PD-L1 immunohistochemistry for non-small cell lung cancer. J Thorac Dis 2018; 10:1217-9.
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Felip E, De Angelis F, et al. Pembroli-zumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018; 378:2078.
Weinberg F, Gadgeel S. Combination pembrolizumab plus chemotherapy: a new standard of care for patients with advanced non-small-cell lung cancer. Lung Cancer (Auckl) 2019;10:47–56.
Tunthanathip T. Impact of IDH1 mutation and MGMT promoter methylation in patients with glioblastoma [dissertation]. Songkhla: Prince of Songkla University; 2020.