Efficacy and safety of PD-1/PD-L1 inhibitor monotherapy or combination therapy versus platinum-based chemotherapy as a first-line treatment of advanced urothelial cancer: A systematic review and meta-analysis

Abstract

Background: Recent clinical trials have shown that inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand (programmed cell death-ligand 1 [PD-L1]) provide significant efficacy and clinical benefit in the treatment of advanced or metastatic urothelial carcinoma (UC). This systematic review and meta-analysis aimed to compare the effectiveness and safety of PD-1/PD-L1 inhibitors in combination with chemotherapy or PD-1/PD-L1 inhibitor monotherapy versus platinum-based chemotherapy as a first-line treatment for advanced UC.

Materials and methods: From the beginning of the database construction to February 4, 2024, a combination of medical subject headings and free-text words was searched using the Population Intervention Comparison Outcome Study design framework. The PubMed, Cochrane Library, Embase, and Web of Science electronic databases were searched. Meta-analyses of progression-free survival, overall survival, objective response rate (ORR), complete remission rate, duration of remission, and grade ≥3 adverse events were performed.

Results: Four studies were included in the meta-analysis. The PD-1/PD-L1 inhibitors plus chemotherapy therapy is associated with significantly better ORR compared with chemotherapy. Unfortunately, there were no significant differences between PD-1/PD-L1 inhibitor monotherapy and chemotherapy in terms of ORR, duration of remission, or overall survival.

Conclusions: Our findings indicate that PD-1/PD-L1 inhibitors plus chemotherapy therapy provides more oncological advantages than standard chemotherapy and should be recommended as a first-line treatment for advanced or metastatic UC. Attention must also be paid to the adverse effects of the combination of PD-1/PD-L1 inhibitors and chemotherapy.

Keywords

Urothelial carcinoma / Immune-checkpoint inhibitor / Programmed cell death protein 1 / Programmed death-ligand 1 inhibitor

Acknowledgments

None.

Statement of ethics

This meta-analysis was performed in accordance with the 2020 standards of the Preferred Reporting Project for Systematic Review and Meta-Analyses. This study was registered with PROSPERO (registration number, CRD42024510339).

Conflict of interest statement

The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Funding source

This work was supported by the Guangxi Natural Science Foundation Program (no. 2024GXNSFBA010036), the Scientific Research Foundation of Guangxi Health Commission (Z-B20220927), and the Scientific Research Foundation of Guangxi Health Commission (Z-B20220930).

Author contributions

XH: Investigation, data curation, writing - original draft;

SH: Investigation, data curation, writing - original draft;

QJ: Conceptualization, methodology, linguistic polishing;

WL: Investigation, supervision;

CH: Writing - review and editing;

WH: Investigation, data curation.

Data availability statement

The generated/analyzed datasets used in this study can be found at figshare (https://doi.org/10.6084/m9.figshare.25283680).

References

[1] Sakr SA, Mahran HA, Fahmy AM, El-Kholy MA, Meawad M. Expression of c-erb-B2 gene in bladder cancer of Egyptian patients and its correlation with p53 and bcl-2. Biomed Pharmacother 2015;76:73-81.

[2] Richters A, Aben KKH, Kiemeney LALM. The global burden of urinary bladder cancer: An update. World J Urol 2020;38:1895-1904.

[3] Tripathi A, Plimack ER. Immunotherapy for urothelial carcinoma: Current evidence and future directions. Curr Urol Rep 2018;19:109.

[4] Babjuk M, Burger M, Compérat EM, et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) — 2019 update. Eur Urol 2019;76:639-657.

[5] Kim HS, Seo HK. Immune checkpoint inhibitors for urothelial carcinoma. Investig Clin Urol 2018;59:285-296.

[6] Einstein DJ, Sonpavde G. Treatment approaches for cisplatin-ineligible patients with invasive bladder cancer. Curr Treat Options Oncol 2019;20:12.

[7] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249.

[8] Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. J Clin Oncol 2006;24:3451-3457.

[9] Bellmunt J, Théodore C, Demkov T, 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 2009;27:4454-4461.

[10] von der Maase H, Hansen SW, Roberts JT, 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 2023;41:3881-3890.

[11] Meeks JJ, Black PC, Galsky M, et al. Checkpoint inhibitors in urothelial carcinoma—Future directions and biomarker selection. Eur Urol 2023;84:473-483.

[12] Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 2020;383:1218-1230.

[13] Sharma P, Retz M, Siefker-Radtke A, 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.

[14] Reesink DJ, van de Garde EMW, Peters BJM, et al. Treatment patterns and clinical outcomes of chemotherapy treatment in patients with muscle-invasive or metastatic bladder cancer in the Netherlands. Sci Rep 2020;10:15822.

[15] Apolo AB, Infante JR, Balmanoukian A, 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 2017;35:2117-2124.

[16] Liu N, Zhou Y, Lee JJ. IPDfromKM: Reconstruct individual patient data from published Kaplan-Meier survival curves. BMC Med Res Methodol 2021;21:111.

[17] van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma. N Engl J Med 2023;389:1778-1789.

[18] Powles T, van der Heijden MS, Castellano D, et al. 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 Oncol 2020;21:1574-1588.

[19] Powles T, Csőszi T, Özgüroğlu M, et al. 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 Oncol 2021;22:931-945.

[20] Galsky MD, Arija JÁA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2020;395:1547-1557.

[21] Gotwals P, Cameron S, Cipolletta D, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer 2017;17:286-301.

[22] Han Y, Liu D, Li L. PD-1/PD-L1 pathway: Current researches in cancer. Am J Cancer Res 2020;10:727-742.

[23] Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: Signaling, cancer, and beyond. Adv Exp Med Biol 2020;1248:33-59.

[24] Ménard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F. Cancer chemotherapy: Not only a direct cytotoxic effect but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 2008;57:1579-1587.

[25] Eriksson E, Wenthe J, Irenaeus S, Loskog A, Ullenhag G. Gemcitabine reduces MDSCs, Tregs and TGFβ-1 while restoring the Teff/Treg ratio in patients with pancreatic cancer. J Transl Med 2016;14:282.

[26] Chen C, Chen Z, Chen D, Zhang B, Wang Z, Le H. Suppressive effects of gemcitabine plus cisplatin chemotherapy on regulatory T cells in non-small-cell lung cancer. J Int Med Res 2015;43:180-187.

[27] Hato SV, Khong A, de Vries IJ, Lesterhuis WJ. Molecular pathways: The immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res 2014;20:2831-2837.

[28] 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.

[29] Massard C, Gordon MS, Sharma S, 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.

[30] 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.

[31] Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemotherapy. J Clin Oncol 2011;29:2432-2438.

[32] Dash A, Galsky MD, Vickers AJ, et al. Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer 2006;107:506-513.

[33] Mori K, Schuettfort VM, Yanagisawa T, et al. Reassessment of the efficacy of carboplatin for metastatic urothelial carcinoma in the era of immunotherapy: A systematic review and meta-analysis. Eur Urol Focus 2022;8:1687-1695.

[34] Niegisch G. Antibody-drug conjugates (ADC): A novel treatment option in urothelial carcinoma. Methods Mol Biol 2023;2684:293-301.