Immune checkpoint inhibitor therapy as a neoadjuvant treatment for muscle-invasive bladder carcinoma: A narrative review

Abstract

Immunotherapy has become a standard treatment for patients with advanced urothelial carcinoma, and neoadjuvant immunotherapy is currently being extensively explored. This review highlights the initial findings and key clinical therapeutic insights on immune checkpoint inhibitors in the early treatment of muscle-invasive bladder cancer across diverse patient populations. Most available literature consists of clinical investigations involving small sample, single-arm phase II trials, with the primary endpoint being the pathologic complete response rate. Early results of immune checkpoint inhibitors in the neoadjuvant treatment of bladder cancer have demonstrated promising efficacy. However, these findings require confirmation in large phase III clinical trials, with particular emphasis on long-term survival benefits and identifying patients who respond to treatment.

Keywords

Muscle-invasive bladder cancer / Immune checkpoint inhibitor / Tislelizumab / Neoadjuvant immunotherapy

Acknowledgments

None.

Statement of ethics

Not applicable.

Conflict of interest statement

JL is an associate editor of Current Urology. SD is an editorial board member of Current Urology. This article was accepted after normal external review.

Funding source

This study was supported by Shandong Provincial Natural Science Foundation (ZR2023LZL005) and Jinan Science and Technology Development Foundation.

Author contributions

SD: Writing of the main manuscript text;

JL: Conceived and designed the experiments, revised the manuscript, project administration;

SD, CW, JC: Collected and analyzed the data;

All authors: Review of the manuscript.

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

References

[1] Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1054 patients. J Clin Oncol 2001; 19(3):666-675.

[2] Yafi FA, Aprikian AG, Chin JL, et al. Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: A Canadian multicentre experience. BJU Int 2011; 108(4):539-545.

[3] Vale CL. 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(2):202-205 discussion 205-206.

[4] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349(9):859-866.

[5] Zaid HB, Patel SG, Stimson CJ, et al. Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: Results from the National Cancer Database. Urology 2014; 83(1):75-80.

[6] Galsky MD, Guan X, Rishipathak D, et al. Immunomodulatory effects and improved outcomes with cisplatin- versus carboplatin-based chemotherapy plus atezolizumab in urothelial cancer. Cell Rep Med 2024; 5(2):101393.

[7] Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015; 348(6230):56-61.

[8] Desai J, Deva S, Lee JS, et al. Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. J Immunother Cancer 2020; 8(1):e000453.

[9] Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018; 24(11):1655-1661.

[10] Liu J, Blake SJ, Yong M CR, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 2016; 6(12):1382-1399.

[11] Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 2020; 367(6477):eaax0182.

[12] Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020; 382(9):810-821.

[13] Godoy LA, Chen J, Ma W, et al. Emerging precision neoadjuvant systemic therapy for patients with resectable non-small cell lung cancer: Current status and perspectives. Biomark Res 2023; 11(1):7.

[14] Hermans TJN, Voskuilen CS, van der Heijden MS, et al. Neoadjuvant treatment for muscle-invasive bladder cancer: The past, the present, and the future. Urol Oncol 2018; 36(9):413-422.

[15] Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med 2019; 25(11):1706-1714.

[16] Szabados B, Kockx M, Assaf ZJ, et al. Final results of neoadjuvant atezolizumab in cisplatin-ineligible patients with muscle-invasive urothelial cancer of the bladder. Eur Urol 2022; 82(2):212-222.

[17] Kaimakliotis HZ, Adra N, Kelly WK, et al. Phase II neoadjuvant (N-) gemcitabine (G) and pembrolizumab (P) for locally advanced urothelial cancer (laUC): Interim results from the cisplatin (C)-ineligible cohort of GU14-188. J Clin Oncol 2020; 38(15suppl):5019.

[18] Brown J, Kaimakliotis HZ, Kelly WK, et al. HCRN GU14-188: Phase Ib/II study of neoadjuvant pembrolizumab and chemotherapy for T2-4aN0M0 urothelial cancer. J Clin Oncol 2023: 41(6_suppl):448.

[19] Martinez Chanza N, Carnot A, Barthelemy P, et al. 659MO Avelumab (A) as the basis of neoadjuvant chemotherapy (NAC) regimen in platinum eligible and ineligible patients (pts) with non-metastatic muscle invasive bladder cancer (NM-MIBC). Ann Oncol 2021; 32(Supplement 5):S683.

[20] Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): An open-label, single-arm, Phase II study. J Clin Oncol 2018; 36(34):3353-3360.

[21] Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015; 28(6):690-714.

[22] Hoimes CJ, Adra N, Fleming MT, et al. Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)-eligible cohort of HCRN GU14-188. J Clin Oncol 2020; 38(15_suppl):5047.

[23] Gupta S, Sonpavde G, Weight CJ, et al. Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy. J Clin Oncol 2020; 38(suppl 6):439.

[24] Li K, Zhong W, Fan J, et al. Neoadjuvant gemcitabine-cisplatin plus tislelizumab in persons with resectable muscle-invasive bladder cancer: A multicenter, single-arm, phase 2 trial. Nat Cancer 2024; 5(10):1465-1478.

[25] Rouanne M, Bajorin DF, Hannan R, et al. Rationale and outcomes for neoadjuvant immunotherapy in urothelial carcinoma of the bladder. Eur Urol Oncol 2020; 3(6):728-738.

[26] Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 2015; 68(6):959-967.

[27] Van Allen EM, Mouw KW, Kim P, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 2014; 4(10):1140-1153.

[28] Martini A, Raggi D, Marandino L, et al. The paradoxical role of body mass index in patients with muscle-invasive bladder cancer receiving neoadjuvant immunotherapy. Eur Urol Oncol 2022; 5(3):370-372.

[29] Guo A, Ding S. Progress in the establishment and application of organoids of bladder cancer. J Shandong Univ (Health Sci) 2023; 61(11):20-26.

[30] Jiang Y, Sun X, Song X, et al. Patient-derived bladder cancer organoid model to predict sensitivity and feasibility of tailored precision therapy. Curr Urol 2023; 17(4):221-228.

[31] Neal JT, Li X, Zhu J, et al. Organoid modeling of the tumor immune microenvironment. Cell 2018; 175(7):1972-1988.e16.

[32] Laukhtina E, Pradere B, Lemberger U, Karakiewicz PI, Fajkovic H, Shariat SF. Molecular biomarkers to help select neoadjuvant systemic therapy for urothelial carcinoma of the bladder. Curr Opin Urol 2022; 32(5):561-566.

[33] Miron B, Hoffman-Censits JH, Anari F, et al. Defects in DNA repair genes confer improved long-term survival after cisplatin-based neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol Oncol 2020; 3(4):544-547.

[34] Padua TCD, Basile G, Bandini M, et al. ₁₇₃8P Three-year follow-up update and survival outcomes of the PURE-01 study. Ann Oncol 2022; 33(Supplement 7):S1331-S1332.