Advertisement

Efficacy of Pembrolizumab in Patients With Variant Urothelial Carcinoma: A Multicenter Retrospective Study

      Abstract

      Introduction

      Although variant urothelial carcinoma (VUC, defined here as urothelial carcinoma with any histological variant) is a clinically aggressive disease, the efficacy of pembrolizumab against VUC is not well characterized. This study assessed the therapeutic response and survival outcomes in patients with advanced VUC treated with pembrolizumab for unresectable recurrent or metastatic disease.

      Patients and Methods

      We retrospectively evaluated 103 patients with advanced bladder and upper urinary tract cancer who received pembrolizumab after failure of platinum-based chemotherapy at 6 institutions between January 2018 and June 2021. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with VUC.

      Results

      We identified 81 and 22 patients with PUC and VUC, respectively. Squamous differentiation (n = 14) was the most common variant element, followed by glandular differentiation (n = 3) and micropapillary variant (n = 3). Baseline characteristics were comparable between the groups. Patients with VUC showed significantly better ORR (59.1% vs. 29.6%, P = .014) and comparable DCR (68.2% vs. 49.4%, P = .150) compared to those with PUC. There were no significant differences between the PUC and VUC groups with respect to PFS (median 5.0 months vs. 10.4 months, P = .222) or OS (median 13.5 months vs. 23.8 months, P = .497).

      Conclusion

      Response of VUC to pembrolizumab was not inferior to that of PUC in patients with advanced-stage bladder and upper urinary tract cancer.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Genitourinary Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Bellmunt J
        • de Wit R
        • Vaughn DJ
        • et al.
        Pembrolizumab as second-line therapy for advanced urothelial carcinoma.
        N Engl J Med. 2017; 376: 1015-1026https://doi.org/10.1056/NEJMoa1613683
        • Minato A
        • Noguchi H
        • Moriya R
        • et al.
        Evaluation of the extent of variant histology in urothelial carcinoma as a predictive marker of clinical outcomes after radical cystectomy.
        Cancer Diagn Progn. 2021; 1: 345-351https://doi.org/10.21873/cdp.10046
        • Mori K
        • Abufaraj M
        • Mostafaei H
        • et al.
        A systematic review and meta-analysis of variant histology in urothelial carcinoma of the bladder treated with radical cystectomy.
        J Urol. 2020; 204: 1129-1140https://doi.org/10.1097/JU.0000000000001305
        • Minato A
        • Noguchi H
        • Tomisaki I
        • et al.
        Clinical significance of squamous differentiation in urothelial carcinoma of the bladder.
        Cancer Control. 2018; 25 (https://doi.org/10.1177%2F1073274818800269)1073274818800269
        • Minato A
        • Noguchi H
        • Kimuro R
        • et al.
        Prognostic value of squamous differentiation in upper tract urothelial carcinoma treated with radical nephroureterectomy.
        Anticancer Res. 2022; 42: 263-269https://doi.org/10.21873/anticanres.15481
        • Mori K
        • Janisch F
        • Parizi MK
        • et al.
        Prognostic value of variant histology in upper tract urothelial carcinoma treated with nephroureterectomy: A systematic review and meta-analysis.
        J Urol. 2020; 203: 1075-1084https://doi.org/10.1097/JU.0000000000000523
        • Humphrey PA
        • Moch H
        • Cubilla AL
        • Ulbright TM
        • Reuter VE.
        The 2016 WHO classification of tumours of the yrinary system and male genital organs-part B: Prostate and Bladder Tumours.
        Eur Urol. 2016; 70: 106-119https://doi.org/10.1016/j.eururo.2016.02.028
        • Rink M
        • Robinson BD
        • Green DA
        • et al.
        Impact of histological variants on clinical outcomes of patients with upper urinary tract urothelial carcinoma.
        J Urol. 2012; 188: 398-404https://doi.org/10.1016/j.juro.2012.04.009
        • Mantica G
        • Simonato A
        • Du Plessis DE
        • et al.
        The pathologist's role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection.
        Minerva Urol Nefrol. 2018; 70: 594-597https://doi.org/10.23736/s0393-2249.18.03175-2
        • Miller NJ
        • Khaki AR
        • Diamantopoulos LN
        • et al.
        Histological subtypes and response to PD-1/PD-L1 blockade in advanced urothelial cancer: A retrospective study.
        J Urol. 2020; 204: 63-70https://doi.org/10.1097/JU.0000000000000761
        • Kobayashi M
        • Narita S
        • Matsui Y
        • et al.
        Impact of histological variants on outcomes in patients with urothelial carcinoma treated with pembrolizumab: a propensity score matching analysis.
        BJU Int. 2021; https://doi.org/10.1111/bju.15510
        • Eisenhauer EA
        • Therasse P
        • Bogaerts J
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Cancer. 2009; 45: 228-247https://doi.org/10.1016/j.ejca.2008.10.026
        • Kanda Y.
        Investigation of the freely available easy-to-use software 'EZR' for medical statistics.
        Bone Marrow Transplant. 2013; 48: 452-458https://doi.org/10.1038/bmt.2012.244
        • Bellmunt J
        • Choueiri TK
        • Fougeray R
        • et al.
        Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens.
        J Clin Oncol. 2010; 28: 1850-1855https://doi.org/10.1200/JCO.2009.25.4599
        • Sonpavde G
        • Pond GR
        • Fougeray R
        • et al.
        Time from prior chemotherapy enhances prognostic risk grouping in the second-line setting of advanced urothelial carcinoma: a retrospective analysis of pooled, prospective phase 2 trials.
        Eur Urol. 2013; 63: 717-723https://doi.org/10.1016/j.eururo.2012.11.042
        • Reis H
        • Serrette R
        • Posada J
        • et al.
        PD-L1 expression in urothelial carcinoma with predominant or pure variant histology: Concordance among 3 commonly used and commercially available antibodies.
        Am J Surg Pathol. 2019; 43: 920-927https://doi.org/10.1097/PAS.0000000000001264
        • Lopez-Beltran A
        • Cimadamore A
        • Blanca A
        • et al.
        Immune checkpoint Inhibitors for the treatment of bladder cancer.
        Cancers (Basel). 2021; 13: 131https://doi.org/10.3390/camcers13010131
        • Saxman SB
        • Propert KJ
        • Einhorn LH
        • et al.
        Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study.
        J Clin Oncol. 1997; 15: 2564-2569https://doi.org/10.1200/JCO.1997.15.7.2564
        • Veskimäe E
        • Espinos EL
        • Bruins HM
        • et al.
        What is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer? A European association of urology muscle invasive and metastatic bladder cancer guidelines panel systematic review.
        Eur Urol Oncol. 2019; 2: 625-642https://doi.org/10.1016/j.euo.2019.09.003
        • Hsieh MC
        • Sung MT
        • Chiang PH
        • Huang CH
        • Tang Y
        • Su YL.
        The prognostic impact of histopathological variants in patients with advanced urothelial carcinoma.
        PLoS One. 2015; 10e0129268https://doi.org/10.1371/journal.pone.0129268
        • Epaillard N
        • Parent P
        • Loriot Y
        • et al.
        Treatments outcomes in histological variants and non-urothelial bladder cancer: Results of a multicenter retrospective study.
        Front Oncol. 2021; 11671969https://doi.org/10.3389/fonc.2021.671969
        • Black PC
        • Brown GA
        • Dinney CP.
        The impact of variant histology on the outcome of bladder cancer treated with curative intent.
        Urol Oncol. 2009; 27: 3-7https://doi.org/10.1016/j.urolonc.2007.07.010
        • Hajiran A
        • Azizi M
        • Aydin AM
        • et al.
        Pathological and survival outcomes associated with variant histology bladder cancers managed by cystectomy with or without neoadjuvant chemotherapy.
        J Urol. 2021; 205: 100-108https://doi.org/10.1097/JU.0000000000001325
        • Leite KRM
        • Borges LL
        • Filho LR
        • et al.
        Histological variants of urothelial carcinoma predict no response to neoadjuvant chemotherapy.
        Clin Genitourin Cancer. 2022; 20: e1-e6https://doi.org/10.1016/j.clgc.2021.07.011
        • Minato A
        • Fujimoto N
        • Kubo T.
        Squamous differentiation predicts poor response to cisplatin-based chemotherapy and unfavorable prognosis in urothelial carcinoma of the urinary bladder.
        Clin Genitourin Cancer. 2017; 15: e1063-e1067https://doi.org/10.1016/j.clgc.2017.07.008
        • Zargar-Shoshtari K
        • Sverrisson EF
        • Sharma P
        • et al.
        Clinical outcomes after neoadjuvant chemotherapy and radical cystectomy in the presence of urothelial carcinoma of the bladder with squamous or glandular differentiation.
        Clin Genitourin Cancer. 2016; 14: 82-88https://doi.org/10.1016/j.clgc.2015.08.006
        • Vetterlein MW
        • Wankowicz SAM
        • Seisen T
        • et al.
        Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology.
        Cancer. 2017; 123: 4346-4355https://doi.org/10.1002/cncr.30907
        • Powles T
        • Park SH
        • Voog E
        • et al.
        Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma.
        N Engl J Med. 2020; 383: 1218-1230https://doi.org/10.1056/NEJMoa2002788