Advertisement

Response to Pembrolizumab After Dose-Reduced Cisplatin Plus Gemcitabine Chemotherapy Is Inferior to That After Carboplatin Plus Gemcitabine Chemotherapy in Cisplatin-Unfit Patients With Advanced Urothelial Carcinoma

Published:November 15, 2021DOI:https://doi.org/10.1016/j.clgc.2021.11.006

      Highlights

      • The optimal first-line chemotherapy regimen and dose adjustment for cisplatin-unfit patients with advanced, unresectable and/or metastatic urothelial carcinoma remains unclear.
      • We investigated the association between response to first-line chemotherapy and response to subsequent pembrolizumab treatment.
      • The response to pembrolizumab after dose-reduced cisplatin plus gemcitabine chemotherapy was inferior to that after carboplatin plus gemcitabine chemotherapy.
      • The dose-reduced cisplatin plus gemcitabine chemotherapy is not recommended for cis-unfit patients with advanced urothelial carcinoma in the era of immune checkpoint inhibitors.

      Abstract

      Introduction

      Response to pembrolizumab after first-line chemotherapy is vital to prolonged survival in advanced, unresectable, and/or metastatic urothelial carcinoma (aUC). However, there are sparse clinical data on host-tumor immune modification by first-line platinum-based chemotherapy. This study investigated the association between response to first-line gemcitabine plus cisplatin (GC) or carboplatin (GCarbo) chemotherapy and response to subsequent pembrolizumab treatment.

      Patients and Methods

      A multicenter-derived database registered 454 patients diagnosed with aUC between 2008 and 2020. Of these, 108 patients who received first-line GC or GCarbo followed by second-line or later pembrolizumab were eligible for investigation and were classified into 3 groups: 48 receiving full-dose GC, 21 receiving dose-reduced GC, and 39 receiving GCarbo. Overall survival (OS) was calculated using the Kaplan-Meier method and compared using the log-rank test. Possible factors associated with the response to pembrolizumab were evaluated using binary logistic regression methods.

      Results

      The rate of patients undergoing surgical removal of the primary organ was higher and creatinine clearance was lower in the dose-reduced GC and GCarbo groups than in the full-dose GC groups. Pembrolizumab responders had significantly better survival benefits than nonresponders. The rate of pembrolizumab responders was much higher in first-line chemotherapy responders than in first-line chemotherapy nonresponders. In contrast to the full-dose GC and GCarbo groups, the pembrolizumab responder rate was lower, and no association was observed between response to first-line chemotherapy and response to pembrolizumab in the dose-reduced GC group.

      Conclusion

      Cisplatin and carboplatin may play an important role in the antitumor immune response, which could impact the outcome of subsequent pembrolizumab treatment. Given that the rate of response to pembrolizumab after dose-reduced GC chemotherapy was relatively low, this regimen is not recommended for cis-unfit patients with aUC. Further studies are required to understand the mechanisms responsible for the cross-reactivity of platinum and immune checkpoint inhibitors.

      Keywords

      Abbreviations:

      aUC (advanced, unresectable, and metastatic urothelial carcinoma), CR (complete response), CrCl (creatinine clearance), GC (gemcitabine plus cisplatin combination chemotherapy), GCarbo (gemcitabine plus carboplatin combination chemotherapy), ICD (immunogenic cell death), ICI (immune checkpoint inhibitor), OR (odds ratio), OS (overall survival), PD (progressive disease), PD-1 (programmed cell death protein 1), PD-L1 (programmed death-ligand 1), PR (partial response), SD (stable disease), UC (urothelial carcinoma)
      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

        • 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: 2432-2438https://doi.org/10.1200/JCO.2011.34.8433
        • Galsky MD
        • Hahn NM
        • Rosenberg J
        • et al.
        A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy.
        Lancet Oncol. 2011; 12: 211-221https://doi.org/10.1016/S1470-2045(10)70275-8
        • Bamias A
        • Tzannis K
        • Harshman LC
        • et al.
        Impact of contemporary patterns of chemotherapy utilization on survival in patients with advanced cancer of the urinary tract: a Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC).
        Ann Oncol. 2018; 29: 361-369https://doi.org/10.1093/annonc/mdx692
        • Bamias A
        • Tzannis K
        • Bamia C
        • et al.
        The impact of cisplatin- or non-cisplatin-containing chemotherapy on long-term and conditional survival of patients with advanced urinary tract cancer.
        Oncologist. 2019; 24: 1348-1355https://doi.org/10.1634/theoncologist.2018-0739
        • 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
        • Fradet Y
        • Bellmunt J
        • Vaughn DJ
        • et al.
        Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.
        Ann Oncol. 2019; 30: 970-976https://doi.org/10.1093/annonc/mdz127
        • Bellmunt J
        • Necchi A
        • de Wit R
        • et al.
        Pembrolizumab (pembro) versus investigator's choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer (UC): 5-year follow-up from the phase 3 KEYNOTE-045 trial.
        J Clin Oncol. 2021; 39: 4532https://doi.org/10.1200/JCO.2021.39.15_suppl.4532
        • Rébé C
        • Demontoux L
        • Pilot T
        • et al.
        Platinum derivatives effects on anticancer immune response.
        Biomolecules. 2019; 10: 13https://doi.org/10.3390/biom10010013
        • Fournel L
        • Wu Z
        • Stadler N
        • et al.
        Cisplatin increases PD-L1 expression and optimizes immune check-point blockade in non-small cell lung cancer.
        Cancer Lett. 2019; 464: 5-14https://doi.org/10.1016/j.canlet.2019.08.005
        • de Goeje PL
        • Poncin M
        • Bezemer K
        • et al.
        Induction of peripheral effector CD8 T-cell proliferation by combination of paclitaxel, carboplatin, and bevacizumab in non-small cell lung cancer patients.
        Clin Cancer Res. 2019; 25: 2219-2227https://doi.org/10.1158/1078-0432.CCR-18-2243
        • Galluzzi L
        • Vitale I
        • Warren S
        • et al.
        Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.
        J Immunother Cancer. 2020; 8e000337https://doi.org/10.1136/jitc-2019-000337
        • Kepp O
        • Senovilla L
        • Vitale I
        • et al.
        Consensus guidelines for the detection of immunogenic cell death.
        Oncoimmunology. 2014; 3e955691https://doi.org/10.4161/21624011.2014.955691
        • Carles J
        • Suárez C
        • Mesía C
        • et al.
        Feasiblity study of gemcitabine and cisplatin administered every two weeks in patients with advanced urothelial tumors and impaired renal function.
        Clin Transl Oncol. 2006; 8: 755-757https://doi.org/10.1007/s12094-006-0123-8
        • Morales-Barrera R
        • Bellmunt J
        • Suárez C
        • et al.
        Cisplatin and gemcitabine administered every two weeks in patients with locally advanced or metastatic urothelial carcinoma and impaired renal function.
        Eur J Cancer. 2012; 48: 1816-1821https://doi.org/10.1016/j.ejca.2012.04.002
        • Mourey L
        • Flechon A
        • Tosi D
        • et al.
        Vefora, GETUG-AFU V06 study: randomized multicenter phase II/III trial of fractionated cisplatin (CI)/gemcitabine (G) or carboplatin (CA)/g in patients (pts) with advanced urothelial cancer (UC) with impaired renal function (IRF)—results of a planned interim analysis.
        J Clin Oncol. 2020; 38: 461https://doi.org/10.1200/JCO.2020.38.6_suppl.461
        • Vellinga A
        • Cormican M
        • Hanahoe B
        • et al.
        Opt-out as an acceptable method of obtaining consent in medical research: a short report.
        BMC Med Res Methodol. 2011; 11: 40https://doi.org/10.1186/1471-2288-11-40
        • Cockcroft DW
        • Gault MH.
        Prediction of creatinine clearance from serum creatinine.
        Nephron. 1976; 16: 31-41https://doi.org/10.1159/000180580
        • 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
        • Kato M
        • Kobayashi T
        • Matsui Y
        • et al.
        Impact of the objective response to and number of cycles of platinum-based first-line chemotherapy for metastatic urothelial carcinoma on overall survival of patients treated with pembrolizumab.
        Int J Urol. 2021; 45: 1261-1267https://doi.org/10.1111/iju.14686
        • Galluzzi L
        • Buqué A
        • Kepp O
        • et al.
        Immunogenic cell death in cancer and infectious disease.
        Nat Rev Immunol. 2017; 17: 97-111https://doi.org/10.1038/nri.2016.107
        • de Biasi AR
        • Villena-Vargas J
        • Adusumilli PS.
        Cisplatin-induced antitumor immunomodulation: a review of preclinical and clinical evidence.
        Clin Cancer Res. 2014; 20: 5384-5391https://doi.org/10.1158/1078-0432.CCR-14-1298
        • Park SJ
        • Ye W
        • Xiao R
        • et al.
        Cisplatin and oxaliplatin induce similar immunogenic changes in preclinical models of head and neck cancer.
        Oral Oncol. 2019; 95: 127-135https://doi.org/10.1016/j.oraloncology.2019.06.016
        • Tsai TF
        • Lin JF
        • Lin YC
        • et al.
        Cisplatin contributes to programmed death-ligand 1 expression in bladder cancer through ERK1/2-AP-1 signaling pathway.
        Biosci Rep. 2019; 39BSR20190362https://doi.org/10.1042/BSR20190362
        • Wakita D
        • Iwai T
        • Harada S
        • et al.
        Cisplatin augments antitumor T-cell responses leading to a potent therapeutic effect in combination with PD-L1 blockade.
        Anticancer Res. 2019; 39: 1749-1760https://doi.org/10.21873/anticanres.13281
        • Miyake M
        • Hori S
        • Ohnishi S
        • et al.
        Supplementary granulocyte macrophage colony-stimulating factor to chemotherapy and programmed death-ligand 1 blockade decreases local recurrence after surgery in bladder cancer.
        Cancer Sci. 2019; 110: 3315-3327https://doi.org/10.1111/cas.14158
        • Loh JM
        • Tran AL
        • Ji L
        • et al.
        Baseline glomerular filtration rate and cisplatin-induced renal toxicity in urothelial cancer patients.
        Clin Genitourin Cancer. 2017; S1558-7673: 30271-30279https://doi.org/10.1016/j.clgc.2017.08.016
        • Furubayashi N
        • Negishi T
        • Sakamoto N
        • et al.
        Organ-specific tumor response to pembrolizumab in advanced urothelial carcinoma after platinum-based chemotherapy.
        Onco Targets Ther. 2021; 14: 1981-1988https://doi.org/10.2147/OTT.S299724
        • Bonfante G
        • Fantinel E
        • Masini C
        • et al.
        Exceptional response to immunotherapy in association with radiotherapy in patient with breast metastasis from urothelial carcinoma: a case report.
        Urol Case Rep. 2020; 34101444https://doi.org/10.1016/j.eucr.2020.101444
        • Ishiyama Y
        • Takagi T
        • Yoshida K
        • et al.
        Possible abscopal effect in urothelial carcinoma of the upper urinary tract after treatment with immune checkpoint inhibitors.
        IJU Case Rep. 2019; 3: 25-27https://doi.org/10.1002/iju5.12133
        • Fukushima H
        • Kijima T
        • Fukuda S
        • et al.
        Impact of radiotherapy to the primary tumor on the efficacy of pembrolizumab for patients with advanced urothelial cancer: a preliminary study.
        Cancer Med. 2020; 9: 8355-8363https://doi.org/10.1002/cam4.3445