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Systematic Literature Review and Meta-Analysis of Response to First-Line Therapies for Advanced/Metastatic Urothelial Cancer Patients Who Are Cisplatin Ineligible

Freshwater, Tomoko RPh, PhD*; Li, Haojie MD, PhD; Valiathan, Chandni PhD*; Li, Mengyao PhD*; Perini, Rodolfo MD; Bracco, Oswaldo L. MD, MSc§; Frenkl, Tara MD; Keefe, Stephen MD, MSCE

American Journal of Clinical Oncology: October 2019 - Volume 42 - Issue 10 - p 802–809
doi: 10.1097/COC.0000000000000585
Original Articles: Genitourinary
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Objective: The purpose of this systematic literature review (SLR) and meta-analysis was to compile the response of historic treatment options in first-line settings for patient populations who are cisplatin ineligible.

Materials and Methods: SLR was conducted to compile objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) of historic therapies for this population based on stringent criteria. Clinical trials published in English from January 1991 to June 2016 were identified by searching the PubMed (Medline), Cochrane, and Embase databases.

Results: Eighteen studies (21 arms; N=810) were identified and used for this meta-analysis. For all treatments included in these studies, the pooled ORR was 0.36 (95% confidence interval [CI], 0.30-0.42). The ORR for the carboplatin+gemcitabine arms (6 arms; N=259), which is the National Comprehensive Cancer Network’s recommended first-line treatment (before approval of atezolizumab and pembrolizumab) for this population was 0.36 (95% CI, 0.30-0.42), the median DOR (4 arms) was 7.00 months (95% CI, 4.34-11.29), and the median OS was 8.39 months (95% CI, 7.05-9.98).

Conclusions: The results of this SLR clearly demonstrate the paucity of clinical studies that assess therapeutic intervention in truly cisplatin-ineligible advanced/metastatic urothelial carcinoma subjects and highlight the development of novel therapies that can create real improvement in long-term outcomes. The recent approval of 2 checkpoint inhibitors, atezolizumab and pembrolizumab, were added in the National Comprehensive Cancer Network guidance as recommended first-line treatment for cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma and has provided alternatives for this patient population.

*Quantitative Pharmacology & Pharmacometrics, Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism

Center for Observational and Real-World Evidence

Clinical Research

§Clinical Safety and Risk Management, Merck & Co. Inc., Kenilworth, NJ

Support for all the trials discussed in this manuscript was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ.

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

T.Freshwater.: analysis of the data, interpretation of the results, and drafting of the manuscript. H.L., R.P.: conception, design, or planning of study, interpretation of results. C.V.: conception, design, or planning of study, analysis and acquisition of the data, interpretation of the results, drafting of manuscript. M.L., O.L.B., T.Frenkl: interpretation of results. S.K.: conception, design, or planning of study, analysis and acquisition of the data, interpretation of the results, drafting of manuscript.

T.Freshwater., H.L., R.P., O.L.B., and S.K. are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ. C.V. was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, at the time of analysis and is currently an independent consultant. M.L. was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, at the time of analysis and is currently an employee of Sanofi. T. Frenkl was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ at the time of analysis and is currently an employee of GlaxoSmithKline.

Reprints: Stephen Keefe, MD, MSCE, Clinical Research, Merck & Co. Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033. E-mail: stephen.keefe@merck.com.

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