Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

  • Shijie RenEmail author
  • Hazel Squires
  • Emma Hock
  • Eva Kaltenthaler
  • Andrew Rawdin
  • Constantine Alifrangis
Review Article


As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company’s submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company’s health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG’s probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed.



This summary of the ERG report was compiled after NICE issued the FAD. All authors have commented on the submitted manuscript and have given their approval for the final version to be published. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of NICE or the Department of Health. Any errors are the responsibility of the authors. The authors would like to thank Mark Clowes for critiquing the literature searches undertaken by the company, and Jonathan Shamash for providing clinical advice to the ERG.

Author Contributions

HS and AR critiqued the mathematical model provided and the cost-effectiveness analyses submitted by the company. EK and EH critiqued the clinical effectiveness data reported by the company. SR critiqued the STC and ITC performed by the company and conducted the addition analysis for extrapolation. CA provided clinical advice to the ERG throughout the project. All authors were involved in the drafting of and commenting on the final document. SR acts as the guarantor of this work. This summary has not been externally reviewed by PharmacoEconomics.

Compliance with Ethical Standards


This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme (Project Number 17/56/02). Visit the HTA programme website for further project information (

Conflicts of Interest

Shijie Ren, Hazel Squires, Emma Hock, Eva Kaltenthaler, Andrew Rawdin and Constantine Alifrangis have no conflicts of interest to declare.


  1. 1.
    National Institute for Health and Care Excellence. Guide to the methods of technology appraisal. 2013 [cited 15 Jun 2018]. Accessed 15 June 2018.
  2. 2.
    Ren S, Squires H, Kaltenthaler E, Hock E, Rawdin A, Clowes M, et al. Pembrolizumab for untreated locally advanced or metastatic urothelial cancer when cisplatin is unsuitable. 2018 [cited 15 Jun 2018]. Accessed 15 June 2018.
  3. 3.
    National Institute for Health and Care Excellence. Pembrolizumab for untreated locally advanced or metastatic urothelial cancer when cisplatin is unsuitable. 2018 [cited 15 Jun 2018]. Accessed 15 June 2018.
  4. 4.
    Eble J, Sauter G, Epstein J, Sesterhenn I. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. WHO Classification of Tumours. International Agency for Research on Cancer; 2004. p. 7.Google Scholar
  5. 5.
    Cancer Research UK. Bladder Cancer, Types, Stages and grades. 2016 [cited 15 Jun 2018]. Accessed 15 June 2018.
  6. 6.
    Cancer Research UK. Bladder Cancer Incidence Statistics. 2016 [cited 15 Jun 2018]. Accessed 15 June 2018.
  7. 7.
    National Cancer Institute. 5-Year Relative and Period Survival (Percent) by Race, Sex, Diagnosis Year, Stage and Age (Stage: Distant), Data cut: 2001-2007 [Table 27.8 p.]. 2017 [cited 15 Jun 2018. Accessed 15 June 2018.
  8. 8.
    National Institute for Health and Care Excellence. NICE Guideline 2: Evidence Review—Bladder Cancer: diagnosis and management. 2015 [cited 15 Jun 2018]. Accessed 15 June 2018.
  9. 9.
    National Institute for Health and Care Excellence. Single Technology Appraisal Atezolizumab for treating metastatic urothelial bladder cancer after platinum based chemotherapy [ID939] Committee Papers. 2017 [cited 15 Jun 2018]. Accessed 15 June 2018.
  10. 10.
    European Medicines Agency. European public assessment report (EPAR). Keytruda International non-proprietary name: pembrolizumab. 2017 [cited 15 Jun 2018]. Accessed 15 June 2018.
  11. 11.
    Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, 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(11):1483–92.CrossRefGoogle Scholar
  12. 12.
    Phillippo DM, Ades AE, Dias S, Palmer S, Abrams KR, Welton NJ. NICE DSU Technical Support Document 18: Methods for population-adjusted indirect comparisons in submissions to NICE. 2016 [cited 15 Jun 2018]. Accessed 15 June 2018.
  13. 13.
    De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191–9.CrossRefGoogle Scholar
  14. 14.
    Bamias A, Lainakis G, Kastritis E, Antoniou N, Alivizatos G, Koureas A, et al. Biweekly carboplatin/gemcitabine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: report of efficacy, quality of life and geriatric assessment. Oncology. 2007;73(5–6):290–7.CrossRefGoogle Scholar
  15. 15.
    Carles J, Nogue M, Domenech M, Perez C, Saigi E, Villadiego K, et al. Carboplatin-gemcitabine treatment of patients with transitional cell carcinoma of the bladder and impaired renal function. Oncology. 2000;59(1):24–7.CrossRefGoogle Scholar
  16. 16.
    Linardou H, Aravantinos G, Efstathiou E, Kalofonos C, Anagnostopoulos A, Deliveliotis C, et al. Gemcitabine and carboplatin combination as first-line treatment in elderly patients and those unfit for cisplatin-based chemotherapy with advanced bladder carcinoma: phase II study of the Hellenic Co-operative Oncology Group. Urology. 2004;64(3):479–84.CrossRefGoogle Scholar
  17. 17.
    Guyot P, Ades A, Ouwens MJ, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12(1):9.CrossRefGoogle Scholar
  18. 18.
    Royston P, Parmar MKB. Flexible parametric proportional-hazards and proportional-odds models for censored survival data, with application to prognostic modelling and estimation of treatment effects. Stat Med. 2002;21:2175–97.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.School of Health and Related Research (ScHARR)University of SheffieldSheffieldUK
  2. 2.University College London Hospitals NHS Foundation TrustLondonUK

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