Pembrolizumab for Previously Treated Advanced or Metastatic Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal
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Pembrolizumab is an intravenously administered monoclonal antibody licensed for locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy. This summary presents the perspective of Warwick Evidence, the Evidence Review Group (ERG) appointed by the National Institute of Health and Care Excellence (NICE) for the single technology appraisal of pembrolizumab for this indication. Pembrolizumab is manufactured by Merck, Sharp and Dohme (MSD). The major source of clinical effectiveness was the KEYNOTE-045 trial, where 542 patients received either pembrolizumab or clinician’s choice of docetaxel, paclitaxel or vinflunine as a second-line treatment. No indirect treatment comparison was performed. The clinical effectiveness was assessed using hazard ratios for overall survival (OS) and progression-free survival (PFS) of the intention-to-treat (ITT) population, together with the subpopulations positive for programmed cell death 1 ligand 1 (PD-L1) expression (combined positive score [CPS] ≥ 1%) and strongly positive for PD-L1 expression (CPS ≥ 10%). In the ITT population, OS improved with pembrolizumab (HR 0.73, 95% CI 0.59–0.91) while PFS outcomes showed no difference (HR 0.98, 95% CI 0.81–1.19). Pembrolizumab demonstrated a better safety profile than its combined comparators, with fewer patients experiencing adverse events (60.9 vs 90.2%). Similar results were observed in populations expressing PD-L1. MSD estimated the cost effectiveness of pembrolizumab using a de novo partitioned survival model. The model had three health states: pre-progression, post-progression and death, where OS and PFS estimates excluded patients who received vinflunine. The largest uncertainty was over the selection of the parametric models used to extrapolate OS and PFS and the time point for when to begin their extrapolation. The company preferences for extrapolation were not well supported and the ERG disagreed with their selection for OS. Utility values were also contentious, with the company preferring to use pooled time-to-death–based utilities pooled across treatment arms, whilst the ERG preferred pooled progression-based utilities. The company preferred to use data from patients receiving vinflunine when calculating the utility values, which the ERG disagreed with as this is not recommended treatment within the UK. The company assumed a lifetime treatment effect for their model; however, the lack of evidence made it difficult to confidently provide a realistic estimate of treatment effect duration. Various durations were explored (3, 5 and 10 years). The first appraisal committee meeting concluded that pembrolizumab was not cost effective, largely due to uncertainty in the OS and PFS extrapolations. The company’s second submission included an additional 4 months follow-up to survival data. The company in this new submission maintained their original assumptions in their base-case analysis, changing only the choice of parametric curve for PFS. This change resulted in the OS and PFS curves intersecting at 6 years in the pembrolizumab arm, at which point PFS identically followed OS. This resulted in no patients in the post-progression health state beyond this time point, and therefore, the majority of pembrolizumab’s benefit came from pre-progression survival. Given the unclear PFS benefit, the ERG found this implausible and maintained their original base-case model assumptions. Considerable uncertainty remained over the specification of the extrapolations and the duration of treatment effect. Based on a new-value proposition submitted by the company, the appraisal committee concluded that pembrolizumab had plausible potential to be cost effective. Pembrolizumab was referred for funding through the Cancer Drugs Fund, so that further data could be collected with the aim of diminishing the outstanding uncertainties pertaining to its clinical effectiveness.
We thank Prof. Aileen Clarke for her advice and support. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of NICE or the Department of Health. This work is Crown copyright (UK).
DG, XA, PA, RC, TM, JP, MDS, JC and HM all formed part of the ERG report that this paper describes. DG produced the first draft of the manuscript, which was developed with assistance from XA, PA and HM. All authors commented on the manuscript and approved the final version. This summary has not been externally reviewed by PharmacoEconomics.
Compliance with Ethical Standards
This project was funded by the NIHR HTA programme (project number 16/108/19). See the HTA programme website (http://www.hta.ac.uk) for further project information.
Conflict of interest
DG, XA, PA, RC, TM, JP, JC and HM have no other conflicts of interest that are directly relevant to the content of this article. MDS has received consulting fees/honoraria from Amgen, Astellas Pharma, AstraZeneca, Bayer AG, Bristol-Myers Squibb, Celgene, Dendreon, Eisai, ESSA Pharma, Ferring Pharmaceuticals, GlaxoSmithKline, Incyte, Ipsen, Janssen, Merck, MSD, Novartis, Pfizer, Pierre Fabre Group, Roche, Sanofi, Seattle Genetics, Shionogi, Synthon, Takeda and Teva/Oncogenex.
- 1.National Institute for Health and Care Excellence. Technology appraisal guidance. 2017. https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-technology-appraisal-guidance. Accessed 7 Nov 2017.
- 2.National Institute for Health and Care Excellence. Pembrolizumab for urothelial cancer: Technology appraisal guidance in development [GID-TA10113]. 2017. https://www.nice.org.uk/guidance/indevelopment/gid-ta10113. Accessed 7 Nov 2017.
- 3.Cancer Research UK. About bladder cancer. 2016. http://www.cancerresearchuk.org/about-cancer/bladder-cancer/about. Accessed 28 Feb 2017.
- 4.Cancer Research UK. Bladder Cancer: Types. 2015. http://www.cancerresearchuk.org/about-cancer/bladder-cancer/types-stages-grades/types. Accessed 07 Nov 2017.
- 6.Cancer Research UK. Bladder Cancer: Symptoms. 2015. http://www.cancerresearchuk.org/about-cancer/bladder-cancer/symptoms. Accessed 07 Nov 2017.
- 7.Cancer Research UK. Bladder Cancer: Stages. 2015. http://www.cancerresearchuk.org/about-cancer/bladder-cancer/types-stages-grades/stages. Accessed 07 Nov 2017.
- 8.Cancer Research UK. Bladder Cancer Incidence Statistics. 2016. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer/incidence#heading-Zero. Accessed Feb 2017.
- 9.Cancer Research UK. Survival. 2016. http://www.cancerresearchuk.org/about-cancer/bladder-cancer/survival. Accessed 28 Feb 2017.
- 10.National Institute for Health and Care Excellence. Bladder cancer: diagnosis and management (NG2): 1 Recommendations. 2015. https://www.nice.org.uk/guidance/ng2/chapter/1-Recommendations. Accessed 7 Nov 2017.
- 11.National Institute for Health and Care Excellence. Vinflunine for the treatment of advanced or metastatic transitional cell carcinoma of the urothelial tract: Technology appraisal guidance [TA272]. 2013. https://www.nice.org.uk/guidance/ta272. Accessed 10 Mar 2017.
- 12.National Institute for Health and Care Excellence. Pembrolizumab for treating PD-L1-positive non-small-cell lung cancer after chemotherapy: Technology appraisal guidance [TA428]. 2017. https://www.nice.org.uk/guidance/ta428. Accessed 10 Mar 2017.
- 13.National Institute for Health and Care Excellence. Pembrolizumab for treating advanced melanoma after disease progression with ipilimumab: Technology appraisal guidance [TA357]. 2015. https://www.nice.org.uk/guidance/ta357. Accessed 07 Nov 2017.
- 14.National Institute for Health and Care Excellence. Pembrolizumab for untreated PD-L1-positive metastatic non-small-cell lung cancer [TA447]: 1 Recommendations. 2017. https://www.nice.org.uk/guidance/ta447/chapter/1-Recommendations. Accessed 3 Jan 2018.
- 15.National Institute for Health and Care Excellence. Pembrolizumab for locally advanced or metastatic urothelial cancer where cisplatin is unsuitable: Technology appraisal guidance in development [GID-TA10215]. 2017. https://www.nice.org.uk/guidance/indevelopment/gid-ta10215. Accessed 3 Jan 2018.
- 18.National Institute for Health and Care Excellence. Single Technology Appraisal: Pembrolizumab for previously treated advanced or metastatic urothelial cancer: Committee Papers [for Appraisal Consultation]. 2017. https://www.nice.org.uk/guidance/ta519/documents/committee-papers. Accessed 1 May 2018.
- 19.Cancer Research UK. Bladder Cancer Survival Statistics (Sourced from the Office for National Statistics and The National Cancer Registration Service Eastern Office [data available on request]). 2016. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer/survival. Accessed Dec 2016.
- 20.Office for National Statistics. Population estimates—summary for the UK, mid-2015. 2016. https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates. Accessed 10 Mar 2017.
- 21.Department of Health. Drugs and pharmaceutical electronic market information (eMit). 2016. https://www.gov.uk/government/publications/drugs-and-pharmaceutical-electronic-market-information-emit. Accessed 10 Mar 2017.
- 22.Department of Health. National reference costs 2015 to 2016. 2016. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/577083/Reference_Costs_2015-16.pdf. Accessed 10 Mar 2017.
- 23.Curtis L, Burns A. Unit Costs of Health and Social Care 2016. 2016. http://www.pssru.ac.uk/project-pages/unit-costs/2016/index.php. Accessed 10 Mar 2017.
- 24.Brown T, Pilkington G, Bagust A, Boland A, Oyee J, Tudur-Smith C, et al. Clinical effectiveness and costeffectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer: a systematic review and economic evaluation. Health Technol Assess. 2013;17(31):1–277.CrossRefGoogle Scholar
- 25.National Institute for Health and Care Excellence. Single Technology Appraisal: Pembrolizumab for previously treated advanced or metastatic urothelial cancer [for Final Appraisal Determination]. 2018. https://www.nice.org.uk/guidance/ta519/documents/committee-papers-3. Accessed 1 May 2018.
- 26.Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov L, Daugaard G, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27(27):4454–61.CrossRefGoogle Scholar
- 27.von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602–8.CrossRefGoogle Scholar
- 28.Brahmer J, Horn L, Jackman D, Spigel D, Antonia S, Hellmann M, et al. Abstract CT077: Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors. Cancer Res. 2017;77(13 Supplement):CT077-CT.Google Scholar
- 30.Latimer NR. Survival analysis for economic evaluations alongside clinical trials–extrapolation with patient-level data: inconsistencies, limitations, and a practical guide. MedDecisMaking. 2013;33(6):743–54.Google Scholar
- 31.Latimer NR. NICE DSU Technical Support Document 14: Undertaking survival analysis for economic evaluations alongside clinical trials—extrapolation with patient-level data. 2011. Available from: http://nicedsu.org.uk/wp-content/uploads/2016/03/NICE-DSU-TSD-Survival-analysis.updated-March-2013.v2.pdf.
- 32.National Institute for Health and Care Excellence. Pembrolizumab for treating locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy: technology appraisal guidance [TA519]: 3 Committee discussion. 2018. https://www.nice.org.uk/guidance/ta519/chapter/3-Committee-discussion. Accessed 1 May 2018.