Nivolumab for Treating Metastatic or Unresectable Urothelial Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

Abstract

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Bristol-Myers Squibb) of nivolumab (Opdivo ®) to submit evidence of its clinical and cost effectiveness for metastatic or unresectable urothelial cancer. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG), which produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission to NICE. Nivolumab was compared with docetaxel, paclitaxel, best supportive care and retreatment with platinum-based chemotherapy (cisplatin plus gemcitabine, but only for patients whose disease has had an adequate response in first-line treatment). Two ongoing, phase I/II, single-arm studies for nivolumab were identified, but no studies directly compared nivolumab with any specified comparator. Evidence from directly examining the single arms of the trial data indicated little difference between the outcomes measured from the nivolumab and comparator studies. A simulated treatment comparison (STC) analysis was used in an attempt to reduce the bias induced by naïve comparison, but there was no clear evidence that risk of bias was reduced. Multiple limitations in the STC were identified and remained. The effect of an analysis based on different combinations of covariates in the prediction model remains unknown. The ERG's concerns regarding the economic analysis included the use of a non-established response-based survival analysis method, which introduced additional uncertainty. The use of time-dependent hazard ratios produced overfitting and was not represented in the probabilistic sensitivity analysis. The use of a treatment stopping rule to cap treatment cost left treatment effectiveness unaltered. A relevant comparator was excluded from the base-case analysis. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company's Appraisal Consultation Document response were £58,791, £78,869 and £62,352 per quality-adjusted life-year gained versus paclitaxel, docetaxel and best supportive care, respectively. Nivolumab was dominated by cisplatin plus gemcitabine in the ERG base case. Substantial uncertainties about the relative treatment effectiveness comparing nivolumab against all comparators remained. NICE did not recommend nivolumab, within its marketing authorisation, as an option for treating locally advanced, unresectable or metastatic urothelial carcinoma in adults who have had platinum-containing therapy, and considered that nivolumab was not suitable for use within the Cancer Drugs Fund.

Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?

“…NICE did not recommend nivolumab as an option for treating locally advanced, unresectable or metastatic bladder cancer who have had platinum-containing therapy [ 88 ]. The cost-effectiveness was not better than cisplatin plus gemcitabine.…”

A comparative study of nivolumab and axitinib in terms of overall survival, treatment continuation, and cost for patients with metastatic renal cell carcinoma

“…In the UK, the cost-effectiveness assessment of expensive drugs is conducted by the National Institute for Health and Clinical Excellence (NICE). NICE did not recommend using market-authorized nivolumab within the Cancer Drugs Fund to treat locally advanced, unresectable, or metastatic urothelial carcinoma in adults who had previously received platinum-containing therapy (13). The cost-effectiveness of nivolumab for patients with recurrent/metastatic head and neck squamous cell carcinoma and advanced non-flat non-small-cell lung cancer is lower (14,15).…”

“…However, the dose of axitinib can be increased to 20 mg/day for patients that present a low blood level elevation, which can increase the annual drug cost. The cost-effectiveness of using nivolumab and axitinib in clinical practice is not available; however, both drugs are expected to be less cost-effective (13)(14)(15).…”

Uncertainty and Coverage With Evidence Development: Does Practice Meet Theory?

“…5 They further advocate for a clear prespecification of the conditions of the CED schemes, something that is lacking in the US context according to Garrison et al 2 To our knowledge, in these jurisdictions, as in The Netherlands, no systematic identification of uncertainties takes place. Therefore, the categorization of uncertainties presented in this article is relevant for reimbursement agencies internationally because they increasingly face assessments in which uncertainty is difficult to quantify (eg, use of single-arm trials or simulated treatment comparisons 38 ). The current categorization helps to express why the presented evidence is uncertain, hopefully helps to raise awareness and acceptance of uncertain information, and assists choices concerning CED research designs.…”