Cost-eff ectiveness of cabozantinib versus sunitinib or pazopanib as fi rst-line treatment of patients with advanced renal cell carcinoma in the UK PCN94 Eleonora Skentzou,1* Jie Meng,2 Johanna Lister,2 Liz Gray1 1Ipsen Ltd, Slough, UK; 2Analytica Laser, a Certara company, Lörrach, Germany *Corresponding author: Eleonora Skentzou (email: [email protected])

BACKGROUND AND OBJECTIVES Figure 2. One-way sensitivity analyses results: cabozantinib vs comparator A Sunitinib OWSA: the impact of changing one parameter at a time B Pazopanib OWSA: the impact of changing one parameter at a time • Cabozantinib is an oral tyrosine kinase inhibitor (TKI) of MET, AXL and vascular endothelial growth factor (VEGF) receptors.1 It is approved for the treatment of advanced Cost of cabozantinib 60 mg daily 5 16 Cost of cabozantinib 60 mg daily 4 14 renal cell carcinoma (aRCC): Cost of sunitinib 50 mg daily 7 13 Cost of pazopanib 800 mg daily 6 12 – in adults following previous VEGF-targeted therapy, based on fi ndings from the METEOR trial (NCT01865747)2,3 Relative dose intensity of sunitinib 9 13 Relative dose intensity of pazopanib 7 13 – in treatment-naïve adults with intermediate- or poor-risk aRCC in accordance with the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) Cost discount 9 13 Cost discount 8 12 4,5 criteria, based on fi ndings from the CABOSUN trial (NCT01835158). Utilities: pre-progression state 9 13 Utilities: pre-progression state 8 11 • CABOSUN was a randomised, open-label, phase 2 trial that demonstrated superior progression-free survival (PFS) with cabozantinib compared with sunitinib in Effect discount 9 12 Effect discount 8 10 4,5 treatment-naïve adults with intermediate- or poor-risk aRCC. Relative dose intensity of cabozantinib 9 11 Relative dose intensity of cabozantinib 8 10 • In England, the TKIs pazopanib, sunitinib and tivozanib, as well as cabozantinib, are Cost of outpatient Cost of outpatient 6 10 11 9 10 recommended as fi rst-line therapies for aRCC. consultation (follow-up) consultation (follow-up) • We evaluated the cost-eff ectiveness of cabozantinib compared with pazopanib and sunitinib as fi rst-line treatment for patients with aRCC in the National Health Service Cost of nivolumab 3 mg 10 11 Cost of nivolumab 3 mg 9 10 Duration of second-line treatment: Duration of second-line treatment: (NHS) in England. 10 11 9 10 cabozantinib cabozantinib – When this cost-eff ectiveness model was designed, tivozanib was not recommended Duration of second-line treatment: Duration of second-line treatment: 10 11 9 10 as a fi rst-line treatment option for patients with aRCC and was therefore not nivolumab nivolumab Relative dose intensity of Relative dose intensity of included in this model. 10 11 9 10 • Since the abstract was submitted, new results based on a recently updated price have second-line cabozantinib second-line cabozantinib been generated and are shown in this poster. Cost of everolimus 10 mg 10 11 Cost of everolimus 10 mg 9 9 Duration of second-line treatment: Duration of second-line treatment: 10 11 9 9 everolimus everolimus Duration of second-line treatment: Duration of second-line treatment: METHODS 10 11 9 9 bevacizumab bevacizumab Model design 2 4 6 8 10 12 14 16 18 2 4 6 8 10 12 14 16 18 • A partitioned, three-state survival model (area under the curve) was used to estimate ICER (thousands GBP per QALY); base case = 10.403 ICER (thousands GBP per QALY); base case = 9.099 the proportion of patients in each state and the total costs associated with each Scenarios resulting with values lower than the base case Scenarios resulting with values higher than the base case treatment (Figure 1). GBP, British pounds sterling; OWSAs, one-way sensitivity analyses; QALY, quality-adjusted life-year. – Three health states were specifi ed: pre-progression, post-progression and dead. • Key inputs to the model included the effi cacy outcomes of overall survival (OS), PFS and Analyses time to treatment discontinuation (TTD), as well as adverse events (AEs). Figure 3. Probabilistic sensitivity analyses: scatterplots and cost-eff ectiveness curves • The model estimated costs, life-years and quality-adjusted life-years (QALYs). – The time horizon for the model was 20 years (corresponding to the time at which for cabozantinib vs sunitinib and pazopanib • Incremental cost-eff ectiveness ratios (ICERs) were calculated by dividing the diff erence 99.9% of patients have died). A Scatterplot: cabozantinib vs sunitinib in cost by the diff erence in QALYs. 25,000 • Parameter uncertainty was examined through one-way sensitivity analyses (OWSAs), Figure 1. Model structure Mean probabilistic sensitivity analyses (PSAs) and scenario analyses. 20,000 • Costs and eff ects were discounted at 3.5% in accordance with NICE guidelines. 15,000

Pre-progression Post-progression RESULTS 10,000

• Compared with sunitinib, cabozantinib treatment was associated with an incremental 5,000 gain of 0.54 QALYs at an incremental cost of £5,600 per patient, corresponding to an Dead 0 ICER of £10,403 per QALY gained. • Compared with pazopanib, cabozantinib treatment resulted in an incremental gain of –5,000 Incremental total costs (GBP) costs total Incremental 0.54 QALYs at an incremental cost of £4,877 per patient, corresponding to an ICER of Effi cacy outcomes £9,099 per QALY gained. –10,000 • Data from randomised controlled trials were used to calculate the proportion of patients –3 –2 –1 0 1 2 3 4 • The OWSAs of cabozantinib versus sunitinib and pazopanib showed that the results in each treatment arm at any time point after starting treatment. Incremental QALYs were most sensitive to drug costs, relative dose intensity, cost and eff ect discounts, and – For cabozantinib and sunitinib, OS, PFS and TTD data were derived from choice of utilities in the pre-progression state (Figure 2A and B). B Scatterplot: cabozantinib vs pazopanib CABOSUN.4,5 • Scenario analyses showed that variation in individual values and parameters did not 25,000 • �The data cut-off dates were 1 July 2017 for OS and 15 September 2016 for PFS. Mean have a large eff ect on the results (Table 3). – For pazopanib, OS, PFS, TTD and subsequent treatments were assumed to be the 20,000 8,9 same as for sunitinib (based on clinical experience) (Table 1). Table 3. Scenario analyses of cabozantinib vs sunitinib or pazopanib – For all three agents, the estimated proportions of patients receiving subsequent 15,000 treatments were based on CABOSUN data. Scenario ICER vs sunitinib ICER vs pazopanib 10,000 – The model used separately fi tted distributions for OS (Gompertz distribution), PFS (GBP/QALY) (GBP/QALY) and TTD (log-normal distribution). 5,000 Base case 10,403 9,099 Safety outcomes Discount 0% 10,794 9,746 0 • Treatment-emergent AEs were included in the model if they aff ected at least 5% of the 6% 10,083 8,583 population and had implications for resource use. –5,000 Time horizon 10 years 10,262 8,766 (GBP) costs total Incremental – For cabozantinib and sunitinib, AE data were derived from CABOSUN.4,5 CABOSUN data – For pazopanib, AE data were derived from the COMPARZ trial (pazopanib vs sunitinib –10,000 –3 –2 –1 0 1 2 3 4 in aRCC; NCT00720941).8,9 PFS curves Exponential 9,651 8,269 Weibull Incremental QALYs Utility values 9,260 7,679 Gompertz 10,361 8,952 C Cost-effectiveness acceptability curve: D Cost-effectiveness acceptability curve: • The CABOSUN trial did not collect health-related quality of life data or any other cabozantinib vs sunitinib cabozantinib vs pazopanib OS curves Exponential 11,960 10,405 generic preference-based measure to estimate utilities. Therefore, utility values were 100 100 health-state-specifi c and based on the sunitinib National Institute for Health and Care Weibull 13,888 11,826 Excellence (NICE) technology appraisal.10 OS and PFS benefi t to persist only 12,016 10,231 for 5 years 80 80 – This technology appraisal was based on clinical evidence from a randomised TTD curves Exponential controlled trial conducted in 750 patients with metastatic renal cell carcinoma and 8,041 6,682 60 60 a good performance status (Eastern Cooperative Oncology Group status 0 or 1) Weibull 8,070 6,653 (Table 2).10 Gompertz 9,171 7,873 40 40 • The utility decrements due to AEs were based on a cost-eff ectiveness study comparing Gamma 9,625 8,179 pazopanib with sunitinib in aRCC (Table 2).11 Utility values Swinburn 9,924 8,678 20 20 Cost inputs Pazopanib NICE STA 11,551 10,108 • Drug costs were based on the British National Formulary (BNF).12 Dose intensity, Tivozanib NICE STA 11,172 9,774 0 0 Age-adjusted utilities Excluded (%) cost-effectiveness of Probability (%) cost-effectiveness of Probability publicly available discounts and administration costs for all treatments were taken into 10,113 8,844 0 40,000 80,000 120,000 0 40,000 80,000 120,000 consideration. AE disutility source METEOR AE disutilities 10,385 9,055 Willingness-to-pay threshold (GBP) Willingness-to-pay threshold (GBP) • The model included costs associated with treatment acquisition, pre-progression and Cost Wastage excluded 10,557 9,253 GBP, British pounds sterling; QALYs, quality-adjusted life-years. post-progression disease states, AEs and terminal care. Total cost of subsequent 12,037 10,740 • Costs for resource-use items were based on NHS reference costs for 2016/201713 and treatment (UK clinicians) included: initial outpatient consultations; follow-up outpatient consultations; nurse visits; Blood test (comprehensive test) 10,695 9,392 computed tomography scans; and blood tests. Health resource (UK clinicians) 9,069 7,760 • It was assumed that the pre-progression and post-progression health states would have End-of-life cost excluded 10,785 9,483 CONCLUSIONS diff erent resource-use frequencies. AE, adverse event; GBP; British pounds sterling; ICER, incremental cost-eff ectiveness ratio; NICE, National Institute for Health and Care Excellence; OS, overall survival; PFS, progression-free survival; QALY, quality-adjusted life-year; STA, single • Based on the results of the CABOSUN trial, which demonstrated that technology appraisal; TTD, time to treatment discontinuation. Table 1. Second-line aRCC therapy cabozantinib was associated with a clinically meaningful and statistically signifi cant prolongation of PFS compared with sunitinib,4,5 cabozantinib • Probabilistic results for cabozantinib versus sunitinib or pazopanib were similar to represents a cost-eff ective alternative to sunitinib or pazopanib for the fi rst-line Second-line therapy Proportion (%) of patients receiving each second-line therapy after deterministic results (Tables 4 and 5). disease progression on: treatment of aRCC of intermediate- or poor-risk in England. • PSA scatterplots for comparisons of cabozantinib with sunitinib and pazopanib show • Limitations that should be noted for this analysis include: Cabozantinib Sunitinib Pazopanib similar distributions (Figure 3A and B). – CABOSUN was a phase 2 trial with a small sample size (157 patients) Axitinib 23 19 19 • PSA cost-eff ectiveness acceptability curves are similar for both comparators, – the study did not have a pre-specifi ed hypothesis for the treatment eff ect on Pazopanib 16 12 12 demonstrating that cabozantinib had a probability of 68% and 73% of being OS, so inference tests should be interpreted accordingly. Sunitinib 13 13 13 cost-eff ective at the £20,000 threshold compared with sunitinib and pazopanib, Temsirolimus 9 4 4 respectively (Figure 3C and D). Nivolumab 13 15 15 Everolimus 8 19 19 Table 4. Mean probabilistic base case results for cabozantinib vs sunitinib References 1. Yakes FM et al. Mol Cancer Ther 2011;10:2298–308. 8. Motzer RJ et al. N Engl J Med 2013;369:722–31. Sorafenib 1 3 3 2. Choueiri TK et al. N Engl J Med 2015;373:1814–23. 9. Motzer RJ et al. N Engl J Med 2014;370:1769–70. Bevacizumab 0 6 6 3. Choueiri TK et al. Lancet Oncol 2016;17:917–27. 10. National Institute for Health and Care Excellence (NICE). Diff erence in cost Diff erence in Diff erence in ICER 4. Choueiri TK et al. J Clin Oncol 2017;35:591–7. Technology appraisal guidance TA169. Sunitinib for the Cabozantinib 1 6 6 (GBP) QALYs (years) life-years (years) (GBP/QALY) 5. Choueiri TK et al. Eur J Cancer 2018;94:115–25. fi rst-line treatment of advanced and/or metastatic renal Sunitinib 6. National Institute for Health and Care Excellence (NICE) cell carcinoma. 25 March 2009. Available at: https://www. Lenvatinib + everolimus 0 0 0 - - - - Pathways. Renal cancer overview. 2 October 2018. nice.org.uk/guidance/ta169/resources/sunitinib-for- Best supportive care 16 3 3 Cabozantinib 5,536 0.592 0.791 9,358 Available at: https://pathways.nice.org.uk/pathways/ the-fi rstline-treatment-of-advanced-andor-metastatic- renal-cancer#content=view-node%3Anodes-fi rst-line- renal-cell-carcinoma-pdf-82598383607749 (Accessed Data taken from the CABOSUN Clinical Study Report.7 GBP, British pounds sterling; ICER, incremental cost-eff ectiveness ratio; QALY, quality-adjusted life-year. treatment-for-advanced-and-metastatic-renal-cancer 24 October 2018). (Accessed 31 October 2018). 11. Amdahl J et al. Curr Oncol 2016;23:e340–54. 7. Exelixis Inc. Clinical Study Report: A031203 randomized 12. BNF Publications. Books. 2017. Available at: https://www. phase II study comparing cabozantinib (NSC #761968 bnf.org/products/books (Accessed 8 December 2017). Table 2. Base case utility values Table 5. Mean probabilistic base case results for cabozantinib vs pazopanib and IND #116059) with commercially supplied sunitinib 13. National Health Service (NHS) Improvement. Reference in subjects with previously untreated locally advanced or costs. Available at: https://improvement.nhs.uk/ metastatic renal cell carcinoma. Report dated 31 July 2017. resources/reference-costs (Accessed 8 December 2017). (Confi dential). Health state Utility value (SE) Source Diff erence in cost Diff erence in Diff erence in ICER Pre-progression 0.780 (0.078) NICE sunitinib technology appraisal TA16910 (GBP) QALYs (years) life-years (years) (GBP/QALY) Acknowledgements This study was supported by Ipsen Pharma SAS, Paris, France. Post-progression 0.705 (0.071) NICE sunitinib technology appraisal TA16910 Pazopanib - - - - The authors thank Dr Vicky Sanders of Oxford PharmaGenesis, Oxford, UK for providing medical writing support, which was sponsored by Ipsen Pharma SAS, Paris, France, in accordance with Good Publication Practice guidelines. AEs of grade 3 or 4 −0.204 (0.068) Amdahl J et al. 201611 Cabozantinib 4,684 0.604 0.821 7,750 AE, adverse event; NICE, National Institute for Health and Care Excellence; SE, standard error. GBP; British pounds sterling; ICER, incremental cost-eff ectiveness ratio; QALY, quality-adjusted life-year. Disclosures E Skentzou and L Gray are employees of Ipsen Ltd, UK. J Meng and J Lister are employees of Analytica Laser, Germany, a Certara company, which has received consulting fees from Ipsen Pharma SAS.

Presented at ISPOR Europe 2018 | Barcelona, Spain | 10–14 November 2018 This study was sponsored by Ipsen