Health Technology Assessment (Aug 2024)
Lenvatinib plus pembrolizumab for untreated advanced renal cell carcinoma: a systematic review and cost-effectiveness analysis
Abstract
Background Renal cell carcinoma is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced renal cell carcinoma are the focus of this National Institute for Health and Care Excellence multiple technology appraisal. A patient’s risk of disease progression depends on a number of prognostic risk factors; patients are categorised as having intermediate/poor risk or favourable risk of disease progression. Objectives The objectives of this multiple technology appraisal were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus relevant comparators listed in the final scope issued by the National Institute for Health and Care Excellence: sunitinib, pazopanib, tivozanib, cabozantinib and nivolumab plus ipilimumab. Methods The assessment group carried out clinical and economic systematic reviews and assessed the clinical and cost-effectiveness evidence submitted by Eisai, Hatfield, Hertfordshire, UK (the manufacturer of lenvatinib) and Merck Sharp & Dohme, Whitehouse Station, NJ, USA (the manufacturer of pembrolizumab). The assessment group carried out fixed-effects network meta-analyses using a Bayesian framework to generate evidence for clinical effectiveness. As convergence issues occurred due to sparse data, random-effects network meta-analysis results were unusable. The assessment group did not develop a de novo economic model, but instead modified the partitioned survival model provided by Merck Sharp & Dohme. Results The assessment group clinical systematic review identified one relevant randomised controlled trial (CLEAR trial). The CLEAR trial is a good-quality, phase III, multicentre, open-label trial that provided evidence for the efficacy and safety of lenvatinib plus pembrolizumab compared with sunitinib. The assessment group progression-free survival network meta-analysis results for all three risk groups should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons owing to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. The assessment group overall survival network meta-analysis results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the overall survival for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption, the assessment group overall survival network meta-analysis results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. Only one cost-effectiveness study was included in the assessment group review of cost-effectiveness evidence. The study was limited to the all-risk population, undertaken from the perspective of the US healthcare system and included comparators that are not recommended by the National Institute for Health and Care Excellence for patients with untreated advanced renal cell carcinoma. Therefore, the extent to which resource use and results are generalisable to the NHS is unclear. The assessment group cost-effectiveness results from the modified partitioned survival model focused on the intermediate-/poor-risk and favourable-risk subgroups. The assessment group cost-effectiveness results, generated using list prices for all drugs, showed that, for all comparisons in the favourable-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated fewer benefits than all other treatments available to NHS patients. For the intermediate-/poor-risk subgroup, treatment with lenvatinib plus pembrolizumab costs more and generated more benefits than treatment with cabozantinib and nivolumab plus ipilimumab. Conclusions Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab with sunitinib is available from the CLEAR trial. For most of the assessment group Bayesian hazard ratio network meta-analysis comparisons, it is difficult to reach conclusions due to within-trial proportional hazards violations or uncertainty regarding the validity of the proportional hazards assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the economic model are relevant to NHS clinical practice and can be used to inform National Institute for Health and Care Excellence decision-making. The assessment group cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration This study is registered as PROSPERO CRD4202128587. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information. Plain language summary What was the problem? Renal cell carcinoma is the most common type of kidney cancer. Several drug treatment options are available for NHS patients with advanced or metastatic disease, and the choice of treatment varies depending on a patient’s risk of disease progression. A new drug combination, lenvatinib plus pembrolizumab, may soon become available to treat NHS patients. This review explored whether treatment with lenvatinib plus pembrolizumab offered value for money to the NHS. What did we do? We reviewed the effectiveness of treatment with lenvatinib plus pembrolizumab versus other NHS treatment options. We also estimated the costs and benefits of treatment with lenvatinib plus pembrolizumab versus current NHS treatments for patients with higher and lower risks of disease progression. What did we find? Compared with current NHS treatments, treatment with lenvatinib plus pembrolizumab may increase the time that people with a higher risk of disease progression (i.e. worsening disease) were alive. However, for patients with a lower risk of disease progression, the available evidence is limited and only shows that treatment with lenvatinib plus pembrolizumab may prolong the time that patients have a stable level of disease. For all patients, compared to all current NHS treatments, treatment with lenvatinib plus pembrolizumab is very expensive. What does this mean? Compared with current NHS treatments for untreated renal cell carcinoma, using published prices (which do not include any discounts that are offered to the NHS), treatment with lenvatinib plus pembrolizumab may not provide good value for money to the NHS. Scientific summary Background Renal cell carcinoma (RCC) is the most common type of kidney cancer, comprising approximately 85% of all renal malignancies. Patients with advanced RCC (aRCC) have Stage 3 (locally advanced) or Stage 4 (metastatic) disease. A patient’s risk of disease progression depends on a number of prognostic risk factors. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is used in NHS clinical practice to categorise patients into one of two groups, namely favourable risk or intermediate/poor risk. This systematic review and cost-effectiveness analysis has been conducted to inform the following National Institute for Health and Care Excellence (NICE) multiple technology appraisal: lenvatinib with pembrolizumab for untreated aRCC (ID3760). In November 2021, the Medicines and Healthcare products Regulatory Agency approved the use of lenvatinib plus pembrolizumab as a treatment for all patients with untreated aRCC. Objectives The comparators listed in the final scope issued by NICE differ depending on the risk of disease progression. The objectives of this assessment were to appraise the clinical effectiveness and cost-effectiveness of lenvatinib plus pembrolizumab versus: cabozantinib and nivolumab plus ipilimumab in the intermediate-/poor-risk subgroup sunitinib, pazopanib and tivozanib in the favourable-risk subgroup sunitinib, pazopanib and tivozanib in the all-risk population. Clinical and economic systematic review methods The assessment group (AG) carried out a systematic review of clinical effectiveness evidence following the general principles outlined by the Centre for Reviews and Dissemination (CRD). The review was reported using the criteria recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Searches were conducted between 11 October 2021 and 22 November 2021 in accordance with the general principles recommended by the European Network for Health Technology Assessment. The protocol is registered with PROSPERO (registration number: CRD42021285879). The AG reviewed only randomised controlled trials (RCTs) and full economic analyses identified by the searches. However, the group also considered evidence provided by the manufacturers of lenvatinib (Eisai Ltd) and pembrolizumab (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) provided in submissions to NICE; company submission (CS) reference lists were searched for relevant RCTs. In line with the final scope issued by NICE, the outcomes considered by the AG were overall survival (OS), progression-free survival (PFS), objective tumour response rate, adverse events (AEs), health-related quality of life (HRQoL), incremental cost per life-year gained and incremental cost per quality-adjusted life-year (QALY) gained. Clinical effectiveness results Direct clinical effectiveness evidence (CLEAR trial) The AG systematic review included one RCT, the CLEAR trial. The CLEAR trial was a good-quality, phase III, multicentre, open-label RCT (with an ongoing extension phase) that provided evidence for the comparison of the efficacy of lenvatinib plus pembrolizumab versus sunitinib. Results for all outcomes were assessed at the third interim analysis (August 2020, median OS follow-up of 26.6 months), that is the final data cut-off for PFS. The companies also presented OS results from an updated OS analysis (March 2021, median OS follow-up of approximately 33 months). At the time of the third interim analysis, the CLEAR trial hazard ratio (HR) results showed statistically significant improvements in PFS and objective tumour response rate for patients treated with lenvatinib plus pembrolizumab versus patients treated with sunitinib for the intermediate-/poor-risk subgroup, the favourable-risk subgroup and the all-risk population. The HR results from the updated OS analysis showed a statistically significant improvement for patients treated with lenvatinib plus pembrolizumab versus patients treated with sunitinib for the intermediate-/poor-risk subgroup and the all-risk population; there were too few events in the favourable-risk subgroup for robust OS conclusions to be drawn. Eisai carried out a treatment-switching analysis to test whether adjusting for the effect of subsequent treatments affected OS results. Results were generated only for the all-risk population and were marked as academic-in-confidence. Nearly all the patients in the CLEAR trial lenvatinib plus pembrolizumab and sunitinib arms experienced at least one all-grade AE, with more Grade ≥ 3 AEs reported in the lenvatinib plus pembrolizumab arm than in the sunitinib arm. The proportion of patients who discontinued treatment of either lenvatinib or pembrolizumab due to AEs was approximately twice as high as patients who discontinued treatment of sunitinib; the proportion of patients who withdrew treatment of both lenvatinib and pembrolizumab due to AEs was approximately the same as the proportion of patients who withdrew treatment with sunitinib. Health-related quality of life was measured using three tools, including the EuroQol-5 Dimensions, three-level version questionnaire. When compared with treatment with sunitinib, treatment with lenvatinib plus pembrolizumab did not result in any clinically meaningful differences (as measured by predefined minimally important differences) in HRQoL measured using any of the three tools. Indirect clinical effectiveness evidence To compare the effectiveness of lenvatinib plus pembrolizumab versus relevant comparators other than sunitinib, the AG carried out Bayesian HR network meta-analyses. It was decided not to undertake a flexible modelling approach for network meta-analysis (NMA), which relaxes the proportional hazards (PH) assumption, such as fractional polynomial network meta-analyses because interpretation of the estimates provided by these complex modelling techniques can be difficult and results are often not intuitive. While deviance information criterion (DIC) statistics provide an approach to compare the fit of different models, they do not provide information about whether a model is a good fit to the data or whether the estimates generated by the model, including projections of results beyond the follow-up times of trials included in the NMA, are clinically plausible. Furthermore, flexible models, which appear similar according to model fit (i.e. according to DIC statistics), may generate very different long-term survival estimates. The AG assessed the feasibility of conducting Bayesian HR NMAs for the three population risk groups (intermediate-/poor-risk subgroup, favourable-risk subgroup and all-risk population) for all outcomes listed in the final scope issued by NICE. However, due to limited data availability, it was not possible to carry out NMAs for all outcomes for all three patient risk groups. Further, as networks were sparse, it was only possible to generate results using fixed-effect NMAs. The AG PFS NMA results for the intermediate-/poor-risk subgroup, the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons because of within-trial PH violations or uncertainty regarding the validity of the PHs assumption. The AG OS NMA results for the intermediate-/poor-risk subgroup suggested that there was a numerical, but not statistically significant, improvement in the OS for patients treated with lenvatinib plus pembrolizumab compared with patients treated with cabozantinib or nivolumab plus ipilimumab. Because of within-trial PH violations or uncertainty regarding the validity of the PH assumption, the AG OS NMA results for the favourable-risk subgroup and the all-risk population should not be used to infer any statistically significant difference (or lack of statistically significant difference) for any of the treatment comparisons. The AG objective tumour response rate NMA results for the intermediate-/poor-risk subgroup suggested that, although treatment with lenvatinib plus pembrolizumab led to a statistically significant improvement in objective tumour response rate compared to treatment nivolumab plus ipilimumab, it did not lead to a statistically significant improvement in objective tumour response rate for the comparison of lenvatinib plus pembrolizumab versus cabozantinib. It was not possible to generate results for the IMDC/MSKCC (Memorial Sloan-Kettering Cancer Center) favourable-risk subgroup due to data limitations. The AG objective tumour response rate NMA results for the all-risk population suggest that treatment with lenvatinib plus pembrolizumab led to a statistically significant improvement in objective tumour response rate versus treatment with sunitinib and versus treatment with pazopanib. The AG Grade ≥ 3 AE NMA results for the intermediate-/poor-risk subgroup suggested that treatment with lenvatinib plus pembrolizumab led to statistically significantly more Grade ≥ 3 AEs versus treatment with cabozantinib. It was not possible to generate results for the IMDC/MSKCC favourable-risk subgroup. The AG Grade ≥ 3 AE NMA results for the all-risk population suggested that treatment with lenvatinib led to statistically significantly more Grade ≥ 3 AEs versus treatment with sunitinib and versus treatment with pazopanib. Economic systematic review results The AG systematic review identified one relevant cost-effectiveness study. This study compared the cost-effectiveness of lenvatinib plus pembrolizumab versus sunitinib (and vs. other treatments). However, the study was undertaken from the perspective of the US healthcare system and generated results only for the all-risk population and included comparators that are not recommended by NICE as treatment options for patients with aRCC. Therefore, the extent to which these results were generalisable to the NHS was unclear. Cost-effectiveness analysis methods The Eisai and Merck Sharp & Dohme CSs to NICE included partitioned survival models built in Microsoft Excel. The AG considered that results from both models could be used to inform decision-making but that, in some instances, the companies could have made more appropriate assumptions and parameter choices. The AG did not develop a de novo economic model; instead, it modified the model provided by Merck Sharp & Dohme [referred to as the Merck Sharp & Dohme/Assessment Group (MSD/AG) model]. Neither of the companies produced cost-effectiveness results for the comparison of lenvatinib plus pembrolizumab versus nivolumab plus ipilimumab (intermediate-/poor-risk subgroup) despite both models having the functionality for this comparison. Furthermore, Eisai did not generate any cost-effectiveness results for the favourable-risk subgroup. The MSD/AG model was populated with OS, PFS and time to treatment discontinuation (TTD) data from the CLEAR trial (lenvatinib plus pembrolizumab versus sunitinib for favourable-risk subgroup and the all-risk population). The AG PFS and OS NMA results were used to estimate effectiveness for the comparison of lenvatinib plus pembrolizumab versus cabozantinib and versus nivolumab plus ipilimumab for the intermediate-/poor-risk population. NICE appraisal committees have concluded that sunitinib and pazopanib are of equivalent effectiveness and that, at best, tivozanib may have a similar effect to sunitinib or pazopanib. These conclusions were based on all-risk population data; the AG has assumed that this assumption holds for the favourable-risk population. The most important changes made by the AG to the Merck Sharp & Dohme model were different choices for estimating PFS, OS and TTD for the intervention and comparator treatments and for modelling two lines, rather than one line, of subsequent treatment. Cost-effectiveness analysis results The AG cost-effectiveness results presented in this report were estimated using list prices. Also, the AG cost-effectiveness results generated using confidential discounted prices were supplied to NICE in a confidential appendix, but cannot be presented here. For the intermediate-/poor-risk subgroup, the AG base-case cost-effectiveness results suggested that treatment with lenvatinib plus pembrolizumab generated more QALYs versus treatment with cabozantinib and versus nivolumab plus ipilimumab, but at a greater overall cost than either of these two treatments. Using list prices, the incremental cost-effectiveness ratios per QALY gained for the comparison of lenvatinib plus pembrolizumab versus cabozantinib and versus nivolumab plus ipilimumab exceed £100,000. For the favourable-risk subgroup, the AG base-case cost-effectiveness results suggested that treatment with sunitinib generated more QALYs than treatment with lenvatinib plus pembrolizumab at a lower overall cost, that is treatment with lenvatinib plus pembrolizumab was dominated by treatment with sunitinib (and, using the assumption of equivalent effectiveness, by pazopanib and tivozanib). The AG carried out extensive one-way sensitivity analyses, scenario analyses and probabilistic sensitivity analyses. Results from these analyses demonstrate that the AG base-case cost-effectiveness results are robust. Clinical and cost-effectiveness conclusions Good-quality clinical effectiveness evidence for the comparison of lenvatinib plus pembrolizumab versus sunitinib was available from the CLEAR trial. For most of the AG Bayesian HR NMA comparisons, it was difficult to reach conclusions due to within-trial PH violations or uncertainty regarding the validity of the PHs assumption. However, the data (clinical effectiveness and cost-effectiveness) used to populate the MSD/AG model are relevant to NHS clinical practice and can be used to inform NICE decision-making. The all-risk population comprises patients with intermediate-/poor-risk and patients with favourable-risk disease. The AG cost-effectiveness analyses have focused on the two subgroups, and the AG cost-effectiveness results, generated using list prices for all drugs, show that lenvatinib plus pembrolizumab is less cost-effective than all other treatment options. Study registration This study is registered as PROSPERO CRD4202128587. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR134985) and is published in full in Health Technology Assessment; Vol. 28, No. 49. See the NIHR Funding and Awards website for further award information.
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