Authors' objectives: Inhibitors of cyclin-dependent kinases 4/6 (CDK4/6) are a relatively recent addition to the treatment options available for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer (HR+/HER2- LA/MBC). Three CDK4/6 inhibitors – palbociclib (PAL), ribociclib (RIB) and abemaciclib (ABE) – are currently available in Switzerland. They are approved and reimbursed in combination with endocrine therapy (ET; aromatase inhibitors [AIs] in patients without endocrine resistance; fulvestrant [FUL] in patients with endocrine resistance) in HR+/HER2- LA/MBC patients. This health technology assessment (HTA) report assesses 1) the efficacy, effectiveness, safety and cost-effectiveness of the three CDK4/6 inhibitors (in the respective treatment combinations) compared with each other and with endocrine monotherapies, 2) the costs and cost-effectiveness of the CDK4/6 inhibitors and the budget impact of a potential disinvestment in any one of the three CDK4/6 inhibitors, 3) related ethical and organisational issues.

Authors' results and conclusions: Results: The systematic literature searches identified 35 RCTs of which 24 could be included in the NMA. Of the identified NRSs, we included 56 in the descriptive analysis of adverse events. Based on the NMA results it is likely that CDK4/6 inhibitors provide superior efficacy when compared to ET monotherapies. At the same time it is highly likely that the ET monotherapies show superior tolerability when compared to the combination therapies with CDK4/6 inhibitors. Differences be-tween the individual CDK4/6 inhibitors are not very robust and some efficacy data on individual CDK4/6 inhibitors from primary studies are not yet available. We performed two cost-effectiveness analyses (CEA) based on partitioned-survival models com-paring four different AI-related treatment regimens (PICO 1) and four different FUL-related treatment regimens (PICO 2). For patients without endocrine resistance, based on our results ABE+AI was most effective in terms of quality-adjusted life years gained (QALYG) compared to RIB+AI and AI monotherapy, resulting in a discounted incremental cost-effectiveness ratio (ICER) of ABE+AI vs. RIB+AI of 166,787 CHF per QALYG and a discounted ICER of RIB+AI vs. AI of 126,860 CHF per QALYG. The combination therapy PAL+AI was dominated. For patients with endocrine resistance, based on our results RIB+FUL was most effective in terms of QALYG compared to PAL+FUL and FUL monotherapy, resulting in a discounted ICER of PAL+FUL vs. FUL of 147,808 CHF per QALYG and a discounted ICER of RIB+FUL vs. PAL+FUL of 148,342 CHF per QALYG. The combination therapy ABE+FUL was dominated. The results were sensitive to variations in the hazard ratios for overall survival (OS) and progression-free survival (PFS) and in several other conducted sensitivity analyses. Based on official drug prices, delisting PAL or ABE would lead to budget savings within an incident cohort, whereas delisting RIB would lead to additional costs, given that, in each scenario, patients are allocated to the other two CDK4/6 inhibitors. The ethical issue concerning the choice of primary endpoints in clinical trials is controversially dis-cussed in the scientific literature. The extent to which progression-free survival can be considered a patient-relevant outcome for patients with LA/MBC is currently unclear. Regarding organisational aspects of the assessed interventions, the addition of CDK4/6 inhibitors to the treatment with ET leads to additional doctor’s visits and examinations for the monitoring of adverse events (AEs) and requires special considerations regarding concomitant medications. Conclusions: Our analyses suggest that ET+CDK4/6 inhibitor combination therapy is more efficacious but also associated with more AEs than ET monotherapy. Comparative efficacy results between individual CDK4/6 inhibitors are uncertain and inconclusive. A substantial number of currently ongoing RCTs studying CDK4/6 inhibitors in relevant patient groups might provide further insight in the future. The CEAs suggest that ABE+AI is most effective and can be considered cost-effective at a willingness-to-pay (WTP) threshold of 170,000 CHF per QALYG for patients without endocrine resistance and RIB+FUL is most effective and can be considered cost-effective at a WTP threshold of 150,000 CHF per QALYG for patients with endocrine resistance. However, the certainty of these analyses is lim-ited because several input parameters had to be based on assumptions. Our CEAs should be up-dated when mature OS and quality of life (QoL) data for all CDK4/6 inhibitor combination therapies are available from clinical trials. The budget impact analysis shows a potential for reducing direct treatment costs in the assessed populations by disinvesting in either PAL or ABE.

Authors' methods: We performed two separate systematic literature searches to identify (1) randomised controlled trials (RCTs) for the assessment of efficacy and safety and (2) non-randomised studies (NRSs) for the other assessment domains. The available body of evidence from RCTs provides comparisons between any one of the CDK4/6 inhibitors with endocrine monotherapies but no direct comparisons between different CDK4/6 inhibitors. We therefore performed indirect comparisons through network meta-analysis (NMA) for the efficacy outcomes (overall survival, quality of life and progression-free survival) and safety outcomes (adverse events and treatment discontinuations). In addition, we conducted a descriptive analysis of non-randomised studies for an extended assessment of potential adverse events associated with CDK4/6 inhibitors. To assess cost-effectiveness, we developed a de novo economic model. Cost data and other rele-vant model parameters were gathered from several sources including the Swiss Specialties List, published literature and the input of Swiss clinical oncology experts. For the budget impact analysis, we considered changes in direct treatment related costs in an incident cohort and calculated several scenarios, separately assessing the consequence of disinvestment in either one of the three CDK4/6 inhibitors.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/cdk46inhibitoren.html

Year Published: 2021

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0046palb-hta-report.pdf.download.pdf/h0046palb-hta-report.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health