Hormone receptor-positive (HR+) and human epidermal growth factor receptor-2-negative (HER2−) breast cancer is the most common molecular subtype of breast cancer in many countries. Endocrine therapy continues to be a pillar in its treatment. Patients with resistance to this therapeutic option often have a poor prognosis after disease progression due to insufficient effective treatment strategies.
Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of orally administered targeted agents and are recommended for use in combination with endocrine therapy as first- and second-line treatments for breast cancer. HR+/HER2− advanced. However, their high prices make it very difficult to use these drugs in real-world settings.
To provide a new basis for future research, we investigated the cost-effectiveness of combinations of CDK4/6 inhibitors with endocrine therapy in the treatment of HR+/HER2− advanced breast cancer.
| Methods |
Several commonly used databases were systematically searched. Since the first CDK4/6 inhibitor (palbociclib) was marketed in the United States in February 2015, the search period was set from that date to April 2021.
The systematic review was conducted after retrieving the papers and extracting data according to the inclusion and exclusion criteria. The quality of each selected economic evaluation was assessed by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS).
| Results |
The literature search yielded 161 articles , among which fourteen studies (15 articles) with CHEER scores ranging between 58.33% and 87.50% entered the final analysis. Markov models were used in most studies.
Based on currently available data, CDK4/6 inhibitors plus endocrine therapy were less cost-effective in the first- or second-line treatment of patients with HR+/HER2− advanced breast cancer. However, ribociclib plus letrozole was more cost-effective than palbociclib plus letrozole in the first-line treatment of postmenopausal women.
The economic impacts of CDK4/6 inhibitors plus endocrine therapy in non-postmenopausal patients or second-line therapy cannot be fully evaluated due to the limited number of studies. The three most common factors affecting economic outcomes were prices of CDK4/6 inhibitors, hazard ratios for progression-free survival and overall survival, and health state utility values.
| Discussion |
CDK4/6 inhibitors plus endocrine therapy have shown significantly improved efficacy outcomes in the first- and second-line treatment of HR+/HER2− metastatic breast cancer (mBC)/advanced breast cancer (ABC) for endocrine-sensitive and endocrine resistant, while more potential fields, including neoadjuvant and adjuvant settings, are being identified to benefit a broader range of breast cancer patients.
Clinical trials demonstrated that there was a higher incidence of grade 3 or 4 hematologic adverse events with ribociclib and palbociclib, while gastrointestinal toxicity appeared to be more predominant with abemaciclib. Meanwhile, the risk of serious adverse events that are more likely to occur in patients treated with CDK4/6 inhibitors may lead to reduced quality of life and higher medical costs that patients must pay.
The cost related to adverse drug reactions has been explored in several economic burden studies to be primarily due to hospitalizations and outpatients. However, most studies focused on adverse events caused by chemotherapy and endocrine therapy, and research on the economic burden of therapy containing CDK4/6 inhibitors is currently unpublished. Therefore, evaluating the cost associated with adverse events of CDK4/6 inhibitors is worth developing in the future.
Many economic evaluations have truly concluded that CDK4/6 inhibitors combined with endocrine therapy are unlikely to be more cost-effective than endocrine therapy alone. Several studies have performed cost analyzes of CDK4/6 inhibitors. Drug waste costs were higher in the palbociclib regimen than in the ribociclib regimen due to different dosing patterns. Furthermore, current economic evaluations showed that ribociclib plus letrozole had better economic benefits than palbociclib plus letrozole for the first-line treatment of postmenopausal women with HR+/HER2− ABC .
In the future, more budget impact analyzes of CDK4/6 inhibitors should be conducted to evaluate their impact on national health insurance systems to inform drug pricing and increase drug accessibility.
This review had some limitations . First, only three studies compared cost-effectiveness between different CDK4/6 inhibitors, all of them on first-line treatment of postmenopausal patients with HR+/HER2− ABC. The small number made the basic analysis less persuasive. Since there is no pharmacoeconomic evaluation of the new CDK4/6 inhibitor abemaciclib, it is impossible to compare its cost-effectiveness with endocrine therapy and two other inhibitors. Therefore, the evaluation system among CDK4/6 inhibitors remains incomplete.
Second, several studies did not adjust for the inclusion of different costs based on job perspective. For example, the impact of indirect costs, including labor loss, on the cost-effectiveness of CDK4/6 inhibitors was not considered from a society-wide perspective. The cost difference had a significant impact on the results observed in the univariate sensitivity analysis.
As a third consideration, there is insufficient literature evaluating the economic properties of CDK4/6 inhibitors for different subgroups of target populations, including patients receiving second-line treatment and non-postmenopausal women. As shown in clinical trials, the efficacies of CDK4/6 inhibitors vary in different subgroups in terms of type of endocrine therapy drug, metastatic site, age, and race, and consequently, economic outcomes may also differ markedly. However, a more detailed analysis is currently impossible due to the small volume of literature.
Finally, the studies were conducted in different countries, so there may be heterogeneity between the works in different dimensions, including costing, monetary units, and health preferences, which may affect the conclusions. Most of the included studies were from developed countries, which may be related to access to CDK4/6 inhibitors.
Conclusions
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