Cost-Effectiveness Analysis of Abemaciclib plus Fulvestrant versus Placebo plus Fulvestrant in Patients with Hormone Receptor-Positive, ERBB2-Negative Breast Cancer

Abstract

Purpose

Abemaciclib is a selective and potent small-molecule inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) which is administered orally. Compared to placebo plus fulvestrant (PF), abemaciclib plus fulvestrant (AF) significantly improved progression-free survival (PFS) and overall survival (OS). However, an economic evaluation of these two treatments is currently lacking. The purpose of this article was to evaluate the cost-effectiveness of the two treatments for HR*, HER2− advanced breast cancer (ABC) in the USA.

Methods

A Markov simulation model was constructed using data from a published clinical trial (MONARCH 2). The two simulated treatment strategies included AF or PF. Costs were obtained from the clinical trials and the website, and utility was derived from the published literature. Incremental cost-effectiveness ratios (ICERs) were calculated to compare the two treatment strategies.

Results

The total costs were USD 400,377.43 and USD 89,937.77 for AF and PF treatment, respectively. The AF treatment produced 2.09 long-term quality-adjusted life years (QALYs), and the PF treatment produced 1.08 QALYs. Hence, patients who received AF treatment spent an additional USD 310,439.66 and generated an increase of 1.01 QALYs, resulting in an ICER of USD 307,366 per QALY. At current prices, AF was not cost-effective assuming a willingness-to-pay threshold of USD 150,000 per QALY gained.

Conclusion

Despite significant gains in PFS over AF, it is not a cost-effective treatment for HR*, HER2− ABC in the USA at current drug prices.

Introduction

Breast cancer is not only the most common cancer in women but also one of the three most common cancers worldwide, along with lung and colon cancer [1]. During their lifetime, at least 10% of women will develop breast cancer. Hence, breast cancer is still the most common cause of death from cancer in women [2, 3].

Two main molecular targets have been identified in breast cancer pathogenesis. One is estrogen receptor alpha (ERα), which can be expressed in approximately 70% of advanced breast cancer (ABC). The other molecular target is epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu), which is a transmembrane receptor tyrosine kinase in the epidermal growth factor receptor family that is overexpressed in approximately 20% of breast cancers and is also associated with poor prognosis [1]. Most patients with metastatic breast cancer are hormone receptor (HR)-positive and are initially treated with endocrine therapy (ET) [4]. ET in combination with CDK4 and CDK6 inhibitors has become a standard treatment for ABC patients who are HR-positive and ERBB2 (formerly HER2)-negative [5, 6, 7].

Abemaciclib is a selective and potent small-molecule inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) which is orally administered. Abemaciclib in combination with ET is approved for the treatment of HR-positive, ERBB2-negative ABCs that progress on ET with fulvestrant (MONARCH 2) [8]. Our study was based on MONARCH 2, which is a phase III randomized, double-blind study of placebo or abemaciclib in combination with fulvestrant for patients who had progressed on ET with HR-positive, ERBB2-negative ABC.

Compared with placebo plus fulvestrant (PF), abemaciclib plus fulvestrant (AF) significantly improved progression-free survival (PFS; median, 16.4 vs. 9.3 months; HR, 0.553; 95% CI, 0.449–0.681; p < 0.001) and overall survival (OS; median, 48.8 vs. 40.7 months; HR, 0.787; 95% CI, 0.606–1.021; p = 0.01) [8]. Graded 3 or higher adverse events (AEs) in the AF group included neutropenia (n = 131 [29.9%]), leukopenia (n = 49 [11.1%]), and anemia (n = 40 [9.1%]). The most common nonhematologic AE reported in the AF group was diarrhea, with 64 (14.5%) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 events [9].

Supplementation with new active agents (such as abemaciclib) for the treatment of HR*/HER2− ABC is associated with a high monthly cost. In practice, it is important to evaluate whether AF is a cost-effective option compared with PF and improves quality-adjusted life years (QALYs) in the USA.

Methods

Health States

A total of 669 patients were enrolled in the study (MONARCH 2) and randomly assigned to the AF group (n = 446) or the PF group (n = 223). The patients received fulvestrant (500 mg) on days 1 and 15 of the first cycle and on day 1 of each cycle thereafter by intramuscular injection plus abemaciclib (150 mg) or placebo twice a day in each cycle [9]. The patients in the placebo arm received a mean of 13.7 cycles of treatment compared to 18.9 cycles in the abemaciclib arm [9]. We estimated disease progression or death rates using available PFS and OS data observed in the trial, which were 16.4 versus 9.3 months and 48.8 versus 40.7 months for the AF and PF treatments, respectively.

Model Structure

A Markov cohort model was developed to simulate PFS and OS based on the MONARCH 2 clinical trial and to evaluate the cost-effectiveness of treatment with AF versus PF in patients with HR-positive, ERBB2-negative ABC that progressed during ET. We used three health states to simulate the disease process: progressive disease (PD), PFS, and death. In the model, patients who had progressed on ET with HR-positive, ERBB2-negative ABC were assumed to be in the PFS state; they could either enter the PD state or the death state when the disease progressed, while patients in the PD state could either enter the death state or remain in this state (Fig. 1). Transition probabilities (p) were calculated according to the following formula: probability (1 month) = 1 − (0.5) (1/median time to event) [10]. The cycle length was 1 month, and the time horizon of this Markov model was 10 years. We used QALYs to measure the health outcomes and computed them with TreeAge software 2020.

Fig. 1.

A Markov structure was built to compare two treatments. PFS, progression-free survival; PD, progressive disease.

Costs and Utility

In this study, we only considered the direct costs, including costs for medicine, necessary tests, and treatments for AEs of grade 3–4. Medicine costs were obtained on Drugs.com (online) 2019 [11]. The costs of common AEs treatment per patient (such as severe neutropenia, anemia, thrombocytopenia, and diarrhea) were calculated (Table 1). The cost for the PF (placebo plus fulvestrant 500 mg) regimen was USD 21,997.97 and that for the AF (abemaciclib 150 mg twice a day plus fulvestrant 500 mg) regimen was USD 8,303.51 each month. Every 3 months, progression was assessed, and the cost for two groups per month was calculated (Table 2). The European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30) was used to assess quality of life. The utility of two groups was estimated by dividing the QLQ-C30 score by 126; 1 stands for perfect health and 0 stands for death. The utility was 0.64 in the PFS state and 0.55 in the PD state in the AF group, and it was 0.635 in the PFS state and 0.55 in the PD state in the PF group [12]. All QALYs and costs were discounted at a 3% annual rate.

Table 1.

Costs per patient of common treatment-related adverse events in the MONARCH 2 trial [25]

	AF group (n = 441)		PF group (n = 223)
	Grade 3/4, %	Costs per patient, USD	Grade 3/4, %	Costs per patient, USD
Neutropenia	26.5	284.84	1.8	18.12
Leukopenia	8.8	57.21	0	0
Anemia	7.3	102.27	0.9	10.72
Thrombocytopenia	3.4	18.75	0.4	2.47
Nausea	2.7	0.98	0.9	0.32
Vomiting	0.9	0.33	1.8	0.65
Increased ALT	4.1	12.20	2.7	1.99
Diarrhea	13.4	0.79	0.4	0.05

Table 2.

Clinical efficacy, baseline input costs, and baseline transition probability based on the MONARCH 2 trial

	AF	PF	References
Costs per month, USD
Abemaciclib	15,288.56	−	[11]
Fulvestrant	2,393.89	3,213.45	[26]
Tests	1,273.79	1,677.88	[27]
Best supportive care	2,564.36	3,377.86	[28]
Major AEs	477.37	34.32
Transition probabilities
p PFS-PFS	0.946	0.910
p PFS-PFS	0.040	0.072
p PFS-death	0.014	0.018
p PD-PD	0.977	0.935
p PD-death	0.023	0.065

AEs, adverse events; p, probability; PFS, progression-free survival; PD, progressive disease.

Sensitivity Analysis

One-way probabilistic sensitivity analyses were performed in the study. Key parameters were used within a range of ±30% to explore their influence on incremental cost-effectiveness ratio (ICERs) in sensitivity analyses. Additionally, a Monte Carlo simulation was used to evaluate the probabilistic sensitivity of the model through 1,000 simulations with 10,000 individuals. The willingness-to-pay (WTP) threshold was set at USD 150,000 per QALY in the USA [10].

Results

Baseline Analysis

The results of the analysis presented in Table 3 showed that the total costs were USD 400,377.43 and USD 89,937.77 for AF and PF treatment, respectively. The AF treatment produced 2.09 QALYs, and the PF treatment produced 1.08 QALYs. Hence, patients who received AF treatment spent an additional USD 310,439.66 and generated an increase of 1.01 QALYs, resulting in an ICER of USD 307,366 per QALY.

Table 3.

Results of base-case analysis of the AF and PF group

	AF group	PF group
Costs, USD	400,377.43	89,937.77
Incremental costs, USD	310,439.66
Effectiveness, QALYs	2.09	1.08
Incremental effectiveness, QUALYs	1.01
ICER, USD/QALY	307,366

QALY, quality-adjusted life year; ICER, Incremental cost-effectiveness ratio.

Sensitivity Analyses

The one-way sensitivity analyses demonstrated that the utility of PFS in the AF group was the most sensitive parameter influencing the results (Fig. 2). For utilities ranging from 0.448 to 0.832, the ICERs ranged from USD 240,589.85 to USD 420,045.01 per QALY, which exceeded the WTP threshold. Additionally, the cost-effectiveness acceptability curve and scatter diagram suggested that below the WTP threshold of USD 150,000, AF treatment was not cost-effective for patients with ABC who were HR-positive and ERBB2 (formerly HER2)-negative (Fig. 3, 4). We used the simulation model to identify the prices at which AF or PF treatment would reach a cost-effectiveness threshold of USD 150,000 per QALY gained. Abemaciclib must decrease by 60.75% to USD 6,000 per month to become cost-effective in this patient population.

Fig. 2.

Tornado diagram of one-way sensitivity analyses. The impact of parameters on the ICER was listed. ICER, incremental cost-effectiveness ratio; PFS, progression-free survival; PD, progressive disease.

Fig. 3.

The cost-effectiveness acceptability curve showed the probability at the current WTP threshold. WTP, willingness to pay; QALY, quality-adjusted life year.

Fig. 4.

The scatter plot diagram showed the probability at the current WTP threshold. WTP, willingness to pay.

Discussion

Breast cancer is the second most common cause of death from cancer in developed countries and the most common cause of death from cancer in less developed countries. In Africa, South America, and Asia, the morbidity of breast cancer is increasing, most likely caused by lifestyle changes and initiated screening programs. Mortality from breast cancer in these regions is also increasing, probably because of a lack of access to diagnosis and therapy [13, 14].

Breast cancer includes 3 major tumor subtypes categorized according to ERBB2 gene amplification and estrogen or progesterone receptor expression. The 3 subtypes have distinct treatment strategies and risk profiles [1]. A total of 155,000 women were living with ABC in the USA in 2017 according to a recent study, of which approximately 70% were HR* [15]. Suitable therapy for each patient depends on the tumor subtype, anatomic cancer stage, and patient preferences.

For women with advanced HER2− and HR* breast cancer taking CDK4/6 inhibitors, recent clinical trials have demonstrated significant improvements in PFS and OS. In 2015, the first CDK4/6 inhibitor, palbociclib, gained accelerated approval as a first-line therapy for postmenopausal women with HR*, HER2− ABC. Ribociclib and abemaciclib were approved for the same indication [16]. With more than 100,000 women living with ABC, the cost of treatment with CDK4/6 inhibitors could exceed USD 17 billion annually. The introduction of these new strategies for the treatment of HR*/HER2− ABC is associated with a relevant increase in costs; therefore, it is important to balance the increased value caused by the improvement of the clinical parameters of interest, such as PFS and the costs of treatment.

Our simulation model shows that the AF treatment is not cost-effective at current drug prices. The results of our simulation model are similar to those of previous studies which found that CDK4/6 inhibitors (palbociclib or ribociclib) were not cost-effective in the USA or the UK [17, 18, 19]. However, a study in Italy showed that all three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) are cost-effective treatments in postmenopausal women with HR*/HER2− ABC in first-line therapy associated with letrozole or anastrozole [20]. And also, the price of abemaciclib is much lower in Germany, which will be USD 2,987.65 (1 EUR = USD 1.214) per month. So, we calculated our model using the price in Germany as an example for an European country based on the price of abemaciclib and fulvestrant due to the published literature [21, 22]. The ICER was USD 92,005.25, which means that AF was cost-effective in Europe with the WTP threshold of USD 121,400 (1 EUR = USD 1.214) [22, 23, 24].

Our analysis has several limitations. We gathered available published data from the MONARCH 2 clinical trial to calculate the PD-to-death transition probabilities for both treatment arms. Differences in the MONARCH 2 trial may exist, including the smaller enrollment of the PF treatment arm. We did not consider other potential costs, such as hospital costs and physician visits.

Conclusions

At current prices, treatment with AF for patients who had progressed on ET with HR-positive, ERBB2-negative ABC is not cost-effective in the US healthcare system. Therefore, a reduction in the pharmacological costs of abemaciclib is necessary if we want to consider AF treatment even more advantageous in terms of cost-effectiveness.

Statement of Ethics

This article does not contain any studies with human participants or animals performed by any of the authors. Informed consent was obtained from all individual participants included in the study.

Conflict of Interest Statement

The authors declare that they have no conflicts of interest.

Funding Sources

This study was funded by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYJC18010).

Author Contributions

Conception and design: Qiu Li, Qian Xie. Development of methodology: Qiu Li, Qian Xie, Hanrui Zheng. Analysis and interpretation of data: Qian Xie, Hanrui Zheng.

Data Availability Statement

All data generated or analyzed during this study are included in this article.