Cost-effectiveness comparison of dalpiciclib and abemaciclib combined with an aromatase inhibitor as first-line treatment for HR+/HER2− advanced breast cancer

ABSTRACT Objectives CDK4/6 inhibitors dalpiciclib and abemaciclib have been approved by the Chinese National Medical Products Administration as first-line treatment for postmenopausal females with hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2−) advanced breast cancer (ABC). We aimed to assess the cost-effectiveness of dalpiciclib plus letrozole/anastrozole (non-steroidal aromatase inhibitor [NSAI]) compared with abemaciclib plus NSAI as a first-line treatment for HR+/HER2− ABC in China. Methods We constructed a Markov model with three health states to evaluate health and economic outcomes of first-line treatment with dalpiciclib plus NSAI and abemaciclib plus NSAI for HR+/HER2− ABC. Efficacy data was obtained from MONARCH3 and DAWNA-2 trials. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were calculated. Results Compared with abemaciclib plus NSAI, dalpiciclib plus NSAI resulted in 4.27 additional QALYs, with an ICER of $14827.4/QALY. At a willingness-to-pay threshold of 3 times gross domestic product per capita in China for 2023 ($37721.5/QALY), the cost-effectiveness probability of dalpiciclib plus NSAI was 77.42%. Conclusions From the perspective of Chinese payers, dalpiciclib plus NSAI appears to be a cost-effective strategy compared with abemaciclib plus NSAI for the first-line treatment of patients with HR+/HER2− ABC in China. Clinical trial registration MONARCH3, www.clinicaltrials.gov, identifier is NCT02246621 and DAWNA-2, www.clinicaltrials.gov, identifier is NCT03966898.


Introduction
According to the Global Cancer Statistics 2020, female breast cancer was the most commonly diagnosed cancer and the fifth leading cause of cancer-related deaths worldwide [1].In China, breast cancer accounted for 16.72% of all new cancer cases, and breast cancer-related deaths accounted for 9.9% of all female cancer deaths [2].The majority of patients with breast cancer were initially diagnosed with localized disease (94-97%), and 3-6% had new metastatic disease at diagnosis.Additionally, 10-30% of patients with early-stage breast cancer subsequently developed systemic recurrence [3].Approximately 70% of patients with metastatic breast cancer exhibited the HR+/HER2− subtype [4].Unfortunately, advanced breast cancer (ABC) has a poor prognosis.The 5-year survival rate for distant HR+/HER2-breast cancer is only 26% [5].Given that ABC remains incurable, treatment goals should encompass not only improving survival but also maintaining the quality of life and palliation of symptoms [6,7].
In postmenopausal females with HR+/HER2− ABC, primary treatment involves the use of single-agent endocrine therapy, typically encompassing aromatase inhibitors (AIs) such as letrozole or anastrozole; however, resistance is eventually encountered [8].Reportedly, the addition of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to a non-steroidal aromatase inhibitor (NSAI) can substantially enhance efficacy.Consequently, the combination of endocrine therapy and a CDK4/6 inhibitor has become the preferred first-line treatment for patients with HR +/HER2− ABC in most parts of the world [9][10][11].The Chinese National Medical Products Administration (NMPA) has approved abemaciclib and dalpiciclib, both CDK4/6 inhibitors, for first-line use in combination with NSAI for patients with HR+/HER2− ABC in 2020 and 2023, respectively.This approach is also recommended by the Chinese Society of Clinical Oncology (CSCO) Diagnosis and Treatment of Breast Cancer Guideline as the firstline treatment for patients with HR+/HER2− ABC [12].
The clinical efficacy of abemaciclib in combination with a NSAI was evaluated in the MONARCH 3 study [13][14][15].MONARCH 3 was a randomized, phase III, double-blind study involving postmenopausal females with HR+/HER2− locoregionally recurrent breast cancer who had not received prior systemic therapy.A total of 493 patients were assigned to receive either abemaciclib (150 mg twice daily continuously; n = 328) or placebo (once daily; n = 165), both in combination with 1 mg anastrozole or 2.5 mg letrozole daily.The primary objective was progression-free survival (PFS).The results of the study revealed that the abemaciclib arm achieved a significantly longer median PFS than the placebo arm (28.18 vs. 14.76 months, hazard ratio = 0.54, 95% confidence interval (CI) 0.418-0.698,p < 0.0001); the secondary outcome of overall survival (OS) was reported at the ESMO Congress in 2022 (67.1 vs. 54.5 months, hazard ratio = 0.754, 95% CI 0.584-0.974,p = 0.0301) [16].
Efficacy data for dalpiciclib plus NSAI can be derived from the DAWNA-2 study [17].DAWNA-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial conducted in 42 hospitals in China.DAWNA-2 assessed the efficacy and safety of dalpiciclib plus NSAI as first-line therapy for patients with HR +/HER2− ABC who had not received prior systemic therapy in the advanced setting.In total, 456 patients were eligible and randomly assigned to either the dalpiciclib group (150 mg per day for 3 weeks, followed by 1 week off in a 4-week cycle; n = 303) or the placebo group (once daily for 3 weeks, followed by 1 week off in a 4-week cycle; n = 153).Both groups also received endocrine therapy with either 2.5 mg letrozole or 1 mg anastrozole orally once daily continuously.The primary endpoint was PFS, and results showed that the dalpiciclib group achieved a significantly longer median PFS than the placebo group (30.6 vs. 18.2 months, hazard ratio = 0.51, 95% CI 0.38-0.69,p < 0.0001).Serious adverse events were reported in 36 (12%) patients in the dalpiciclib group and 10 (7%) patients in the placebo group.
As the first domestically developed CDK4/6 inhibitor in China, no previous economic evaluation of dalpiciclib has been undertaken.Therefore, the objective of the current study was to assess the cost-effectiveness of dalpiciclib compared with that of abemaciclib when combined with a NSAI for the first-line treatment of HR+/HER2− ABC in China.

Model overview
This study adhered to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guidelines [18,19].We developed a Markov model to simulate the costs and health benefits associated with the treatment of HR +/HER2-ABC with abemaciclib and dalpiciclib plus a NSAI.The model incorporated three discrete health states representing different stages of the disease: progression-free (PF), progressive disease (PD), and death (Figure 1).Given that the treatment schedule for dalpiciclib was 21 days followed by 7 days off, the cycle length in the Markov model was set to one month.The lifetime horizon was 15-years because the 5-year survival rate was 26% and the initial health status for all patients was PFS [20,21].All patients entered the model in the PF state and remained in this state until disease progression or death.Patients in the PD state could either remain in this state or die.
The outcomes of this model included life years, qualityadjusted life years (QALYs), and costs.According to Chinese guidelines for pharmacoeconomic evaluations, costs and QALYs were discounted at an annual rate of 5%.Incremental cost-effectiveness ratios (ICERs) were calculated, representing the cost per additional QALY gained.The cost-effectiveness threshold in China was set at $37721.5 (3 times the per capita gross domestic product of China in 2023) [22,23].

Clinical efficacy
Survival parameters were mainly obtained from the Kaplan -Meier (KM) curve of the MONARCH 3 and DAWNA-2 trials [13][14][15][16][17].As patients in DAWNA-2 trials were followed for a limited period of time, with most patients not reaching the endpoint event by the trial's conclusion, we simulated OS curves to account for incomplete data.These OS curves predicted the median survival benefit of first-line treatment with CDK4/6 inhibitors plus aromatase inhibitors.
Owing to the lack of a head-to-head trial comparing dalpiciclib plus NSAI and abemaciclib plus NSAI, we used an indirect comparison method to calculate the hazard ratios of PFS and OS for the two regimens.For the best available data, NSAI was used as a control arm to perform an indirect comparison based on the DAWNA-2 and MONARCH 3 trials [13][14][15][16][17].A Bayesian network meta-analysis (NMA) was conducted using NSAI as the connecting therapy.Hazard ratios of OS and PFS between the dalpiciclib arm and the abemaciclib arm were calculated in NMA.The hazard ratio of PFS for the dalpiciclib arm vs. the abemaciclib arm was 0.94 (95% CI 0.27-
We utilized the Engauge Digitizer software to extract digitized data points from the PFS and OS Kaplan -Meier (KM) curves of the MONARCH 3 and DAWNA-2 trials.Individual patient data were reconstructed using standard statistical analyses as described by Guyot et al. [24].The following parametric survival functions were considered: the Exponential distribution, Weibull distribution, Log-logistic distribution, Gompertz Distribution, and Lognormal Distribution.The bestfitted distribution was selected for the model based on the Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC), selecting the distribution with the smallest AIC or BIC value [25].

Cost estimates
This analysis adopted the perspective of healthcare payers in China, considering only direct medical costs.These costs included first-and second-line treatment, management of treatment-related serious adverse events, disease management costs (including outpatient visits, hospitalizations, laboratory scans, and tests), and terminal care.Drug costs were estimated based on patient dosing schedules and unit costs, with costs calculated per cycle.Unit drug costs were obtained from the Shenzhen pharmaceutical trading platform [26].Costs related to subsequent treatment, adverse event management, and end-of-life care were sourced from published literature [27][28][29][30][31][32].Regarding end-of-life care and disease management, we assumed that patients taking oral abemaciclib plus NSAI and dalpiciclib plus NSAI would receive the same end-of-life care and disease management.For adverse event management costs, only grade ≥ 3 events in the MONARCH 3 and DAWNA-2 trials were included [14,17].All costs were adjusted to US dollars in 2023.Chinese Yuan was converted to US dollars using the exchange rate formula: 1 US $ = 7.1104 CNY [33].Key costs are shown in Table 1.

Utility estimates
QALYs were estimated using health state utility (HSU) values, and separate HSU values were estimated for patients in the PF and PD states.The HSU values for different health states in the MONARCH 3 trial population were collected from patientreported outcomes, utilizing the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and Breast Cancer Questionnaire (BR23) to measure the health-related quality of life [34][35][36].Given the lack of specific health utility studies based on the dalpiciclib cohort, the model employed health utility values derived from the wider metastatic breast cancer population [37].Additionally, the disutility of adverse events was considered [28].Table 1 presents the value and source of HSU and other disutility.

Sensitivity analysis
In the base-case analysis, ICERs were presented as costeffectiveness outcome measures and calculated as the incremental cost per additional life-years.In accordance with Chinese guidelines for pharmacoeconomic evaluations, we *NSAI letrozole/anastrozole, PFS Progression-free survival, OS Overall survival, SAEs Severe adverse events, PD Progressed disease, AE adverse event.
adopted 3 times the per capita gross domestic product (GDP) of China in 2023 as the willingness-to-pay (WTP) threshold, equating to $37721.5 per QALY [22,23].
One-way deterministic and probabilistic sensitivity analyses (PSA) were performed to assess the uncertainty of the results.In the one-way deterministic sensitivity analyses (DSA), key model input parameters were adjusted individually to their respective low and high values, as detailed in Table 1.The ranges for parameters were determined based on credible intervals or by assuming a variance of 20% from the base-case values.The results of the one-way sensitivity analyses are presented in a Tornado diagram.For the PSA, parameters were sampled using the Monte Carlo method, generating 10,000 replicated outcomes.Results were presented on a cost-effectiveness plane and cost-effectiveness acceptability curve.Each parameter was entered into the model with different distribution types: Gamma distributions for costs related to disease management, drug acquisition, monitoring, and adverse events, and Beta distributions for the utility weights assigned to PF and PD states [38].

Base-case analysis
The results of the deterministic analysis are presented in Table 2.In patients with HR+/HER2− ABC, compared with abemaciclib plus NSAI, dalpiciclib plus NSAI yielded an additional 4.27 QALYs (31.18 QALYs vs. 26.91QALYs), corresponding to an incremental cost of $63303.40.The calculated ICER was $14827.40/QALYgained, which was lower than the WTP of three times the GDP per capita in China.

Sensitivity analysis
According to the one-way DSA, the results of the model were more sensitive to the utility of PFS for dalpiciclib plus NSAI group and the utility of PD for abemaciclib plus NSAI group (Figure 2).Considering PSA, the cost-effectiveness plane illustrated the results of 1,0000 Monte Carlo iterations (Figure 3).Comparing dalpiciclib plus NSAI with abemaciclib plus NSAI, the cost-effectiveness acceptability curve indicated a nearly 77.42% probability of cost-effectiveness at the WTP threshold of $37721.5, consistent with the base-case analysis results (Figure 4).

Discussion
The rising costs of oncologic treatments globally, particularly for cancer drugs, are a considerable concern in both developed and developing countries.In 2020, the expenditure on cancer treatments reached up to $164 billion and is predicted to increase to approximately $260 billion by 2025 [39].The high cost of oncology drugs not only places a strain on health insurance systems but also directly impacts patients through heightened out-of-pocket expenses.This, in turn, can result in reduced adherence to treatment plans, ultimately leading to  unfavorable outcomes for patients.Moreover, the persistent escalation of costs poses a societal challenge as it accumulates a shared financial burden.This situation has raised concerns regarding the long-term sustainability of healthcare systems [40].In response to growing costs, the Chinese government has initiated measures like centralized price negotiations since 2017 to improve the affordability of anticancer medications.Economic evaluation plays a substantial role in national price negotiations [41].Cost-effectiveness analysis (CEA) has become a standard method to evaluate the value of cancer care and treatments.Considering the first-line treatment of HR +/HER2-ABC, CDK4/6 inhibitors such as palbociclib, ribociclib, dalpiciclib, and abemaciclib plus NSAI have been found to markedly prolong survival when compared with placebo plus NSAI.However, the high costs of CDK4/6 inhibitors imposes a huge financial burden on patients and healthcare systems.
The cost-effectiveness of CDK4/6 inhibitors in HR+/HER2-ABC has garnered considerable interest [28,[42][43][44][45]. Costeffectiveness studies are crucial for different stakeholders, including patients, payers, regulators, and clinicians.A majority of published CEA studies have found that CDK4/ 6 inhibitors plus NSAI were not cost-effective when compared with endocrine therapy alone.Two studies conducted a CEA of the application of the three CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) from the perspective of Europe and the U.S.A., revealing that the three CDK4/6 inhibitors plus NSAI were not more cost-effective than endocrine therapy alone [42,43].In a similar CEA, Zeng N et al. have observed that only abemaciclib + NSAI was cost-effective compared to placebo + NSAI at the WTP of $38,029/QALY from the Chinese payers' perspective.However, the palbociclib + NSAI and ribo-ciclib+ NSAI groups were not cost-effective at the current  price, unless the drug prices were adjusted to 50% or 10% of their current prices ($320.67 per cycle or $264.60 per cycle) [44].In China, economic evidence comparing dalpiciclib plus NSAI with abemaciclib plus NSAI is lacking.To address this gap, we constructed a Markov model to assess the costeffectiveness of dalpiciclib plus NSAI versus abemaciclib plus NSAI as a first-line treatment for patients with HR+/HER2− ABC from the perspective of the healthcare system.Our results indicated that dalpiciclib plus NSAI therapy afforded an additional 4.27 QALYs when compared with abemaciclib plus NSAI.The calculated ICER was $14827.40/QALYgained, which was below the WTP threshold of three times GDP per capita in China.Accordingly, this finding indicated that dalpiciclib plus NSAI strategy may afford a cost-effective option.
The sensitivity analyses were performed to assess the impact of uncertainty on the results.Both one-way sensitivity analysis and PSA showed that the model was robust.One-way sensitivity analyses showed that when the utility of PFS for the dalpiciclib plus NSAI group increased to 0.95, the ICERs were higher than the WTP of $37721.5/QALY.The utility of PFS for the dalpiciclib group in our model was not taken directly from the study population but from the literature on similar populations, which may limit the accuracy of our results.However, sensitivity analyses showed that the disutility of AEs had little impact on the ICER.This might be because patients experienced AEs only for short periods of time and the AE disutility was significantly outweighed by improvements in survival and prolongation of stable disease.The PSA of the different parameters simultaneously showed that most of the scatter was below the dotted diagonal line, which indicated that dalpiciclib combination therapy may be more cost-efective than the abemaciclib combination therapy.
To compare abemaciclib plus NSAI and dalpiciclib plus NSAI treatments indirectly, it is essential to ensure comparable baselines between the groups.According to the baseline characteristics of patients reported in the MONARCH 3 and DAWNA-2 trials, the proportion of disease-free interval (De novo metastatic,41% vs. 41%), Visceral metastases at study entry (61% vs. 55%) in the two groups were similar.Nonetheless, certain disparities were observed, such as the proportion of prior endocrine therapy, median age, post-menopausal status, and the inclusion of letrozole as an endocrine therapy partner [13][14][15][16][17].The DAWNA-2 trial, conducted in China, provided insights into the local epidemiological nuances of ABC.Compared with their Western counterparts, Chinese patients tend to be younger and exhibit a lower frequency of prior endocrine therapy and post-menopausal status, indicative of a more favorable prognosis.
This study has several limitations that need to be addressed.(1) There is a lack of local utility data for patients with HR+/HER2− ABC from the DAWNA-2 trial; hence, the accuracy of the model will need to be updated when such data become available in China.(2) As OS data were not available for dalpiciclib plus NSAI at the time of this analysis, we assumed equivalent OS to ribociclib plus NSAI because of the similar mechanism of action and hazard ratios in PFS benefit.(3) Given certain inconsistencies in the baseline characteristics, the heterogeneity of baseline characteristics cannot be well balanced, which may increase the bias of the results.(4) There is a gap between China's level of economic development and that of Europe and the United States, and it is necessary to consider the differences between different geographical areas.There is also an imbalance in the level of economic development between different regions of China, not only is there a huge difference in the level of medical care between the eastern coastal regions and the western regions, but there is also a huge difference in people's ability to pay, so adjustments should be made when making decisions.It is crucial to note that this analysis is based on updated data published in 2023.We plan to revisit and update our results once the final data are accessible for analysis.

Conclusions
The results of the current study revealed that dalpiciclib plus NSAI could be cost-effective when compared with abemaciclib plus NSAI for the first-line treatment of patients with HR +/HER2-ABC from the perspective of the Chinese healthcare system at a WTP threshold of $ 37721.5/QALY.This finding could guide clinicians and health policymakers to reach more informed decisions for the management of patients with HR +/HER2-ABC.

Figure 1 .
Figure 1.The Markov state transition model.

Figure 2 .
Figure 2. Tornado plot generated in the one-way deterministic sensitivity analysis.Only the top 12 most influential parameters are presented.PFS progression-free survival, PD progressed disease, WTP willingness-to-pay, QALY quality-adjusted life-year, ICER Incremental cost-efectiveness ratio.

Figure 3 .
Figure 3. Cost-effectiveness plane generated in the probabilistic sensitivity analysis.WTP, willingness-to-pay.

Table 1 .
Model parameters of clinical data, costs and utilities: baseline values, ranges, and distributions.

Table 2 .
Summary of results of the base-case analysis.