Cost-effectiveness of trastuzumab deruxtecan for previously treated HER2-low advanced breast cancer

Demin Shi; Xueyan Liang; Yan Li; Lingyuan Chen

doi:10.1371/journal.pone.0290507

. 2023 Aug 24;18(8):e0290507. doi: 10.1371/journal.pone.0290507

Cost-effectiveness of trastuzumab deruxtecan for previously treated HER2-low advanced breast cancer

Demin Shi ^1,^#, Xueyan Liang ^2,^#, Yan Li ², Lingyuan Chen ^3,^*

Editor: Mirosława Püsküllüoğlu⁴

PMCID: PMC10449172 PMID: 37616309

Abstract

Objective

The clinical efficacy and safety profile of trastuzumab deruxtecan (T-DXd) have been demonstrated in previously treated patients with human epidermal growth factor receptor 2 (HER2)-low advanced breast cancer (BC). It is, however, necessary to evaluate the value of T-DXd considering both its clinical efficacy and its cost, given that it is high. This study aimed to evaluate the cost-effectiveness of T-DXd versus chemotherapy in patients with previously treated HER2-low advanced BC.

Methods

We used a partitioned survival model that included three mutually exclusive health states. The patients in the model were identified based on their clinical characteristics and outcomes from the DESTINY-Breast04. Probabilistic and one-way sensitivity analyses were performed to evaluate the model’s robustness. Subgroup analyses were also conducted. The measures included costs, life years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratios (ICERs), incremental net health benefits (INHBs), and incremental net monetary benefits (INMBs).

Results

The ICERs of T-DXd vs. chemotherapy were $83,892/QALY, $82,808/QALY, and $93,358/QALY in all HER2-low advanced BC patients, HER2-positive (HER2+) advanced BC patients and HER2-negative (HER2-) advanced BC patients, respectively. In one-way sensitivity analysis, the cost of T-DXd and hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) were also identified as key drivers. If the price of T-DXd decreased to $17.00/mg, $17.13/mg, and $14.07/mg, it would be cost-effective at a willingness to pay (WTP) threshold of $50,000/QALY in all HER2-low advanced BC patients, HER2+ advanced BC patients and HER2- advanced BC patients, respectively. At a WTP threshold of $100,000/QALY, the probability of T-DXd being cost-effective was 81.10%, 82.27%, and 73.78% compared to chemotherapy for all HER2-low advanced BC patients, HER2+ advanced BC patients and HER2- advanced BC patients, respectively. Most subgroups of patients with HER2+ disease had a cost-effectiveness probability of > 50%.

Conclusion

From a third-party payer’s perspective in the United States, the findings of the cost-effectiveness analysis revealed that, at the current price, T-DXd is a cost-effective alternative to chemotherapy for patients with prior HER2-low advanced BC, at WTP threshold of $100,000/QALY.

Introduction

Breast cancer (BC) is the most common cancer among women [1]. Early detection, surgery, radiation therapy, and systemic treatment have improved the overall survival (OS) rate of patients diagnosed with stage I-III BC to 70–80% [2], however, approximately 30% of women diagnosed with early-stage BC progress to advanced or metastatic cancer [3]. Poor prognosis coupled with the high incidence of BC has made it the second leading cause of cancer-related mortality in women worldwide after lung cancer, primarily because of the adverse prognosis for most patients with advanced disease [1, 4].

In addition to patient and disease characteristics, the molecular subtypes of BC play an important role in prognosis and therapeutic decision-making. Approximately 20% of all BC cases are associated with overexpression of human epidermal growth factor receptor 2 (HER2) [5]. In the last two decades, the landscape of systemic treatment for advanced BC has changed significantly, with main developments occurring in the treatment of hormone receptor-positive (HR+)/HER2-negative (HER2-) as well as HER2-positive (HER2+) cases [4]. Several types of HER2-targeted therapies have been used in metastatic setting, including trastuzumab-emtansine, trastuzumab, pertuzumab, and lapatinib [6]. About 60% of BC cases with HER2- metastatic expression exhibit low levels of HER2, defined as an immunohistochemical (IHC) score of 1+ or 2+ IHC score combined with a negative in situ hybridization result (ISH) [7, 8]. The term "HER2-low" is used to describe both HR+ and hormone receptor-negative (HR-) BCs that will respond differently to systemic chemotherapy depending on their prognosis [7, 8]. Patients with this subtype have not benefited from existing HER2-directed therapies [9, 10]; therefore, BC with a HER2-low status is currently treated as HER2- (HER2-low and HER2-zero), with patients stratified by hormone receptor status [4, 8, 11]. In general, patients who progress after primary therapy have limited options for targeted treatment, and most commonly receive palliative chemotherapy containing a single agent [4, 8, 11].

Trastuzumab deruxtecan (formerly DS-8201, T-DXd), has been approved to treat metastatic HER2+ BC patients with a cleavable linker containing a humanized anti-HER2 monoclonal antibody linked to topoisomerase I inhibitor [12, 13]. Through its bystander effect, T-DXd can deliver its cytotoxic payload to neighboring tumor cells that are heterogeneously expressing HER2 in addition to targeting HER2-expressing tumor cells with high levels of HER2 [13, 14]. Previously published RCTs have demonstrated promising results in pretreated patients with metastatic HER2-low advanced BC [15, 16]. As reported in the recently published phase 3 RCT DESTINY-Breast04, 52.3% of HER2-low advanced BC patients had an overall response, ranging from 9.0 to 11.3 months of progression-free survival [16]. The results of these studies suggest that T-DXd is highly effective in treating HER2-low advanced BC patients [16, 17].

To the best of our knowledge, no cost-effectiveness analyses have been conducted comparing T-DXd with chemotherapy for advanced BC. To effectively distribute the limited healthcare resources to clinicians and decision-makers, cost-effectiveness analyses are necessary. Thus, T-DXd was evaluated from the perspective of a third-party payer in the United States (USA) for the treatment of patients with previously treated HER2-low advanced BC patients.

Materials and methods

Patients and intervention

This study was conducted following the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) [18]. This study did not require approval from the institutional review board because it used data available in the public domain and open databases instead of individual patient data.

Hypothetical target patients with HER2-low metastatic BC were selected from the DESTINY-Breast04 randomized clinical trial [16]. This study included patients with unresectable or metastatic BC that was HR+ (inferred from local testing that 1% of tumor cell nuclei are immunoreactive for estrogen or progesterone receptors) or HR-. In the DESTINY-Breast04 trial [16], patients in the T-DXd group received 5.4 mg per kilogram every three weeks, whereas those in the physician’s choice group received eribulin (51.1%), capecitabine (20.1%), nab-paclitaxel (10.3%), gemcitabine (10.3%), and paclitaxel (8.2%).

Model structure

A partitioned survival model was used to evaluate the economic impact of progression-free survival (PFS), progressive disease (PD), and death [19–21]. Both treatment arms had a 10-year time horizon and > 98% of the patients died during that period. The cycle length was one week. Based on the results of the DESTINY-Breast04 study, the proportions of target patients with OS and PFS were used [16]. The area under the OS curve was evaluated as a measure of the proportion of patients living with PD, and the difference between the OS and PFS curves was calculated as a measure of the proportion of patients living with PD.

The main outcomes were overall costs, incremental cost-effectiveness ratios (ICERs), quality-adjusted life years (QALYs), life years (LYs), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were the main outcomes of our study. A willingness to pay (WTP) threshold of $100,000/QALY was established [22]. A discount of 3% per year was applied to all cost and utility outcomes [19, 21].

Clinical data input

Patients with HER2-low advanced BC in the T-DXd and chemotherapy groups were obtained from the DESTINY-Breast04 trial [16]. According to the algorithm developed by Guyot et al., OS and PFS were extrapolated beyond the trial follow-up period [23]. To extract individual patient data, GetData Graph Digitizer version 2.26 [24] was used to generate Kaplan-Meier survival curves for OS and PFS. We fitted the following parametric survival functions to these data points: exponential, Weibull, gamma, lognormal, Gompertz, log-logistic, and generalized gamma. Subsequently, the Akaike information criterion (AIC) and Bayesian information criterion (BIC) values were used to determine the best-fit parametric model for the reconstructed K-M survival curves. The survival functions and parametric models for T-DXd and chemotherapy treatment are presented in Table 1 and S1 Table provides the goodness-of-fit results for these two treatments. The OS and PFS K-M curves of T-DXd and chemotherapy in different scenarios were fitted using log-normal and log-logistic models, which are presented in S1 Table and S1 Fig.

Table 1. Key model inputs.

Parameter	Value (95% CI)	Distribution	Source
Clinical input
Scenario 1 All patients
Survival model for trastuzumab deruxtecan
Log-logistic model for OS^a	γ = 1.6742, λ = 0.0095	ND	[16]
Lognormal model for PFS^a	μ = 3.7343, σ = 1.1400	ND	[16]
Survival model for chemotherapy
Log-logistic model for OS^a	γ = 1.7826, λ = 0.0136	ND	[16]
Lognormal model for PFS^a	μ = 3.0558, σ = 1.0395	ND	[16]
Scenario 2 Hormone receptor-positive cohort
Survival model for trastuzumab deruxtecan
Log-logistic model for OS^a	γ = 1.79219, λ = 0.0093	ND	[16]
Lognormal model for PFS^a	μ = 3.77703, σ = 1.12199	ND	[16]
Survival model for chemotherapy
Log-logistic model for OS^a	γ = 1.72949, λ = 0.0125	ND	[16]
Lognormal model for PFS^a	μ = 3.11192, σ = 1.04968	ND	[16]
Scenario 3 Hormone receptor-negative cohort
Survival model for trastuzumab deruxtecan
Log-logistic model for OS^a	γ = 1.3437, λ = 0.0120	ND	[16]
Lognormal model for PFS^a	μ = 3.48501, σ = 1.21098	ND	[16]
Survival model for chemotherapy
Lognormal model for OS^a	μ = 3.692111, σ = 0.837671	ND	[16]
Lognormal model for PFS^a	μ = 2.731798, σ = 0.889911	ND	[16]
Cost input
Drug costs per 1 mg
Trastuzumab deruxtecan	29.68 (23.74 to 35.62)	Gamma	[26]
Capecitabine	0.0027 (0.0022 to 0.0033)	Gamma	[29]
Eribulin	1294 (1035 to 1552)	Gamma	[29]
Gemcitabine	0.0199 (0.0159 to 0.0239)	Gamma	[29]
Paclitaxel	0.128 (0.102 to 0.154)	Gamma	[29]
Nab-paclitaxel	14.19 (11.35 to 17.02)	Gamma	[29]
Cost of terminal care per patient^b	20409 (16327 to 24491)	Gamma	[32]
Disease management and monitoring costs
CT scan of chest (per time)	135 (58 to 256)	Gamma	[27]
Best supportive care (per cycle)	472 (377 to 566)	Gamma	[28]
Cost of managing AEs (grade ≥ 3) ^c
Trastuzumab Deruxtecan	4586 (3669 to 5503)	Gamma	[3, 30, 31]
Chemotherapy	5896 (4717 to 7076)	Gamma	[3, 30, 31]
Administration cost
First hour	159 (130 to 206)	Gamma	[27]
Additional hour	34 (28 to 42)	Gamma	[27]
Follow-up cost per events	251 (223 to 318)	Gamma	[27]
Health utilities
Disease status utility per year
Stable disease	0.830 (0.664 to 0.935)	Beta	[3, 34]
Disease progression	0.443 (0.354 to 0.532)	Beta	[3, 35]
Death	0	NA
Disutility due to AEs ^d
Trastuzumab Deruxtecan	0.027 (0.022 to 0.033)	Beta	[3, 30, 31]
Chemotherapy	0.023 (0.018 to 0.028)	Beta	[3, 30, 31]
Other parameters
Body surface area, m²	1.82 (1.44 to 2.16)	Normal	[36]
Body weight, kg	74 (59 to 90)	Normal	[36]

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^aOnly expected values are presented for these survival model parameters

^bOverall total cost per patient regardless of treatment duration.

^cCalculated as the average cost of toxic effects using weighted frequencies of grade ≥ 3 treatment related adverse events for each treatment arm in the DESTINY-Breast04 trial. Costs of individual toxic effects were derived from the literature and include all care required to manage each toxic effect. References for individual toxic effect costs are summarized in S2 Table in the Supplement.

^dCalculated as the average disutility of toxic effects using weighted frequencies of grade ≥ 3 treatment-related adverse events for each treatment arm in the DESTINY-Breast04 trial. Disutilities of individual toxic effects were derived from the literature. References for individual toxic effect disutilities are summarized in S2 Table in the Supplement.

Abbreviations: CMS, Centers for Medicare & Medicaid Services.

Cost data input

In this study, we evaluated direct medical costs, including the cost of drugs, costs associated with supportive care, administration costs, costs associated with terminal care, costs associated with adverse events (AEs), and costs associated with CT scans (Table 1). The prices of drugs were gathered from public databases [25, 26]. The Medicare Clinical Laboratory Fee Schedule was used to obtain the cost of CT scans [27], supportive care [28], administration fees [27], and follow-up fees [29]. We estimated the cost of treating severe adverse events [3, 30, 31] and terminal care [32] using published costs and applied them as one-time events (Table 1). According to the Medical-Care Inflation data obtained from Tom’s Inflation Calculator, all costs have been adjusted to US dollars for 2021 and were inflated to 2021 monetary values [33].

Health utility inputs

Health utility scores were assigned on a scale ranging from 0 (death) to 1 (perfect health). Since DESTINY-Breast04 does not provide health utility scores for PFS and PD, we used the health utility obtained from published scores [3, 34]. The utilities of PFS and PD associated with advanced BC were 0.830 and 0.443, respectively, which were derived from a cost-effectiveness analysis that included patients with advanced BC [3, 34, 35]. The disutility values related to adverse events were also obtained from the literature (S2 Table) [3, 30, 31].

Base case analysis

Three scenarios were analyzed (Fig 1), including all HER2-low advanced BC patients (scenario 1), HER2+ advanced BC patients (scenario 2), and HER2- advanced BC patients (scenario 3). Throughout all scenarios, the treatment regimens received by the patients remained the same, and only the survival data differed. Base-case analysis was performed using the ICER to measure additional QALYs. According to published literature [22], the WTP threshold in the United States is $100,000. According to the recommendations, cost-effectiveness was assumed in cases where the ICER was lower than the WTP threshold ($100,000/QALY). To estimate the chemotherapy dosage, we assumed that a typical patient had a body surface area of 1.82 m² and a weight of 74 kg [36]. Additionally, we calculated the INHB and INMB [19, 21]. The INHB and INMB are calculated as follows: $I N H B (λ) = (μ E_{T - D X d} - μ E_{C h e m o t h e r a p y}) - \frac{(μ C_{T - D X d} - μ C_{C h e m o t h e r a p y})}{λ} = Δ E - \frac{Δ C}{λ}$ and $I N M B (λ) = (μ E_{T - D X d} - μ E_{C h e m o t h e r a p y}) \times λ - (μ C_{T - D X d} - μ C_{C h e m o t h e r a p y}) = Δ E \times λ - Δ C$ , where μC and μE were the cost and utility of T-DXd or chemotherapy, respectively, and λ was the WTP threshold.

Sensitivity analysis

We conducted a one-way sensitivity analysis to identify variables that were significantly sensitive and assessed the model’s robustness. One-way sensitivity analyses were conducted according to various variables such as costs and utilities, and the uncertainty was estimated by applying the 95% confidence intervals (CIs) in the literature or assuming that the fundamental parameters would vary by 20% (Table 1). Monte Carlo simulations were utilized for probabilistic sensitivity analysis, which was conducted with 10,000 iterations. In all cases, a suitable distribution was determined based on different parameters. For cost parameters, proportion and probability, and baseline characteristics, gamma, beta, and normal distributions were assigned, respectively. Subsequently, a cost-effectiveness acceptability curve was constructed to illustrate the possible value of T-DXd and chemotherapy at various WTP levels/QALY gains.

Subgroup analyses

We conducted subgroup analyses to examine the variability in outcomes from different subgroups of patients with advanced HER2+ BC that were reported in the trials of DESTINY-Breast04 based on different PFS estimates. All statistical analyses were performed using R, version 4.0.5, 2021 (R Foundation for Statistical Computing), with the hesim and heemod packages.

Results

Base case analysis

A summary of all base-case results is presented in Table 2.

Table 2. Summary of cost and outcome results in the base-case analysis.

Factor	Scenario 1			Scenario 2			Scenario 3
	HER2-Low advanced BC patients			HER2+ advanced BC patients			HER2- advanced BC patients
	Trastuzumab deruxtecan	Chemotherapy	Incremental change	Trastuzumab deruxtecan	Chemotherapy	Incremental change	Trastuzumab deruxtecan	Chemotherapy	Incremental change
Cost, $
Drug^a	62,971	19,507	43,464	63,311	19,783	43,528	60,819	17,911	42,908
Nondrug^b	88,642	65,523	23,119	93,784	69,710	24,074	69,085	43,116	25,969
Overall	151,613	85,030	66,583	157,095	89,493	67,602	129,904	61,027	68,877
Life-years
Progression-free	1.728	0.695	1.033	2.064	1.247	0.817	1.135	0.437	0.698
Overall	3.268	2.142	1.126	3.523	2.343	1.18	2.315	1.089	1.226
QALYs	1.945	1.151	0.794	2.064	1.247	0.817	1.371	0.634	0.737
ICERs, $
Per life-year	NA	NA	59,129	NA	NA	57,309	NA	NA	56,217
Per QALY	NA	NA	83,892	NA	NA	82,802	NA	NA	93,358
INHB, QALY, at threshold 100,000^a	NA	NA	0.727	NA	NA	0.141	NA	NA	0.048
INMB, $, at threshold 100,000^a	NA	NA	727,417	NA	NA	14,098	NA	NA	4,823

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Abbreviations: BC, breast cancer; HER2, human epidermal growth factor receptor 2; HER2+, human epidermal growth factor receptor 2 positive; HER2-, human epidermal growth factor receptor 2 negative; ICER, incremental cost-effectiveness ratio; INHB, incremental net health benefit; INMB, incremental net monetary benefit; NA, not applicable; QALYs, quality-adjusted life years.

^aCompared with chemotherapy.

^bNondrug cost includes the costs of adverse event management, subsequent best supportive care per patient, and follow-up care covering physician monitors, drug administration, and terminal care.

Scenario 1

In the base case analysis of the whole cohort of HER2-low advanced BC, T-DXd was associated with an increase in the effectiveness of 0.794 QALYs and 1.126 LYs, with an additional cost of $66,583 compared to chemotherapy. Accordingly, the ICER was $83,892/QALY. Furthermore, compared to chemotherapy, T-DXd had an INHB and INMB of 0.727 QALYs and $727,417 at a $100,000/QALY WTP threshold, respectively (Table 2).

Scenario 2

Compared to chemotherapy, T-DXd enhanced the effectiveness of 0.817 QALYs and 1.18 LYs in patients with HER2+ advanced BC, with an added cost of $67,602. In this case, the ICER was $82,802/QALY. Moreover, compared to chemotherapy, the INHB and INMB of T-DXd, at a $100,000/QALY WTP threshold, were 0.141 and $14,098, respectively (Table 2).

Scenario 3

Compared with chemotherapy, T-DXd led to an increase in the effectiveness of 0.737 QALYs and 1.226 LYs at an additional cost of $68,877. It is estimated that the ICER was $93,358/QALY. Additionally, T-DXd had an INHB of 0.048 QALYs and an INMB of $4,823 at a $100,000/QALY WTP threshold, compared to chemotherapy (Table 2).

Sensitivity analysis

One-way sensitivity analyses suggested that the cost of T-DXd was the primary driver of the model outcome as well as its utility for PD and PFS in the three scenarios (S2 Fig). The key variables related to ICER were evaluated between T-DXd and chemotherapy in the three scenarios. For all HER2-Low advanced BC patients (Scenario 1), HER2+ advanced BC patients (Scenario 2), and HER2- advanced BC patients (Scenario 3), T-DXd was cost-effective at a WTP threshold of $50,000/QALY with a price of less than $17.00/mg, $17.13/mg, $14.07/mg, respectively (S3 Fig). The upper limit of the price range of T-DXd considered cost-effective at a WTP threshold of $100,000/QALY was $35.70/mg for all HER2-low advanced BC patients, $35.27/mg for all HER2+ advanced BC patients and $32.07/mg for all HER2- advanced BC patients.

The cost-effectiveness acceptability curves provide a visual representation of the results of the probabilistic sensitivity analysis (Fig 2). As the WTP threshold increased, there was a greater likelihood that T-DXd would be cost-effective. In comparison to chemotherapy, the probabilities of T-DXd being considered cost-effective were 81.10%, 82.27%, and 73.78%, respectively, based on a WTP threshold of $100,000/QALY for patients with HER2-low advanced BC patients, HER2+ advanced BC patients, and HER2- advanced BC patients.

Subgroup analysis

A subgroup analysis was performed by varying the hazard ratios (HRs) of PFS. Based on the subgroup analysis, T-DXd was associated with lower HRs than chemotherapy in most of the subgroups; therefore, at a WTP of $100,000/QALY, T-DXd was > 70%. Hence, T-DXd may be considered cost-effective (Table 3).

Table 3. Summary of subgroup analyses obtained by varying the HRs for PFS.

Subgroup	Unstratified HR for PFS (95% CI)^a	Change in cost, $^b	Change in QALY^b	ICER, $/QALY	T-DXd vs. chemotherapy at WTP threshold of $100,000/QALY
Subgroup	Unstratified HR for PFS (95% CI)^a	Change in cost, $^b	Change in QALY^b	ICER, $/QALY	Cost-effectiveness probability of T-DXd, %	INHB
Prior CDK 4/6 inhibitors
Yes	0.55 (0.42, 0.73)	66,992	0.760	88,100	78.88	0.090
No	0.42 (0.28, 0.64)	69,043	0.978	70,608	88.11	0.287
IHC status
IHC 1+	0.48 (0.35, 0.64)	68,071	0.864	78,766	84.64	0.184
IHC 2+/ISH-	0.55 (0.38, 0.80)	66,992	0.760	88,100	78.49	0.090
Prior lines of chemotherapy in the metastatic setting
1	0.54 (0.40, 0.73)	67,143	0.774	86,786	79.63	0.102
> 2	0.47 (0.33, 0.68)	68,229	0.881	77,412	85.74	0.199
Age
< 65	0.51 (0.39, 0.67)	67,586	0.815	82,802	82.54	0.140
≥ 65	0.47 (0.29, 0.77)	68,229	0.881	77,412	85.04	0.199
Race
White	0.64 (0.44, 0.91)	65,678	0.660	99,510	57.74	0.003
Asian	0.40 (0.28, 0.56)	69,379	1.022	67,884	88.97	0.328
Other	0.83 (0.41, 1.69)	63,112	0.524	120,356	8.49	-0.107
Region
Asian	0.41 (0.28, 0.58)	69,210	0.999	69,245	88.02	0.307
Europe and Israel	0.62 (0.43, 0.89)	65,964	0.680	97,047	65.15	0.020
North America	0.54 (0.30, 0.97)	67,143	0.774	86,786	79.71	0.102
ECOG performance status
0	0.56 (0.40, 0.77)	66,842	0.748	89,406	76.43	0.079
1	0.45 (0.32, 0.64)	68,551	0.918	74,695	87.03	0.232
Visceral disease at baseline
Yes	0.54 (0.42, 0.69)	67,143	0.774	86,786	79.42	0.102
No	0.23 (0.09, 0.55)	70,789	1.239	57,122	90.62	0.531

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Abbreviations: CDK, cyclin-dependent kinase; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; ICER, incremental cost-effectiveness ratio; IHC, immunohistochemical, INHB, incremental net health benefits; PFS, progression-free survival; QALY, quality-adjusted life-year; WTP, willingness to pay.

^aHR for PFS represents the HR of T-DXd vs. chemotherapy for PFS

^bChange in cost and change in QALYs represent the results of T-DXd minus chemotherapy.

Discussion

In this study, we conducted a cost-effectiveness analysis of T-DXd vs chemotherapy for previously treated HER2-low advanced BC, and the results revealed that compared with chemotherapy, the ICERs of T-DXd was $83,892/QALY, $82,808/QALY, and $93,358/QALY in all HER2-Low advanced BC patients (Scenario 1), HER2+ advanced BC patients (Scenario 2) and HER2- advanced BC patients (Scenario 3), respectively. Even the highest ICER value remains below the threshold for WTP of $100,000/QALY. Based on the results of this analysis, it was apparent that the HER2+ group had a higher survival rate, which was related to a lower ICER. The results of this model were robust, as determined by comprehensive deterministic and probabilistic sensitivity analyses. The results of the one-way sensitivity analysis suggested that T-DXd cost, HR for PFS, and OS played a significant role in determining sensitivity. T-DXd would be cost-effective if its price were reduced to $17.00/mg, $17.13/mg, and $14.07/mg at a WTP threshold of $50,000/QALY for all HER2-low advanced BC and HER2-advanced BC, respectively. The probabilistic sensitivity analysis of T-DXd revealed that for all advanced BC patients with HER2-Low, HER2+, and HER2-status, the probability of cost-effectiveness of T-DXd was 81.10%, 82.27%, and 73.78%, respectively, at $100,000/QALY. In patients with previously treated HER2-low advanced BC, T-DXd treatment is a cost-effective alternative to chemotherapy.

This cost-effectiveness analysis for T-DXd in treating HER2-low advanced BC is a novel approach that considers both parametric and structural uncertainties. We believe that this is the first study to examine the cost-effectiveness of T-DXd compared to chemotherapy for patients with previously treated advanced HER2-low BC. Cancer treatment is often limited by the fact that the most clinically effective drugs are not the most cost-effective. By establishing prices for novel treatments based on the value of the treatment they provide, value-based pricing is a new method of setting prices for novel treatments that are logically based on the fact that the optimal oncology treatment is becoming increasingly less cost-effective [37]. Therefore, it is important to discuss the clinical outcomes of the study. The effectiveness of T-DXd in the treatment of metastatic BC associated with HER2+ status was previously compared with that of trastuzumab emtansine. Despite its clinical benefits in the treatment of HER2+ metastatic BC, T-DXd is not cost-effective because of its high cost [38]. Nevertheless, in this study, we conclude that T-DXd may be a cost-effective alternative to chemotherapy in patients with previously treated HER2-low advanced BC.

The results of the one-way sensitivity analysis suggested that T-DXd cost was a sensitive variable. The price of T-DXd remains the most sensitive variable, and reducing the price of T-DXd is important to increase its feasibility. On August 5, 2022, the Food and Drug Administration approved trastuzumab deruxtecan for adult patients with HER2-low advanced BC who had received prior chemotherapy in a metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy. However, T-DXd is not included in Medicare Part B in the United States. If Medicare Part B covers T-DXd and patients pay the Medicare Part B deductible, Medicare beneficiaries will have a certain percent co-insurance cost for T-DXd. The government announced American Patients First and aimed to construct a blueprint for cutting drug prices and reducing out-of-pocket payments in the United States [39, 40]. The availability of innovative treatments requires significant reductions in price and financial assistance.

It is important to note the advantages of this study. First, to our knowledge, this is the first study comparing T-DXd treatment with chemotherapy in patients with previously treated advanced HER2-low BC from the perspective of a third-party payer in the United States. The partitioned survival model was adopted to evaluate cost-effectiveness analysis. Second, T-DXd treatment may be a cost-effective alternative to chemotherapy in patients with previously treated HER2-low advanced BC. Third, physicians and patients may benefit from economic information regarding the expression levels of HER2 and other subgroups to make more informed treatment decisions.

Some limitations of the study warrant further consideration. First, health outcomes that extended beyond the duration of the DESTINY-Breast04 trial were assumed by fitting parametric distributions to the K-M OS and PFS data, which may have resulted in inaccurate results. Based on the results of the sensitivity analysis, this limitation may not be a significant factor; accordingly, this conclusion is generally considered robust. Second, the clinical parameters in the model were based on the results of the DESTINY-Breast04 clinical trial. Thus, biases within the trial may have affected the cost and effectiveness of the results. Clinical trial participants had a higher rate of adherence to treatment regimens than those participating in real-world settings. Third, it is important to note that the utilities used in the model were not estimated using DESTINY-Breast04, but rather from other health utility surveys in patients with advanced HER2-low BC. The cost-effectiveness analysis is also influenced by the assumption that patients in both groups have the same utility, which may lead to some bias in the results. Last, the grades 1 and 2 AEs were not taken into account. The findings in the one-way sensitivity analyses suggest that these limitations may not have a significant impact, as the costs and disutilities associated with AEs were relatively minor. In clinical practice, these adverse events cannot be ignored.

Conclusion

The results of these estimates indicate that from the perspective of third-party payers in the United States, T-DXd treatment may be a cost-effective alternative to chemotherapy for patients with prior treatment for HER2-low advanced BC. Economic outcomes can be improved by tailoring treatments to patients’ needs. Clinicians may use these results to select appropriate treatment options for patients with HER2-low advanced BC.

Supporting information

S1 Fig. Model fitting analysis.

(PDF)

Click here for additional data file.^{(461.5KB, pdf)}

S2 Fig. Tornado diagram of 1-way sensitivity analyses of pembrolizumab versus chemotherapy.

(PDF)

Click here for additional data file.^{(332.3KB, pdf)}

S3 Fig. One-way sensitivity analyses result of ICER when varying cost of trastuzumab deruxtecan in participants.

(PDF)

Click here for additional data file.^{(211.6KB, pdf)}

S1 Table. Estimated parameters and AIC and BIC values from each survival model.

(PDF)

Click here for additional data file.^{(349.1KB, pdf)}

S2 Table. Associated costs and disutility of grade ≥ 3 treatment-related adverse events.

(PDF)

Click here for additional data file.^{(172KB, pdf)}

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

This work was supported by the scientific research and technological development projects of Hechi, Guangxi Province of China (Heke B1824–4). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0290507.r001

Decision Letter 0

Mirosława Püsküllüoğlu

13 Jun 2023

PONE-D-23-04529Cost-effectiveness of Trastuzumab Deruxtecanfor Previously Treated HER2-Low Advanced Breast CancerPLOS ONE

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Reviewer #1: This study evaluated the cost-effectiveness of trastuzumab deruxtecan (T-DXd) among HER2-Low advanced breast cancer (BC) patients, and the results showed that T-DXd is a cost-effective alternative to chemotherapy at willingness to pay threshold of $100,000/QALY. This discovery is intriguing and could have significant implications for the patients, clinicians and third-party payers. The methods are appropriate and results are reliable. However, I have several minor comments.

1. For subgroup analyses, why did you only focus on PFS, how about OS? How did the PFS variate?

2. For one-way sensitivity analyses among HER2- advanced BC patients (Supplementary Figure S2-C), the results showed that variation of the top 5 parameters might result in the ICER being over $100,000/QALY, which indicated that T-DXd was not cost-effective. How do we understand this result since you mentioned the results of this model are robust?

3. I did not find Figure 2 in the manuscript.

4. For the result of subgroup analysis, the manuscript stated “T-DXd was associated with lower HRs than chemotherapy in most of the subgroups”, how can conclude it from Table 3?

5. Is the T-DXd sole drug that is cost-effective for HER2-Low advanced BC patients? If not, what are the advantages of T-DXd?

6. I suggested that the coverage information of T-DXd in public healthcare systems such as Medicare should be added.

Reviewer #2: The manuscript is technically sound. Only a few minor suggestions:

Please clearly highlight the limitations of the study in the discussion section with some justifications

There are some typo and grammatical errors so a proof reading is advised.

Overall the paper is structured well.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2023 Aug 24;18(8):e0290507. doi: 10.1371/journal.pone.0290507.r002

Author response to Decision Letter 0

7 Jul 2023

Dear Reviewers and Editors,

Thank you for your extremely efficient and earnest work on our manuscript. The comments are all valuable and very helpful for revising and improving our paper. The main corrections in the manuscript and the response to the Referees' comments are listed below point by point:

Reviewer(s)' Comments:

1. For subgroup analyses, why did you only focus on PFS, how about OS? How did the PFS variate?

Reply: We conducted subgroup analyses to examine the variability in outcomes from different subgroups of patients with advanced HER2+ BC that were reported in the trials of DESTINY-Breast04. Due to the subgroup results of OS was not provided, we did not perform the subgroup analysis focus on OS. In the DESTINY-Breast04 trial, a consistent benefit was observed for trastuzumab deruxtecan across analyzed subgroups, trastuzumab deruxtecan showed superior activity over standard chemotherapy options in patients with HER2-low advanced breast cancer in most subgroups except for other race. Furthermore, the unstratified HR for PFS was shown in Table 3. For most subgroups in this study, the ICERs were greatly influenced by HRs, and trastuzumab deruxtecan performed better when the risks of death were lower.

Reply: Due to we considered a wider range of the base-case values (± 20%) for the parameters and ICER being very close to $100,000/QALY, the results showed that variation of the top 5 parameters might result in the ICER being over $100,000/QALY.

In all cases, a suitable distribution was determined based on different parameters. In terms of cost parameters, proportion and probability, and baseline characteristics, gamma, beta, and normal distributions were assigned, respectively. We selected the justified distribution and sensitivity analysis undertaken to assess the robustness of estimates to this choice. In the past, the most common form of sensitivity analysis was to undertake a one-way analysis. Here estimates for each parameter are varied one at a time in order to investigate the impact on study results. A common way to present the results of a one-way analysis is in a ‘tornado diagram’. The impact that variation in each parameter has on the study result is shown by the width of the respective band. These diagrams are normally arranged so that the parameter in which variation has the biggest impact on the study result is at the top. A variant of one-way sensitivity analysis is to undertake a threshold analysis. Here the critical value(s) of a parameter or parameters central to the decision are identified. For example, a decision-maker might specify an increase in cost, or an ICER, above which the program would not be acceptable. Then the analyst could assess which combinations of parameter estimates could cause the threshold to be exceeded. Alternatively, the threshold values for key parameters that would cause the program to be too costly or not cost-effective could be defined. The decision-makers could then make a judgment about whether particular thresholds were likely to be breached or not.

Hence, the conclusion of this study is that the result is robust.

3. I did not find Figure 2 in the manuscript.

Reply: We have reuploaded Figure 2.

4. For the result of subgroup analysis, the manuscript stated “T-DXd was associated with lower HRs than chemotherapy in most of the subgroups”, how can conclude it from Table 3?

Reply: The results were illustrated in Table 3, and the unstratified HR for PFS (95% CI) showed the results that T-DXd was associated with lower HRs than chemotherapy in most of the subgroups.

5. Is the T-DXd sole drug that is cost-effective for HER2-Low advanced BC patients? If not, what are the advantages of T-DXd?

Reply: The aim of this study was to evaluate the cost-effectiveness of T-DXd vs. chemotherapy for previously treated HER2-low advanced BC, and the comparison of this study was T-DXd and chemotherapy, and no other drugs were evaluated. From a third-party payer's perspective in the United States, the findings of the cost-effectiveness analysis revealed that, at the current price, T-DXd is a cost-effective alternative to chemotherapy for patients with prior HER2-low advanced BC, at WTP threshold of $100,000/QALY, and this is the advantage of T-DXd.

6. I suggested that the coverage information of T-DXd in public healthcare systems such as Medicare should be added.

Reply: Thank you for your suggestion. We have added that information in the section of discussion.

Reviewer #2: The manuscript is technically sound. Only a few minor suggestions:

Please clearly highlight the limitations of the study in the discussion section with some justifications

There are some typo and grammatical errors so a proof reading is advised.

Overall the paper is structured well.

Reply: Thank you for your suggestion.

We have provided and highlight the limitations of the study in the discussion section with justifications.

We have corrected the typo and grammatical errors in our manuscript and English has been edited and proofread by editage.

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PLoS One. doi: 10.1371/journal.pone.0290507.r003

Decision Letter 1

Mirosława Püsküllüoğlu

10 Aug 2023

Cost-effectiveness of Trastuzumab Deruxtecan for Previously Treated HER2-Low Advanced Breast Cancer

PONE-D-23-04529R1

Dear Dr. Chen

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0290507.r004

Acceptance letter

Mirosława Püsküllüoğlu

15 Aug 2023

PONE-D-23-04529R1

Cost-effectiveness of Trastuzumab Deruxtecan for Previously Treated HER2-Low Advanced Breast Cancer

Dear Dr. chen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Model fitting analysis.

(PDF)

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S2 Fig. Tornado diagram of 1-way sensitivity analyses of pembrolizumab versus chemotherapy.

(PDF)

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S3 Fig. One-way sensitivity analyses result of ICER when varying cost of trastuzumab deruxtecan in participants.

(PDF)

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S1 Table. Estimated parameters and AIC and BIC values from each survival model.

(PDF)

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S2 Table. Associated costs and disutility of grade ≥ 3 treatment-related adverse events.

(PDF)

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Attachment

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Data Availability Statement

All relevant data are within the paper and its Supporting Information files.

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PERMALINK

Cost-effectiveness of trastuzumab deruxtecan for previously treated HER2-low advanced breast cancer

Demin Shi

Xueyan Liang

Yan Li

Lingyuan Chen

Roles

Abstract

Objective

Methods

Results

Conclusion

Introduction

Materials and methods

Patients and intervention

Model structure

Clinical data input

Table 1. Key model inputs.

Cost data input

Health utility inputs

Base case analysis

Fig 1. The partitioned survival model consisting of three discrete health states.

Sensitivity analysis

Subgroup analyses

Results

Base case analysis

Table 2. Summary of cost and outcome results in the base-case analysis.

Scenario 1

Scenario 2

Scenario 3

Sensitivity analysis

Fig 2. Acceptability curves of cost-effectiveness for trastuzumab deruxtecan versus chemotherapy.

Subgroup analysis

Table 3. Summary of subgroup analyses obtained by varying the HRs for PFS.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Mirosława Püsküllüoğlu

Roles

Author response to Decision Letter 0

Decision Letter 1

Mirosława Püsküllüoğlu

Roles

Acceptance letter

Mirosława Püsküllüoğlu

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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