Cost-effectiveness of inavolisib-based therapy in PIK3CA-mutated advanced breast cancer in the USA

Abstract

Purpose

Inavolisib plus palbociclib and fulvestrant has been approved for treating PIK3CA-mutated, hormone receptor-positive human epidermal growth factor receptor 2-negative (HR + HER2-), advanced breast cancer in the USA. This study evaluated the cost-effectiveness of inavolisib plus palbociclib and fulvestrant compared with palbociclib plus fulvestrant from the US payer perspective.

Methods

We developed a partitioned survival model at a 28-day cycle length over 15-year time horizons to predict total costs, life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental cost-utility ratio (ICUR) at willingness-to-pay (WTP) threshold of $150,000 per QALY. Survival data were extracted from the INAVO120 clinical trial, costs and utilities were obtained from the department of Veterans Affairs, published literature and quality-of-life studies using the EQ-5D-5L scale. Uncertainty was addressed via scenario, one-way and probabilistic sensitivity analyses.

Results

In the base-case, inavolisib plus palbociclib and fulvestrant resulted in 1.99 life-years and 1.43 QALYs at an incremental cost of $211,639.64 with an ICER of $106,595.61 per life-year and an ICUR of $148,417.37 per QALY. The utility value of progression-free survival was the most influential parameter on the base-case results. Alterations in each model parameter did not significantly impact on the conclusions. The probability of inavolisib plus palbociclib and fulvestrant was cost-effective at the WTP threshold of $150,000 was 54.59%.

Conclusion

Inavolisib plus palbociclib and fulvestrant may be a high-value treatment option for patients with PIK3CA-mutated, HR + HER2-, advanced breast cancer in the USA.

Graphical abstract

Highlights

• •Inavolisib-based therapy provided significant clinical benefits for PIK3CA-mutated, HR + HER2-, advanced breast cancer.
• •Compared with palbociclib plus fulvestrant, inavolisib plus palbociclib and fulvestrant resulted in an ICUR of $148,417.37 per QALY.
• •Inavolisib plus palbociclib and fulvestrant was cost-effective at the willingness-to-pay threshold of $150,000 in the USA.
• •The cost-effectiveness of inavolisib in the high-burden subgroup warrants further exploration.

1. Introduction

Breast cancer is the most common malignancy and the second cause of cancer-related death among women in the United States, with 313,510 new cases and 42,780 deaths in 2024 [1]. Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR + HER2-) is the predominant molecular subtype of breast cancer, accounting for 70% of diagnosed cases [2]. Activation of the phosphatidylinositol-3-kinase (PI3K) pathway by PIK3CA mutations is present in 28%-46% of HR + HER2-advanced breast cancers [3,4]. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor plus endocrine therapy is the standard treatment for HR + HER2-advanced breast cancer [5,6]. However, acquired resistance to endocrine therapy remains a major challenge in clinical practice [7], signaling an urgent need for promising treatment options.

Inavolisib is a highly potent and selective PI3K inhibitor of the alpha isoform of the p110 catalytic subunit, which also promotes the degradation of mutated p110α [8,9]. The INAVO120 trial indicated that inavolisib plus palbociclib and fulvestrant significantly improved progression-free survival (PFS) [hazard ratio (HR): 0.42, 95% confidence interval (CI): 0.32-0.55] and overall survival (OS) (HR: 0.67, 95% CI: 0.48-0.94) compared with palbociclib plus fulvestrant for patients with PIK3CA-mutated, HR + HER2-, locally advanced or metastatic breast cancer, who have recurrence during or within 12 months of completion of adjuvant endocrine therapy [9,10]. Neutropenia, thrombocytopenia, leukopenia and anemia were the most common treatment-related adverse events (AEs) in the inavolisib plus palbociclib and fulvestrant group [9,10]. Based on evidence in the INAVO120 trial, inavolisib plus palbociclib and fulvestrant was approved by the Food and Drug Administration on October 10, 2024, and has been recommended by the NCCN Clinical Practice Guidelines for patients with endocrine-resistant, PIK3CA-mutated, HR + HER2− advanced breast cancer [11].

Considering the high cost of inavolisib-based therapy, whether the significant survival benefit from inavolisib could be matched by its pricing needs to be further explored. Cost-effectiveness became a pivotal consideration for policy-makers, providers, and patients in implementing novel treatment regimens [12]. Thus, this study aimed to investigate the cost-effectiveness of inavolisib plus palbociclib and fulvestrant versus palbociclib plus fulvestrant in the treatment of PIK3CA-mutated, HR + HER2-, advanced breast cancer from the payer perspective in the United States. These economic findings could support oncologists or policy-makers in making clinical decisions and allocating limited healthcare resources.

2. Methods

This economic evaluation was based on modeling techniques, price databases, and published literature, so ethics committee approval was exempted. This study followed the consolidated health economic evaluation reporting standards 2022 (CHEERS 2022) [13] (Supplementary Table 1).

2.1. Patients and treatments

Eligible patients were premenopausal, perimenopausal, or postmenopausal women or men with PIK3CA-mutated, HR + HER2-, locally advanced or metastatic breast cancer [9,10]. Patients received inavolisib (9 mg administered orally on days 1 to 28 of each 28-day cycle) plus palbociclib (125 mg administered orally on days 1 to 21 on a 3-week-on, 1-week-off schedule) and fulvestrant (500 mg administered intramuscularly on days 1 and 15 of cycle 1 and approximately at 28-day intervals thereafter), or palbociclib plus fulvestrant [9,10]. Treatment continued until disease progression, intolerable toxicity or death [9,10]. Consistent with the INAVO120 clinical trial, the proportions of discontinuation of treatment due to AEs were 8.7% and 0.6% in inavolisib group and palbociclib plus fulvestrant group, respectively, and dose modifications were 87.0% and 77.3% [9,10]. Following disease progression, subsequent therapeutic modalities included chemotherapy (capecitabine, paclitaxel and eribulin), antibody-drug conjugates (trastuzumab deruxtecan and sacituzumab govitecan), PI3K inhibitor (alpelisib), mTOR kinase inhibitor (everolimus), CDK4/6 inhibitor (ribociclib and abemaciclib) and best supportive care [9,10]. Detailed proportional allocations for these post-progression therapies are provided in Supplementary Table 2.

2.2. Model structure

A partitioned survival model was constructed with three mutually exclusive health states (PFS, progressive disease, and death) to predict disease regression and clinical benefits over a 15-year time horizon from the US payer perspective (Fig. 1). Patients entered the model from a default PFS state, which could develop into progressed disease or death states [14]. The cycle length of the model was 28 days with a half cycle correction to accommodate the administration cycle of treatment regimens. Primary model outcomes included the total costs, life years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), and incremental cost-utility ratio (ICUR) under the willingness-to-pay (WTP) threshold of $150,000 [15]. The ICUR was estimated as incremental costs per QALY gained by comparing the data of inavolisib plus palbociclib-fulvestrant and palbociclib plus fulvestrant [16]. All costs and health outcomes were discounted at an annual rate of 3%, with a range of 0% to 5%. The model was programmed in Microsoft Excel 2019 and R 4.5.2. All costs were inflated to 2026 US dollars using the Consumer Price Index for healthcare.

Fig. 1.

The structure of the partitioned survival model. HR + HER2-hormone receptor-positive human epidermal growth factor receptor 2-negative.

2.3. Clinical data

The Kaplan-Meier curves of PFS and OS for intervention strategies were extracted using GetData Graph Digitizer 2.26 to reconstruct individual patient data. To extrapolate progression and survival beyond the observation period, multiple parameter distributions were employed to fit survival curves of various treatments in the INAVO120 clinical trial, including Exponential, Weibull, Gamma, Generalised Gamma, Gompertz, Lognormal and Log-logistic distributions [17]. The Akaike information criterion (AIC) and Bayesian information criterion (BIC) value of each distribution were calculated, and the best fitted distribution was determined based on AIC, BIC, visual inspection, and clinical plausibility [18]. We selected the parametric distribution with the lowest AIC value for our model, which were Generalised Gamma and Gamma distributions for PFS and OS in the palbociclib plus fulvestrant group, and Log-logistic distributions for PFS and OS in the inavolisib plus palbociclib and fulvestrant group, respectively. According to the ISPOR-SMDM Task Force Report on Model Transparency and Validation, the face validity of the model was assessed by a clinician, and internal validity was assessed by extreme parameters and substantial code checking [19]. The parameters of the best fitted distributions are shown in Supplementary Table 3 and Supplementary Figs. 1–4.

2.4. Costs

Direct medical expenditures were calculated, which covered medications, routine surveillance, outpatient physician visits, management of severe AEs, follow-up treatment and palliative care. The unit drug costs were derived from the Federal Supply Schedule pharmaceutical pricing data from the department of Veterans Affairs, one of the largest consumers of pharmaceuticals in the United States [20]. A standardized body surface area (BSA) of 1.86 m², extrapolated from the National Center for Health Statistics (NCHS) mean female metrics of 77.5 kg and 1.61 m, was utilized for dosage determination [21]. Routine surveillance was conducted based on the National Comprehensive Cancer Network guidelines [11], involving laboratory tests, computed tomography of the chest, abdomen and pelvis, bone scan, and magnetic resonance imaging [[22], [23], [24]]. Laboratory tests and CT were conducted biannually, and other examinations were performed annually [25]. The management costs of severe AEs were estimated by multiplying costs associated with grade 3 or 4 AEs extracted from published literature by the probability of occurrence of individual AEs reported in the INAVO120 trial [[26], [27], [28], [29]]. Grade 3 to 4 AEs with an incidence of 5% or more were included, and were applied in the first cycle of the decision model. The costs of follow-up treatment and palliative care were gathered from previously published literature, and were adjusted with Consumer Price Index to accommodate the current model [21,30].

2.5. Health state utilities

Each health state should be assigned a health utility value anchored in 0 (death) and 1 (perfect health) [31]. Health state utility values were retrieved from the Adelphi Real World Advanced Breast Cancer Disease Specific Programmes, which gathered patient-reported outcomes using the EuroQol 5-Dimensions 5-Level (EQ-5D-5L) scale in patients with HER2-advanced breast cancer from the United States, European Union, and Israel [32]. The EQ-5D-5L was scored based on value sets from general population in the United States [32]. The utility value for HER2-advanced breast cancer was 0.83 (95% CI: 0.79-0.87), and would decrease by 0.272 after disease progression [32,33]. Disutility values caused by severe AEs were obtained from published studies [24,[33], [34], [35]]. The costs and utilities are presented in Table 1.

Table 1.

Model parameter.

Parameters	Baseline	Range		Distribution	Source
		Minimum	Maximum
Costs ($)
Inavolisib (9 mg)	614.14	491.31	736.97	Gamma	VA
Palbociclib (125 mg)	565.72	452.57	678.86	Gamma	VA
Fulvestrant (250 mg)	55.00	44.00	66.00	Gamma	VA
Capecitabine (500 mg)	1.67	1.34	2.00	Gamma	VA
Paclitaxel (30 mg)	7.03	5.63	8.44	Gamma	VA
Eribulin (1 mg)	761.61	609.29	913.93	Gamma	VA
Trastuzumab deruxtecan (100 mg)	2008.60	1606.88	2410.32	Gamma	VA
Sacituzumab govitecan (180 mg)	1866.65	1493.32	2239.98	Gamma	VA
Alpelisib (150 mg)	290.91	232.73	349.09	Gamma	VA
Everolimus (1 mg)	7.50	6.00	9.00	Gamma	VA
Ribociclib (200 mg)	105.54	84.43	126.65	Gamma	VA
Abemaciclib (200 mg)	205.32	164.26	246.39	Gamma	VA
Cost of BSC per cycle	1397.29	1117.83	1676.75	Gamma	[30]
Outpatient visit per time	51.98	41.59	62.38	Gamma	[22]
Laboratory tests per time	560.16	448.12	672.19	Gamma	[22]
CT (chest/abdomen/pelvis) per time	575.58	460.46	690.70	Gamma	[23]
Bone scan per time	218.92	175.13	262.70	Gamma	[23]
Magnetic resonance imaging per time	1334.13	1067.31	1600.96	Gamma	[24]
Palliative care per time	10953.24	8762.60	13143.89	Gamma	[21]
Cost of Neutropenia	18181.50	14545.20	21817.80	Gamma	[27]
Cost of Thrombocytopenia	27768.61	22214.89	33322.33	Gamma	[26]
Cost of Stomatitis	9182.75	7346.20	11019.30	Gamma	[28]
Cost of Anemia	15730.85	12584.68	18877.02	Gamma	[29]
Cost of Hyperglycemia	11396.50	9117.20	13675.80	Gamma	[29]
Cost of Leukopenia	18181.50	14545.20	21817.80	Gamma	[27]
Utility values
Utility of PFS	0.830	0.790	0.870	Beta	[32]
Utility of PD	0.558	0.446	0.670	Beta	[32,33]
Disutility of Neutropenia	0.150	0.120	0.180	Beta	[33]
Disutility of Thrombocytopenia	0.108	0.086	0.130	Beta	[34]
Disutility of Stomatitis	0.151	0.121	0.181	Beta	[33]
Disutility of Anemia	0.073	0.058	0.088	Beta	[35]
Disutility of Hyperglycemia	0.120	0.096	0.144	Beta	[24]
Disutility of Leukopenia	0.150	0.120	0.180	Beta	[33]
Adverse events (%)
Neutropenia of P + F	80.37	64.29	96.44	Beta	[10]
Leukopenia of P + F	10.49	8.40	12.59	Beta	[9]
Neutropenia of inavolisib	82.61	66.09	99.13	Beta	[10]
Thrombocytopenia of inavolisib	13.66	10.93	16.40	Beta	[10]
Stomatitis of inavolisib	5.59	4.47	6.71	Beta	[10]
Anemia of inavolisib	6.83	5.47	8.20	Beta	[10]
Hyperglycemia of inavolisib	6.83	5.47	8.20	Beta	[10]
Leukopenia of inavolisib	6.79	5.43	8.15	Beta	[9]
Other parameters
Discount rate (%)	3	0	5	Beta	[21]
Body surface (m2)	1.86	1.49	2.23	Gamma	[21]
Patient Weight (kg)	77.50	62.00	93.00	Gamma	[21]

VA Veterans Affairs, CT computed tomography, PFS progression-free survival, PD progressive disease, P + F palbociclib plus fulvestrant.

2.6. Sensitivity analyses

One-way sensitivity analyses (OWSA) and probabilistic sensitivity analyses (PSA) were conducted to assess the robustness of the base-case results and determine which input parameters had a significant impact on these results. In the OWSA, each parameter was adjusted successively to its plausible range, which were obtained from 95% CI in the published literature or estimated by a variance of 20% from the base-case values [36]. The results of OWSA were presented as tornado diagrams. For the PSA, we carried out 10,000 Monte Carlo simulations by simultaneously sampling the critical parameters from prespecified distributions [37]. Beta distributions were selected for incidence, utility and disutility values, and Gamma distributions were adopted for costs [38]. Incremental cost-effectiveness scatterplots and acceptability curves were generated from the results of PSA.

2.7. Scenario analyses

First, we intensified the monitoring regimen by reducing the interval of imaging and laboratory surveillance from a semi-annual baseline to every one, two, or three months, depending on clinical progression. Second, the utility value for the PFS state was assumed to be 0.82 [39]. Ndirangu et al. [39] used the EQ-5D-5L scale to measure quality of life for HR + HER2-advanced breast cancer in three European countries and the United States. Third, we assumed that the time horizon was adjusted to 5 and 10 years to evaluate the ICUR with less extrapolation and efficacy assumptions. Finally, we modeled the effect of discounted pricing for inavolisib and palbociclib on the resulting ICURs.

3. Results

3.1. Base-case results

Compared with palbociclib plus fulvestrant, inavolisib plus palbociclib and fulvestrant provided incremental cost of $211,639.64, with additional QALY of 1.43, resulting in an ICUR of $148,417.37 per QALY for PIK3CA-mutated, HR + HER2-, locally advanced or metastatic breast cancer from the payer perspective in the United States (Table 2).

Table 2.

Base-case results.

Strategy	Costs, $	LYs	QALYs	ICER ($/LY)	ICUR ($/QALY)
Palbociclib plus fulvestrant	248,343.70	3.28	1.97	—	—
Inavolisib plus palbociclib and fulvestrant	459,983.34	5.27	3.40	106,595.61	148,417.37

LY life-year, QALY quality-adjusted life-year, ICER incremental cost-effectiveness ratio, ICUR incremental cost-utility ratio.

3.2. Sensitivity analyses

The base-case results were sensitive to the cost of inavolisib, utility values of PFS and PD states, and discount rate (Fig. 2). The best-case and worst-case ICERs and ICURs were $83,585.39 and $129,605.83 per LY, and $116,379.31 and $194,677.32 per QALY, respectively. The CEAC showed that inavolisib plus palbociclib and fulvestrant was almost 54.59% of being cost-effective at the WTP threshold of $150,000 per QALY. When the WTP threshold was set at $200,000, the probability of inavolisib plus palbociclib and fulvestrant being cost-effective reached 95.86% (Fig. 3, Fig. 4).

Fig. 2.

Tornado diagram of the one-way sensitivity analysis results. PFS progression-free survival; PD progressive disease; ICUR incremental cost-utility ratio; ICER incremental cost-effectiveness ratio; QALY quality-adjusted life-year.

Fig. 3.

The incremental cost-effectiveness scatterplot of the probabilistic sensitivity analysis results.

Fig. 4.

The cost-effectiveness acceptability curve of the probabilistic sensitivity analysis results. WTP willingness to pay; QALY quality-adjusted life-year.

3.3. Scenario analyses

As the surveillance interval for imaging and laboratory tests progressively contracted, the total costs increased; conversely, the ICURs for inavolisib plus palbociclib and fulvestrant sequentially declined, yielding greater cost-effectiveness (Supplementary Table 4). When the utility value for the PFS state was 0.82, inavolisib plus palbociclib and fulvestrant provided a relatively lower QALY of 1.42, and yielded a relatively higher ICUR of $149,332.55 per QALY (Supplementary Table 4). At the 5- and 10-year time horizons, the ICURs of inavolisib plus palbociclib and fulvestrant increased to $172,720.94 and $163,068.76 per QALY, respectively, compared with palbociclib plus fulvestrant (Supplementary Table 4). Reducing the unit cost of inavolisib would decrease the ICURs of the inavolisib-palbociclib-fulvestrant triplet, thereby enhancing its cost-effectiveness; conversely, decreasing the cost of palbociclib would elevate the ICURs (Supplementary Table 5). Supplementary Table 6 presented the impact of price reductions for inavolisib and palbociclib on ICURs. Assuming a fixed price for inavolisib, lower palbociclib costs drove higher ICURs of the inavolisib-based triplet therapy; in contrast, assuming an unaltered price for palbociclib, lower inavolisib costs generated lower ICURs of inavolisib plus palbociclib and fulvestrant.

4. Discussion

Adding inavolisib to palbociclib plus fulvestrant resulted in significantly longer median PFS and OS time in premenopausal, perimenopausal, or postmenopausal women or men with endocrine-resistant, PIK3CA-mutated, HR + HER2-, locally advanced or metastatic breast cancer [9,10]. To our knowledge, this was the first cost-effectiveness analysis of inavolisib-based therapy for PIK3CA-mutated, HR + HER2-, advanced breast cancer from the US public-payer perspective. Compared with palbociclib plus fulvestrant, inavolisib plus palbociclib and fulvestrant yielded an ICUR of $148,417.37 per QALY, which was below the WTP threshold of $150,000 in the United States. Therefore, the pricing of the inavolisib-based triple therapy was highly commensurate with its profound clinical benefits, offering a greater than 50% chance of cost-effectiveness. These results might inform reimbursement decision making and individualized treatment selection in clinical practice.

Beyond base-case analyses, OWSA provided important insights into the real-world applicability of inavolisib-based triple therapy regimen. The most substantial parameter observed in the model was the utility value of PFS state. In the base-case analysis, we used the utility values associated with germline BRCA1/2-mutated HER2-advanced breast cancer patients receiving poly (ADP-ribose) polymerase inhibitors [32], due to the fact that BRCA1/2 and PIK3CA belong to commonly mutated tumor suppressor genes. Other sources of utility values for PFS state were evaluated in the scenario analysis [39]. However, the results of the scenario analysis were comparable to the base-case analysis, suggesting that the influence of utility values on the model was extremely limited. Another important parameter was the cost of inavolisib. Previous published studies consistently indicated that inavolisib was not cost-effective for PIK3CA-Mutated, HR + HER2-advanced breast cancer in the United States, with an ICUR ranging from $249,487.22 to $886,440 per QALY [30,40,41]. In contrast, our findings established the economic viability of combining inavolisib with palbociclib and fulvestrant, which was largely underpinned by the marginal utility accrued from substantial price reductions of inavolisib and palbociclib in the last biennial period. Over the foreseeable horizon, declining drug prices will significantly enhance clinical accessibility and patient affordability. In our scenario analyses, we evaluated the impact of various price reduction combinations for inavolisib and palbociclib on the ICURs, providing robust economic evidence to inform future clinical decision-making and health resource allocation.

In the long-term results of the INAVO120 clinical trial, inavolisib exhibited heightened antitumor activity and superior survival benefits in patients with high-burden, PIK3CA-mutated, HR + HER2-advanced breast cancer [9,10]. As sufficient subgroup survival data were not available to parameterize our models, related economic evaluation could not be conducted. Addressing the cost-effectiveness of inavolisib in distinct high-burden subgroups of PIK3CA-mutated, HR + HER2-advanced breast cancer—including patients with visceral metastases, liver disease, or postmenopausal status—remains an essential task for future health technology assessments. At the same time, expanding genomic testing coverage in advanced breast cancer is essential to identify inavolisib-eligible patients, thereby broadening access to this triplet regimen.

Apart from inavolisib-based therapy, alpelisib was another available PI3K inhibitor for the treatment of PIK3CA-mutation, HR + HER2-, advanced breast cancer [3,4]. The SOLAR-1 clinical trial demonstrated that alpelisib plus fulvestrant improved PFS (HR: 0.65, 95% CI: 0.50-0.85) and OS (HR: 0.86, 95% CI: 0.64-1.15) compared with placebo plus fulvestrant for men and postmenopausal women with PIK3CA-mutated, HR + HER2-, advanced breast cancer whose disease progressed on or after aromatase inhibitors [3,4]. Its efficacy was recognized and the approval provided a new option in clinical treatment. In the United States, Wu et al. developed a markov model to investigate the cost-effectiveness of alpelisib plus fulvestrant for treating PIK3CA-mutation, HR + HER2-, advanced breast cancer, and the ICURs were $340,153.30 per QALY versus fulvestrant from the US payer perspective [42]. Alpelisib plus fulvestrant would be cost-effective when the cost of alpelisib was lower than $71 per 300 mg (36.5% of the original price) at the WTP threshold of $150,000 [42]. The Canadian Agency for Drugs and Technologies in Health (CADTH) constructed a semi-markov cohort model to assess the cost-effectiveness of alpelisib plus fulvestrant from the perspective of Canadian publicly funded healthcare payer [43]. Compared with everolimus plus exemestane, alpelisib plus fulvestrant was associated with an ICUR of $319,592 per QALY [43]. At the WTP threshold of $50,000, alpelisib plus fulvestrant would require a 99% price reduction to be cost-effective in Canada [43].

Palbociclib was the first approved CDK4/6 inhibitor around the world, followed by ribociclib and abemaciclib [44]. An economic evaluation comprehensively evaluated palbociclib, ribociclib, and abemaciclib versus letrozole monotherapy in the first-line treatment of HR + HER2− metastatic breast cancer over a 40-year time horizon from the US third-party payer perspective [22]. The results indicated that combining CDK4/6 inhibitors plus letrozole was not cost-effective with slight increases in QALYs at higher costs [22]. Among all available CDK4/6 inhibitors, abemaciclib plus letrozole represented the preferred treatment option, with lower cost and higher QALY [22]. Therefore, abemaciclib plus fulvestrant was the most appropriate comparator agent in this study. Due to insufficient direct comparative clinical efficacy and safety data for inavolisib plus palbociclib and fulvestrant versus abemaciclib plus fulvestrant, we followed the protocol of the INAVO120 clinical trial [9,10]. Future studies could further explore the cost-effectiveness of inavolisib-based therapy compared with abemaciclib plus fulvestrant, employing head-to-head or indirect comparison data, thereby establishing a complete chain of evidence for reimbursement decisions.

Our model has several limitations. First, clinical benefits of the INAVO120 clinical trial beyond the observation time were forecasted by fitting parametric survival models to follow-up survival data. Due to the maturity of the survival data and inherent methodological uncertainties, validation based on updated data was warranted. Second, since the price of innovative drugs varied dramatically among different payers in the United States, our analyses were restricted to the public-payer perspective because the costs were extracted from the department of Veterans Affairs. Third, this model only considered the impact of severe AEs (grade 3 or 4) on costs and disutility values, which might lead to underestimation of costs and overestimation of health outcomes than those in clinical practice. Future studies should include the costs and disutility values of all AEs, which would contribute to the significant reduction of uncertainty in the economic evaluation of the field. Fourth, the outcomes about health-related quality of life were not reported in the INAVO120 clinical trial, multiple real-world data and the reduction of utility values caused by disease progression were used to estimate the health outcomes of various treatment options. Fortunately, utility values did not substantially affect the model results. Notwithstanding these limitations in our model, we believed our conclusions were justified.

5. Conclusion

Compared with palbociclib plus fulvestrant, inavolisib plus palbociclib and fulvestrant is cost-effective in the treatment for PIK3CA-mutated, HR + HER2-, advanced breast cancer at the WTP threshold of $150,000 per QALY in the United States. Future research is warranted to evaluate the cost-effectiveness of inavolisib-based triple therapy in patients with high-burden disease.

Ethics approval and informed consent

This economic evaluation was based on modeling techniques, price databases, and published literatures, so ethics committee approval was exempted.

Data availability

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

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Shixian Liu: Conceptualization, Data curation, Methodology, Software, Writing – original draft, Writing – review & editing. Kaixuan Wang: Conceptualization, Data curation, Methodology, Validation, Writing – review & editing. Hao Chen: Conceptualization, Data curation, Software, Writing – review & editing. Ziming Wan: Conceptualization, Data curation, Validation, Writing – review & editing. Lei Dou: Conceptualization, Methodology, Supervision, Writing – review & editing. Shunping Li: Methodology, Supervision, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following is the Supplementary data to this article: