Abstract
Aim
To estimate brain metastases (BM) management costs in Chinese ALK+ advanced non-small-cell lung cancer (NSCLC) patients receiving first-line (1 L) ALK tyrosine kinase inhibitors (TKIs).
Methods
A survey of 105 clinical experts across 23 Chinese regions evaluated healthcare resource utilization (HCRU). Total annual costs with TKIs were calculated by weighting the management costs of patients with and without BM using the cumulative incidence rate (CIR) of BM from ALK-TKI clinical trials.
Results
First-year management cost averaged ¥24,974 per-patient without BM versus ¥89,859 per-patient with BM, saving ¥64,885. Subsequent years saved ¥33,231. Applying 12-month CIR of BM, the annual costs per-patient were ¥26,791 for 1 L lorlatinib versus ¥46,516 for crizotinib in the intention-to-treat (ITT) population. Subgroup analysis showed annual costs of ¥25,623 per-patient with lorlatinib in those without BM and ¥29,775 in those with BM. Alectinib’s and brigatinib’s costs were ¥31,073 and ¥32,760 respectively, using the 12-month CIR of BM. Lorlatinib’s cost savings increased progressively over 1–4 years. Limited CIR beyond 12 months existed for brigatinib and ensartinib. Results from the Asian group’s CIR aligned with global trials.
Conclusion
Due to lower BM CIR, lorlatinib showed higher BM management cost savings compared to crizotinib and alectinib in Chinese 1 L patients.
Keywords: ALK-positive, NSCLC, brain metastases, management cost, ALK TKIs
ARTICLE HIGHLIGHTS
Patients with ALK-positive advanced non-small-cell lung cancer with brain metastases had significant management costs.
Lorlatinib, alectinib, brigatinib and ensartinib can lower the incidence of brain metastases compared to crizotinib, resulting in cost savings.
Higher savings in BM management costs were observed as a trend in Chinese patients who received 1L lorlatinib.
Results from the Asian group’s data were similar to those from global trials.
PLAIN LANGUAGE SUMMARY
This study looked at the management costs of treating lung cancer that had spread to the brain in Chinese patients with a specific type of advanced lung cancer (ALK-positive NSCLC). The patients were being treated with targeted medicines called ALK inhibitors. We asked 105 cancer experts across China about the medical care needed for these patients. We then calculated the average yearly management cost of care by combining the costs for patients with and without brain spread, using data from clinical trials on how often this brain spread occurs. We found that the management cost of care was much higher for patients whose cancer spread to the brain. In the first year, managing a patient without brain spread cost about ¥25,000, while managing a patient with brain spread cost nearly ¥90,000. A medicine called lorlatinib was found to be very effective at preventing cancer from spreading to the brain. Because of this, the average yearly management cost per patient was much lower for lorlatinib (¥26,791) compared to crizotinib (¥46,516). In conclusion, using lorlatinib as a first treatment can lead to significant cost savings by more effectively preventing the high expenses associated with treating cancer that has spread to the brain.
1. Background
Lung cancer is one of the malignant tumors with high morbidity and mortality rate both worldwide and in China. In 2022, the incidence of lung cancer accounted for 18.06% of new cancer cases, and the mortality rate was 23.9% in China, ranking first [1,2]. Non-small cell lung cancer (NSCLC) accounts for 80%–85% of all lung cancers [3], with Anaplastic lymphoma kinase (ALK) gene rearrangement, notably the EML4-ALK, present in 2%–7% of these cases [4,5]. Current guidelines from the Chinese Medical Association [3] and the Chinese Society of Clinical Oncology (CSCO) [6] recommend ALK tyrosine kinase inhibitors (TKIs) as the first-line treatment for ALK-positive advanced NSCLC patients. These include first-generation ALK-TKI crizotinib, second-generation ALK-TKIs such as ceritinib, alectinib, ensartinib, brigatinib, envonalkib and iruplinikib, as well as the third-generation ALK-TKI lorlatinib.
Prevalence of BM in ALK-positive advanced NSCLC patients is higher than other NSCLC types, ranging between 15% and 35% [7], and significantly impacts morbidity and mortality [8]. Drug resistance and disease progression limit the effectiveness of crizotinib and chemotherapy, with up to 60% of patients developing BM. BMs result in severe complications, including neurocognitive issues, behavioral abnormalities, and psychological disorders, seriously affecting patients’ quality of life, with a natural mean survival time of only 1–2 months [9]. BM patients usually require radiotherapy (either whole-brain radiotherapy or stereotactic radiosurgery), surgical resection (for isolated metastases or cases with a good prognosis), and/or chemotherapy, as well as post-treatment rehabilitation due to deterioration of neurocognitive function and neurotoxicity [10]. Managing these cases significantly inflates medical expenses, as shown in a US study highlighted increased resource use post-BM diagnosis on lung cancer patients [11].
The newer generations of inhibitors demonstrate stronger inhibitory ability and higher blood-brain barrier permeability. Prevention or early treatment of ALK-positive advanced NSCLC can reduce the risk of central nervous system (CNS) progression and subsequent healthcare costs [12,13]. At present, these ALK-TKIs have been marketed and covered by social medical insurance in China, which can alleviate the financial burden on patients and improve their quality of life despite the substantial economic burden posed by BM.
Two studies investigated the management cost savings resulting from a lower risk of BM in patients treated with different ALK-TKIs. The Spanish study [14] assessed that annual management costs were €6,173.42 per patient-year without BM and €21,637.50 per patient-year with BM. The UK study [15], which employed a similar methodology adjusted for the local healthcare system, reported the management costs of £4,893 per patient-year without BM and £13,732 per patient-year with BM. Using the CIR of BM progression from trials, 1 L lorlatinib and alectinib had lower costs than crizotinib. Specifically, in the first year, lorlatinib resulted in saving of £2,687 per patient-year in the ITT population, £1,485 per patient-year in patients without BM, £5,736 per patient-year in patients with BM, with these savings increasing over two years compared to crizotinib. And alectinib saved £2,828 per patient-year in the ITT population, £2,377 per patient-year in patients without BM, £3,739 per patient-year in patients with BM in the first year. Overall, BM significantly increases cost burden. The use of second- or third-generation ALK-TKIs can reduce management costs compared to crizotinib, highlighting research significance.
There is a lack of relevant research in China, highlighting an urgent need to investigate the cost and economic burden of brain metastases in ALK-positive NSCLC patients based on the Chinese population. The objective of this study was to estimate the costs of managing BM in patients with ALK-positive advanced NSCLC receiving lorlatinib, crizotinib, alectinib, brigatinib or ensartinib as first-line treatment in China.
2. Material and methods
2.1. Data collection
In the initial phase of this study, data were collected on the healthcare resources utilization (HCRU) by ALK-positive advanced NSCLC patients with and without BM.
A structured questionnaire was designed for this study, referencing the lung cancer guidelines from the Chinese Medical Association [3] and the CSCO [6], to capture potential HCRU for ALK-positive advanced NSCLC patients with and without BM. The questionnaire included surgical resection, radiotherapy, medical visits, hospitalizations, laboratory tests, imaging, ALK gene tests and specialized treatments for BM, depending on the presence or absence of BM. Five lung cancer specialists from China conducted preliminary interview, and the questionnaire was subsequently modified and refined based on their feedback.
The survey encompassed 105 clinical experts randomly selected from tertiary hospitals across 23 regions (Table 1), using the following pre-defined criteria. Inclusion Criteria: (1) experience in managing patients with ALK-positive advanced NSCLC or prescribing ALK-TKIs; (2) affiliation with relevant departments; (3) the title of Associate Chief Physician or higher; and (4) practice at a tertiary Grade A hospital or a provincial-level cancer specialty hospital. Experts were excluded if they had not managed advanced NSCLC within the past five years or had incomplete responses (>20%) to core questionnaire items.
Table 1.
Clinical experts detailed information.
| Department | No. |
|---|---|
| Medical oncology | 87 |
| Surgical oncology | 8 |
| Radiation oncology | 5 |
| Surgery | 5 |
| District | |
| Northeast | 11 |
| North | 16 |
| Eastern | 38 |
| Central and southern | 31 |
| Western | 9 |
| Physician’s title | |
| Chief Physician | 39 |
| Deputy Chief Physician | 66 |
| Total | 105 |
The frequency and annual rates of HCRU were determined using the median values from our questionnaire results (Table 2), with the specific upper and lower quartiles detailed in the supplemental table. The unit costs for these health resources were based on expert estimates derived from patient prescriptions and clinical experience, and were calculated as the average value (Table 2). These cost values were then validated against provincial and municipal medical service price lists. The annual cost of managing ALK-positive NSCLC patients with or without BM was estimated by multiplying resource consumption by the corresponding unit cost. Based on expert interviews, patients without disease progression undergo regular follow-ups and show comparable healthcare resource utilization between the first year and subsequent years. Therefore, it is assumed that HCRU remains consistent for patients without BM throughout the first year and subsequent treatment years.
Table 2.
Consumption of resources associated with the management of patients with vs without BM and unit costs.
| Resources | Patients without BM (FY and SYs) |
Patients with BM (FY) |
Patients with BM (SYs) |
||||||
|---|---|---|---|---|---|---|---|---|---|
| Patients (%) | Tests/year (n) | Unit cost (¥) | Patients (%) | Tests/year (n) | Unit cost (¥) | Patients (%) | Tests/year (n) | Unit cost (¥) | |
| Visitors | |||||||||
| Medical oncology | |||||||||
| Medical oncology (first visit) | 60% | 6 | 27.83 | 65% | 8 | 27.83 | 65% | 8 | 27.83 |
| Medical oncology (successive visits) | 65% | 70% | 70% | ||||||
| Pneumology department | |||||||||
| Pneumology department (first visit) | 15% | 5 | 23.23 | 10% | 5 | 23.23 | 10% | 5 | 23.23 |
| Pneumology department (successive visits) | 10% | 8% | 8% | ||||||
| Radiation oncology | |||||||||
| Radiation oncology (first visit) | 15% | 4 | 24.43 | 20% | 5 | 24.43 | 20% | 5 | 24.43 |
| Radiation oncology (successive visits) | 20% | 20% | 20% | ||||||
| Surgery | |||||||||
| Surgery (first visit) | 10% | 4 | 22.99 | 5% | 4 | 22.99 | 5% | 4 | 22.99 |
| Surgery (successive visits) | 5% | 2% | 2% | ||||||
| Hospitalizations | |||||||||
| General admission (medication or examinations) | |||||||||
| Medical oncology | 47% | 4 | 4,005.85 | 50% | 5 | 5,277.88 | 50% | 4 | 4,188.42 |
| Radiation oncology | 20% | 3 | 5,882.81 | 29% | 3 | 7,203.38 | 24.5% | 3 | 5,270.36 |
| Pneumology department | 20% | 3 | 4,143.28 | 20% | 3 | 5,256.15 | 22% | 3 | 3,603.51 |
| Surgery | 16.5% | 2 | 4,373.08 | 17% | 2 | 5,719.75 | 17% | 2 | 3,799.83 |
| Hospitalizations (metastases-procedures specific treatment) | |||||||||
| Surgical excision | 0% | 0 | 0 | 15% | 1 | 23,256.50 | 10% | 1 | 24,546.15 |
| Stereotactic radiotherapy | 0% | 0 | 0 | 33% | 2 | 23,963.57 | 30% | 1 | 21,644.32 |
| Holocranial brain radiotherapy | 0% | 0 | 0 | 30% | 1 | 22,562.10 | 20% | 1 | 21,134.07 |
| Laboratory tests | |||||||||
| Blood routine (18 items) | 99% | 8 | 38.87 | 99% | 10 | 38.87 | 99% | 10 | 38.87 |
| Urine routine (11 items) | 43% | 6 | 31.14 | 50% | 6 | 31.14 | 50% | 6 | 31.14 |
| Blood biochemical | 94% | 6 | 246.13 | 99% | 6 | 246.13 | 99% | 6 | 246.13 |
| Arterial gasometry | 20% | 2 | 146.37 | 22% | 3 | 146.37 | 22% | 3 | 146.37 |
| Electrocardiogram | 67.5% | 4.5 | 39.49 | 60.5% | 5 | 39.49 | 60.5% | 5 | 39.49 |
| Pulmonary function test | 40% | 2 | 130.47 | 31% | 3 | 130.47 | 31% | 3 | 130.47 |
| Thyroid function test | 40% | 3 | 170.65 | 40% | 4 | 170.65 | 40% | 4 | 170.65 |
| Coagulation function | 60% | 6 | 98.00 | 68% | 6 | 98.00 | 68% | 6 | 98.00 |
| Tumor Marker (CEA) | 96.5% | 4.5 | 76.70 | 96.5% | 6 | 76.70 | 96.5% | 6 | 76.70 |
| Tumor Marker (CA199) | 60.5% | 4.5 | 79.53 | 74% | 6 | 79.53 | 74% | 6 | 79.53 |
| Tumor Marker (SCC) | 75% | 4 | 84.58 | 79.5% | 6 | 84.58 | 79.5% | 6 | 84.58 |
| Tumor Marker (NSE) | 71% | 5 | 93.12 | 80.5% | 6 | 93.12 | 80.5% | 6 | 93.12 |
| Imaging techniques | |||||||||
| Cerebral MRI | 50% | 2 | 1,035.69 | 80% | 4 | 1,035.69 | 80% | 4 | 1,035.69 |
| Brain computed tomography | 20.5% | 2 | 627.05 | 33.5% | 2 | 627.05 | 33.5% | 2 | 627.05 |
| Chest plain scan CT | 40% | 3 | 341.64 | 47% | 4 | 341.64 | 47% | 4 | 341.64 |
| Chest enhanced CT | 57.5% | 3 | 597.74 | 57% | 3 | 597.74 | 57% | 3 | 597.74 |
| Upper abdominal plain scan CT | 38.5% | 2 | 337.31 | 39.5% | 2 | 337.31 | 39.5% | 2 | 337.31 |
| Upper abdominal enhanced CT | 46% | 3 | 620.10 | 42.5% | 3 | 620.10 | 42.5% | 3 | 620.10 |
| Upper abdominal ultrasound | 23.5% | 3 | 173.63 | 34% | 3 | 173.63 | 34% | 3 | 173.63 |
| PET-CT | 17% | 1 | 6,681.27 | 19.5% | 1 | 6,681.27 | 19.5% | 1 | 6,681.27 |
| Chest x-ray | 1% | 2 | 153.15 | 0% | 2 | 153.15 | 0% | 2 | 153.15 |
| Bone scan | 38% | 1 | 1,061.21 | 30% | 1 | 1,061.21 | 30% | 1 | 1,061.21 |
| Cervical/supraclavicular lymph node ultrasound | 40% | 3 | 156.61 | 39% | 3 | 156.61 | 39% | 3 | 156.61 |
| Cervical/supraclavicular lymph node plain scan CT | 20% | 2 | 335.96 | 20% | 2 | 335.96 | 20% | 2 | 335.96 |
| Cervical/supraclavicular lymph node enhanced CT | 23% | 2 | 550.16 | 23% | 2 | 550.16 | 23% | 2 | 550.16 |
| Specific tests to diagnose NSCLC | |||||||||
| Lumbar puncture and cerebrospinal fluid examination | 0% | 0 | 1,035.18 | 18% | 2 | 1,035.18 | 18% | 2 | 1,035.18 |
| Biopsy of brain metastases | 0% | 0 | 3,514.98 | 6% | 1 | 3,514.98 | 6% | 1 | 3,514.98 |
| ALK gene tests | |||||||||
| DNA-NGS | 0% | 0 | 7,328.79 | 62% | 1 | 7,328.79 | 62% | 1 | 7,328.79 |
| RNA-NGS | 0% | 0 | 10,000.00 | 1% | 1 | 10,000.00 | 1% | 1 | 10,000.00 |
| PCR | 0% | 0 | 4,125.71 | 2% | 3 | 4,125.71 | 2% | 3 | 4,125.71 |
| IHC | 0% | 0 | 200.00 | 1% | 1 | 200.00 | 1% | 1 | 200.00 |
| Specific procedures for the treatment of metastases | |||||||||
| Holocranial brain radiotherapy | 0% | 0 | 0 | 30% | 1 | 12,621.27 | 20% | 1 | 11,698.12 |
| Stereotactic radiotherapy | 0% | 0 | 0 | 40% | 2 | 15,557.51 | 30% | 1 | 16,185.32 |
| Surgical resection | 0% | 0 | 0 | 15% | 1 | 25,810.65 | 10% | 1 | 27,918.70 |
Note: BM: brain metastasis; FY: First year; SYs: Subsequent years.
2.2. Cost analysis model
A cost analysis model was developed to compare the annual treatment costs of patients treated with crizotinib, alectinib, lorlatinib, ensartinib or brigatinib in the 1 L setting, with a focus on the risk of BM emergence within each treatment regimen. Figure 1 shows the overview of this study.
Figure 1.
Overview of this study.
2.2.1. Population
The target population was ALK-positive advanced NSCLC patients treated with TKIs as first-line therapy in China. For subgroup analysis, patients were divided into two groups: patients without BM at baseline and patients with BM at baseline.
2.2.2. Intervention and comparator
This study primarily focused on the cost difference in management costs compare crizotinib with lorlatinib and alectinib. Due to data limitations regarding the CIR of BM progression in existing clinical trials, the results of ensartinib and brigatinib were analyzed only for the first year. Ceritinib, iruplinikib and envonalkib were not included in this analysis due to the lack of 12/24/36/48-month CIR of BM progression data in phase III trials, and the available data were not comparable.
2.2.3. Study perspective and cost
This study was conducted from a healthcare system perspective, so only direct medical resource costs were considered. Costs were derived from the results of questionnaire surveys of clinical experts. The costs of diagnostic tests and ALK-TKIs were excluded because this study explored management costs and because the diagnostic tests performed on the patients at the initial diagnosis were the same for patients with and without BM. Based on insights from expert interviews, a proportion of patients (Table 2) underwent surgical resection and radiotherapy in the first year and follow-up year after the diagnosis of BM, which were considered specialized treatments for BM.
2.2.4. Time horizon
The time horizon was the first year of ALK-TKI treatment. However, due to limitations in available data, some interventions were compared for 2–4 years. According to expert interviews, it was assumed that the HCRU for patients without BM progression remains constant from the first year through subsequent years.
2.2.5. CIR of BM progression
In the base-case analysis, the CIR of BM progression across different patient subgroups was obtained through phase III global clinical trials of ALK-TKIs (Table 3). In scenario analysis, the CIR of BM progression in Asian patients was derived from clinical trials based on the Asian group (Table 4). The 12-month cumulative incidence results reflect the management costs for the first year of treatment, while the 24-month/36-month/48-month cumulative incidence results represent the costs for the second/third/fourth year of treatment, respectively.
Table 3.
Cumulative incidence of progression of BM in global clinical trials.
| CROWN trial |
ALEX trial |
eXalt3 trial |
ALTA trial |
Reference | |||||
|---|---|---|---|---|---|---|---|---|---|
| Lorlatinib N = 149 | Crizotinib N = 142 | Alectinib N = 152 | Crizotinib N = 151 | Ensartinib N = 143 | Crizotinib N = 143 | Brigatinib N = 136 | Crizotinib N = 137 | ||
| 12-month | |||||||||
| ITT population | 2.8% | 33.2% | 9.4% | 41.4% | NR | NR | 12.0% | 22.6% | [7,16–17] |
| Without BM at baseline | 1.0% | 17.8% | 4.6% | 31.5% | 4.2% | 23.9% | NR | NR | [18–20] |
| With BM at baseline | 7.4% | 72.3% | 16.0% | 58.3% | NR | NR | NR | NR | [18,19] |
| 24-month | |||||||||
| ITT population | 5.0% | 45.0% | NR | NR | NR | NR | NR | NR | [21] |
| Without BM at baseline | 1.1% | 28.8% | 7.20% | 45.3% | NR | NR | NR | NR | [21,22] |
| With BM at baseline | 18.0% | 91.00% | NR | NR | NR | NR | NR | NR | [21] |
| 36-month | |||||||||
| ITT population | 7.8% | 72.7% | NR | NR | NR | NR | NR | NR | [23] |
| Without BM at baseline | 4.7% | 63.6% | NR | NR | NR | NR | NR | NR | [23] |
| 48-month | |||||||||
| ITT population | 7.8% | 72.7% | NR | NR | NR | NR | NR | NR | [23] |
| Without BM at baseline | 4.7% | 63.6% | NR | NR | NR | NR | NR | NR | [23] |
Note: BM, brain metastases; ITT, intention-to-treat; NR, not report.
Table 4.
Cumulative incidence of progression of BM in asian group.
| CROWN trial | J-ALEX | ALESIA | eXalt3 trial | ALTA trial | Reference | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Lorlatinib N = 65 | Crizotinib N = 65 | Alectinib N = 103 | Crizotinib N = 104 | Alectinib N = 125 | Crizotinib N = 62 | Ensartinib NR | Crizotinib NR | Brigatinib NR | Crizotinib NR | ||
| 12-month | |||||||||||
| ITT population | 0.8%* | 40.5%* | 5.9% | 16.8% | NR | NR | NR | NR | NR | NR | [24] |
| Without BM at baseline | 0%* | 28.9%* | NR | NR | NR | NR | NR | NR | NR | NR | |
| With BM at baseline | 0%* | 68.0%* | NR | NR | NR | NR | NR | NR | NR | NR | |
| 24-month | |||||||||||
| ITT population | 1.6%* | 65.4%* | NR | NR | NR | NR | NR | NR | NR | NR | |
| Without BM at baseline | 0%* | 48.9%* | NR | NR | NR | NR | NR | NR | NR | NR | |
| With BM at baseline | NR | NR | NR | NR | NR | NR | NR | NR | NR | NR | |
| 36-month | |||||||||||
| ITT population | 2.0%* | 73.1%* | NR | NR | 11.6% | 34.0% | NR | NR | NR | NR | [25] |
| Without BM at baseline | 0%* | 60.9%* | NR | NR | 9.1% | 23.1% | NR | NR | NR | NR | [25] |
| 48-month | |||||||||||
| ITT population | 2.0%* | 73.1%* | NR | NR | NR | NR | NR | NR | NR | NR | |
| Without BM at baseline | 0%* | 60.9%* | NR | NR | NR | NR | NR | NR | NR | NR | |
Note: BM, brain metastases; ITT, intention-to-treat; NR, not report. * Data were provided by Pfizer.
2.2.6. Outcomes
The total annual costs associated with TKIs were estimated by weighting the annual costs of managing patients with and without BM using the CIR of BM progression.
2.2.7. Sensitivity analysis
A one-way sensitivity analysis was performed in the base-case analysis on key model parameters, including healthcare resource management costs and CIR of BM progression. The variation ranges for these parameters (±25% for costs and ±20% for CIR) were determined based on expert recommendations.
3. Results
3.1. Annual management costs
Based on resource consumption and the corresponding unit costs estimated by clinical expert questionnaires, the annual management cost for patients with ALK-positive advanced NSCLC without BM was ¥24,974 per patient-year. In contrast, for patients with ALK-positive advanced NSCLC with BM, costs were notably higher, at ¥89,859 in the first year post-diagnosis and ¥58,204 in subsequent treatment years. The presence of BM was associated with an additional annual cost of ¥64,885 in the first year, and ¥33,231 in subsequent treatment years (Figure 2). The primary cost differences between patients with and without BM stemmed from hospitalizations, followed by expenses related to surgical resection and radiotherapy, ALK gene tests, imaging, laboratory tests, specialized BM tests, and medical visits.
Figure 2.
Annual management costs of patients with and without BM. The cost for the management of the patients without BM ¥24,974 per patient-year. in contrast with the management of the patient with BM, which was ¥89,859 in the first year post-diagnosis and ¥58,204 in subsequent treatment years.
3.2. Base-case analysis
Applying the 12-month cumulative incidence of BM progression in patients receiving lorlatinib and crizotinib as first-line (1 L) treatment observed in the CROWN trial, lorlatinib therapy showed a trend of reducing management costs compared with crizotinib. This resulted in savings of ¥42,110 per patient-year in patients with BM, ¥10,901 per patient-year for those without BM, and ¥19,725 per patient-year for the ITT population (Figure 3A–C). Compared with crizotinib, the management cost savings associated with 1 L lorlatinib increased progressively from the second to fourth year of treatment in the ITT population and patients without BM. (Figure 3A,B). For patients with BM, cost savings increased in the second year (Figure 3C). Patients without BM had 2.3/4.9/8.3 times greater cumulative cost savings at 24/36/48 months of 1 L lorlatinib treatment compared to 12 months. Patients with BM had 2.1 times greater cumulative cost savings at 24 months compared to 12 months.
Figure 3.
Management costs of patients with 1 L ALK-TKIs based on global clinical trials (per patient per year). Results of the base case: annual management cost per patient treated with crizotinib was higher than patients treated with lorlatinib, alectinib, brigatinib or ensartinib.
In the first year, the annual management cost per patient treated with alectinib was ¥31,073 per patient-year, while it was ¥32,760 per patient-year for those treated with brigatinib in the ITT population. For patients without BM, the annual management costs were ¥27,958 per patient-year for those treated with alectinib and ¥27,699 per patient-year for those treated with ensartinib during the first year. It should be noted that data on CIR of BM progression beyond 12 months were unavailable for brigatinib and ensartinib (Figure 3).
3.3. Scenario analysis
As shown in Figure 4, using the CIR of BM progression in the Asian group yielded similar results compared with those from the global clinical trials. Both lorlatinib and alectinib were associated with notable reduced management costs compared with crizotinib. However, data on CIR of BM progression in the Asian group were also not available for brigatinib and ensartinib.
Figure 4.
Management costs of patients receiving 1 L ALK-TKIs based on Asian group (per-patient-per-year). Results of the scenario analysis: both lorlatinib and alectinib were associated with notable reduced management costs compared with crizotinib.
3.4. Sensitivity analysis
The sensitivity analysis demonstrated the robustness of the model (supplemental figure). Variations in parameters within predefined ranges did not alter the conclusion. The CIR of BM progression for crizotinib and the hospitalization costs for patients with BM were identified as the most influential factors.
4. Discussion
Lung cancer is one of the malignant tumors with the highest incidence and mortality rates worldwide and is often diagnosed at an advanced stage, significantly reducing patient survival chances. The management of lung cancer patients imposes a substantial economic impact on healthcare systems globally. The annual cost amounts to €18.8 billion in the EU [26], while the average cost per patient with advanced NSCLC was €12,482 in Spain [27]. A retrospective survey conducted in multicenter hospitals across China found that the direct medical expenditure for lung cancer amounted to ¥39,015 per patient in 2021 [28].
The occurrence of BM is common among patients with advanced NSCLC, contributing significantly to the clinical and economic burdens. International studies have reported incremental costs associated with BM-related resource consumption ranging from $4,263 to $16,662 per-patient-per-month [11–13,29]. Most studies derived patient cost data through retrospective analysis, largely focusing on the substantial economic burden caused by the increased medical resources utilization post BM development. However, these analyses often overlook the direct impacts of various ALK-TKIs on BM progression incidence and the potential cost and resource savings from preventing BM progression with different ALK-TKIs.
Previous studies in Spain and the UK, which utilized classified resource consumption data from local oncologists, highlighted a direct relationship between 1 L lorlatinib or alectinib and reduced BM incidence. These studies suggest that using lorlatinib or alectinib in patients with ALK-positive advanced NSCLC could reduce management costs due to their effect in preventing BM appearance.
Our study evaluated the management cost savings in patients treated with different ALK-TKIs compared to crizotinib, attributable to the reduced BM risk. This study has a series of strengths. It is the first study conducted in China to present resource consumption data associated with the management of ALK-positive advanced NSCLC patients, considering BM presence through clinical expert interviews. It is also the first study to correlate these costs with cumulative BM incidence data from treatment with lorlatinib, alectinib, brigatinib, ensartinib and crizotinib. By quantifying the differences in BM-related management costs between different ALK-TKIs and crizotinib, our findings demonstrate significant clinical and health economic value. The cumulative incidence of BM progression in patients treated with 1 L lorlatinib is lower than that with crizotinib, leading to substantial management cost savings of BM that increase annually over four years. Moreover, the results calculated using the cumulative incidence of BM progression in the Asian group align with global clinical trials data. This study also concluded that first-line use of alectinib, brigatinib, and ensartinib in patients can reduce medical resource utilization by reducing the risk of BM compared to crizotinib.
Most studies published to date have utilized retrospective analysis to collect data on medical resource utilization. However, such retrospective analysis in China may encounter several challenges, including the difficulty of obtaining a sufficient amount of data that meets the inclusion criteria, issues with data that are incomplete, missing, or inaccurate, challenges in determining the proportion of medical resource use for individual cases, high patient loss rates, and potential errors in classification or labeling. These issues may arise because the data collection was not originally designed for research purposes. Given the limitations of retrospective analyses mentioned above, this study designed a structured expert survey questionnaire and obtained patient medical resource data through clinical expert interviews.
However, this study has several limitations. First, while the expert survey methodology has certain subjective limitations and lacks regional representativeness, efforts were made to expand the sample size of the clinical experts to mitigate bias from differences in patient management across institutions. Second, our survey-based results were not validated against real-world or NHSA data due to limited accessibility of such sources in China, which may affect generalizability. Future studies should use real-world evidence for validation. Third, this study adopts a healthcare system perspective, consequently excluding indirect costs. While this study primarily focuses on costs, data constraints precluded the incorporation of QALY gains associated with the prevention of BM across different ALK-TKIs. Moreover, drug costs and medication-related adverse events costs were not considered in this study, as the main objective was to estimate and quantify the direct costs associated with healthcare consumption related to BM development. This scope may affect the generalizability of our results for broader economic assessments. Future research incorporates these cost components into a comprehensive model would be of high value. Fourth, due to the absence of head-to-head clinical trials comparing other ALK-TKIs, and considering the potential biases in network meta-analysis stemming from varying baseline patient characteristics, this study focused solely on comparing the outcomes of second/third-generation ALK-TKIs with crizotinib based on available clinical trials. Fifth, comparisons for brigatinib and ensartinib were limited by scarce data on cumulative incidence rates beyond 12 months. Given the differential follow-up durations, comparisons of long-term cost outcomes are limited. The progressive long-term cost savings of lorlatinib over 1–4 years are solely derived from its comparison with crizotinib. As this study was conducted from a national perspective and therefore does not capture regional variations.
Despite these limitations, this study provides valuable insights for clinical decision-making in China. Choosing therapies that reduce BM incidence could lower patient management costs for the national health system. Considering both the clinical impact on patients and economic implications for healthcare systems due to CNS metastasis in patients with advanced NSCLC, it is vital to adopt effective strategies for preventing brain metastases and to implement screening strategies for detecting ALK rearrangements to help physicians prescribe the most effective treatment at an early stage.
5. Conclusion
In conclusion, patients with ALK-positive advanced NSCLC with BM incurred higher management costs compared with those without BM. Second- and third-generation ALK-TKIs may lower the incidence of BM compared to first-generation crizotinib, leading to potential cost savings. Notably, 1 L lorlatinib compared with crizotinib demonstrated a pronounced reduction in cumulative incidence of BM progression and, with most data available from 1 to 4 year, was associated with a trend of higher cost savings in BM management.
Supplementary Material
Acknowledgment
All authors would like to extend our sincere gratitude to the clinical experts who participated in the investigation and supported this study.
Grammarly was used to check and correct grammatical errors in the manuscript to improve its readability and language quality.
Funding Statement
This study was sponsored by Pfizer. The sponsor provided the Asian subgroup CIR data for lorlatinib in this study. Beyond the provision of these specific data, Pfizer had no role in the study design, data collection, data analysis, interpretation of the results.
Author contributions
Bingqi Hu: Conceptualization, Methodology, Software, Writing – Original draft preparation. Jing Xue: Data curation, Investigation, Software. Dingsiman Li: Data curation, Investigation. Jia Duan: Data curation, Investigation. Luan Luan: Supervision, Writing – Reviewing and Editing. Hannah Le: Resources, Writing – Reviewing and Editing. Peng Dong: Writing – Reviewing and Editing. Rifi, Nada: Writing – Reviewing and Editing. Fanfan Zhu: Writing – Reviewing and Editing. Hongchao Li: Supervision, Project administration, Writing – Reviewing and Editing.
Disclosure statement
No potential competing interest was reported by the authors.
References
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