Cost-Effectiveness Analysis of Afatinib versus Gefitinib in Non-small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) Mutation in Indonesia: Observational studies with Retrospectives

Seftika Sari¹*, Tri Murti Andayani², Dwi Endarti³, Kartika Widayati⁴

¹Sekolah Tinggi Ilmu Farmasi Riau, Pekanbaru, Indonesia.

²Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy,

Gadjah Mada University, Yogyakarta, Indonesia.

³Department of Pharmaceutics, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia.

⁴Department of Internal Medicine, Division of Hematology and Medical Oncology,

Faculty of Medicine Gadjah Mada University - Dr. Sardjito Hospital, Yogyakarta, Indonesia.

*Corresponding Author E-mail: seftika1987.apt@gmail.com

ABSTRACT:

Background: A cost effectiveness study is a method in pharmacoeconomic research that can be used as a reference for decision makers or clinicians in determining effective and efficient treatment for patients, one of which is a Non-Small Cell Lung Cancer patient who has an EGFR mutation. Research related to the cost effectiveness of the benefits afatinib and gefitinib is still very limited, especially in Indonesia. This study aims to determine the cost-effectiveness of afatinib versus gefitinib in NSCLC with EGFR mutation patients. Methods and Material: This study is an observational study with a retrospective approach that observes medical record records (to determine clinical outcomes) and financial records (to determine direct medical costs) in NSCLC patients with EGFR mutations at dr Sardjito Hospital Yogyakarta and Dr Kariadi Hospital Semarang, Java Island., Indonesia in the period January 2016 - June 2019. Result: Direct medical cost for NSCLC patients with EGFR mutations who received afatinib therapy was an average of Rp. 120,881,289, - ± 5,353,480.07 per patient, while those who received gefitinib therapy were an average of 90,750,186, - ± 3,369,967,722. Effectiveness data have been published in previous studies. The ICER PFS value shows that afatinib is cost-effectiveness compared to gefitinib with a value of Rp. 106, 345, 069.4/PFS (year). This ICER value is less than 2 times the value of Gross Domestic Product/GDP (Rp. 118, 200,000, -) which is around 1.8 times the value of GDP, whereas in OS afatinib is no better than gefitinib. Conclusion: Afatinib cost effectiveness based on real world retrospectively compared to gefitinib with ICER PFS value of Rp. 106, 345, 069.4/year.

KEYWORDS: Cost effectiveness analysis, Afatinib, Gefitinib, NSCLC.

INTRODUCTION:

Lung cancer is one of the cancers with the highest incidence and mortality rate in Indonesia, with an incidence rate of 19.4 per 100,000 population and an average death rate of 10.9 per 100,000 population¹.

The most common type of lung cancer is non-small cell lung cancer/NSCLC (85%) and in Asian countries up to 50% of NSCLC patients experience mutations of Epidermal Growth Factor Receptor (EGFR) at an advanced stage^2,3. The National Comprehensive Cancer Network has recommended Tyrosine kinase inhibitors (TKIs) as first-line therapy in NSCLC patients with EGFR mutations, namely gefitinib and erlotinib (first generation), afatinib (second generation)⁴. The first generation TKIs reversibly bind and inhibit the EGFR signal, while the second generation can inhibit the erythroblastosis oncogene B (ErbB) family which irreversibly inhibits the signals of all the homodimers and heterodimers of the ErbB family receptors (EGFR/ ErbB1, HER2 / ErbB2, ErbB3 and ErbB4)^5,6,7,8.

Several randomized control trials (RCTs) have shown the advantages of this class of TKIs compared to platinum-based chemotherapy which has a better response rate, longer progression-free survival (PFS), better tolerance, and a superior quality of life^9,10,11,12. There have also been many studies related to the efficacy among other groups of TKIs. The Lux-Lung 7 study and a meta-analysis study showed that afatinib was superior to gefitinib because it prolonged both PFS and OS, although it did not significantly improve OS^13,14,15. Previous research conducted in Indonesia based on a retrospective observational study by Sari et al (2019) also showed that afatinib had a significantly longer PFS compared to gefitinib (14.7 months vs 11.3 months, p = 0.002)¹⁶. In addition to seeing from the point of view of efficacy, economic considerations in the treatment of NSCLC patients with EGFR mutations are needed because considering the costs incurred by patients are not small and can have an impact on the treatment that patients will receive¹⁷.

Afatinib was shown to be cost effective compared to gefitinib in Mexico, where afatinib was shown to be significantly cost effective (p = 0.00095) with better PFS and OS than gefitinib although not significantly different (p> 0.05)¹⁸, however, cost effectiveness research is still very limited, especially in Indonesia. Cost effectiveness data can be used to provide a reference for policy makers or clinicians in making decisions regarding effective and efficient patient treatment¹⁹, so that this study is expected to provide an overview of the cost-effectiveness of treatment between afatinib and gefitinib based on clinical outcome progression free survival and overall survival in daily clinical practice as first-line therapy.

MATERIAL AND METHODS:

Subject:

Complete details on the study design of the efficacy of afatinib compared to gefitinib in Dr. Sardjito Hospital Yogyakarta and Dr. Kariadi Hospital Semarang, Java Island, Indonesia have been published¹⁴. The sample used in this study was balanced between afatinib and gefitinib based on age, sex, type of mutation, and comorbids that had met the inclusion and exclusion criteria in the January 2016 - June 2019 period. The inclusion criteria in this study were patients aged 18 years, both inpatient and outpatient who received gefitinib and afatinib as first-line therapy, and patients with advanced stages (IIIB/IV), while the exclusion criteria were patients whose medical records were incomplete, contraindicated to treatment, first line therapy using platinum-based chemotherapy, patients who used afatinib and gefitinib for less than four weeks, and patients whose financial data were incomplete.

Data Collection and Analysis:

Data collection and analysis on the strength of afatinib and gefitinib in Indonesia have been carried out in previous studies using retrospective observational studies¹⁶. The measured direct medical cost is the cost of patient care both inpatient and outpatient based on the provider's perspective by calculating the average total direct medical cost per patient analyzed descriptively. The costs measured consist of registration fees, doctor services, imaging, EGFR examinations, support, chemotherapy, side effects, and radiotherapy. For cost effectiveness analysis is done by using the calculation of the Incremental Cost Effectiveness Ratio (ICER).

Ethical Consideration:

This study had obtained the ethical agreement from Komite Etika Penelitian Medis dan Kesehatan (MHREC) Fakultas Kedokteran, Universitas Gajah Mada Indonesia with reference number KE/FK/0948/EC/2018 and Komite Etik Penelitian Kesehatan RSUP Dr. Kariadi with number 033/EC/KEPK-RSDK-2018

RESULT:

Patient and effectiveness:

A total of 113 NSCLC patients with EGFR mutations who met the inclusion and exclusion criteria, 27 patients used afatinib and 86 patients used gefitinib. The patient characteristics used were the same as previous studies and showed that the characteristics of patients using afatinib were not significantly different from those using gefitinib¹⁶. Based on the results of previous research conducted using the Kaplain Meier test, it showed that afatinib significantly (p = 0.002) had a progression free survival (PFS) value that was superior to gefitinib (14.7 months; 95% CI = 12-17.4 months vs. or 11, 3 months; 95% CI = 8.4-14.3 months), however the overall survival rate for afatinib was not that better than gefitinib (15.5 months; 95% CI = 13.8-17.2 months vs 21, 5 months; 95% CI = 18-24.8 months) with a significance value of p = 0.302¹⁶.

Cost:

The cost data from the search results of the Management Information System in hospitals based on the consumer price index value in Indonesia in 2019. The average direct medical cost required for NSCLC patients with EGFR mutations receiving afatinib therapy is Rp. 120,881,289, - ± 5,353,480.07 per patient can be seen in table 1. The largest cost component was afatinib (chemotherapy) of Rp. 104,727,407, - ± 7,642,678.72 (86.64%).

Table 1. Direct Medical Costs of NSCLC Patients with EGFR Mutations using Afatinib per Patient

S. No	Component	n	Total Cost (Rp)	Average (Rp)	%	SD
		27
1	Registration		6.761.610	250.430	0,21	10.922
2	Medical services		52.236.063	1.934.669	1,6	544.507
3	Imaging		140.089.26	5.188.491	4,29	1.706.874,1
4	EGFR		89.567.51	3.317.315	2,74	376.726
5	Afatinib		2.827.639.989	104.727.407	86,64	7.642.678,72
6	Laboratory		21.577.185	799.155	0,66	511.235
7	Accommodation		66.495.465	2.462.795	2,04	2.865.581
8	Medical treatment		1.462.833	54.179	0,04	41.109
9	BMHP+Medical devices		10.510.344	389.272	0,32	665.626
10	Side Effects		441.639	16.357	0,02	27.430
11	Other drugs		14.015.592	519.096	0,43	820.429
12	Electrocardiogram		939.195	34.785	0,028	1.237
13	Radiotherapi		29.841.156	1.105.228	0,914	130.247
14	Punksi		2.216.970	82.110	0,068	5.817
	Total Cost		3.034.138.041	120.881.289	100	5.353.480,07

The average cost of patients receiving gefitinib therapy is Rp. 90,750,186, - ± 3,369,967,722, with the largest component is the cost of gefitinib (81.44%), this can be seen in table 2.

Table 2. Direct Medical Costs in NSCLC Patients with EGFR Mutations using Gefitinib per Patient.

No	Komponen	n	Biaya Total (Rp)	Rata-Rata (Rp)	%	SD
		86
1	Registration		23.106.136	268.676	0,3	9.266
2	Medical services		132.991.690	1.546.415	1,7	584.870
3	Imaging		391.104.178	4.547.723	5,01	960916,2539
4	EGFR		275.987.502	3.209.157	3,54	373.418
5	Afatinib		6.356.137.708	73.908.578	81,44	4934286,702
6	Laboratory		58.655.200	680.490	0,75	677.044
7	Accommodation		46.962.364	546.074	0,6	1.286.252
8	Medical treatment		3.923.406	45.621	0,05	225.314
9	BMHP+Medical devices		31.870.396	370.586	0,41	899.498
10	Side Effects		488.136	5.676	0,01	21.544
11	Other drugs		60.920.680	708.380	0,78	2.625.006
12	Elektrocardiogram		3.168.154	36.839	0,04	27.872
13	Radiotherapi		213.335.814	2.480.649	2,73	270.351
14	Metastase		192.324.208	2.236.328	2,46	901.244
15	Punksi		13.673.398	158.993	0,18	311.768
	Total Cost		7.804.648.970	90.750.186	100	3.369.967,722

Table 3. Difference in Costs and Outcome in the PFS and OS Groups of Afatinib and Gefitinib Therapy

				Difference
	Cost	PFS (month)	OS (month)	Cost	PFS	OS	ICER (month)	ICER (year)
Gefitinib	90.750.186	11,3	21,5
Afatinib	120.881.289	14,7	15,5	30.131.103	3,4	-6	8.862.089,12	106.345.069,4

Incremental Cost Effectiveness Ratio (ICER) in Cost Effectiveness Analysis

The results of the incremental cost effectiveness ratio (ICER) calculation show that the cost difference between afatinib and gefitinib is Rp. Rp. 30,131,103, -, whereas the difference between afatinib and gefitinib PFS was 3.4 months which indicated that afatinib PFS was greater than gefitinib, but the difference between afatinib and gefitinib OS values was -6 months, which indicates that afatinib OS values were smaller than gefitinib, can be seen in Table 3.

Comparison of costs with PFS and costs with OS between afatinib versus gefitinib is contained in the cost effectiveness plan (CEP) which can be seen in Figure 1 and Figure 2. The x-axis describes the effectiveness while the y-axis describes the cost, which compares the new drug (afatinib) to the standard drug (gefitinib).

Figure 1. The Cost Effectiveness Plane (CEP) PFS of afatinib was compared to gefitinib

Figure 1 shows that the difference between the cost and outcome (PFS) of afatinib compared to gefitinib is in the NorthEast (NE) area which means that afatinib PFS is superior to gefitinib but afatinib has a higher cost than gefitinib. This situation is said to have a "trade-off" (trade-off between output / effectiveness and cost), so in this case it is necessary to prove whether the proposed new intervention has "value for money" that the high cost of the intervention or the proposed drug is commensurate with the increased effectiveness/ outcome, so that the calculation of the ICER value can be done²¹. The ICER value between afatinib and gefitinib was Rp. 106,345,069.4 / PFS (year). This ICER value is less than 2 times the value of Gross Domestic Product /GDP (Rp. 118,200,000, -) which is around 1.8 times the value of GDP which means afatinib cost effectiveness compared to gefitinib.

Figure 2. The Cost Effectiveness Plane (CEP) OS of afatinib was compared with gefitinib

Seen in Figure 2 shows that afatinib has a higher cost, but has a lower OS value than its comparator (gefitinib), then the points are in the NorthWest (NW) area and the ICER value calculation cannot be performed.

DISCUSSION:

This study is a pharmaceconomic study using a cost-effectiveness analysis method that compares costs to clinical outcomes (progression free survival and overall survival) in EGFR mutated NSCLC patients using afatinib and gefitinib therapy. The results showed that the costs of patients using afatinib therapy were more expensive than patients who used gefitinib therapy. this is because the cost of afatinib is almost double that of gefitinib, which is the highest cost component of chemotherapy costs (afatinib and gefitinib). This result is in accordance with the research conducted by Migliorino et al which states that chemotherapy costs are the highest component incurred by cancer patients, namely 50% of the total paid ^21,22,23,24. Patients who used gefitinib also had metastases such as brain metastases and bone metastases and it cost Rp. 2,236,328, - ± 901,244 (2.46%), however, in patients taking afatinib there was no incidence of metastases. This is because afatinib is better at slowing down progression free survival, one of which is the incidence of metastases compared to gefitinib or platinum-based chemotherapy¹⁵. The efficacy of afatinib compared to gefitinib based on the LUX-Lung 7 test and several other studies have also shown that afatinib is superior to gefitinib, not only slows down PFS, but can also prolong overall survival, treatment to failure (TTF) and improve quality of life^13,14,20. The results of this study indicate afatinib cost effectiveness compared to gefitinib in the clinical outcome of PFS, This can be seen from the research results that the ICER value is smaller than 2 times the GDP value. The GDP value is used as an approach to determine the cost-effectiveness threshold value, if the ICER value of a health technology is below the GDP value then the health technology will be implemented as a country's policy²⁵. However, in OS, afatinib has a lower OS value than geftinib but has a higher cost. Previous research conducted in Japan that used the Median Survival Time (MST) as a measured clinical outcome, showed that gefitinib compared to afatinib resulted in an ICER value of JPY 122.070.7/ MST, where afatinib was expensive and also had low outcomes, but research conducted in Korea stated that afatinib had both OS and PFS which were superior to gefitinib^26,27,28,29, however a study conducted in Japan demonstrated that afatinib, gefitinib and erlotinib demonstrated comparable clinical efficacy in EGFR mutated NSCLC patients^30,31.

The weakness of this study is the determination of cost effectiveness using only patient clinical outcomes, namely PFS and OS based on retrospective data, so that some data is incomplete or difficult to obtain. This study is expected to be one of the clinicians' considerations in determining the effective and efficient treatment of EGFR mutation NSCLC patients.

CONCLUSION:

Afatinib cost effectiveness based on real world data retrospectively compared to gefitinib with ICER PFS value of Rp. 106,345,069.4/year. The ICER value obtained is smaller than 2 times the GDP value, namely 1.8 times the GDP value.

CONFLICT OF INTEREST:

The author declares that there is no conflict of interest.

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Received on 20.01.2021 Modified on 13.04.2021

Research J. Pharm.and Tech 2022; 15(4):1598-1602.

DOI: 10.52711/0974-360X.2022.00267