Effectiveness of Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) on Life Expectancy in Non-Small Cell Lung Cancer Patients in Medan City

INTRODUCTION

Cancer is a leading cause of mortality, with an estimated 10 million deaths in 2020, or almost 1 in 6 deaths globally.[1] Breast cancer is the most prevalent, with approximately 2.3 million newly diagnosed cases or 11.7% according to the 2020 Global Burden of Cancer (GLOBOCAN) estimates of the International Agency for Research on Cancer. It is succeeded by gastric (5.6%), prostate (7.3%), colorectal (10.0%), and lung cancer (11.4%).[2]

Lung cancer is the most prevalent type of cancer globally, representing 11.4% of all diagnosed cancer cases and being a significant contributor to mortality due to cancer. Indonesia has three times as many cases of lung cancer as any other cancer type, following breast and cervical cancers, with over 30,000 deaths attributed to it. In North Sumatra, data from Haji Adam Malik Hospital in Medan recorded 278 lung cancer cases in 2019, comprising 180 men, 98 women, and 68 deaths.[3] Lung cancer has a complicated pathogenesis that is still poorly understood. Exposure to carcinogens, especially from smoking, is believed to result in dysplasia in the epithelial cells of the lungs. Continuous exposure can cause genetic changes that affect the production of proteins, disturb normal cell cycle regulation, and promote cancer development. MYC, BCL2, and p53 are frequently associated with genetic mutations in small-cell lung cancer (SCLC), while EGFR, KRAS, and p16 are commonly involved in mutations of non-small-cell lung cancer (NSCLC).[4-6]

The EGFR gene frequently undergoes mutations in NSCLC, especially in about 50% of lung adenocarcinoma cases among Asian populations. EGFR has a physiological function in regulating the development and homeostasis of epithelial tissues. G protein-coupled receptors have the ability to transactivate EGFR which can affect the proliferation and growth of cells through many signal transduction pathways. Mutations in the EGFR gene may cause overactivation of its tyrosine kinase domain, leading to unchecked cell growth and proliferation.[7]

Tumor cell proliferation, apoptosis suppression, tumor-driven angiogenesis, metastasis, and DNA damage repair are all significantly impacted by EGFR activation. This makes EGFR a key target in cancer therapy, particularly lung cancer. Chemotherapy and radiotherapy may be improved by inhibiting EGFR.[8] Thus, identifying cancer genotypes enables a more targeted approach to lung cancer treatment. The extracellular ligand-binding region of EGFR has been the target of a class of monoclonal antibodies since it was discovered in 1962, blocking receptor activation and reducing its surface expression through antibody-induced receptor dimerization. Additionally, EGFR is inhibited by small molecule tyrosine kinase inhibitors (TKIs) via competition with ATP for attaching to the intracellular tyrosine kinase subunit, suppressing the receptor’s catalytic activity and downstream signaling pathways. TKIs have shown substantial antitumor efficacy in cancers characterized by EGFR overexpression.[8]

Determining the correct treatment for NSCLC patients is crucial, and this involves assessing their EGFR mutation status. Patients with EGFR mutations should be given TKIs as their first-line therapy. For patients with wild-type EGFR, TKIs are also possible treatment options, but they should be considered for second or third-line therapy.[9] TKIs like Erlotinib have shown efficacy in halting tumor progression in EGFR-mutated NSCLC. However, tumor control may be lost as resistance mechanisms evolve, such as the mutation in exon 20 known as T790M.[10]

In previous studies, the T790M mutation was stated to be the leading pathway of acquired resistance in more than half of patients treated receiving first- and second-TKIs for EGFR-mutated NSCLC.[5] This resistance can impact treatment outcomes, including life expectancy. The data indicates different survival outcomes associated with various TKIs, with afatinib showing a progression-free survival (PFS) of 19.1 months, gefitinib at 13.7 months, and erlotinib at 14.0 months.[11] Regarding overall survival (OS), the results showed that afatinib had a 22.8-month OS, erlotinib a 17.8-month OS, and gefitinib a 15.5-month OS.[12] TKI resistance in the first and second generations, which can affect the life expectancy in EGFR-positive lung cancer, makes researchers interested in researching the effectiveness of TKIs on life expectancy in EGFR mutations-positive NSCLC patients in Medan.

METHOD

This study applied a retrospective cross-sectional design. Total sampling method was used in selecting the sample, where all population members meeting the research criteria were included. The subjects were patients diagnosed with NSCLC with positive EGFR mutations and treated with TKIs, based on medical records from Haji Adam Malik Hospital Medan, Elisabeth Hospital, Prof. Dr. Chairuddin Panusunan Lubis USU Hospital, and Pirngadi Hospital.

Patients diagnosed with NSCLC between January 2017 and December 2022, aged over 18 years, with EGFR mutation results positive for exon 18, 19, or 21 (single or combination), who received first, second, or third-generation TKIs, and with complete medical record data were included in this study. Exclusion criteria included patients with other malignancies, those treated with TKIs outside of the first, second, or third generation, and patients negative for EGFR mutations.

The data obtained was analyzed using the SPSS program. Univariate analysis was carried out to examine the descriptive aspects of the data. The distribution of numerical data was evaluated using the Kolmogorov-Smirnov test. Distributions were reported using mean and standard deviation, whereas non-normal data used median and range. Bivariate analysis employed hypothesis testing with the independent sample t-test for normally distributed data and the Mann-Whitney test for non-normally distributed data to assess the effectiveness of two sample groups.

Data normality was determined by the Shapiro-Wilk test. To assess the effectiveness of two or more sample groups, Kaplan-Meier survival analysis was used. The log-rank test was used to evaluate the effectiveness differences across groups. The survival proportion difference between groups was significant if the p-value was less than 0.05 and the chi-square value was more than the critical value. Because data will be taken from medical records, all subjects of this research will not be asked for consent. The Health Research Ethics Committee of Universitas Sumatera Utara has granted the study ethical approval.

RESULTS

In this study, 67 research subjects were diagnosed with NSCLC and positive EGFR mutation. They were treated with TKIs based on medical records from Haji Adam Malik Hospital Medan, Elisabeth Hospital, Prof Dr Chairuddin Panusunan Lubis USU Hospital, and Pirngadi Hospital since January 2017-December 2022. Table 1 provides study participants' baseline characteristics.

Table 1. Demographic and Clinical Characteristics

Characteristics	Mean ± SD / n (%)
Age, by year	59,08 ± 10,82
≤ 60 years	29 (43,3)
> 60 years	38 (56,7)
Gender
Male	34 (50,7)
Female	33 (49,3)
Working
Yes	39 (58,2)
No	28 (41,8)
Smoking
Yes	23 (34,3)
No	44 (65,7)
Location of mutation
Multiple	4 (6,0)
Single	63 (94,0)
Histopathology Type
Adenocarcinoma	66 (98,5)
Squamous Cell Carcinoma	1 (1,5)

Subjects in this study have a mean age of 59.08 ± 10.82 years. Most participants were non-smokers (65.7%), had a single cancer mutation site (94.0%), and presented with adenocarcinoma histopathology (98.5%). Among the study subjects, 50.7% were male, and 58.2% were employed. The characteristics of the subjects based on TKI treatment are detailed in Table 2

Patients received either first or second-generation TKIs. While 44.8% received first-generation treatment, 55.2% were given second-generation TKIs. In the second-generation group, all patients received afatinib treatment. Among the first-generation group, 37 patients were given erlotinib, and 6 underwent gefitinib treatment. The average duration of TKI therapy was 9.04 ± 5.89 months. The treatment resulted in a stable disease response for 92.6% of patients, and 64.2% were at stage IVA.

Table 2 Characteristics of TKI Treatment

Treatment Characteristics	Mean ± SD / n (%)
Generation of TKI
Generation 1	30 (44,8)
Generation 2	37 (55,2)
Drug
Erlotinib	37 (55,2)
Gefitinib	6 (9,0)
Afinitib	24 (35,8)
Duration of TKI treatment (months)	9,04 ± 5,89
Drug response
Stable disease	62 (92,6)
Progressive disease	4 (6,0)
Partial response	1 (1,5)
Stage
IIIA	13 (19,4)
IIIB	8 (11,9)
IVA	43 (64,2)
IVB	3 (4,5)

In NSCLC patients with positive EGFR mutations, the efficacy of first- and second-generation TKIs was compared in terms of PFS, Median Survival Time, and OS (Table 3).

Table 3. Characteristics of TKI Treatment Effectiveness of TKIs in NSCLC Patients With Positive EGFR Mutations

Characteristics	Progression (Months)	CI 95%	P-Value
Progression Free Survival
Generation 1	8,00	6,670-9,330	<0,001**
Generation 2	11,00	9,819-12,181
Median Survival Time
≤ 60 years	4,00	3,335-4,665	<0,001**
> 60 years	5,00	4,958-6,042
Overall Survival
Male	8,00	6,670-9,330	<0,001**
Female	11,00	9,515-12,485

Notes: Kaplan Meier and Log-rank test, *Significant at p < 0.05, **Significant at p < 0.001.

As shown in Table 3, PFS, median survival time, and OS were significantly higher in EGFR mutations-positive NSCLC patients receiving second-generation TKIs in contrast to first-generation (p < 0.05). Figure 1 shows a comparison of these findings.

Figure 1. Differences in (a) PFS, (b) MST, and (c) OS between first and second-generation TKI

The results of the analysis of length of life using the Kaplan-Meier method and Log-rank test are presented in Table 4.

Table 4. Length of Life Analysis on TKIs in NSCLC Patients with Positive EGFR Mutations

Characteristics	Median Length Of Life (Months)	CI 95%		P-Value
EGFR TKI
Generation 1	8,00	6,670-9,330		< 0,001**
Generation 2	11,00	9,515-12,485
Age (years)
≤ 60 years	11,00	8,740-13,260		0,176
> 60 years	10,00	8,705-11,295
Gender
Male	10,00	8,413-11,587		0,116
Female	10,00	8,750-11,250
Working
Yes	10,00	7,977-12,023		0,241
No	10,00	9,145-10,855
Smoking
Yes	10,00	8,209-11,791		0,090
No	10,00	9,001-10,099
Location of Mutation
Multiple	3,00	0,000-8,880		0,065
Single	10,00	9,356-10,644
Histopathology Type
Adenocarcinoma	10,00	9,341-10,659		< 0,001**
Squamous Cell Carcinoma	2,00	-

Notes: Kaplan Meier and Log-rank test, *Significant at p < 0.05, **Significant at p < 0.001.

Figure 2. Differences in Length of Life Based on The Characteristics of Research Subjects

Analysis showed that histopathological type, EGFR TKI production, and survival length are significantly correlated (p < 0.05). The median survival for second-generation EGFR TKIs was 11 months, longer than first-generation TKIs, which was eight months. Additionally, the median survival for SCC was much lower at two months, compared to ten months for those with adenocarcinoma or NSCLC. Age, gender, occupation, smoking status, and EGFR mutation location failed to demonstrate a significant correlation with survival (p > 0.05). Figure 2 compares survival times based on the characteristics of the study population.

DISCUSSION

The average age of NSCLC patients in this study who had positive EGFR mutations was 59.08 ± 10.82 years. Likewise, an Algerian study found that NSCLC patients with positive EGFR mutations ranged in age from 44 to 94 years old, with a mean age of 59.[13] Similar results were found in China, where patients ranged from 33-78 years of age and a median of 60.6 years.[14]

The majority of patients with EGFR mutations and NSCLC do not smoke. Compared to active smokers (4.9%) and former smokers (13.5%), never-smokers had a greater frequency of EGFR mutations (42.5%). Exposure to high levels of smoke from burning coal has been considered a contributing factor to lung cancer, and air pollution is also a significant risk factor.[15] The majority of individuals with EGFR mutations are either moderate smokers or do not smoke. Due to the rising prevalence of non-smoking behaviors, more female patients are found to carry EGFR mutations compared to males.[16] Smoking continues to be a substantial risk factor regarding lung cancer, and those who smoke and those who don't have been found to have quite different patterns of gene alteration. Notably, nonsmokers are more likely than smokers to have mutations in the EGFR gene.

Males made up 50.7% of the study's participants, and 58.2% of them had occupations. Similar outcomes were observed in 44.7% of male patients according to a Chinese study.[14] A different Taiwanese study found that 52.1% of patients with positive EGFR mutations in NSCLC were male.[17,18] The majority of individuals with EGFR mutations in NSCLC had only one mutation, often at exon 19. The exon 19 deletion (Del 19) and the mutation in exon 21 comprise 90% of all EGFR mutations and are associated with sensitivity to EGFR TKIs.[19]

The majority of EGFR mutations-positive NSCLC patients have adenocarcinoma as their histopathological type. Research conducted in Algeria has shown similar results, indicating that most NSCLC patients who have positive EGFR mutations also have the adenocarcinoma histological type.[13] Accounting for 60% of NSCLC cases, adenocarcinoma is the most prevalent form of lung cancer. A peripheral mass with center fibrosis and pleural wrinkling is the typical appearance of lung adenocarcinoma. It can also manifest in a variety of ways, including a centrally located mass, diffuse lobar consolidation, bilateral multinodular distribution, or pleural thickening. Histologically, lung adenocarcinoma is defined as a cancerous epithelial tumor with glandular differentiation or mucin secretion.[20]

Most EGFR mutations-positive NSCLC patients are diagnosed at stage IVA. These results are in line with those of Setiawan et al. in Malang, who discovered that, 54.71% of patients with NSCLC and positive EGFR mutations had a stage IVA diagnosis.[21] In this study, 55.2% of patients received second-generation TKI therapy, while 44.8% received first-generation therapy. In the second-generation group, all patients received afatinib treatment. Among the first-generation group, 37 patients were administered erlotinib, and 6 patients were given gefitinib. In contrast, a study by Wu et al. in China found that patients with NSCLC who have positive EGFR mutations were treated with gefitinib (71.1%), erlotinib (25.7%), and afatinib (3.2%).[18]

Compared to patients treated with first-generation TKIs, those with EGFR-positive NSCLC who received second-generation TKIs exhibited a longer median PFS, MST, and OS. This findings are similar to those of the LUX-Lung 7 study, which showed that afatinib had a better PFS rate than gefitinib because it had a broader inhibitory profile. This broader profile aids in postponing resistance processes, particularly in cases of Leu858Arg mutation and exon 19 deletion.[22] Kim et al. similarly reported that the median PFS durations for afatinib, gefitinib, and erlotinib were 19.1, 13.7, and 14.0 months, respectively.[11] Additionally, Brzozowska et al. discovered that afatinib had a median OS of 22.8 months, longer than erlotinib (17.8) and gefitinib (15.5).[12] Gefitinib and erlotinib are first-generation TKIs that bind to and block EGFR signaling in a reversible manner, whereas afatinib is a second-generation TKI that inhibits ErbB family receptors (EGFR/ErbB1, HER2/ErbB2, ErbB3, and ErbB4) irreversibly. Gefitinib and afatinib are two TKIs that are widely preferred over chemotherapy for NSCLC patients who have EGFR mutations. These TKIs exhibit significantly higher response rates, prolonged PFS, and enhanced quality of life. Afatinib has demonstrated higher efficacy than gefitinib, with a PFS of 11 months and an OS of 27.9 months in contrast to gefitinib's 24.5 months.[17]

The initial TKI is gefitinib, which attaches to the enzyme's ATP binding site. Similarly, erlotinib, another first-EGFR TKI, inhibits the formation of phosphotyrosine residues and the associated downstream signaling pathways. In contrast, afatinib achieves irreversible inhibition of ATP binding through the formation of covalent bonds and has demonstrated efficacy in preclinical studies against mutations such as Thr790Met.[22] Afatinib irreversibly binds to all ErbB receptors (EGFR, ErbB2, ErbB4) due to its covalent attachment to the EGFR C797 site, resulting in irreversible EGFR tyrosine kinase inhibition.[23] The activity of afatinib has been shown to target both activating EGFR mutations and wild-type EGFR. It also shows efficacy against the exon 20 T790M mutation at higher concentrations, the leading cause of secondary resistance to first-generation EGFR TKIs.[16]

The superior efficacy of afatinib in contrast to first-generation TKIs is due to the irreversible inhibition of ErbB, leading to better tumor control and prolonging PFS and OS in EGFR mutations-positive NSCLC patients.[17] Survival in NSCLC patients treated with EGFR TKIs was not correlated with age, gender, occupation, smoking, or the location of the EGFR mutation. These factors were not confounding variables in the relationship between TKI generation and patient survival.

CONCLUSION

The research was carried out retrospectively and experienced limitations related to incomplete data. This study only examined the effectiveness of TKI and did not examine the side effects. Sixty-seven patients diagnosed with NSCLC and positive EGFR mutations were included. Second-generation TKIs significantly improved PFS, Median Survival Time, and OS than first-generation TKIs, with a p-value of <0.05. Conclusion: EGFR TKI in the second generation is more effective than the first TKI in NSCLC.

DECLARATIONS

This study adhered to the procedures and ethics guidelines of The Health Research Ethics Committee of Universitas Sumatera Utara. Ethical clearance certificate issued by the committee is No. 148/KEPK/USU/2024.

CONSENT FOR PUBLICATION

The Authors agree to publication in Journal of Society Medicine.

FUNDING

None

COMPETING INTERESTS

The authors declare that there is no conflict of interest in this report.

AUTHORS’ CONTRIBUTIONS

All authors significantly contribute to the work reported execution, acquisition of data, analysis, and interpretation, or in all these areas. Contribute to drafting, revising, or critically reviewing the article. Approved the final version to be published, agreed on the journal to be submitted, and agreed to be accountable for all aspects of the work.

ACKNOWLEDGMENTS

None

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