Introduction

Lung cancer is a disease that has a high incidence and death rate in the world. Indonesia, in 2018, the highest lung cancer incidence rate in men is 19.4 per 100,000 population, with an average death rate of 10.9 per 100,000 population (Bray et al., 2018).

Non-Small Cell Lung Cancer is the most common type of lung cancer. About 85% of the NSCLC incidence of lung cancer overall and 80% of NSCLC cases are patients with advanced-stage (Stage IIIB / IV) (Chouaid et al., 2014). Epidermal growth factor receptor mutations (EGFR) are often found in advanced NSCLC patients; there are 10-15% of cases in western countries and up to 50% in Asian countries (Shi et al., 2015). First-line therapy used in the treatment of NSCLC with EGFR mutations based on the National Comprehensive Cancer Network (NCCN), namely the tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib (first generation), afatinib (second generation) (Ettinger, Govindan, & Martins, 2017).

Tyrosine Kinase Inhibitors in the first generation have a mechanism of action that reversibly binds and inhibits EGFR signals, whereas in the second generation it can inhibit the family of erythroblastosis oncogene B (ErbB) which irreversibly inhibits signals from all homo-dimers and hetero-dimers of the ErbB family receptor (EGFR) / ErbB1, HER2 / ErbB2, ErbB3 and ErbB4) (Chi, Remick, & Tse, 2013; Solca et al., 2012). TKIs groups such as gefitinib (first generation) and afatinib (second generation) show a progression Free Survival (PFS) and Overall Survival (OS) that are superior to platinum-based chemotherapy (Ellis, Coakley, Feld, Kuruvilla, & Ung, 2015; Liang et al., 2014).

One that can affect PFS and OS is patient characteristics such as gender, smoking status, mutation type, and comorbidities. Female sex, never smoking, exon 21 (L858R), and deletion 19 are very responsive to the TKIs group that leads to an increase in PFS, whereas comorbidities can affect OS as first-line therapy (Inoue et al., 2013; Mitsudomi et al., 2010).

Several studies related to the efficacy of afatinib and gefitinib in the Lux-Lung 7 study and meta-analysis, show that afatinib is superior to gefitinib in both PFS and OS, and quality life (Li, 2014; Liang et al., 2014; Park et al., 2016; Paz-Ares et al., 2017; Sari, Andayani, Endarti, & Widayati, 2019) and research related to effectiveness in daily clinical practice seen retrospectively also shows that PFS TKIs (gefitinib and erlotinib) are superior to other chemotherapy (Xu et al., 2016; Xu, Liu, Yang, Zhang, & Shi, 2017), however data regarding the effectiveness of gefitinib and afatinib specifically in daily clinical practice is still limited, especially in Indonesia. The effectiveness data can describe the results or performance of an intervention (treatment) in daily clinical practice or the real world, in contrast to the efficacy data that illustrates the outcome or performance of intervention in ideal conditions. Effectiveness data can also be used to provide recommendations to policymakers about whether or not a health technology is necessary (Drummond, Sculpher, Torrance, O’brien, & Stoddart, 2005). Need to do effectiveness research related to the use of afatinib and gefitinib in NSCLC patients who have EGFR mutations, which aims to provide an overview of the effectiveness of afatinib and gefitinib in daily clinical practice as first-line therapy.

Materials and Methods

Subject

This study was a retrospective observational study, by looking at the medical records of NSCLC patients with EGFR mutations using afatinib and gefitinib therapy at Dr. Sardjito General Hospital Yogyakarta and Dr. Kariadi General Hospital Semarang, Java, Indonesia in the January 2016 - March 2019 period. The sample in this study was balanced between the two groups based on age, gender, type of mutation, comorbidities, and duration of treatment that had previously fulfilled the inclusion and exclusion criteria. As for the inclusion criteria in this study were patients aged 18 years who were both hospitalized and outpatient who received gefitinib and afatinib as first-line therapy, as well as patients with advanced stages (IIIB / IV), while exclusion criteria were patients whose medical records were incomplete, contraindications to treatment, first-line treatment using platinum-based chemotherapy, as well as patients who used afatinib and gefitinib for less than four weeks.

Data Collection and Analysis

Retrieval of patient data is done by reviewing the patient's medical record to see the effectiveness of treatment therapy and patient characteristics (age, gender, type of mutation, duration of treatment, and comorbidities). The effectiveness measured is Progress Free Survival/PFS (the time from being diagnosed until the development of the severity of the disease or recurrence is clinically proven and imaging or cytology examination of tissue and Overall Survival/OS (the time from being diagnosed to death). Effectiveness was analyzed using the Kaplan Meier test to obtain patient survival, and using the Chi-Square test to see the distribution of patient characteristics data, and Mann-Whitney test, Kruskal-Wallis test, and ANNOVA test to see the effect of patient characteristics on the effectiveness of treatment therapy.

Ethical Considerations

This study has received ethical approval from the Medical and Health Research Ethics Committee (MHREC) Faculty of Medicine, Gadjah Mada University Indonesia, with reference number KE/FK/0948/EC/ 2018 and the Health Research Ethics Committee of Dr. Kariadi General Hospital with number 033/E / KEPK -RSDK-2018.

Results and Discussion

113 NSCLC EGFR mutation patients met the inclusion and exclusion criteria. On average, patients affected by NSCLC EGFR mutations aged 51-60 years (38.9%), all of whom were advanced stage IIIB / IV patients. The most common gender was patients with a female (56.6%), while the male was 43.4%. The most common type of mutation was exon 19 (56.6%), while the least was exon 18 (3.5%). The most common comorbid based on Charlson Comorbidity Index (CCI) is a score of 1 (37.2%) such as peptic ulcer disease, while the least with a score of 2 (28.3%) such as diabetes mellitus, peptic ulcer disease, and hemiplegia. Regarding the duration of treatment, the average length of treatment of patients was highest at the duration of treatment <90 days by 43.4%. There is no significant difference between the characteristics of patients using afatinib and those using gefitinib. This can be seen from Table 1, showing that a significance value > 0.005 for age, gender, mutation, comorbidities, and duration of treatment.

Figure 2; Figure 1. This is consistent with the LUX-Lung 7 phase 2B clinical trial research and a meta-analysis has been found that afatinib has a longer PFS than gefitinib and is significantly (p <0.005) superior to gefitinib (11 months vs. 10.9 months) (Liang et al., 2014) (Park et al., 2016) (Krawczyk et al., 2017; Shen et al., 2017). Afatinib can irreversibly block ErbB more effectively than reversible inhibition of EGFR on gefitinib in the treatment of NSCLC with EGFR mutations. The mechanism of action of afatinib, which is broader and irreversible, can result in better tumor control to prolong the PFS of NSCLC patients with EGFR mutations (Park et al., 2016; Xu et al., 2017). However Overall Survival on afatinib was not so better compared to gefitinib and did not differ significantly (P = 0.302). This can be seen in Table 3; Table 2.

Based on Lux-Lung 7, research that has been done shows that afatinib OS is better than gefitinib, although it is not significantly different (P> 0.2580) (Paz-Ares et al., 2017). The low value of OS afatinib in this study is likely due to patients who have less OS than gefitinib. Besides, overall survival can also be influenced by the chemotherapy used, disease progression, or tumor/cancer progression, and have a better prognosis with radiotherapy (Warth et al., 2012).

The progression of free survival in gefitinib and afatinib is not influenced by age, gender, type of mutation, or comorbid, but it is influenced by the duration of treatment. This can be seen in Table 4. This is consistent with research conducted by Otsuka et al. There is no correlation between patient characteristics with PFS and OS (Otsuka et al., 2015). Similar to OS in afatinib, it is only affected by the length of treatment. OS patients who get afatinib will be longer than those who get gefitinib, especially in the subpopulation of patients with Deletion 19 and Exon 21 (Park et al., 2016), and gefitinib is also influenced by the length of treatment and comorbidities. Comorbidity has the potential to reduce overall survival, progression-free survival, and mortality compared to patients who do not have comorbidities (Chiang et al., 2002; Dima, Chen, Wang, Wang, & Teng, 2018). This is due to the lack of observation of the early symptoms of the disease that can be observed at an early stage, whereas on average in lung cancer patients are often diagnosed at an advanced stage whose treatment is limited so that it impacts on the patient's survival rate (Chang et al., 2015; Chiang et al., 2002). Comorbidity can also disguise the symptoms of cancer, which can cause delays in diagnosis but can also influence the choice of treatment, which indirectly prevents patients from receiving aggressive lung cancer treatment (Iachina, Green, & Jakobsen, 2014) But for the type of mutation and gender, based on previous research, shows that mutations can affect the effectiveness of afatinib and gefitinib. atients with Exon / Del 19 mutations, showed an average afatinib OS better than gefitinib (30.7 months vs. 26.4 months), and in patients with L858R / Exon 21 mutations (25.0 vs 21.2 months), and in patients with female sex are also very responsive to the TKIs group that leads to an increase in PFS (Mitsudomi et al., 2010; Vyas, Dudek, & Gtazewski, 2017), however, the results of this study do not have the effect of mutations in PFS or OS.

Weaknesses in this study are the limitations in the number of samples so that it might affect generalization. Besides, the effectiveness measured in the study is coprimary endpoint (PFS and OS) without looking at the secondary endpoint (objective response rate and symptom reduction).

Conclusions

Afatinib has progression-free survival that is superior to gefitinib, but not to overall survival as first-line therapy in NSCLC patients with EGFR mutations. Conflict of Interest

The author declares that there is no conflict of interest.