Lung cancer is the leading cause of cancer mortality world-wide and in South Korea [1,2]. However, the implementation of screening programs, smoking cessation, and advancements in treatment modalities have led to improved survival rates in patients with lung cancer [3,4]. The 5-year relative survival rate in lung cancer patients from South Korea has improved from 12.5% (1993–1995) to 30.2% (2013–2017) [5]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. The discovery of specific driver mutations and application of immunotherapy have served as breakthroughs in the treatment of metastatic NSCLC [5].

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are an important class of agents for the targeted therapy of advanced NSCLC with EGFR-activating mutations [6]. The incidence of EGFR mutations is higher among the Asian population than among the people in Western countries, with the South Korean population displaying high rates, with 34.3% for NSCLC and 43.3% for adenocarcinoma [7]. EGFR mutation positivity is predictive for better overall survival (OS), and EGFR-TKIs have been found to be more effective and better tolerated than chemotherapy [8,9]. Consequently, testing for EGFR mutations is a crucial step in the treatment decision process, and EG- FR-TKIs are the recommended first-line (1L) treatment for patients with EGFR mutation-positive advanced NSCLC [6].

Starting from gefitinib, several EGFR-TKIs have been approved and used in South Korea for the management of EGFR-positive NSCLC based on the positive results of clinical trials. Clinical trials are meticulously designed to evaluate the efficacy and safety of treatments under controlled conditions. They have limitations in that they may not fully reflect real-world patient outcomes [10]. Currently, nationwide data on Korean patients with EGFR-positive NSCLC are lacking. The purpose of this real-world investigation was to describe the treatment outcomes and patterns in patients who received 1L EGFR-TKIs.

In this retrospective cohort study using real-world Korean insurance claims data, we evaluated survival outcomes in 9,478 patients with NSCLC who received 1L first-(1G) or second-generation (2G) EGFR-TKIs. Our study showed that patients with tumors harboring EGFR mutations had a median OS ranging from 23.9 to 28.8 months when treated with the three EGFR-TKIs, which was comparable to the results reported in their randomized clinical trials [12–16]. Similarly, a recent real-world study in the USA (n = 1,029) reported a median OS of 27.2 months (95% CI, 25.9–30.0) in patients in whom 1G or 2G EGFR-TKIs were administered between 2011 and 2018 [17]. In our study, the OS of patients treated with afatinib was longer than that of patients treated with 1G EGFR-TKIs. The LUX-LUNG 7 study, which compared afatinib with gefitinib as 1L treatment, demonstrated that afatinib significantly improved response rate and progression-free survival (PFS), although it was associated with more serious drug-related adverse events and frequent dose reductions [16]. While the improvement in OS with afatinib did not reach statistical significance, younger patients (< 65 years) showed an OS benefit [18]. Based on these findings, the better OS in the afatinib group may be explained by the preferential use of afatinib in fitter patients, such as those who are younger and have a better performance status, in the real-world clinical setting [19].

TTNT and time to treatment discontinuation (TTD) are endpoints used to assess treatment efficacy in real-world oncology data and can serve as proxies for PFS [20]. TTD, also called time on treatment, is defined as the duration from the initiation of the index treatment to the date of treatment discontinuation, regardless of the reason for discontinuation, including toxicity, disease progression, or death [21]. We used TTNT as the endpoint because the HIRA database does not provide information on drug discontinuation and disease progression dates. The median TTNT of 16.4 to 18.8 months in our study was longer than the median PFS of 10–14 months observed in clinical trials using 1G or 2G EGFR-TKIs [6]. Our findings should be interpreted cautiously because TTNT may be longer than real-world PFS [20]. Another explanation for this difference could be that, in clinical practice, EGFR-TKIs are occasionally continued after disease progression, particularly in cases of oligoprogression in which local therapy is employed [22].

Detection of the acquired EGFR T790M mutation is crucial, as it guides subsequent treatment strategies and predicts prognosis [1]. Current therapeutic options in T790M-negative tumors are predominantly limited to cytotoxic chemotherapy with low-response rates. While the T790M mutation is detected, third-generation EGFR-TKIs are the standard of choice for 2L or subsequent treatment. Our study revealed the prognostic significance of acquired T790M mutation. Patients who received osimertinib treatment experienced an increased survival time (> 4 years) compared with those who did not. A recent Korean study showed a median OS of 36.7 months (95% CI, 30.9 to not reached) from the time of initiation of osimertinib [23]. These findings indicate that the detection of the acquired T790M mutation after the failure of 1G or 2G EGFR-TKIs is crucial. Although the T790M mutation accounts for 50% of the resistance mechanisms to early generation EGFR-TKIs [24], our study showed that only approximately 20% of patients received osimertinib as a 2L treatment. This observation can be explained by the fact that 2L osimertinib was approved for insurance coverage in South Korea in December 2017 for patients with EGFR T790M mutation. However, it suggests that identifying the acquired T790M mutation in a real-world clinical setting is challenging. The relatively longer OS observed in patients treated with osimertinib in our study, compared to that of the 1L osimertinib group in the FLAURA study [25], suggests that sequential treatment with early generation EGFR-TKIs followed by osimertinib may be an effective strategy to maximize survival benefits. Identifying patients at diagnosis who are likely to acquire the T790M mutation after early generation TKI treatment could be crucial for selecting personalized treatment approaches. Recent studies indicate that radiomics hold promise in predicting the emergence of the acquired T790M mutation at the time of diagnosis [26,27].

In our study, the use of osimertinib after afatinib resulted in a shorter median TTNT than that observed after gefitinib or erlotinib. Conversely, other studies reported a longer PFS of osimertinib in the afatinib group than in the 1G TKI group [28,29]. Drawing a conclusion regarding the impact of different 1L EGFR-TKIs on the clinical outcome of subsequent osimertinib treatment in patients with acquired T790M mutation is challenging because several factors could affect the efficacy of 2L osimertinib. Recent studies revealed that tumor genomic complexity increased over the course of EGFR-TKI treatment and other resistance alterations co-occurred with T790M mutation during 1L therapy [28,30,31]. These accompanying alterations can affect the response of osimertinib [32]. Clinical features such as age, performance status, and hepatic metastases could be associated with outcome in patients receiving 2L osimertinib [23,33,34]. It is crucial to acknowledge the possibility of differences in these molecular and clinical features that could influence the efficacy of osimertinib between treatment groups. The limitation of our study is that we could not incorporate such detailed information into the analysis due to its unavailability in the HIRA database.

Currently, no optimal chemotherapy regimen has been established for patients with T790M-negative metastatic NSCLC whose disease has progressed on early generation EGFR-TKIs [35]. Platinum doublet chemotherapy, including pemetrexed and carboplatin, is considered one of the treatment options for eligible patients. In our study, pemetrexed monotherapy was the most commonly used regimen because the combination of pemetrexed and platinum was not covered by the insurance system until October 2019. Interestingly, a recent study comparing the effectiveness of pemetrexed plus cisplatin with pemetrexed alone in patients with an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 who have failed 1L EGFR-TKIs revealed that there were no statistically significant differences in terms of PFS and OS between the two treatment arms [36].

Osimertinib has been shown to result in significantly longer PFS and OS than 1G EGFR-TKIs in patients with common EGFR mutations (exon 19 deletion or L858R mutation), making it a preferred option for 1L treatment in EGFR-mutant NSCLC [37]. A recent real-world study based on a US claims database revealed that osimertinib has become the most commonly prescribed 1L EGFR-TKI since 2018 [38]. However, this situation differs in South Korea. The 1L treatment of osimertinib was approved in December 2018, but it was not covered by the national insurance until January 2024. Consequently, we were unable to obtain real-world data on the use of osimertinib in a 1L setting. Notably, data supporting superior OS associated with 1L osimertinib therapy could not be obtained in the Asian subset analysis of the FLAURA trial [25] and the FLAURA China study [39]. Therefore, future real-world studies evaluating the use of 1L osimertinib are necessary to provide a comprehensive understanding of its impact on long-term outcomes in Korean patients.

In conclusion, our real-world study involving patients with NSCLC who were treated with 1G or 2G EGFR-TKIs revealed a comparable median OS of 23.9 to 28.8 months, consistent with the findings from randomized clinical trials. Our study also highlighted the importance of detecting the acquired T790M mutation after failure of early generation EGFR-TKIs or subsequent chemotherapy, as patients who received osimertinib treatment showed improved survival. Future real-world studies are warranted to evaluate the impact of third-generation EGFR-TKIs, including osimertinib and lazertinib, for 1L treatment and to further understand their long-term outcomes in Korean patients.