Population aging is increasing more rapidly than in the past. According to the World Health Organization, the proportion of the world’s population aged > 60 years will nearly double from 12% to 22% between 2015 and 2050 [1]. In South Korea, lung cancer ranks third after thyroid and colorectal cancers; however, it is the most prevalent cancer type among individuals aged ≥ 65 years [2]. Moreover, 66.4% of patients newly diagnosed with lung cancer are aged ≥ 65 years in South Korea, which is consistent with global data [2,3].

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been the preferred treatment regimen for advanced EGFR-mutant non-small cell lung cancer (NSCLC) since the FLAURA trial [4]. However, several first- and second-generation EGFR-TKIs, including afatinib, continue to be used as the first-line standard of care for many patients [5,6]. In addition, afatinib is the preferred option for uncommon EGFR mutations, such as S768I, L861Q, and G719X [6].

Afatinib, an irreversible ErbB family blocker used as a second-generation EGFR TKI, has been approved for its efficacy in pivotal clinical trials of the LUX-Lung series [7-9]. The most common treatment-related adverse events (AEs) observed with afatinib include diarrhea, rash/acne, stomatitis/mucositis, and paronychia. Due to its irreversible binding to the EGFR, the rate of AEs for all grade AEs of afatinib is generally higher than that of first-generation EGFR TKIs [5]. Dose adjustments were recommended based on predefined tolerability criteria. A post-hoc analysis in the phase III LUXLung 3 trial showed that dose reductions occurred in 53% (122/229) of patients and the majority (86%) within the first six months of treatment [8,10]. Dose reduction tends to be more common in female patients, older patients, patients of Eastern Asian ethnicity, and patients with lower body weight [11].

The number of older patients is increasing; however, no prospective EGFR-TKI trials have been conducted specifically in older patients. Therefore, subgroup analyses from prospective studies and extensive real-world data relative to this population are required. In this study, we investigated the efficacy and safety of first-line afatinib treatment in older patients with advanced EGFR-mutated NSCLC using real-world data.

In our study involving older patients, the median TOT was 13.6 months (95% CI 11.0–16.2), and the median PFS and OS were 15.7 (95% CI 11.2–20.2) and 35.5 months (95% CI 26.9–44.1), respectively. This result is consistent with that of previous prospective studies [7-9,12]. An observational real-world study recently described the efficacy of afatinib in older patients. The GIDEON study was conducted in Germany and involved patients with EGFR-positive NSCLC who received first-line treatment with afatinib [13]. The authors conducted a subset analysis of older patients (≥ 70 years of age) and reported the efficacy and safety of first-line treatment with afatinib compared with those of patients aged < 70 years. The median PFS and OS (17.2 and 30.4 months, respectively) in patients aged ≥ 70 years were similar to those in our study [14]. Therefore, the antitumor effects of afatinib are independent of age. In 2021, real-world data on afatinib was presented by 15 centers in South Korea, and the updated survival data of this study were published in 2023 (median PFS: 20.2 months, median OS: 48.6 months) [15,16]. In our study, we observed a median PFS of 15.7 months and an OS of 35.5 months. The potential reasons for these differences may include the larger cohort size (n = 422) used in the previous multicenter Korean study, with a mean age of 63.8 years [15,16]. Moreover, in the earlier study, the frequency of the 19del mutation, one of the most prominent prognostic factors for EGFR-TKIs, was 59.0% [15,16]. In contrast, our study focused on patients aged 75 years and older, with a mean age of 80 years, and the frequency of the 19del mutation was relatively lower at 43.7%. However, when analyzing efficacy outcomes specifically in patients with the 19del mutation in our study, we observed a PFS of 23.5 months and an OS of 35.5 months, which is comparable to the results from the multicenter Korean study. These findings suggest that factors such as age and mutation frequency influence survival outcomes.

In this study, the median PFS (15.7 months) was slightly longer than the median TOT (13.6 months). This suggests that some cases of afatinib termination were due to toxicity or other reasons, despite which patients continued to have durable benefits, and in other patients, they were treated well beyond progression, based on the decision by the attending physicians, which likely contributed to the extension of TOT. This approach may have allowed continued clinical management even after disease progression, potentially explaining the relatively prolonged TOT compared to PFS.

The frequency and severity of afatinib-related AEs in our study population were similar to those reported in previous studies [7-9,12]. However, the frequency of dose modification due to AEs was higher (89%) in this study than in the LUX-Lung 7 study, in which 42% of patients underwent dose modification [7,12]. Certain trials included an older cohort, such as the EURTAC trial [17] and the BR.21 study [18], which indicated that EGFR-TKIs improved survival but yielded a worse AE profile in older patients. In the older cohort of the BR.21 study, older patients experienced significantly more overall and severe (grade 3 and higher) toxicity than younger patients and were more likely to cease treatment owing to treatment-related AEs [19]. In South Korea, starting doses of afatinib of 40 and 30 mg are allowed in clinical practice. No significant differences in efficacy between the two starting doses were observed in this study; however, the frequency of dose reduction was significantly higher in the 40 mg starting dose group. Therefore, we suggest that a starting dose of 30 mg is a good treatment strategy for older patients.

In the current study, re-biopsy was performed in 43 patients (58.1%); however, tissue re-biopsy was performed in only 18 patients (24.3%). Among the patients who underwent tissue re-biopsy, six patients (33.3%) harbored the T790M mutation. In only three patients (10.3%), T790M-positivity was detected among the 29 blood samples. This is consistent with previous data showing that plasma samples have a lower sensitivity for T790M mutation detection than tissue samples [20].

Thirty-four patients (45.9%) received their anticancer therapy after discontinuation of afatinib. All patients with documented T790M mutations (n = 9) were treated with third-generation EGFR TKIs. Therefore, we suggest thorough tissue re-biopsy even in older patients. Among the 25 patients who received cytotoxic chemotherapy, 21 (84.0%) were administered pemetrexed monotherapy, whereas only four received platinum-based chemotherapy. In the FLAURA study, 48% of patients in the osimertinib group received subsequent treatment, and most patients (90/133) received chemotherapy. Among patients treated with chemotherapy, 93% (84/90) received platinum-containing chemotherapy [21]. Thus, older patients who were not positive for the T790M mutation tended to be undertreated, indicating that subsequent therapies may not provide a survival benefit in this population.

This study has several limitations. First, this was a retrospective study with an inevitable bias. Second, this study had a relatively small number of enrolled patients, and certain patient characteristics, such as a relatively higher proportion of stage III and L858R mutations and initial brain metastases, could have influenced the results. Third, several factors influencing the decisions of the physician, such as the starting dose of afatinib, may have played a role in patient management. Fourth, although 75 years of age was chosen as the reference point in this study, the optimal reference point for older patients remains unclear. Finally, the frequency and severity of afatinib-related AEs in our older study population were similar to those of previous prospective studies that did not target older patients, which might be underestimated owing to the retrospective nature of the study.

In conclusion, this study supports the efficacy of first-line afatinib treatment for EGFR-mutant NSCLC in older patients. However, the dose modification frequency was higher in this population despite the similar frequency and safety profiles of AEs reported in other studies. A 30 mg starting dose of afatinib and a predefined dose adjustment may be suitable strategies for the older population. Post-TKI management, such as tissue re-biopsy and platinum-based chemotherapy, tended to be underprescribed in this age group. Proactive management is considered necessary, particularly for older patients with good performance status.