Introduction
Lung cancer continues to be one of the most widespread and fatal cancers globally [
1]. Treatment strategies for advanced non-small cell lung cancer (NSCLC) are now personalized and guided by molecular tests. Studies show that patients with specific mutations in lung adenocarcinoma who receive matched targeted therapies experience longer overall survival (OS) [
2].
EGFR mutations, found in 30 to 50% of lung adenocarcinomas, commonly include exon 19 deletions (in 45% of patients) and the exon 21 L858R mutation (in 40% of patients). These are known as sensitizing
EGFR mutations [
3]. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have greatly improved the prognosis and quality of life for NSCLC patients with
EGFR mutations, making them the first-line standard treatment over cytotoxic chemotherapy [
4]. Three generations of EGFR-TKIs are available. First-generation EGFR-TKIs (erlotinib and gefitinib) reversibly block ATP-binding sites, stopping downstream signaling. Second-generation EGFR-TKIs (afatinib and dacominitib) form irreversible bonds with ErbB receptors, inhibiting signaling and offering an alternative for acquired resistance to first-generation TKIs. Third-generation EGFR-TKIs (osimertinib) treat T790M
EGFR-mutant tumors, which represent the most common resistance mechanism, occurring in approximately 50% of patients who have used first- and second-generation EGFR-TKIs [
5].
The selection of these three generations of drugs as first-line treatment is an important issue. In the case of first-generation EGFR-TKIs, several studies demonstrated that gefitinib and erlotinib had comparable efficacy, with gefitinib exhibiting a more favorable safety profile than erlotinib [
6‐
8]. In the LUX-Lung 7 study, the irreversible ErbB family blocker afatinib notably improved results in
EGFR-mutated NSCLC treatment-naive patients compared to gefitinib [
9]. Dacomitinib, another irreversible ErbB family blocker, significantly enhanced progression-free survival (PFS) compared to gefitinib in the first-line treatment of
EGFR mutation-positive NSCLC patients [
10]. In the FLAURA study, first-line osimertinib treatment provided a clinically significant improvement in both PFS and OS compared to first-generation EGFR TKIs [
11,
12]. The new generation of EGFR-TKIs appears to offer better clinical efficacy than first-generation EGFR-TKIs. However, there have been no randomized controlled trials (RCTs) comparing second- and third-generation EGFR-TKIs. A few real-world studies do not strongly favor osimertinib over afatinib in terms of longer median PFS and OS in first-line treatment [
13,
14]. Osimertinib was effective in patients with brain metastasis, while afatinib demonstrated potential benefits in patients with the L858R mutation who did not have brain metastasis [
14]. Since subsequent treatment after the failure of third-generation EGFR-TKIs is not well established, sequential afatinib and osimertinib showed promise in Asian NSCLC patients with
EGFR mutations and T790M-mediated resistance, especially in those with Del19-positive disease [
15]. Therefore, using second-generation EGFR-TKIs as a first-line follow-up to third-generation EGFR-TKIs remains a favorable treatment option. In addition to assessing medication efficacy and determining subsequent treatment strategies, factors such as patients’ tolerance to medication side effects, for example, the higher toxicity of second-generation EGFR-TKIs, and regulations within each country’s healthcare system regarding medications, for instance, the limited coverage of third-generation EGFR-TKIs, as well as physicians’ medication preferences can influence first-line treatment decisions.
There is currently limited research comparing these 2 second-generation EGFR TKIs. Li et al. [
16] reported that in patients with NSCLC carrying uncommon
EGFR mutations, dacomitinib displayed more favorable activity with manageable toxicity and distinct progression patterns compared to afatinib. To the best of our knowledge, there are currently no studies comparing the clinical treatment outcomes of these 2 second-generation EGFR-TKIs in NSCLC patients with common EGFR mutations. The purpose of this study was to compare the therapeutic effectiveness and adverse effects of afatinib and dacomitinib in NSCLC patients with common
EGFR mutations.
Discussion
This study is the first to explore the clinical effectiveness of dacomitinib and afatinib in Taiwanese NSCLC patients with common EGFR mutations. Our findings reveal that both afatinib and dacomitinib treatment achieved comparable median PFS and TTF in real-world practice. Afatinib and dacomitinib have slightly different drug side effects. Furthermore, no disparity in median PFS and TTF was observed between the standard and reduced dose groups. Among patients, there was no significant difference in median PFS and TTF when comparing elderly (age ⩾75 years) and younger individuals (age < 75 years) receiving 2nd generation EGFR-TKIs as first-line treatment.
Dacomitinib and afatinib, both second-generation EGFR-TKIs, irreversibly disrupt the signaling of the pan-Erb B family of receptors [
21,
22]. In vitro studies show that afatinib and dacomitinib have lower 50% inhibitory concentrations against
EGFR-mutant cell lines compared to first-generation EGFR-TKIs such as gefitinib and erlotinib [
23,
24]. Existing evidence supports that in individuals with common
EGFR mutations and NSCLC, 2nd generation TKIs (afatinib or dacomitinib) are associated with improved PFS compared to the 1st generation TKI gefitinib [
9,
10]. Another pooled subset analysis from two randomized trials has shown promising trends, indicating that dacomitinib may offer superior PFS compared to erlotinib, particularly for patients with EGFR activation mutations [
25]. Afatinib outperformed erlotinib as a second-line treatment for advanced squamous cell carcinoma, showing improved PFS and OS [
26]. Huang et al. [
27] confirmed that in real-world practice, afatinib reduced the risk of progression compared to first-generation EGFR-TKIs, with an HR of 0.73 (95% CI 0.57–0.94;
p = 0.017). According to the aforementioned studies, it appears that both afatinib and dacomitinib, both second-generation EGFR-TKIs, exhibit similar efficacy. However, there is a lack of both clinical trials and real-world studies directly comparing the 2 second-generation EGFR-TKIs.
For further clarification of the disparities in clinical efficacy between dacomitinib and afatinib, Li et al. [
16] demonstrated that dacomitinib exhibited a more favorable response with manageable side effects and distinct progression patterns in individuals with NSCLC bearing uncommon
EGFR mutations. In the current study, we found that afatinib and dacomitinib offer comparable PFS and TTF in NSCLC patients with common
EGFR mutations. We did not include uncommon
EGFR mutations in our analysis, so the results differ slightly. Dacomitinib and afatinib exhibited a similar range of adverse events, primarily encompassing rash, diarrhea, oral mucositis, paronychia, and dry skin with itching. In the current study, we observed some differences in side effects between dacomitinib and afatinib. Dacomitinib was associated with a higher incidence of paronychia (58.1% vs. 31.4%;
p = 0.004), whereas afatinib was associated with a greater likelihood of experiencing diarrhea (75.8% vs. 35.5%;
p < 0.001). Li et al. [
16] also found higher rates of grade 1 adverse events with dacomitinib than with afatinib (
p = 0.006). However, grade 3 diarrhea occurred significantly more frequently with afatinib than with dacomitinib (
p = 0.036). This may be related to the initial standard dose of treatment. In this study, dacomitinib was used at a standard dose less frequently than afatinib. However, the study by Li et al. [
16] did not provide information on initial dose and dose adjustments.
Dose reductions were necessary for 53.3% of patients on 40 mg afatinib daily in the LUX-Lung 3 trial and 28.0% in the LUX-Lung 6 trial. Lowering the dose to 30 mg daily reduced ADR incidence while maintaining comparable PFS in subanalyses of these trials [
28]. In the ARCHER 1050 study, dacomitinib dose reduction was necessary in 66% of the patients due to intolerable adverse events [
10]. Dose reductions of dacomitinib also helped manage adverse events, and the PFS and OS benefits remained for patients with dose reductions of dacomitinib [
29]. A meta-analysis also showed that the 30 mg afatinib dose led to fewer severe adverse reactions in NSCLC patients, with comparable effectiveness for those without brain metastasis [
30]. Li et al. [
31] demonstrated that 65.6% of patients who received an initial treatment dose of 30 mg dacomitinib showed favorable responses in NSCLC patients with uncommon
EGFR mutations. In this study, only 29 patients (28.7%) received the initial standard dose of irreversible EGFR-TKIs as their first-line therapy. When comparing the standard doses of the second-generation EGFR-TKIs (40 mg of afatinib or 45 mg of dacomitinib) to the reduced-dose groups, we found that PFS and TTF were similar. This result demonstrates that using reduced doses of second-generation EGFR-TKIs to minimize drug-related side effects helps patients maintain their treatment without interruptions, resulting in better treatment outcomes.
The use of second-generation EGFR-TKIs in older patients is also a noteworthy consideration. In a subgroup analysis of the LUX-Lung 3, 6, and 7 trials, afatinib proved effective and well tolerated in
EGFR mutation-positive NSCLC patients, irrespective of their age at diagnosis [
32]. In the NEJ027 study, dose adjustments (78.9%) were common in older Japanese patients with
EGFR mutation-positive NSCLC, but treatment discontinuation (21.1%) was rare, allowing most to continue treatment for over a year [
33]. Chang et al. [
34] conducted a study to assess the effectiveness of EGFR-TKIs in older patients, including those with a poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), and showed that afatinib as a first-line treatment was associated with a longer PFS. This study also found that using the second-generation EGFR-TKI, the obtained PFS and TTF were comparable in both age groups, those aged 75 and older and those younger than 75. This suggests that second-generation EGFR-TKIs are effective and safe in older patients.
Patients with common
EGFR mutations (such as exon 19 deletions and exon 21 L858R mutations) significantly benefit from EGFR-TKIs; common
EGFR mutations constitute over 85% of cases, while uncommon
EGFR mutations (within exons 18–21) make up the remaining 10–15% [
35]. Recent developments in NGS show that approximately 10% of patients have compound
EGFR mutations, meaning multiple distinct
EGFR genetic changes initially [
36]. Kohsaka et al. [
37] reported that
EGFR compound mutations were detected in 15.9% of 390
EGFR-mutated NSCLC specimens. Notably, L858R exhibited a higher rate (19.5%) than Del19 (4.7%).Patients with compound
EGFR mutations tend to be less responsive to TKI therapies than those with a single
EGFR mutation [
38,
39]. Yang et al.’s [
40] studies confirmed afatinib’s efficacy in NSCLC with major uncommon mutations (G719X, S768I, L861Q). Li et al. [
16,
31] reported dacomitinib’s efficacy in NSCLC patients with uncommon
EGFR mutations, both in first-line and later-line treatments. Our study found that patients with L858R and Del19 mutations had comparable PFS when receiving second-generation EGFR-TKIs as first-line treatment. This suggests that L858R patients, who may have compound mutations, might benefit from second-generation EGFR-TKIs for improved treatment outcomes.
Although our study is the first study in Taiwan comparing afatinib and dacomitinib in NSCLC patients with common EGFR mutations, it does have several limitations. First, this study is limited by being single center-based in Taiwan and by its retrospective design, potentially introducing more bias compared to prospective studies. Therefore, our results might not be applicable to different ethnic groups. Second, due to the relatively small sample size in our study, we need to interpret the data from subgroup analyses with caution. Third, the clinical physicians determined the initial administration and dosage of second-generation EGFR-TKIs, representing another potential bias in our study. Consequently, only 28.7% of the patients received the standard dosage of EGFR-TKIs, potentially affecting treatment efficacy and side effects. Finally, the rate of T790M mutation and subsequent treatment with osimertinib in the dacomitinib group was slightly higher than that in the afatinib group, but it did not reach statistical significance. This could be influenced by whether patients underwent rebiopsy and their willingness to receive subsequent treatment. Despite these limitations, our study provides valuable evidence that another second-generation EGFR-TKI, dacomitinib, offers clinical treatment efficacy similar to afatinib, with slight differences in side effects. However, larger or even prospective studies may be needed to verify the similarities and differences between these two drugs.
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