Introduction
Lung cancer is one of the most common malignancies in the world, with non-small cell lung cancer (NSCLC) accounting for 85% [
1]. Currently, the most established target is the epidermal growth factor receptor (EGFR), a member of the ErbB kinase family of structurally related receptor tyrosine kinases. In human, the ErbB family consists of EGFR (HER1, ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) [
2]. The prevalence of EGFR mutation is 50% in Asian patients with NSCLC [
3].
NSCLC with EGFR mutations is recommended to treat with molecular target therapy with EGFR-tyrosine kinase inhibitors (TKIs) [
4‐
8]. Recently, a phase III FLAURA trial revealed that osimertinib has better progression-free survival (PFS) than the first-generation EGFR-TKIs (gefitinib and elrotinib) [
9]. Afatinib, a second-generation EGFR-TKI, irreversibly blocks signaling through not only EGFR but also HER2 and ErbB4 [
10,
11]. In two pivotal phase III studies, afatinib showed better PFS than standard platinum-based chemotherapy [
8,
12]. In subgroup analysis of Lux-lung 3 and Lux-lung 6 trials, afatinib provided a better overall survival (OS) benefit than standard chemotherapy [
12]. The OS benefit with afatinib could be associated with its potential advantages in targeting the entire ErbB family rather than EGFR alone. In addition, Lux-lung 7 study revealed that afatinib might offer improved PFS compared with gefitinib [
13].
Preclinical data suggested that afatinib is more active than first-generation EGFR-TKIs in NSCLC that acquired resistance to gefitinib or erlotinib [
14]. Lux-lung 1 study, which examined the efficacy of afatinib in a re-challenge setting, did not show significant improvement in the OS, although the EGFR mutation status of the study subjects was not shown [
15]. The efficacy of re-challenge treatment with afatinib for patients with EGFR-mutated metastatic NSCLC previously responsive to first-generation TKIs has not been clear. Here, we report a real-world data of afatinib in first-line or re-challenge settings for Japanese patients with EGFR mutant NSCLC.
Discussion
This is one of the largest real-world studies that evaluated the efficacy of afatinib for patients with advanced NSCLC harboring EGFR mutations in both the first-line and the re-challenge settings. In the first-line setting, we revealed afatinib provided PFS of 17.8 months and OS of 39.5 months, which were longer than the numbers shown in Lux-lung 3 (11.1 months and 33.3 months, respectively), Lux-lung 6 (11.0 months and 31.4 months, respectively), and Lux-lung 7 (11.0 months and 27.9 months, respectively) studies [
8,
13,
16]. Recently, Liang and colleagues evaluated the real-world efficacy of afatinib in patients with EGFR mutations in Taiwan and reported that median PFS and OS were 12.8 and 36.7 months, respectively [
17]. Although the OS was close to our data, the PFS was longer.
A third-generation EGFR-TKI, osimertinib, has recently been compared with gefitinib or erlotinib in the global phase III FLAURA trial [
9]. The median PFS was 18.9 months in the osimertinib arm, although OS data are currently immature. However, second-generation EGFR-TKIs were not included in the comparator arm, which made it difficult to draw conclusions regarding potential benefits of osimertinib over afatinib or dacomitinib in the first-line setting. In our study, the PFS data were comparable to that of osmertinib shown in the FLAURA trial. Moreover, in an observational study, Hochmair and colleagues reported long OS outcome in patients with EGFR mutation-positive NSCLC receiving sequential afatinib and osimertinib, especially in those with exon 19 deletion (30.3 months [90% CI 27.6–44.5]) or Asian (46.7 months [90% CI 26.8-not reached]) [
18]. They suggested that first-line afatinib followed by osimertinib in patients with NSCLC who acquire T790 M might be a feasible therapy.
In our study, which included elderly patients (31.6%), there were no differences in median PFS and OS between younger patients and elderly. There have been a few reports that prospectively evaluated the efficacy and safety profile of afatinib in the elderly patients. Imai and colleagues recently reported the first study of afatinib (30 mg/day) for the elderly (70 ≤) patients harboring sensitive EGFR mutations. The median PFS was 12.9 months [
19]. Our data of the PFS in elderly were 15.4 months. Paz-Ares and colleagues reported that there was no difference in OS among patient subgroups and that similar median OS was seen at cutoffs of 60, 65, 70, and 75 years old [
13,
20]. Moreover, we previously reported the phase I trial of afatinib for elderly patients (75 ≤). Although dose reduction rate of afatinib was high, the response rate was as high as 73.3% and PFS was 22 months (95% CI 13.1- not reached) [
21].
The most frequent drug-related AEs in the current study were diarrhea, rash, paronychia, and oral mucositis, which were main reasons for the dose modification. However, the dose reduction did not affect the efficacy of afatinib. Preferably, the patients with dose reduction showed even longer PFS than those without dose reduction. In our study, interstitial lung disease was observed in 5.7%, which was similar to the numbers in previous reports [
21].
In the present study, two patients with G719X, one of minor mutations of EGFR gene, were included and their median PFS was 7.8 months, although the sample size was too small to discuss the efficacy of afatinib for NSCLC with minor mutations. EGFR mutations G719X and L861Q are found in approximately 3% and 2% in NSCLC with EGFR mutation, respectively [
22]. In a retrospective study that included 16 patients with minor mutations, first-generation EGFR-TKIs provided the median PFS of 1.5 months and the RR of 25.0% [
23]. Yang and colleagues reported the efficacy of afatinib in 38 patients with advanced NSCLC harboring minor mutations. The RR was 71.1%, and the median PFS and OS were 10.7 and 18.6 months, respectively [
24]. These data suggest that, in NSCLC patients with minor mutations, afatinib may have greater efficacy than first-generation EGFR-TKIs.
In the re-challenge setting, the RR was 25%, and 29 patients (55.9%) had SD. The median PFS was 8.0 months (95% CI 4.9–9.5). We summarized 4 prospective studies and 1 retrospective study that evaluated the efficacy of afatinib on NSCLC patients in whom prior EGFR-TKIs failed (Table
4). The Lux-lung 1 investigated the efficacy of afatinib in patients who had PD after first-generation EGFR-TKI, which showed improvement of a median PFS in those treated with afatinib without improvement in the OS. EGFR mutation status was not evaluated in the Lux-lung 1 study [
25]. Lux-lung 4 study was a phase II trial in Japan, which evaluated the efficacy of afatinib monotherapy as the in third- or fourth-line treatment in patients with NSCLC who had PD while receiving erlotinib and/or gefitinib treatment. The ORR was 8.2%, which did not meet the primary endpoint, and the median PFS was 4.4 months [
26]. In another prospective study, Lee and colleagues reported afatinib might offer improved PFS and ORR compared with erlotinib in Chinese patients [
27]. Other studies also showed that afatinib provided approximately 4 months of PFS [
28,
29]. Our study showed better PFS compared to these previous reports.
Table 4
Summary of previous trials
LUX-Lung1 (25) (n = 585) prospective | Afatinib vs Placebo | NE | 7% vs < 1% | 3.3 vs 11.1 |
LUX-Lung 4 (26) (n = 62) prospective | Afatinib | 72.6% | 8.2% | 4.4 |
Lee et al. (27) (n = 53) prospective | Afatinib vs. erlotinib | 100% | 20% vs 7.1% | 4.1 vs 3.3 |
Chang et al. (28) Retro (n = 205) | Gefitinib Afatinib Erlotinib | 100% | 7.3% | 4.1 |
Schuler et al. (29) prospective (n = 325) | Afatinib | 100% | NE | 4.6 |
Present Study | Afatinib | 100% | 25% | 8.0 |
In our study, 14 patients (26.9%) received afatinib as the second line treatment. Twelve patients (85.7%) of them discontinued prior EGFR-TKI treatment due to toxicity, which might be one of the main reasons for their long PFS.
Chemotherapy has been a common option for the patients who had PD for EGFR-TKI. In the previous clinical trials, ORR ranged about 8.8–22.9% and median PFS was 2.9–4.5 months for patients who received chemotherapy [
30,
31]. The hematologic adverse effects were more common in chemotherapy. Considering the efficacy and toxicity, afatinib could be a treatment choice as salvage therapy.
In our clinical practice, osimertinib has been used in the first-line treatment for EGFR mutant NSCLC. The efficacy data of the first- or second-generation EGFR-TKIs for patients with T790 M negative NSCLC who had PD after osimertinib is needed.
The present study has some limitations. First, because our study was retrospective, the schedule of image inspection of tumor was not determined, which might affect the PFS estimation. Second, efficacy measurements were not taken by central review but by each investigator. Finally, as we collected the data before approval of osimertinib in Japan, T790 M mutation was not examined. Since T790 M positive patients are currently treated with osimertinib, re-challenge data in patients with T790 M negative NSCLC will be required.
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