The Efficacy and Safety of Afatinib in Non-Small Cell Lung Cancer Patients with Brain Metastasis: A Meta-Analysis

Aim The aim of this study is to evaluate the efficacy and safety of afatinib in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastasis based on meta-analysis. Methods Related literatures were searched in the following databases: EMbase, PubMed, China Knowledge Network (CNKI), Wanfang, Weipu, Google Scholar, the China Biomedical Literature Service System, and other databases. Clinical trials and observational studies that met the requirements were selected for meta-analysis using Revman 5.3. The hazard ratio (HR) was used as an indicator of the impact of afatinib. Results A total of 142 related literatures were acquired, but after screening, five literatures were selected for data extraction. The following indices were compared: the progression-free survival (PFS), overall survival (OS), and common adverse reactions (ARs) of grade 3 and above. A total of 448 patients with brain metastases were included and were divided into two groups: the control group (no afatinib treatment, with chemotherapy alone and the first-generation EGFR-TKIs) and the afatinib group. The results showed that afatinib could improve PFS (HR: 0.58, 95% CI: 0.39–0.85, P < 0.05) and ORR (OR = 2.86, 95% CI: 1.45–2.57, P < 0.05), but had no benefit on OS (HR: 1.13, 95% CI: 0.15–8.75, P > 0.05) and DCR (OR = 2.87, 95% CI: 0.97–8.48, P > 0.05). For the safety of afatinib, the incidence of grade-3-and-above ARs was low (HR: 0.01, 95% CI: 0.00–0.02, P < 0.05). Conclusion Afatinib improves the survival of NSCLC patients with brain metastases and shows satisfactory safety.


Introduction
Te incidence of advanced non-small cell lung cancer (NSCLC) with brain metastases is 20-40% and increases to 44-63% in EGFR-positive patients [1,2]. Te traditional treatment for NSCLC patients with brain metastasis is whole-brain radiotherapy (WBRT). However, after receiving WBRT, cognitive dysfunction will lead to a decrease in the quality of life. With the application of a tyrosine kinase inhibitor (TKI), the survival of NSCLC patients with brain metastasis has been signifcantly prolonged, with a median overall survival (OS) of about 14.8 months [3][4][5].
Te epidermal growth factor receptor (EGFR) signaling pathway plays an important role in carcinoma [6]. In recent years, the use of EGFR-TKIs as a targeted therapy for NSCLC patients with brain metastases has been widely practiced. Afatinib, as a second-generation EGFR-TKI, is a powerful and irreversible dual inhibitor of EGFR and HER2 tyrosine kinases, with a longer inhibition time and elevated efcacy [7][8][9][10]. Te NCCN guidelines have listed EGFR-TKIs as the frst-line treatment for advanced NSCLC with EGFR mutations [7,11]. However, afatinib has not been recommended as the frst-line agent for NSCLC patients with brain metastases. EGFR-TKIs have a small molecular weight, good fat solubility, and a great ability to penetrate the blood-brain barrier (BBB). It has been shown that afatinib can easily penetrate the blood brain barrier to control the brain metastasis of EGFR-mutant NSCLC [9]. However, there is a lack of multicenter clinical evidence currently. Terefore, a meta-analysis was performed in this study by including diferent studies on the treatment of NSCLC patients with brain metastasis with afatinib, and the results will provide a reference for promoting the clinical application of afatinib.

Inclusion and Exclusion
Criteria. PROSPERO registration number for this meta-analysis is 373151. According to the PICOS principle, the inclusion criteria were as follows: (1) Aged at least 18 years, advanced recurrent or metastatic NSCLC (confrmed by histology or cytology) with EGFR mutation, the brain metastasis was confrmed by CT or MRI.
(2) Intervention measures included at least two groups: control and afatinib (single afatinib or afatinib combined with other treatments), (3) with the following data: primary outcome indicators including progression-free survival (PFS), overall survival (OS), and hazard ratio (HR), and secondary outcome indicators including treatment-related deaths and AEs (Grade 3 or 4, according to the National Cancer Institute's common toxicity standards). (4) Research types: RCT, non-RCT, observational studies (cohort studies, case-control studies, and cross-sectional studies); the language should be either Chinese or English. Animal experiments, mechanistic studies, repeated publications, case reports, and reviews were excluded.

Search Strategy.
Te following databases were searched: CNKI, Wanfang, PUBMED, EMBASE, CBM, OVID, Cochrane library, ClinicalTrials, and OpenGrey. Te latest date was May 31, 2021. Te search terms were "Afatinib" or "Gilotrif," "non-small cell lung cancer" or "lung cancer," "brain metastases" or "CNS." For each acquired paper, we also reviewed its references. Our analysis was in accordance with the "Cochrane Intervention System Evaluation Manual" and the PRISMA statement.

Literature Screening.
Te inclusion criteria for literature were as follows: (1) A study that included patients with NSCLC and brain metastases; (2) Tere are clear result data verifying the safety and/or efcacy of afatinib; (3) If multiple articles were published based on the same original data, only the latest and most complete articles were used.

Data Extraction.
Two investigators independently conducted the search process and evaluated the included articles, and any inconsistencies were discussed until a consensus was reached. For each article, we collected the frst author, publication year, number of registrations, number of patients, treatment plan, and demographic factors (such as age and histological type). Besides, a treatment for patients who had not received systemic treatment (e.g., chemotherapy) before was defned as the frst-line treatment, and a treatment for patients who had received platinumbased chemotherapy was defned as the second-line treatment.

Statistical
Analysis. Te Revman 5.3.0 software was used for efcacy meta-analysis focusing on PFS, OS, and hazard ratio (HR). First, the heterogeneity was evaluated, if there was signifcant heterogeneity (I 2 > 50%, P < 0.1), we analyzed the reasons (such as clinical heterogeneity), then subgroup analysis was conducted to eliminate the heterogeneity. If the heterogeneity was not due to clinical heterogeneity but statistical heterogeneity, the random efects model was used for pooled analysis. If there was no heterogeneity (I 2 ≤ 50%, P ≥ 0.1), the fxed efects model was used for pooled analysis. If the sample size was sufcient, a funnel plot analysis was performed to observe whether there was a publication bias.

Search Results.
We acquired 142 articles from all available databases. After reviewing the title and abstract, ffty-six articles were included. After reading the full text and checking the indices, nine articles were included, and fnally fve articles were screened for meta-analysis [9,[12][13][14][15]. Te fowchart is shown in Figure 1.

Basic Characteristics of Included Studies.
For the nine included studies, they are all cohort studies. All cases included were confrmed NSCLC patients with brain metastases, and afatinib was used in the treatment. Te possible factors related to the risk of brain metastasis were recorded, including age, histological characteristics, the dose of afatinib (40 mg), the early-stage treatment for brain metastasis (such as WBRT), and drugs used in the control group (such as platinum, gemcitabine, erlotinib, pemetrexed, etc.). To evaluate the efcacy and safety of afatinib, the median PFS, OS, and HR of each group were extracted (Table 1).

Afatinib Prolongs the PFS of NSCLC Patients with Brain
Metastasis. In the included fve studies, the total HR of afatinib as the frst-line treatment is 0.58 (95% CI: 0.39-0.85), and the inverted funnel fgure shows no publication bias ( Figure 2). Tis result proves that afatinib can prolong the PFS of NSCLC patients with brain metastasis.

Afatinib Provides Better Objective Response Rate (ORR) and Disease Control Rate (DCR).
In the three included studies, the results of the ORR were heterogeneous (I 2 > 50%), and the odds ratio (OR) is 2.86 (95% CI: 1.45-2.57). In comparison with chemotherapy, afatinib can provide a better ORR (Figures 4 and 5). Meanwhile, the heterogeneity of the disease response rate (DCR) is extremely low (I 2 � 0%), and the odds ratio (OR) is 2.87 (95% CI: 0.97-8.48).

Adverse Reactions (ARs) of Afatinib in the Treatment of NSCLC with Brain Metastases.
Te common ARs were investigated [19,20]. Overall, the incidence of ARs is high. Te overall OR of ARs is 1.56 (95% CI: 1.44-1.70). Diarrhea, stomatitis, and paronychia were among the most common ones. Te overall OR of Grade ≥ 3 ARs is 2.04 (95% CI: 1.47-2.82). Diarrhea was among the most common one ( Figure 6).

Discussion
Te incidence and mortality of lung cancer are still remarkably high currently [17]. About 10% of patients have brain metastasis at the time of diagnosis, and about 40% may develop brain metastasis during treatment [16]. At present, the commonly used local treatments for this cohort are: WBRT, stereotactic radiotherapy (SRT), and surgical   Afatinib is an oral ErbB-family blocker [8]. Compared with the frst-generation EGFR TKI, afatinib binds to EGFR irreversibly and suppresses the carcinogenic signaling pathway. Afatinib can control tumor progression and improve the prognosis of EGFR mutant NSCLC patients with brain metastasis [9]. By reviewing real-world data, this study used frst-line chemotherapy or the frst-generation EGFR-TKIs as the control group and observed the efcacy and safety of the afatinib group as the frst-line therapy. In the afatinib  Journal of Oncology group, the HR of PFS is 0.58 (95% CI: 0.39-0.85), with a reduced risk of progression. Te OR of the ORR is 2.86 (95% CI 1.45-2.57) and the OR of the DCR is 2.87 (95% CI 0.97-8.48) in comparison with controls, suggesting that afatinib can provide a better treatment response. Tis is consistent with the conclusion of the LUX-Lung3/6 trials [9]. In these trials, especially among the brain metastasis cohort, the PFS of the afatinib group was signifcantly better than the chemotherapy group. In the LUX-Lung 3 trial, the PFS of the afatinib group was 11.1 months, and that of the cisplatinpemetrexed was 5.4 months. In the LUX-Lung 6 trial, the PFS periods of afatinib and cisplatin-gemcitabine groups were 8.2 months and 4.7 months, respectively. However, we found no benefts of afatinib on OS (HR 1.13, 95% CI: 0. 15-8.75). In the LUX-Lung3/6 trails, a negative result of OS was also reported in the total population, but an OS beneft was observed in the EGFR19del subgroup. So far, although afatinib can control the progression of brain metastasis, it does not bring OS beneft versus chemotherapy or the frst-generation EGFR-TKIs. In the treatment efcacy assessment, afatinib had a better ORR and DCR versus chemotherapy and the frstgeneration EGFR-TKI. Overall, this is also consistent with the conclusion of the LUX-Lung3/6 trails. It should be noted that we did not stratify the oral dose of afatinib in our selected studies because a meta-analysis reported no diference between the efcacy of the 30-mg group and the 40-mg groups [21]. Te common AEs of afatinib include skin rash, diarrhea, loss of appetite, stomatitis, vomiting, fatigue, and paronychia. Compared with the frst-generation EGFR-TKIs, afatinib has a higher incidence of stomatitis, diarrhea, and paronychia among all grades of AEs, and the incidence of rashes is similar. Among grades 3 and above AEs, afatinib is associated with a higher incidence of diarrhea, while the incidences of rash, stomatitis, and paronychia are similar.
At present, it is still disputable whether TKIs in combination with radiotherapy are benefcial for controlling brain metastasis. Radiotherapy may provide clinical benefts for brain metastasis caused by NSCLC with rare EGFR mutations [22]. Early treatment such as WBRT and chemotherapy can increase the permeability of the BBB. Terefore, a pretreatment of radiotherapy and chemotherapy before the use of afatinib may assist afatinib in penetrating the BBB [23]. In the LUX-lung 3/6 trial, among patients who had received WBRT, afatinib can signifcantly improve PFS and OS in elderly patients [24]. However, there are also controversial conclusions [18]. A retrospective study of NSCLC patients with EGFR-sensitive mutation and brain  metastasis found that adding WBRT to EGFR-TKI therapy has no additional survival beneft [25]. Another retrospective study showed that the OS of patients receiving early radiotherapy was similar to that of the delayed radiotherapy group [26]. A meta-analysis also showed that only the EGFR-TKI group (but not the WBRT plus EGFR-TKI group) showed superior intracranial PFS. Terefore, it is still too early to answer this question, and further clinical trials and real-world data are needed. Te limitations of this meta-analysis are as follows. First, the small sample size weakens the reliability of the results. Second, we include several retrospective observational studies, and there might be selection bias in these studies.
In conclusion, this meta-analysis suggests that afatinib improves the survival of NSCLC patients with brain metastases and shows satisfactory safety.

Data Availability
All data are available upon reasonable request to the corresponding author.

Conflicts of Interest
Te authors declare that they have no conficts of interest.