Brain metastasis is an important poor prognostic factor in patients with non–small cell lung cancer (NSCLC) [1]. The incidence of baseline brain metastasis is especially higher in epidermal growth factor receptor (EGFR)-mutant NSCLC than EGFR-wild type tumors [2,3], with rates ranging from 31%–41% in patients with EGFR-mutant NSCLC [3–5]. Therefore, the appropriate treatment for baseline brain metastasis has become an important decision-making step in the treatment of EGFR-mutant NSCLC.

EGFR–tyrosine kinase inhibitors (TKIs) have been well validated for their efficacy in treating brain metastasis in patients with EGFR-mutant NSCLC. The central nervous system (CNS) objective response rate of EGFR-TKI was reported to be 64.7%–91% [4,6–8].

A previous retrospective study investigated the role of brain radiotherapy (RT) delivered prior to first-line EGFR-TKI therapy for baseline brain metastasis [9]. In this study, 351 patients were treated with first-generation (first-G) EGFR-TKIs—mostly erlotinib (n=344)—following brain RT (stereotactic radiotherapy [SRS], n=100; whole-brain radiotherapy [WBRT], n=120) or without prior brain RT (n=131). The median overall survival was significantly longer in the group with brain RT followed by EGFR-TKI therapy than in the group that received EGFR-TKI therapy alone (46 months for SRS and 30 months for WBRT vs. 25 months for EGFR-TKI therapy alone, p < 0.001), leading to the recommendation that brain RT delivery prior to first-line EGFR-TKI therapy be considered for baseline brain metastasis in patients with EGFR-mutant NSCLC.

However, a subsequent small retrospective study with more CNS-penetrating EGFR-TKIs reported different results concerning the role of brain RT in patients with EGFR-mutant NSCLC [10]. This study included patients who received third-generation (third-G) EGFR-TKI therapy (osimertinib or rocilectinib) alone (n=52) or EGFR-TKI therapy with brain RT (n=43) and found no significant difference in progression-free survival (PFS) (8.5 vs. 6.9 months, p=0.13) or time to intracranial progression (14.8 vs. 20.5 months, p=0.51) between the EGFR-TKI alone and EGFR-TKI with brain RT groups of patients with EGFR-mutant NSCLC with brain metastases, suggesting that there is no role for prior brain RT when more CNS-penetrating EGFR-TKIs are administered in patients with baseline brain metastases.

Afatinib is a second-generation, irreversible EGFR-TKI, and its good CNS efficacy has been previously shown in several studies, where it was also superior to first-G EGFR-TKIs for brain metastasis [4,5,11]. Until now, however, the role of brain RT for baseline brain metastasis before afatinib therapy has not been evaluated. In the current study, we tried to evaluate it by comparing survival outcomes between subgroups with or without brain RT in the afatinib therapy group and the first-G EGFR-TKI group, respectively.

In this study, additional brain RT before first-line afatinib therapy had no positive impact on overall survival compared to afatinib alone, while it was associated with longer overall survival in patients treated with first-G EGFR-TKIs. The underlying reason for the contrasting results of overall survival according to brain RT between the first-G EGFR-TKI and afatinib groups might originate from the different CNS efficacies of first-G EGFR-TKIs and afatinib. Afatinib demonstrated a superior CNS efficacy compared to first-G EGFR-TKIs in several studies. An in vivo study showed that afatinib had a higher brain-to-plasma ratio compared to first-G EGFR-TKI therapy [12]. Afatinib also had a lower half-maximal inhibitory concentration for EGFR-mutant NSCLC cell lines than first-G EGFR-TKI therapy [13]. In our retrospective study comparing gefitinib, erlotinib, and afatinib, afatinib achieved a superior CNS PFS rate, cumulative incidence of CNS failure, and PFS rate compared to first-G EGFR-TKI therapy (gefitinib or erlotinib) in EGFR mutant–NSCLC with or without brain metastasis [4].

Brain RT modalities such as GKS or WBRT are good at locally controlling brain metastases and have been universally used to treat brain metastases irrespective of clinical features related to brain metastasis in the oncology field [14]. In many cases, however, WBRT deteriorates a patient’s performance and neuro-cognitive function [14,15], which could negatively affect the subsequent treatment for progressing intracranial or extracranial cancers. In addition, as the expected survival time is being substantially increased by many treatment modalities in the recent oncologic era, the toxicity caused by brain RT could become a big burden to patients. GKS is relatively safer than WBRT in terms of deteriorating a patient’s performance or neuro-cognitive function, but it is still linked to radiation necrosis, which may lead to intractable neurologic symptoms such as prolonged headache and weakness in the extremities [16]. Additionally, in some cases, the radiation necrosis caused by GKS is hard to differentiate from a true progression of brain metastasis [16], which could complicate further treatment decision-making process.

As many good CNS-penetrant TKIs have been developed in the oncology field in recent years, the guideline for brain RT for brain metastasis has been adjusted accordingly. Recently developed EGFR-TKIs such as afatinib, osimertinib, and lazertinib led to dramatic responses in brain meta-stases; reduced the risk of CNS progression [4,8,17]; and could delay the requirement of brain RT, preventing patients from suffering the side effects of brain RT. The recently updated American Society of Radiation Oncology/Society for Neuro-Oncology/American Society for Radiation Oncology (ASCO/SNO/ASTRO) guideline for brain metastasis suggested that systemic treatment alone with good blood–brain barrier penetration, such as osimertinib or icotinib, may be offered to patients with asymptomatic brain metastases of EGFR-mutant NSCLC without performing brain RT before these EGFR-TKIs [8,18,19].

In our current retrospective analysis, the practice of brain RT was greatly affected by clinical features related to brain metastases across the first-G EGFR-TKI and afatinib groups. First, the proportion of brain RT was significantly affected by brain metastasis–related symptoms. In the total study population, 83.3% (215/258) of patients with no brain metastasis–related symptoms did not receive brain RT, while only 5% (5/101) of patients with brain metastasis–related symptoms could delay brain RT. This result is compatible with the ASCO/SNO/ASTRO guideline, which suggested that brain RT should be considered for symptomatic brain metastases regardless of the type of systemic therapy used [19]. Therefore, considering the very small population of patients with symptomatic brain metastases treated without brain RT in our study, our study is unable to answer the question of whether we could also delay brain RT or not for symptomatic brain metastasis, even when highly CNS-penetrating EGFR-TKI therapy is available. However, in clinical practice, it would not be easy to wait for EGFR-mutation testing results when patients have moderate or severe brain metastasis–related symptoms, given that the turn-around time for the testing result is 1–2 weeks. Therefore, cautious decision-making is necessary on whether brain RT should be delayed or not for symptomatic brain metastasis, considering the patient’s performance status, the possibility of positive EGFR-mutation results and vigilant follow-up, and the severity of symptoms.

In addition, the practice of brain RT, including the RT modality (GKS or WBRT), was greatly affected by the number of brain metastases. Patients with fewer (≤ 3) brain metastases were more likely to be treated with brain RT than those with more (≥ 4), which contradicted our expectation that control of a larger brain metastasis burden would be attempted more frequently with additional brain RT, as shown in our current study, concurrent with the finding that larger brain metastases were more often treated with brain RT. Though our retrospective analysis limits the full explanation of this phenomenon, little concern about GKS-related neurotoxicity in patients with small numbers of brain metastases might lead physicians to easily pursue GKS for these individuals, which is also supported by the current guideline suggesting SRS procedures such as GKS to be the standard brain RT modality for small numbers (≤ 3) of brain metastasis [19]. In contrast, only 26 of 100 patients with more (≥ 10) brain metastases received brain RT (GKS: n=6, WBRT: n=20) in our total study population. This phenomenon might be caused by the physician’s discretion based on the less well documented efficacy of GKS for ≥ 10 brain metastases [20], and their concerning of the anticipated neurotoxicity after WBRT.

Meanwhile, to clarify the role for brain RT before EGFR-TKI therapy, several prospective studies are ongoing. Two randomized phase II studies are comparing osimertinib with osimertinib plus brain RT (SRS) (NCT03497767, NCT03769103). In addition, our study group is prospectively investigating the efficacy of dacomitinib, another second-generation EGFR-TKI, alone without brain RT in EGFR-mutant NSCLC patients with symptomatic or non-symptomatic brain metastases in a single-arm phase II study (NCT04675008).

Our current study revealed no survival improvement with additional brain RT following treatment with first-line afatinib therapy. Therefore, considering the toxicity and burden of brain RT, it can be delayed until intracranial progression when first-line afatinib therapy is considered in EGFR-mutant NSCLC patients with asymptomatic brain metastases.