**6. Novel therapeutic approaches**

For many years, the rise of brain metastases of lung cancer has been considered the final stage of the disease. Patients were treated with standard therapeutic options such as palliative care or whole brain radiotherapy (WBRT). However, since the discovery of new systemic and targeted therapies, additional effective treatments for lung cancer were introduced with the aim to enhance local control and survival [106].

### **6.1 Targeted systemic therapy**

The BBB is an obstacle to enter the brain for many agents and has limited the application of drugs used for systemic therapy [107]. The application of drugs targeting EGFR and ALK has heightened the interest in utilizing systemic agents to treat brain metastases [108–111]. In **Table 2** clinical trials of targeted therapy for NSCLC brain metastases are listed.

### **6.2 EGFR tyrosine kinase inhibitors**

Patients with tumors harboring EGFR mutations are prone to develop brain metastases [112, 113]. Although the efficacy of EGFR-TKIs for NSCLCs with EGFR mutations has been proven, its effectiveness is not clear in patients with brain metastases since they were excluded from controlled clinical trials. In a prospective study, 41 patients with unselected NSCLC brain metastasis were treated with Gefitinib resulting in 10% intracranial partial responses (PR) with an average response period of 13.5 months [114]. However, most information on the efficacy of TKIs in patients with brain metastases was obtained from retrospective studies [110]. Firstly, it appeared that recorded concentrations of Afatinib, Erlotinib, and Gefitinib in cerebrospinal fluid (CSF) clearly exceeded those needed to inhibit the growth of cells with EGFR mutations *in vitro*. In patients with lung adenocarcinoma, about 70% intracranial tumor response was obtained with Gefitinib or Erlotinib as first-line treatment [115]. Other retrospective clinical studies revealed that patients with brain metastases from EGFR-mutant NSCLC have more favorable responses to WBRT or TKI therapy than patients with brain metastases from EGFR–wild-type NSCLC [116]. The progression periods were 11.7 months for patients with EGFR-mutant NSCLCs treated with Erlotinib and 5.8 months for patients with EGFR-wild-type NSCLCs, respectively [117]. The potent EGFR-TKI, AZD3759 showed significant penetration of the BBB in pre-clinical models for the treatment of EGFR-mutant NSCLC with brain metastasis [118]. Moreover, the third-generation EGFR inhibitors osimertinib and rociletinib targeting the T790M-EGFR resistance mutation in NSCLC appeared effective in treating patients with NSCLCs with these mutations [119, 120]. Unfortunately, a phase 3 trial conducted by RTOG using WBRT plus SRS with Temozolomide and Erlotinib in unselected patients with a maximum of three brain metastases was closed prematurely because of low accrual [121]. No significant benefit of adding Gefitinib to WBRT in phase 2 trials in patients with unselected NSCLC with brain metastasis was recorded [122].


*Non-Small Cell Lung Cancer Brain Metastasis: The Link between Molecular Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.106385*

> **Table 2.**

*Clinical trials of targeted therapy for the treatment.*

At present, there is not sufficient data to draw conclusions on TKI therapy plus CNS-directed radiation therapy for patients with NSCLCs with EGFR mutations.
