**6.4 MET inhibitors**

In recent years, several MET inhibitors have been approved and have entered clinical trials. There are limited data available on the role and efficacy of monoclonal antibodies that inhibit MET in brain metastasis [127]. The effectiveness of Sym015, which consists of two monoclonal antibodies targeted to non-overlapping epitopes of MET, was high in inhibiting MET-amplified tumors as compared to emibetuzumab, a humanized monoclonal antibody developed for patients with NSCLC [128]. Among the new small inhibitors, cabozantinib, an inhibitor of MET, RET, and VEGFR2, appeared effective in radiation-resistant MET-mutated BM in renal cell carcinoma [129]. In addition, cabozantinib yields rapid responses in crizotinib-resistant NSCLC harboring a MET exon 14 alteration [130]. Simultaneous activation of the MET receptor and the ALK fusion gene in NSCLC yielded effective responses to crizotinib in patients with brain metastases [131]. The oral administered selective MET inhibitor capmatinib came with controllable toxicity profiles in treatment-naive patients with MET-exon14 positive NSCLC. Preliminary studies in mice that were injected with human BM cells from NSCLC showed that capmatinib is able to cross the BBB and is active in the brain. In *in vivo* models, the combination of capmatinib and afatinib was found to suppress tumor growth [132]. Recently it was demonstrated that bozitinib, another novel orally administered PLB-1001 compound, better penetrated the BBB as compared to other MET inhibitors in MET-mutated glioblastoma [133]. These preliminary results raise hopes for the effectiveness of PLB-1001 in the treatment of secondary brain lesions from various primary sites.

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

### **6.5 RET inhibitors**

Cabozantinib and vandetanib are oral multi-kinase, non-selective RET inhibitors that have a modest advantage but significant toxicity. Cabozantinib is effective in RET-rearranged NSCLC and has limited activity against RET, while vandetanib more effectively targets RET. No specific activity against CNS seedings of NSCLC has been reported for these drugs [134, 135]. Selpercatinib and pralsetinib are small highly selective RET inhibitors approved by the FDA for the treatment of NSCLC with RET fusion [136, 137]. Selpercatinib (LOXO-292) is an oral tyrosine-kinase inhibitor specifically targeting the RET kinase domain. Its activity profile and clinical safety were evaluated in phase I/II clinical trial LIBRETTO-001. The study included patients with advanced RET-positive NSCLC who had progressed disease after platinum-based chemotherapy in patients who were treatment naïve. In the phase II trial, 105 patients were pretreated with platinum-based chemotherapy. The ORR was 64% (95% confidence interval (CI): 54% to 73%) with a median duration of response of 17.5 months. A major advantage was observed among the 39 treatment naïve patients, with an ORR of 85% (95% CI: 70% to 94%). Selpercatinib was also designed to have an effect on the CNS. Eleven patients with BM participated and Intracranial responses were observed in 10/11 patients with response rates of 91% (95% CI: 6.7% to NE) [138]. The FDA granted to accelerate the approval of selpercatinib for treating patients with metastatic RET-positive NSCLC, regardless of specific treatment strategy. The RET kinase domain inhibitor Pralsetinib (BLU-667) is currently applied in a multicenter phase I/II ARROW trial. Based on the results of this trial, the FDA approved the efficacy of pralsetinib in patients with RET alteration-positive NSCLC with/without prior therapy. Patients with asymptomatic BM were allowed to be included in this trial. In total, 79 patients participated, and the majority were pretreated primarily with chemotherapy (76%) and immunotherapy (41%). CNS metastasis at the baseline observed in 39% of patients. Efficacy was based on 57 patients, all of whom had at least one follow-up evaluation [139, 140].
