Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases

Abstract

In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.

Keywords: Brain metastases; Everolimus; Exceptional responder; Lung cancer; Next generation sequencing; RET; Vandetanib; mTOR.

Figure 1

Fluorescence in situ hybridization (ISH) of paraffin-embedded tissue sections from pleura, right biopsy. The ISH technique was performed using a Clear-View FISH RET dual-color breakapart probe from Cymogen DX. The probe hybridizes to band 10q11.21 (cmyo-orange on the centromeric side and cymo-green on the telomeric side of the RET gene breakpoint). Deletion of 5’-RET (red signal) was observed in 47.0% of the interphases scanned, indicating a RET gene rearrangement.

Figure 2

Schematic representation of KIF5B-RET fusion gene. An inversion rearrangement event within chromosome 10 involves exons 1 to 15 of Kinesin-1 heavy chain protein (KIF5B), containing the kinesin motor domain and exons 12 to 20 of RET proto-oncogene, containing the protein tyrosine kinase domain.

Figure 3

A–E: Pretreatment MR (A, and C) demonstrates enhancing lesions (arrowheads) on the axial T1-weighted images, decreased in number and size following treatment (B and D). FDG- PET CT reveals pleural hypermetabolism in the right hemithorax (E) with decreased avidity post-therapy (F).