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 bed-side 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 2 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.

RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients

“…Recent studies also demonstrated RET fusions in about 1% to 2% of patients with NSCLC, with several of the fusion partners overlapping with those identified in papillary thyroid carcinoma (e.g., CCDC6, KIF5B, NCOA4, and TRIM33; refs. [13][14][15][16][17][18]24), which is consistent with findings in this current report (Table 1 and Supplementary Table S3; Fig. 2).…”

“…5A). Along with these promising reports (15,21,24), there are multiple ongoing phase I and II trials targeting RET fusions in patients with NSCLC and other advanced solid tumors (Supplementary Table S1). …”

“…However, none of these inhibitors are FDA approved on the basis of targeting RET aberrations. Meanwhile, there are a series of reports suggesting that matched therapies against RET aberrations can yield significant responses (8,15,(21)(22)(23)(24)(25)(26)(27). Further clinical trials with a focus on RET-aberrant advanced cancer are being conducted to determine impact on outcome (Supplementary Table S1).…”

Novel targeted therapeutics for MEN2

“…The idea is based on everolimus activity against ABC transporters, which limit drug efficacy, especially in the central nervous system. Indeed, a first successful case has been reported (Subbiah et al 2015). Whether these results will be relevant to the MEN2/MTC population remains to be seen.…”

Towards precision oncology in RET-aberrant cancers

“…Given that resistance develops eventually to multi-kinase drugs that have RET inhibitor activity, 7 it would be worthwhile to evaluate the clinical responses to the highly selective RET inhibitors which possess more potent RET inhibitory activity in pre-clinical models than the current tyrosine kinase inhibitors. However, data from Kato et al show that RET aberrant patient samples also harbored coalterations that can lead to tumorigenesis as well.…”