title: 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.
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States. Electronic address: vsubbiah@mdanderson.org.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Jenny
authors.initials: J
authors.lastname: Berry
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Roxas
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Nandita
authors.initials: N
authors.lastname: Guha-Thakurta
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Ishwaria Mohan
authors.initials: IM
authors.lastname: Subbiah
authors.affiliation: Foundation Medicine, Boston, MA, United States.
authors.forename: Siraj M
authors.initials: SM
authors.lastname: Ali
authors.affiliation: Foundation Medicine, Boston, MA, United States.
authors.forename: Caitlin
authors.initials: C
authors.lastname: McMahon
authors.affiliation: Foundation Medicine, Boston, MA, United States.
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Tina
authors.initials: T
authors.lastname: Cascone
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Shobha
authors.initials: S
authors.lastname: Pai
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: Zhenya
authors.initials: Z
authors.lastname: Tang
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, United States.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D005784:Gene Amplification; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010880:Piperidines / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: C573239:KIF5B-RET fusion protein, human; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D011799:Quinazolines; D000068338:Everolimus; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C452423:vandetanib
keywords: Brain metastases; Everolimus; Exceptional responder; Lung cancer; Next generation sequencing; RET; Vandetanib; mTOR