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Ref Type Journal Article
PMID (37879233)
Authors Phadnis S, Wang X, Daw NC, Herzog CE, Subbiah IM, Zaky W, Gouda MA, Morani AC, Amini B, Harrison DJ, Piha-Paul SA, Meric-Bernstam F, Gorlick R, Schwartz CL, Subbiah V
Title Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study.
Journal Vol Issue Date Pages Journal Short Title
ESMO open 8 6 2023 Dec 101609 ESMO Open
URL
Abstract Text Combined use of inhibitors of mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF-2) receptors is a potential strategy to overcome resistance to either class of drugs when used alone.We designed a phase 1 trial to test the drug combination of a multikinase VEGF receptor 2 inhibitor, vandetanib, and an mTOR inhibitor, everolimus, in a pediatric and young adult patient cohort with advanced cancers. Exceptional responders were probed for tumor mutational profile to explore possible molecular mechanisms of response.Among 21 enrolled patients, clinical benefit was observed in 38% (one patient with partial response and eight patients with stable disease) with a median progression-free survival of 3.3 months. The most common treatment-related adverse event was rash (n = 13). Other treatment-related toxicities included diarrhea, fatigue, hypertension, QT prolongation, hypertriglyceridemia/hypercholesterolemia, transaminitis, thrombocytopenia, and weight loss. None of the patients experienced dose-limiting toxicities. Three exceptional responders were analyzed and were found to harbor genetic alterations including kinase insert domain receptor (KDR) Q472H mutation, EWSR1-CREB3L1, CDKN2A/B loss, and ASPL/ASPSCR1-TFE3 fusion.The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KDR Q472H epithelioid sarcoma predicted - sensitive Everolimus + Vandetanib Case Reports/Case Series Actionable In a Phase I trial, treatment with the combination of Afinitor (everolimus) and Caprelsa (vandetanib) was well tolerated and resulted in a median progression-free survival of 3.3 months, median overall survival of 4.6 months, clinical benefit rate of 38% in pediatric and young adult patients with advanced solid tumors, including 1 partial response in a 20 year-old patient with metastatic epithelioid sarcoma harboring germline KDR Q472H (PMID: 37879233; NCT01582191). 37879233