Everolimus in combination with vandetanib in children, adolescents, and young adults: a phase I study

• Published in: ESMO open Vol. 8; no. 6; p. 101609
• Main Authors: Phadnis, S., Wang, X., Daw, N.C., Herzog, C.E., Subbiah, I.M., Zaky, W., Gouda, M.A., Morani, A.C., Amini, B., Harrison, D.J., Piha-Paul, S.A., Meric-Bernstam, F., Gorlick, R., Schwartz, C.L., Subbiah, V.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2023; Elsevier
• Subjects: Adolescent; Child; everolimus; Everolimus - adverse effects; Humans; Neoplasms - drug therapy; Neoplasms - genetics; Original Research; pediatrics; phase I trial; Piperidines - adverse effects; Quinazolines - adverse effects; sarcoma; Sirolimus - adverse effects; vandetanib; Vascular Endothelial Growth Factor A; Young Adult; phase I trial; everolimus; sarcoma; vandetanib; pediatrics
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1016/j.esmoop.2023.101609

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. •Combination of vandetanib and everolimus is active in pediatric patients with advanced cancers.•Combination of vandetanib and everolimus has tolerable safety profile in pediatric patients with advanced cancers.•Exceptional responders harbored KDR Q472H mutation, CDKN2A/B loss, or ASPL/ASPSCR1-TFE3 fusion.