Author: ["Michael J. Fisher","Chie-Schin Shih","Steven D. Rhodes","Amy E. Armstrong","Pamela L. Wolters","Eva Dombi","Chi Zhang","Steven P. Angus","Gary L. Johnson","Roger J. Packer","Jeffrey C. Allen","Nicole J. Ullrich","Stewart Goldman","David H. Gutmann","Scott R. Plotkin","Tena Rosser","Kent A. Robertson","Brigitte C. Widemann","Abbi E. Smith","Waylan K. Bessler","Yongzheng He","Su-Jung Park","Julie A. Mund","Li Jiang","Khadijeh Bijangi-Vishehsaraei","Coretta Thomas Robinson","Gary R. Cutter","Bruce R. Korf","Chie-Schin Shih","Amy E. Armstrong","Jaishri O. Blakeley","D. Wade Clapp"]
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Abstract
Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN ( NCT02101736 ). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to −36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement. Cabozantinib, an inhibitor of multiple receptor tyrosine kinases, has efficacy in a mouse model of neurofibromatosis type I and has clinical activity in reducing plexiform neurofibroma volume in a phase II trial of patients with NF1.Cite this article
Fisher, M.J., Shih, CS., Rhodes, S.D. et al. Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial. Nat Med 27, 165–173 (2021). https://doi.org/10.1038/s41591-020-01193-6 