Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial
- 13 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 27 (1), 165-173
- https://doi.org/10.1038/s41591-020-01193-6
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (U54-CA196519-04)
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12-HD000850)
- Exelixis
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