Clinical trials targeting neurofibromatoses-associated tumors: a systematic review

Abstract

Background There is a paucity of literature that comprehensively analyzes previous and current clinical trials targeting neurofibromatoses-related tumors. This article aims to provide readers of drug development efforts targeting these tumors by analyzing translational and clinical findings. Methods This systematic review was written according to the PRISMA guidelines. Inclusion criteria were clinical trials involving patients with neurofibromatosis type 1, type 2, or schwannomatosis that were treated with therapies targeting neurofibromatoses-associated tumors and that were registered on clinicaltrials.gov. In addition, a search was performed in PubMed, Web of Science, Google Scholar, and Embase European for articles fully describing these clinical trials. Results A total of 265 clinical trials were registered and screened for eligibility. Ninety-two were included in this systematic review involving approximately 4,636 participants. The number of therapies analyzed was more than 50. Drugs under investigation mainly act on the MAPK/ERK and PI3K/AKT/mTOR pathways, tumor microenvironment, or aberrantly over-expressed cell surface receptors. Selumetinib was the most effective medication for treating a neurofibromatosis type 1-associated tumor with approximately 68-71% partial response for inoperable or progressive plexiform neurofibromas in children 2 years of age and older and bevacizumab for a neurofibromatosis type 2-related tumor with approximately 36-41% partial response for vestibular schwannomas in patients 12 years of age and older. Conclusions This systematic review presents the results of previous clinical investigations and those under development for neurofibromatoses-associated tumors. Clinicians may use this information to strategize patients to appropriate clinical trials.

The genetic landscape and possible therapeutics of neurofibromatosis type 2

“…A comprehensive understanding of molecular mechanisms in tumor progression of NF2-related tumors will provide opportunities for exploring more efficient treatments. Currently, many drugs are being examined targeting pathways involved in the pathogenesis of NF2 [ 14 , 94 , 143 ]. In this section, clinical trials evaluating the targeted therapies for NF-related tumors are discussed (Fig.…”

“…Bevacizumab (an anti-VEGF antibody) has demonstrated encouraging results in patients with NF2-associated VS. [ 13 , 14 ] In patients with progressive disease, it has successfully controlled the growth rate and helped to improve the hearing status [ 81 , 154 – 156 ]. Different studies indicated a 36%–41% partial response of bevacizumab for NF2-related VS in patients 12 years and older [ 14 ]. The therapeutic effect of bevacizumab in pediatrics and adults with smaller and slow-growing tumors was less prominent [ 156 – 158 ].…”

“…It has been demonstrated that treatment of progressive meningioma (after surgery and radiotherapy) with bevacizumab led to disease stabilization with 6-month progression-free survival rates of 87, 77, and 46% in grades I to III meningiomas [ 83 ]. Studies on other inhibitors of VEGF (endostatin) and VEGFR (axitinib) did not demonstrate encouraging results [ 14 , 163 ].…”

“…Moreover, the clinical trial (NCT03071874) has administered vistusertib to treat recurrent grade II or III NF2-mutated meningiomas to inhibit the mTORC1/C2 complexes. [ 14 ].…”

Recommendations for assessing appearance concerns related to plexiform and cutaneous neurofibromas in neurofibromatosis 1 clinical trials

“…5,6 A recent systematic review highlighted the significant increase in active and planned clinical trials for neurofibromatosis-associated tumors, including plexiform neurofibromas and cutaneous neurofibromas. 7 Plexiform neurofibromas occur in up to 50% of individuals with NF1 and can cause severe morbidity, including pain, disfigurement, motor dysfunction, and airway obstructions. Cutaneous neurofibromas occur in almost all adults with NF1, with the number of individual tumors ranging widely (from a few to multiple thousands) and typically increasing with age.…”