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Neurofibromatosis type 1 (NF1) is an autosomal dominant neoplastic disease caused by mutations in the NF1 gene, with an incidence of approximately 1 in 3000 people worldwide. Plexiform Neurofibromas (PNs) are characteristic lesions of NF1 and cause motor and sensory dysfunction, pain, and disfigurement in up to 40% of NF1 patients.
As with many histologically benign and slow-growing tumors, PNs are poorly treated with conventional cytotoxic chemotherapeutics. Radiation therapy is also not suitable for PNs, given the risk of promoting the development of secondary malignancies and uncertain efficacy. Although surgical resection is currently the standard treatment for PNs, it is often technically impossible due to the intrinsic relationship between tumors and nerves. Therefore, NF1-related PNs remain one of the urgent medical problems to be solved.
Cabozantinib is a multi-targeted small molecule tyrosine kinase inhibitor, which has been approved for medullary thyroid carcinoma, renal cell carcinoma, hepatocellular carcinoma, etc. First- and second-line treatment of cancer. Previous preclinical and translational studies have demonstrated that treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib effectively reduces the volume and number of PNs and differentially modulates the kinases that drive PN growth across cell lineages.
In January 2021, Dr. D. Wade Clapp from Indiana University and Dr. Jaishri O. Blakeley from Johns Hopkins University, etc. The researchers published an article titled Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial in Nature Medicine, which published Cabozantinib in the treatment of NF1-related PN Results of a multicenter, open-label, non-randomized Simon two-phase clinical trial. The results of the trial showed that cabozantinib has good safety and can effectively reduce tumor volume, with a partial response rate of 42%, indicating that the drug has the potential to be a treatment option for NF1-related PN.
The research team first verified through preclinical mouse models that cabozantinib can significantly reduce PN tumor burden in Nf1 mutant mice. After 12 weeks of cabozantinib treatment, the number of PNs per mouse was reduced by approximately 60%, the mean volume of proximal peripheral nerve roots was reduced by 38%, and tumor neovascularization was reduced compared to the blank control group. significantly reduced.
Based on preclinical data, the Neurofibromatosis Clinical Trials Consortium conducted a multicenter, prospective, open-label, single-arm Phase II clinical trial of cabozantinib. Enrollment requirements were 16-year-old NF1 patients with progressive or symptomatic PN who were not candidates for surgery. Using a Simon two-stage optimal design, 9 patients were enrolled in the first stage and 14 patients in the second stage. The patient received cabozantinib once daily for 24 consecutive cycles (28-day cycle), with a dose of 40 mg for the first 2 cycles, which was then increased to 60 mg.
The patient’s tumor volume was assessed by MRI after completing the 4th, 8th, 12th, 18th and 24th treatment cycles. Partial response (PR) was defined as ≥20% tumor volume reduction on MRI. Secondary endpoints included safety and tolerability, patient self-reported tumor pain intensity, daily interventions for pain, disease-specific quality of life assessments, and circulatory endothelial and cytokine levels. Ultimately, 21 patients received at least 1 dose of cabozantinib and could be evaluated for drug toxicity; 19 patients completed ≥2 treatment cycles and 1 MRI and could be evaluated for drug efficacy (Mean age 23 years; mean baseline tumor volume 557 ml).
Clinical trial protocol and CONSORT diagram
Trial results showed cabozantinib was safe and well tolerated. A total of 11 grade 3 adverse events occurred in 8 patients. No grade 4-5 side effects occurred. The most common adverse reactions included diarrhea (17 cases), nausea (14 cases), asymptomatic hypothyroidism (15 cases), fatigue (13 cases), and palmoplantar anesthesia erythema (10 cases). Of the 19 patients who could be evaluated for efficacy, 5 completed the full treatment cycle, and 6 were due to tumor volume reduction in the 8th treatment cycle
Cabotinib has obvious therapeutic effect on patients with PN. Of the 19 patients who could be evaluated for efficacy, 8 patients (42%) achieved a partial response (PR), 11 patients had stable disease (SD), and no patients experienced tumor progression. PN tumor volume decreased by an average of 15.2% (range: +2.2% to -36.9%). In 3 patients, tumor volume remained unchanged or continued to decrease after drug dose reduction. There were no significant differences in tumor location, tumor size, or demographic characteristics.
cabozantinib drug response: a: drug response waterfall b: treatment response time
In conclusion, the results of the Phase II clinical trial show that cabozantinib is safe and effective in the treatment of NF1-related PN. Cabozantinib was well tolerated, and the partial response rate of 42% was the best record to date for PN in adolescents and adults. In addition, self-reports from patients showed that the degree of reduction in tumor pain intensity reached clinical significance, the interference of pain in patients’ daily life was significantly reduced, and the quality of life was improved.
Based on the efficacy of cabozantinib in adolescents and adults, the NF Clinical Trials Consortium recently conducted 2 clinical studies, including a Phase II clinical study of cabozantinib in children with PN, and The study of MEK inhibitor selumetinib in the treatment of NF1-related PN in adults is currently ongoing. Combining these clinical trial results and ongoing laboratory studies, researchers will further explore the possibility of combining cabozantinib with MEK inhibitors in the treatment of PN.
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