Written by | Sun Rui, editor-in-charge of | Early morning rain
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor disease caused by mutations in the NF1 gene, with a global incidence of about 1 in 3000. Plexiform Neurofibromas (PNs) are characteristic lesions of NF1 that cause motor and sensory dysfunction, pain, and distension in up to 40% of NF1 patients.
Like many histologically benign and slow-growing tumors, conventional cytotoxic chemotherapy drugs are not effective against PNs. Given the risk of promoting the development of secondary malignancies and uncertain efficacy, radiation therapy is also not suitable for PNs. Although surgical resection is currently the standard treatment for PNs, it is often not technically possible due to the intrinsic relationship between the tumor and the nerve. Therefore, NF1-related PNs are still one of the medical challenges that need to be solved urgently.
Cabozantinib is a multi-target small molecule tyrosine kinase inhibitor that has been approved for first- and second-line treatments for medullary thyroid, renal cell carcinoma, hepatocellular carcinoma and other cancers. Previous preclinical and translational studies have shown that Nf1fl/fl is treated with cabozantinib; Postn-Cre mice, which effectively reduce the volume and number of PNs and differentially regulate the kinases that drive PN growth in the cell lineage.
In January 2021, Indiana University, USA, D. Researchers such as Dr. Wade Clapp and Jaishri O. Blakeley, Ph.D. of Johns Hopkins University, published an article in Nature Medicine titled Cabozantiniib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. The results of a multicenter, open-label, non-randomized Simon phase II clinical trial of cabozantinib for the treatment of NF1-associated PN were published. The results of the trial showed that cabozantinib was safe and effective in reducing tumor volume, with a partial response rate of up to 42%, indicating that the drug had the potential to become a treatment regimen for NF1-related PN.
The research team first verified through preclinical mouse models that cabozantinib can significantly reduce the PN tumor burden in mice with Nf1 mutations. Compared with the blank control group, after 12 weeks of cabozinib treatment, the number of PN per mouse decreased by about 60%, the average volume of proximal peripheral nerve roots decreased by 38%, and neoangigenesis of tumors was significantly reduced.
Based on preclinical research data, the Neurofibromatosis Clinical Trial Consortium conducted a multicenter, prospective, open-label, single-arm Phase II clinical trial of cabotinib. Admission is required for NF1 patients who are at least 16 years of age, have progressive or symptomatic PN, and are not suitable for surgery. Using Simon's two-stage optimal design, the first phase recruited 9 patients and the second phase recruited 14 patients. Patients took cabozantinib once a day for 24 consecutive cycles (1 cycle over 28 days), with a dose of 40 mg for the first 2 cycles, after which the dose was increased to 60 mg.
Patients were assessed using MRI after completing the 4th, 8th, 12th, 18th, and 24th treatment cycles. A partial response (PR) is defined as an MRI showing a tumor volume reduction ≥ 20%. Secondary endpoints included safety and tolerability, patient self-reported tumor pain intensity, interventions for pain in everyday life, disease-specific quality-of-life assessment, and endothelial cell and cytokine levels in the circulatory system. Ultimately, 21 patients received at least 1 dose of cabotinib, which could be evaluated for drug toxicity; 19 patients completed ≥ 2 treatment cycles and 1 MRI, for which they could be evaluated for drug effectiveness (mean age 23 years; mean baseline tumor volume 557 ml).
Clinical trial protocol and CONSORT diagram
The test results show that cabozantinib is safe and well tolerated. A total of 11 class 3 side effects occurred in 8 patients. No grade 4-5 side effects occurred. The most common adverse effects included diarrhea (17 patients), nausea (14 patients), asymptomatic hypothyroidism (15 patients), fatigue (13 patients), and palpibular sensory loss erythema PPE (10 patients). Of the 19 patients who could be evaluated for efficacy, 5 completed the full treatment cycle and 6 had tumor size reductions in the 8th treatment cycle
The therapeutic effect of cabozantinib on patients with PN is obvious. Of the 19 patients who could be evaluated for efficacy, 8 (42%) achieved a partial response (PR), 11 were stable (SD), and no patients experienced tumor progression. PN tumor volume decreased by an average of 15.2% (range: +2.2% to -36.9%). Among them, 3 patients maintained the same tumor volume after drug reduction or continued to decrease. The results of the trial did not differ significantly in tumor location, tumor size, and demographic characteristics.
Cabozantinib Drug Response: a: Drug Response Waterfall Chart B: Treatment Response Time
In summary, the results of phase II clinical trials show that cabozantinib is safe and effective in the treatment of NF1-related PN. Patients tolerated cabotinib well, and a partial response rate of 42% was currently the best record for PN treatment in adolescents and adults. In addition, patient self-reports showed that the degree of reduction in the intensity of tumor pain reached clinical significance, the interference with pain in the patient's 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 Trial Consortium recently conducted two clinical studies, including a phase II clinical study of cabozantinib in children with PN, and a study of mek inhibitor smetinib in the treatment of adult NF1-related PN, and these two clinical trials are still underway. Combining the results of these clinical trials with ongoing laboratory studies, the researchers will further explore the possibility of cabozantinib combined with MEK inhibitors in the treatment of PN.
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