Appeal type: Experimental/Investigational
Decision: Overturned

Diagnosis: Neurofibromatosis, type 2
Treatment: Everolimus
The insurer denied Everolimus.
The determination is overturned.

This patient has a diagnosis of neurofibromatosis type 2 (NF2) associated with multiple intracranial meningiomas, status surgical resection times two (x2) and proton beam radiotherapy, bilateral vestibular schwannomas, left leg perineuroma status post-surgical resection and nerve transfer, and a cervical (C) 4 schwannoma. The patient has been noted on recent imaging to have stable enhancement along the right optic nerve within the orbit concerning for an intraorbital optic nerve sheath meningioma. Her care team is concerned about risks to her vision and hearing due to these NF2-associated tumors. She is no longer a candidate for surgical intervention and the response to radiotherapy was sub-optimal. Therefore, they have recommended medical therapy with Everolimus, a mammalian target of rapamycin complex 1 (mTORC1) inhibitor, which has been shown to be effective in stabilizing tumor growth in NF2 patients. Coverage for Everolimus has been denied by the patient's health plan and is under review.

NF2 is a rare autosomal-dominant tumor predisposition syndrome caused by a mutation in the NF2 gene at chromosome 22q11.1, manifesting with multiple tumors including vestibular schwannomas, associated with hearing loss, tinnitus, and/or balance disturbances, schwannomas of other cranial, spinal, and cutaneous nerves, cranial and spinal meningiomas, and/or other central nervous system tumors (eg ["for example"], ependymomas and astrocytomas). Additional organ systems that may be affected include the eye (eg, early onset cataracts, optic nerve sheath meningiomas, retinal or pigment epithelial hamartomas, and epithelial retinal membranes) and skin abnormalities (eg, plaques, subcutaneous nodular schwannomas, and cafe-au-lait spots). Merlin, the NF2-encoded protein, has been identified as a novel negative regulator of mTORC1, which plays a role in cellular proliferation. Functional loss of merlin leads to over-expression of mTORC1 in NF2, allowing for uncontrolled tumor growth. Pre-clinical in vitro and in vivo studies have shown that mTORC1 inhibition by Everolimus reduced the severity of NF2-related Schwann cell tumorigenesis in several relevant in vitro without significant toxicity. Based on these findings, a Phase II study was conducted to evaluate the efficacy of Everolimus in patients with NF2. The results showed that 5 of 9 patients (55 percent [%]) had stable disease with a median annual growth rate decreasing from 67%/year before treatment to 0.5%/year during treatment, which is very encouraging and it was well tolerated. Everolimus is Food and Drug Administration (FDA)-approved for treatment of tuberous sclerosis complex- related tumors in children so pediatric dosing is established. While not FDA-approved as of yet for NF2 as more studies are needed, the standard of care in the current landscape of medicine with advanced knowledge of the molecular basis of disease, is to offer molecularly-targeted therapy when appropriate, especially when other front line therapies have failed.

The patient under review has bilateral vestibular schwannomas which may start to cause symptoms such as impaired hearing, tinnitus, or vertigo if they grow in size. She also has several meningiomas including an optic meningioma which may threaten her vision if allowed to grow. She has exhausted upfront treatment strategies including surgical resections and radiation therapy and is no longer considered a candidate for either. Based on the available data regarding the efficacy of mTORC1 inhibition in curbing growth of NF-related tumors, it is reasonable to try an mTORC1 inhibitor for this patient at this time. The proposed treatment of Everolimus 5 milligrams is likely to be more beneficial than any standard treatment for this child's disabling condition.