Appeal type: Medical necessity
Decision: Overturned

Diagnosis: Cancer. 
Treatment: Pharmacy/Prescription Drugs. 
The insurer denied everolimus. 
The denial is overturned.

The patient is a female with relapsed glioblastoma multiforme (GBM). She initially presented with a diffuse optic pathway glioma that left her legally blind in both eyes and was treated with carboplatin/vincristine, lenalidomide, and TPCV (thioguanine, procarbazine, lomustine, and vincristine). However she presented with acute symptoms and magnetic resonance imaging (MRI) showed significant tumor progression and hydrocephalus. She had a ventriculoperitoneal (VP) shut placement and tumor biopsy. Biopsy confirmed an aggressive high-grade tumor that was B-Raf (BRAF)-V600E mutant. She was treated with cranial irradiation for 6 weeks and then oral chemotherapy with trametinib and dabrafenib, when again, MRI imaging showed recurrence of her disease. Another biopsy was performed that showed the tumor had a phosphatase and tensin homolog (PTEN) mutation as well as the BRAF mutation. She was again treated with cranial irradiation after the tumor resection, but MRI showed cerebral edema treated with steroids. She was given Avastin. However, she had more tumor progression, with new leptomeningeal disease affecting the cranial nerves and VP shunt malfunction. She had a revision of the shunt. The provider at this time has recommended a combination of treatment with everolimus and trametinib to slow tumor progression. The medical necessity of everolimus is under review.

The health plan's determination is overturned.

The requested treatment of Everolimus 2.5 milligrams (mg) tablet is medically necessary for this patient. This patient has a multiply-recurrent aggressive brain tumor that has failed multiple different types of treatment to include surgery, radiation therapy, and chemotherapy. The provider is currently recommending a treatment regimen of everolimus and trametinib and the everolimus is under review. As per the National Cancer Institute (NCI), treatment of recurrent high-grade gliomas is quite difficult with no clear treatment that would confidently lead to cure. Treatment options include radiation, surgery, chemotherapy, targeted therapy (such as everolimus) or immunotherapy. The BRAF gene fusion that is present in this patient's tumor is noted to be present in a small number of high-grade tumors and when present can be targeted for treatment.
Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Inhibition of mTOR by everolimus has led to decrease in cell proliferation, angiogenesis, and glucose uptake. As per the review by Jain et al, the combination of mTOR inhibitors and mitogen activated protein kinase (MEK) inhibitors may assist in avoiding emergent drug-resistance in BRAF-fusion driven gliomas. Sen et al noted similar findings where dual inhibition of BRAF and mTOR in these types of pediatric mutant brain tumors resulted in a partial response or stable disease in up to 60% of patients at 12 months. Cacchione et al. showed that up front treatment of pediatric gliomas with everolimus specifically leads to stable disease in a large percentage of patients. Everolimus is well tolerated and an effective treatment in terms of disease stability overall.
For this patient with a multiply-recurrent life-threatening brain tumor that has failed all other methods of treatment, the use of everolimus is clinically appropriate.  There are no other treatment options that can be recommended at this time, and the everolimus is appropriate given the specific tumor tissue seen in this case.
Therefore, based on the clinical information provided for review and the current peer-reviewed literature, standards of care in the field, the request for everolimus is medically necessary at this time.