In this multicenter clinical trial, we assessed the role of everolimus therapy in patients with advanced cancer in different body sites. Everolimus has been FDA-approved for the treatment of renal cell carcinoma and pancreatic tumors; it has also shown activity in multiple tumors occurring in the Tuberous Sclerosis Complex disorder, due to mutations in TSC1/TSC2 genes. Several reports have indicated exceptional responses to everolimus therapy in occasional patients with TSC1 or TSC2 mutations, including patient with bladder cancer with concurrent TSC1–NF2 mutations. These findings prompted us to carry out a study of everolimus for treatment of cancers of any histology that had an inactivating mutation in TSC1 or TSC2. In the cohort of 30 subjects, we sought to identify other factors that might play a role in determining response to everolimus, including pathology, clinical features and co-occurring mutations in other genes. Everolimus therapy showed low overall clinical benefit (4 of 30 patients, 13%) in this clinical trial. Genetic analysis (whole exome sequencing) indicated that two of 4 patients with clinical benefit had uterine cancer with concurrent TSC2-NF1 inactivating mutations; one had perivascular epithelial cell tumor (PEComa-like) features. PEComa features and/or TSC2–NF1 concurrent mutations were associated with favorable response to everolimus.
In this multicenter, histology-agnostic, single-arm prospective phase II trial we assessed the efficacy and safety of everolimus – an oral mTORC1 inhibitor – in patients with advanced solid tumors harboring TSC1/TSC2 or MTOR mutations. Clinical benefit was defined as partial/complete response, or stable disease for longer than 22 weeks with radiographic tumor shrinkage. Whole-exome sequencing was performed to identify other genomic alterations. 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan-Kettering Cancer Center. Patients’ tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30) or MTOR (1/30) mutations. The most common cancer sites were bladder (6/30, 20%) and uterus (5/30, 16.7%). Partial responses were seen in two patients (6.7%, 95% CI: 0.8% to 22%). Clinical benefit was observed in four patients (13.3%, 95% CI: 3.8% to 31%). Median progression-free survival (PFS) was 2.3 months (95% CI: 1.8 to 3.7 months) and median overall survival (OS) was 7.3 months (95% CI: 4.5 to 12.7 months). Two of 4 patients with clinical benefit had uterine leiomyosarcoma with concurrent TSC2-NF1 inactivating mutations; one had PEComa-like pathologic features. Everolimus therapy showed low overall clinical benefit (13%) in this pan-cancer basket study. PEComa features and TSC2–NF1 concurrent mutations were associated with favorable response.