LAUSR

Background/Aim: Advanced sarcoma has a poor prognosis. Dysregulation of the mammalian target of rapamycin (mTOR) occurs in various types of cancer. We aimed to determine the safety and efficacy of mTOR inhibitor nab-sirolimus when combined with the immune checkpoint inhibitor nivolumab. Patients and Methods: Previously treated patients ≥18 years with confirmed diagnosis of advanced sarcoma or tumor with mutations in the mTOR pathway were treated with 3 mg/kg nivolumab intravenously every 3 weeks; escalating doses of nab-sirolimus at 56, 75 or 100 mg/m2 were administered intravenously on days 8 and 15 beginning in cycle 2. The primary aim was to determine the maximum-tolerated dose; we also determined disease control, objective response, progression-free survival, overall survival, and correlation between response using Immune-related Response Evaluation Criteria for Solid Tumors (irRECIST) versus RECIST v1.1. Results: The maximum-tolerated dose was 100 mg/m2. There were two patients with partial response, 12 with stable disease and 11 with progressive disease. Median progression-free and overall survival were 12 and 47 weeks, respectively. The best responders (partial responses) were patients with undifferentiated pleomorphic sarcoma with loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), tuberous sclerosis complex 2 (TSC2) mutation and estrogen receptor-positive leiomyosarcoma. Treatment-related adverse events of grade 3 or more included thrombocytopenia, oral mucositis, rash, hyperlipidemia and increased serum alanine aminotransferase. Conclusion: The data indicate that (i) treatment with nivolumab plus nab-sirolimus is safe with no unexpected adverse events; (ii) treatment outcome parameters were not improved by combining nivolumab with nab-sirolimus; and (iii) best responders were patients with undifferentiated pleomorphic sarcoma with PTEN loss and TSC2 mutation and estrogen receptor-positive leiomyosarcoma. Future direction in sarcoma research with nab-sirolimus will be biomarker-based (TSC1/2/mTOR, tumor mutational burden/mismatch repair deficiency etc.).