Keywords
Alkylating Agent; PD-1 Inhibitor; Chemo-/Immunotherapy; Soft Tissue Sarcoma; Immune Checkpoint Inhibitor
Abstract
Immune checkpoint inhibitors revive pre-existing immune responses that are suppressed in cancer. To restore innate tumour surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with certain immune checkpoint inhibitors. Herein, we report on our clinical experience using two FDA-approved drugs, trabectedin, a marine derived natural alkaloid with pro-apoptosis and immune modulator properties, in combination with nivolumab, a PD-1 immune checkpoint inhibitor, in advanced Soft Tissue Sarcoma (STS). Twenty-eight heavily pre-treated STS patients received trabectedin (1.5 mg/m2 Continuous Intravenous Infusion, CIV, for 24 hours) every 3 weeks, and nivolumab (3 mg/kg IV over 30 minutes) every 2 weeks. Retrospective analysis of safety/toxicity was conducted using the NIH/NCI CTCAE v.4.03. Tumour responses were assessed by RECIST v1.1 and irRECIST. Histologic subtypes in 28 patients include undifferentiated pleomorphic sarcoma (UPS; n=7), myofibroblastic sarcoma (n=1), leiomyosarcoma (n=6), synovial sarcoma (n=4), liposarcoma (n=6), chondrosarcoma (n=2), and Ewing sarcoma (n=2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n=28): Grade 3 treatment emergent adverse events include anaemia (n=2), fatigue (n=1), decreased platelet count (n=1), decreased granulocyte count (n=1) and increased creatine kinase (n=1). Efficacy analysis (n=22): Twenty-two patients were followed for at least 6 months and their results are reported here. There were 4 partial responses (UPS=1, myxoid liposarcoma=1, chondrosarcoma=1, leiomyosarcoma=1), 12 stable disease and 6 progressive disease, with best overall response rate of 18.2%, median progression free survival (PFS) of >45.4 weeks (range: 10->95 weeks), median Overall Survival (OS) of >66.5 weeks (10->95 weeks), 6 month PFS rate of 68.2%, and 6 month OS rate of 95.4%. Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno therapy approach has synergistic activity that can lead to improved clinical outcomes.
Citation
Chawla SP, Sankhala KK, Ravicz JR, Kang GE, Liu S, Assudani N, et al. Clinical Experience with Combination Chemo-/Immunotherapy using Trabectedin and Nivolumab for Advanced Soft Tissue Sarcoma. SM J Sarcoma Res. 2018; 2(1): 1009.