Cancer immunotherapy using trabectedin and nivolumab in advanced soft tissue sarcoma: A retrospective analysis.

Abstract

40 Background: To restore innate tumor surveillance that is lost in cancer patients, a tumoricidal agent may have synergistic activity with an immune checkpoint inhibitor. Herein, we report on a retrospective analysis of our clinical experience using trabectedin, an alkylating agent, and nivolumab, a PD-1 inhibitor in advanced soft tissue sarcoma. Methods: Twenty previously 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. Safety/toxicity was analyzed using the NIH/NCI CTCAE v.4.03. Tumor responses were assessed by RECIST v1.1 and immune-related response criteria (irRECIST). Results: Histologic subtypes in 20 patients include undifferentiated pleomorphic sarcoma (UPS; n = 7), leiomyosarcoma (n = 5), synovial sarcoma (n = 2), myxoid liposarcoma (n = 4) and chondrosarcoma (n = 2). All patients had metastatic disease and a median of 4 lines of prior chemotherapy. Safety analysis (n = 20): Grade 3 treatment emergent adverse events include anemia (n = 2), fatigue (n = 1), decreased platelet count (n = 1), decreased granulocyte count (n = 1) and increased creatine kinase (n = 1). Efficacy analysis (n = 17): Seventeen 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), 7 stable disease, and 6 progressive disease, with best overall response rate of 23.5%, median progression free survival (PFS) of > 11.6 months (range: 2.3- > 16.9 months), median overall survival (OS) of > 14.2 months (4.5- > 24.0 months), 6 month PFS rate of 64.7%, and 6 month OS rate of 94.1%. In a Phase 3 study, the median PFS was 4.2 months using trabectedin alone (Demetri et al., 2015). Conclusions: Taken together, the data suggest that paired administration of trabectedin and nivolumab is safe, and that this chemo-/immuno-therapy approach has synergistic activity.

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…Our group is currently developing a trial of doxorubicin plus dual CTLA‐4/PD‐1 blockade. A previously reported retrospective review of one center's experience with trabectedin plus pembrolizumab reported a favorable safety profile and preliminary evidence of efficacy . However, a previous trial of cyclophosphamide with pembrolizumab, intended to target tumor‐associated macrophages and T regs in addition to checkpoint blockade, showed disappointing results with no objective responses in cohorts of HGUPS and leiomyosarcoma subtypes .…”

“…A previously reported retrospective review of one center's experience with trabectedin plus pembrolizumab reported a favorable safety profile and preliminary evidence of efficacy. 47 However, a previous trial of cyclophosphamide with pembrolizumab, intended to target tumor-associated macrophages and T regs in addition to checkpoint blockade, showed disappointing results with no objective responses in cohorts of HGUPS and leiomyosarcoma subtypes. 48 While these outcomes were not surprising for leiomyosarcoma, which has been shown to have an extremely low response rate to PD-1 monotherapy, 49,50 four of ten patients with HGUPS included in a study of pembrolizumab monotherapy had shown objective response.…”

Immune checkpoint inhibitors in sarcomas: a systematic review

“… 48 Furthermore, a retrospective analysis with nivolumab and trabectedin in advanced STS demonstrated safety and efficiency of this combination against sarcoma. 49 Wagner et al. combined trabectedin with avelumab against advanced LMS and LPS.…”

Nivolumab plus ipilimumab versus nivolumab in individuals with treatment-naive programmed death-ligand 1 positive metastatic soft tissue sarcomas: a multicentre retrospective study

“…These findings may be instructive when placed in the context of presently accessible treatment options for individuals with untreated MSTS [ 16 ]. The classic treatment for MSTS tends to be based on cytotoxic chemotherapy, with first-line therapy predictably accomplishing objective responses in 15–18% of individuals, with a median PFS of 4–6 months [ 7 , 17 ]. Activity beyond the first-line options tends to decline, with less than 10% of individuals reaching objective responses and a median PFS of 1–4 months [ 18 ].…”