Phase 2 study using talimogene laherparepvec, nivolumab, and trabectedin for advanced leiomyosarcoma and liposaroma (NCT03886311).

Abstract

e23560 Background: Advances in gene therapy/immunotherapy present the opportunity to further improve established treatment combinations for soft tissue sarcoma. Here, we present the results of a phase 2 study combining the chemo-immunotherapy regimen of intravenous Trabectedin (T) and Nivolumab (N), with intratumoral Talimogene Laherparepvec (TVEC), a genetically modified Herpes simplex Type 1 oncolytic virus expressing GM-CSF, which evokes a cytotoxic immune response. Methods: Objectives: Primary: To assess progression-free survival (PFS); Secondary: (1) To evaluate the best overall response (BOR) by RECIST v1.1, disease control rate (DCR), 6 month PFS rate, 6 month overall survival (OS) rate, and Incidence of treatment-related adverse events (TRAEs). Key eligibility criteria: ≥ 18 years, locally advanced unresectable or metastatic LMS/LPS, measurable disease by RECIST v1.1, at least one accessible tumor for TVEC intratumoral injection; adequate hematologic and organ function; no concurrent clinical trial; no known hypersensitivity to study drugs; no known autoimmune disorder. Study Design: This is an open label single center phase 2 study. Treatment schedule: N (240 mg i.v. q 2 weeks), T (1.2 mg/m2 i.v. q 3 weeks), and TVEC (1x10e8 PFU intratumorally q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x10e 6 PFU) was initially given, followed by a dose of 1x10e8 PFU q 2 weeks (according to tumor size) three weeks after the test dose. Results: Efficacy: The modified-intention-to-treat population (n=24), which includes patients who completed at least one treatment cycle and had a follow-up CT/MRI was used. Median PFS = 8.0 (95% CI: 4.1- 17.8) months; BOR = 2 PR, 18 SD, 4 PD; DCR = 83.3%; 6 month PFS rate = 62.5%; 6-month OS rate = 87.5%. Safety: The intention-to-treat population (n=35), which includes patients who received at least one dose of T, N, and TVEC, was used to determine safety and overall survival. Median OS = 19.2 (95% CI: 10.2- 37.9) months. Eighteen of 35 patients (51%) experienced Grade 3 TRAEs that included anemia (n=4), fatigue (n=3), ALT increased (n=3), AST increased (n=3), thrombocytopenia (n=3), abdominal pain (n=2), myalgia (n=2), localized edema (n=2), injection site pain (n=2), alkaline phosphatase increased (n=1), LVEF decreased (n=1), pain in extremity (n=1), neutropenia (n=1), colitis (n=1), headache (n=1), flu-like symptoms (n=1). There were no ≥ Grade 4 or unexpected adverse events. Conclusions: Taken together, the results indicate that the combination regimen of Talimogene laherparepvec, Nivolumab, and Trabectedin may be more effective than Trabectedin alone (Median PFS 4.1 months) as treatment for previously treated patients with advanced leiomyosarcoma and liposarcoma with manageable toxicity. A randomized phase 2 clinical trial is warranted to confirm these promising results. Clinical trial information: NCT03886311 .