(P 133) PHASE 2 COMBINATION REGIMEN WITH TALIMOGENE LAHERPAREPVEC (TVEC), NIVOLUMAB AND TRABECTEDIN FOR ADVANCED LEIOMYOSARCOMA [NCT# 03886311]

Objective: Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) is a safe and effective therapy in soft tissue sarcoma (STS). This study aims to determine the safety and efficacy of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS).

Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs).

Methods: Patients and Methods: A LMS subgroup of a larger study of 53 patients with advanced soft tissue sarcoma was evaluated for efficacy and safety of the combinatorial therapy. Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x10e8 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x10e6 PFU/ml) was initially given, followed by a total dose of 1x10e8 PFU/ml q 2 weeks depending on tumor size) three weeks later.

Results: Efficacy: There were 11 evaluable subjects (Modified Intention to Treat [mITT] patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-8). Best Overall Response (BOR) by RECIST v1.1 = 2 PR, 8SD and 1 PD (BOR Rate 18.2%). The disease control rate (PR+SD) was 91%. The median PFS was 8.1(range: 3- 18) months; 6-month PFS rate, 64%; median OS 18.2 months (range: 4- 32); 6-month OS rate, 82%. Response was not related to PD-L1 positivity but both patients with PR were ER+/PR+ and had uterine LMS. There were 15 evaluable subjects for OS analysis under the Intention-to-Treat (ITT) population. The median OS was 12 (range 1-32) months; 6-month OS rate, 60%.

Safety: Eight of 15 (53.3%) patients experienced at least one >= Grade 3 treatment-related adverse event. These grade 3/4 TRAEs include anemia (n=3), thrombocytopenia (n=3), neutropenia (n=1), increased ALT (n=1), increased GGT (n=1), decreased LVEF (n=1), dehydration (n=1), hyponatremia (n=1). There were no new safety signals noted in this study.

Conclusion: These results suggest that (1) The combination regimen using Talimogene Laherparepvec (TVEC), Nivolumab & Trabectedin is an effective second/third-line therapy for advanced leiomyosarcoma with manageable toxicity, (2) Response is not related to PD_L1 positivity and (3) The best responders are patients with ER+/PR+ uterine LMS.