1483O - Results of a phase I/II combination regimen with ipilimumab (I), nivolumab (N) and trabectedin (T) as first line therapy for advanced leiomyosarcoma

Background

A 5-year phase I/II with an expanded phase II study of 101 patients has been recently reported. A subgroup of patients with advanced leiomyosarcoma (LMS) participated in the study. Hypothesis: Sarcoma tumors are more immunogenic at the onset of disease. Immune checkpoint inhibitors that promote sustained T cell activation would be most effective when given as first line therapy, together with a tumoricidal agent such as Trabectedin that depletes growth promoting macrophages in the tumor microenvironment.

Methods

A subgroup of patients (Total: 101 patients with advanced soft tissue sarcoma) included males or females ≥ 18 years of age with locally advanced unresectable or metastatic LMS and measurable disease by RECIST v1.1. Objectives: Primary: To evaluate the DLT and MTD; Secondary: To evaluate response, PFS and OS and incidence of adverse events. Treatment protocol: (I) mg/kg i.v. q 12 wks, (N) 3 mg/kg i.v. q 2 wks, (T) 1.2 mg/m² CIV q 3 wks.

Results

Twenty-six of 101 patients enrolled had advanced leiomyosarcoma. Safety Analysis (n=26). 13/26 (50%) had a > Grade 3 TRAE: cellulitis =2; inc. AST=2; inc. ALT = 5; dec. platelet ct =1; dec. WBC =1; fatigue =2; anemia =2; inc. alk phos = 1; dec TSH = 1; inc. TSH = 1; inc. T4 = 1; inc. CK = 1. There was no incidence of alopecia nor cardiac toxicity reported. The MTD for T was 1.2 mg/m². Efficacy analysis: 22/26 (84.6%) patients were evaluable for efficacy. Phase 1 previously treated (n=3): 3 (100%) had stable disease (SD); Expanded Phase 2, previously untreated (n=19): 2CR, 4PR, 11SD, 2PD. Overall response rate was 31.6%, Disease Control Rate, 89.5%. The median PFS was 7.4 (range: 1.2 - 33.6) months, median OS, 36.1 (range: 1.6 - 45.8) months; 6 month PFS = 63.2%; 6 month OS = 89.5%.

Conclusions

Taken together, these data suggest that first-line combinatorial therapy with Ipilimumab, Nivolumab and Trabectedin may be (1) More effective than standard first line therapy, and (2) Safer than standard first line therapy for advanced LMS. Randomized Phase 2 studies are planned to confirm these findings.

Clinical trial identification

NCT03138161.

Editorial acknowledgement

Legal entity responsible for the study

Sarcoma Oncology Center.

Funding

Bristol Myers Squibb.

Disclosure

All authors have declared no conflicts of interest.