(P 132) PHASE 1/2 COMBINATION REGIMEN WITH IPILIMUMAB (I), NIVOLUMAB (N), AND TRABECTEDIN (T) AS FIRST-LINE THERAPY FOR ADVANCED LEIOMYOSARCOMA [NCT03138161]

Objective: 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. Objectives: Primary: To evaluate best response by RECIST v1.1; Secondary: To evaluate progression-free survival at 6 months and overall survival.

Methods: A subgroup of patients who participated in the Phase 1/2 study of 101 patients included males and females ≥ 18 years of age with locally advanced unresectable or metastatic leiomyosarcoma (LMS) and measurable disease by RECIST v1.1. Objectives: Primary: To evaluate the DLT and MTD; Secondary: To evaluate the best response, PFS, OS, and incidence of adverse events. Treatment protocol: (I) 1 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 (recommended Phase 2 dose, RP2D).

Results: Twenty-six patients of 101 (35.6%) patients had advanced leiomyosarcoma. Three previously treated patients (PTPs) were enrolled in the Phase 1 study, and 23 previously untreated patients (PUPs) were enrolled in the Expanded Phase 2 study.
Safety Analysis (n=26). Thirteen of 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.
Efficacy analysis: Three of 3 (100%) PTPs in the Phase 1 study were evaluable for efficacy analysis, and 19/23 (84.6%) PUPs were evaluable for efficacy in the Phase 2 study. Phase 1 PTPs (n=3): 3 (100%) had stable disease (SD); Expanded phase 2, PUPs (n=19): 2CR, 4PR, 11SD, 2PD. Best 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%.

Conclusion: Taken together, this data suggests that first-line combinatorial therapy with I, N, and T may be (1) More effective than standard first-line therapy (doxorubicin) and (2) Safer than standard first-line therapy for advanced LMS. Randomized Phase 2 studies are planned to confirm these findings.