An open label, phase 1b/2 trial of LVGN6051 (4-1BB agonistic antibody) combined with anlotinib for refractory soft tissue sarcoma (STS).

11554 Background: Refractory soft tissue sarcoma has limited treatment options. LVGN6051 is a conditional 4-1BB agonistic mAb with Fc γ-receptor IIB selective binding in the tumor microenvironment for optimal activity. Anlotinib has been approved for STS in China. Combining immune agonistic and anti-angiogenetic agents for refractory STS warrants a clinical study. Methods: We conducted phase 1b dose finding with a 3+3 design and phase 2 efficacy exploration by tumor response with Simon's two-stage design. Eligible pts with anthracycline refractory locally advanced or metastatic STS received escalating doses of LVGN6051 (1, 2, 3, 4 mg/kg) I.V. q3w plus anlotinib 10 mg or 12 mg per body surface area P.O. day 1-14 q3w in phase 1b, and RP2D as LVGN6051 3 mg/kg plus a standard dose of anlotinib in Phase 2. Results: As of Jan 22, 2024, a total of 39 pts, 18 in phase 1b and 21 in phase 2, were enrolled and received study treatment with LVGN6051 and anlotinib. The median age was 40 years (range 21-66), and the median number of prior systemic therapies was 2; 31 pts (79%) had ECOG PS 1, and 20 pts (51%) had received prior immune checkpoint inhibitors (ICI). In phase 1b, 1 DLT was observed in the LVGN6051 3 mg/kg plus anlotinib cohort and 2 DLTs in the LVGN6051 4 mg/kg plus anlotinib cohort. All those 3 DLTs were Gr 4 thrombocytopenia. LVGN6051 3 mg/kg IV Q3W plus a standard dose of anlotinib was selected as RP2D. Phase 1b/2 pts received a median of 3 cycles and a mean of 6.0 cycles (range 1.0 – 20.0) of study treatment. 38 out of 39 pts (97.44%) experienced any grade treatment-related adverse events (TRAEs). 24 pts (61.54%) showed ≥ grade 3 TRAEs, of which >10% TRAEs included thrombocytopenia (43.59%), AST increased (12.82%), WBC count decreased (10.26%), and neutrophil count decreased (10.26%). Most TRAEs occurred during the first or second cycle of study treatment and were transient, which recovered within 1-2 weeks with clinical symptomatic treatment. Per RECIST 1.1, in 29 efficacy-evaluable pts, the disease control rate was 86.21% with 2 PR and 23 SD. The two PR pts: 1 leiomyosarcoma got a tumor shrinkage of 40.3% at week 21 and now a total of 12 cycles of study treatment, and 1 undifferentiated pleomorphic sarcoma got 36.01% at week 6 and now 3 cycles. Among the SD pts, 4 reached near-PR: 1 synovial sarcoma got 29.03% at week 12 and now 14 cycles, 1 alveolar soft part sarcoma (ASPS) got 28.57% at week 6 and now 14 cycles, 1 epithelioid sarcoma got 28.72% at week 30 and now 10 cycles, and another ASPS got 28.45% at week 57 and now 19 cycles. All above PR and near-PR pts are still under study treatment. Conclusions: LVGN6051 plus anlotinib was well tolerated, and the RP2D is LVGN6051 3 mg/kg plus a standard dose of anlotinib. The combination showed preliminary and encouraging efficacy for refractory STS. As the study is ongoing, additional data will further validate the safety and efficacy of such combination therapy for refractory STS. Clinical trial information: NCT05301764 .