(P 234) DOXORUBICIN PLUS BOTENSILIMAB, A NEXT GENERATION CTLA4 INHIBITOR, WITH OR WITHOUT BALSTILIMAB, A PD1 INHIBITOR, IN PATIENTS WITH ADVANCED SOFT TISSUE SARCOMAS

Objective: Most soft tissue sarcomas (STSs) are immune cold and do not respond to immune checkpoint inhibitors (ICIs) blocking PD1 and CTLA4. Botensilimab (BOT) is an Fc-enhanced, next generation CTLA4 inhibitor engineered to improve T cell priming and activation. Treatment with BOT plus PD1 inhibitor balstilimab (BAL) induced responses in heavily pre-treated immune cold STS pts in a Phase 1 trial. We hypothesized that concurrent doxorubicin (DOX) would improve STS immunogenicity and boost efficacy of ICIs, including BOT with or without BAL.

Methods: We expanded a previously reported Phase 2 trial of DOX plus first-generation CTLA4 inhibitor zalifrelimab (ZAL) plus BAL (NCT04028063). Pts with no prior DOX/ICIs were enrolled to 1 of 3 dose levels: DOX 60 mg/m2 every 3 weeks (q3w) plus BOT 75 mg IV every 6 weeks (q6w); DOX 75 mg/m2 q3w plus BOT 75 mg q6w; or DOX 75 mg/m2 q3w plus BOT 75 mg q6w and BAL 450 mg IV q3w. Primary endpoints were incidence of dose-limiting toxicities (DLTs) within the first 6 wks, using time to Bayesian optimal interval (TITE-BOIN) design and treatment-related adverse events (TRAEs). Secondary endpoints included progression-free survival rate at 6 months (PFS6mo), objective response rate (ORR), disease control rate (DCR), overall survival (OS), and duration of response (DoR).

Results: 21 pts were evaluable for safety and 18 for efficacy. 20 pts (95%) experienced at least 1 TRAE. Most frequent TRAEs were GI (81% of pts), systemic fatigue or flu-like symptoms (62%), hematologic AEs (52%), rash (43%), mucositis (33%), and febrile neutropenia (29%); most were related to DOX. Immune-related TRAEs occurred in 14 pts (67%), with 8 (38%) requiring steroids/anti-TNF-a therapy. 6 pts had colitis (29%), including 1 with concurrent gastroparesis, and 2 other pts had diarrhea not requiring steroids. 3 pts had pneumonitis related to BAL (n=2) or BOT (n=1). Other immune AEs not requiring steroids included thyroid abnormalities (19%), pancreatitis (19%), unilateral hearing loss (DLT, n=1), and adrenal insufficiency (n=1). The ORR was 33.3% [95%CI 13-59], with median DoR of 20.9 wks [range 11-36], and DCR of 83% [59-96]. Median PFS was 25.4 wks [17.9-NA], with PFS6mo of 38.5% (13 evaluable). Median OS was 93.9 wks [68.3-NA].

Conclusion: DOX with BOT +/- BAL exhibits safety and efficacy consistent with prior experience of DOX/ZAL/BAL. Further investigation is needed to determine biomarkers of response/resistance and the optimal timing/sequence of DOX/ICIs to further improve outcomes.