A Single-Arm Phase 2 Trial of Doxorubicin Plus Zalifrelimab (Anti-CTLA-4 Antibody) and Balstilimab (Anti-PD-1 Antibody) in Advanced/Metastatic Soft Tissue Sarcomas.

Abstract

Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STS) but also enhances innate/adaptive immune responses by inducing immunogenic cell death. Most STS are immune "cold" tumors that do not respond to immune checkpoint inhibitors (ICI) blocking PD-1 and cytotoxic T lymphocyte antigen-4. We hypothesized that concurrent doxorubicin would improve tumor immunogenicity and boost the efficacy of ICI in STS. We conducted a single-arm, phase 2 trial of doxorubicin plus zalifrelimab (anti-cytotoxic T lymphocyte antigen-4 antibody) and balstilimab (anti-PD-1 antibody) for patients with advanced/metastatic STS without prior doxorubicin or ICI (NCT04028063). The study was a Simon minimax two-stage design to accrue 28 patients evaluable for primary endpoint of progression-free survival rate at 6 months (PFS6mo) by RECIST 1.1. The study aimed to improve PFS6mo by 20% over a historic null rate of 43.4% with doxorubicin monotherapy. Secondary endpoints included the objective response rate, disease control rate, overall survival, duration of response, and adverse events (AE). The PFS6mo for 28 evaluable patients was 46.4% [95% confidence interval (CI), 27.5-66.1] and not superior to the null rate, with a median PFS of 25.3 weeks (95% CI, 24.0-42). The best objective response rate was 33.3% (95% CI, 17.3-52.8) with a disease control rate of 80.0% (95% CI, 61.4-92.3), including STS types unlikely to respond to doxorubicin or ICI alone. Grade 3/4 treatment-related AE occurred in 45% of patients, with immune-mediated AE requiring immunosuppression in 9%. Although the study did not meet the predefined endpoint for PFS improvement, promising signals of efficacy warrant future investigation including response/resistance biomarkers to inform patient selection.