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

Purpose: Doxorubicin is standard chemotherapy for metastatic soft tissue sarcomas (STSs) but also enhances innate/adaptive immune responses by inducing immunogenic cell death. Most STSs are immune “cold” tumors that do not respond to immune checkpoint inhibitors (ICIs) blocking PD-1 and CTLA-4. We hypothesized that concurrent doxorubicin would improve tumor immunogenicity and boost efficacy of ICIs in STS. Patients and Methods: We conducted a single arm, phase 2 trial of doxorubicin plus zalifrelimab (anti-CTLA-4 antibody) and balstilimab (anti-PD-1 antibody) for advanced/metastatic STS patients without prior doxorubicin or ICIs (NCT04028063). The study was a Simon minimax two-stage design to accrue 28 patients evaluable for primary endpoint of progression-free survival rate at six months (PFS6mo) by RECIST 1.1. The study aimed to improve PFS6mo by 20% over historical null rate of 43.4% with doxorubicin monotherapy. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and adverse events (AEs). Results: PFS6mo for 28 evaluable patients was 46.4% [95% CI 27.5-66.1] and not superior to null rate, with median PFS of 25.3 weeks [95% CI 24.0-42]. Best ORR was 33.3% [95% CI 17.3-52.8] with DCR of 80.0% [95% CI 61.4-92.3], including STS types unlikely to respond to doxorubicin or ICIs alone. Grade 3/4 treatment-related AEs occurred in 45% of patients, with immune-mediated AEs requiring immunosuppression in 9%. Conclusions: 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.