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
Mené sur 28 patients atteints d'un sarcome des tissus mous de stade avancé ou métastatique, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression à 6 mois, et la toxicité d'un traitement combinant doxorubicine, zalifrélimab (un anticorps anti-CTLA-4) et balstilimab (un anticorps anti-PD-1)
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.
Clinical Cancer Research , résumé, 2025