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 (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.

Patients and methods: 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).

Results: 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%.

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.

Figure 1.

In this CONSORT diagram, patients evaluable for safety received a protocol-conforming dose of at least one of the study drugs. Patients evaluable for efficacy received at least one dose of all study drugs and had at least one post-baseline imaging study or clinical progression. Patients who withdrew from study treatment for any reason other than radiographic or clinical progression were replaced for evaluation of the primary endpoint. *One patient had an AE during infusion of the study drug and did not complete the full dose. Another patient had a study drug dosage calculated on erroneous weight, which led to underdosing per protocol. Dox, doxorubicin.

Figure 2.

Efficacy evaluation for all patients. A, Kaplan–Meier curve showing PFS calculated from the time of baseline scan (first dose of doxorubicin). B, Waterfall plot showing the best objective response by RECIST 1.1. CCS, clear cell sarcoma; PD, progressive disease; uLMS, uterine LMS.

Figure 3.

OS for all patients. Kaplan–Meier curve showing OS for efficacy-evaluable patients calculated from the date of baseline scan. NA, not reached; OS, overall survival.

Figure 4.

Time course and durability of responses for efficacy-evaluable patients (n = 30). A, Spider plot showing change in tumor measurements over the course of the study, starting at baseline scan (cycle 2 for stage 1 patients, screening scan for stage 2 patients). B, Swimmer plot showing timing and duration of tumor responses by RECIST 1.1 and reasons for discontinuation of study. Bars reflect time from treatment start to the most recent available scan on study follow-up. Black bars represent patients treated past radiographic progression. Immune priming cycle (St1–C1) shown as gray bar for stage 1 patients. Dashed vertical lines reflect the last dose of doxorubicin (Dox) or the primary endpoint (24 weeks), CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.