Phase IB/II Trial with Correlative Analyses of Doxorubicin plus Durvalumab Combination in Patients with Advanced Soft Tissue Sarcoma

Purpose: This open-label, phase IB/II study evaluated the efficacy and safety of standard-of-care doxorubicin combined with durvalumab (a programmed death 1 ligand [PD-L1] immune checkpoint inhibitor) in patients with advanced anthracycline-naïve soft tissue sarcoma (STS) and to identify patients who would most likely benefit from this combination treatment. Methods: This trial (NCT03802071) included patients with metastatic and/or recurrent STS not previously treated with anthracycline or a PD-1/PD-L1 inhibitor. Phase IB assessed the safety and tolerability of doxorubicin (level 1 [75 mg/m2]; level –1 [60 mg/m2]), in combination with durvalumab 1500 mg once every 3 weeks until documented disease progression or unacceptable toxicity. Phase II evaluated treatment efficacy, with the primary endpoint being the objective response rate (ORR). Results: As no dose-limiting toxicities were observed during the phase IB trial (n=3), the recommended phase II dose was 75 mg/m2 of doxorubicin. Of 41 evaluable patients, 1 (2.4%) achieved a complete response and 12 (29.3%) achieved a confirmed partial response, yielding an ORR of 31.7%. Median progression-free survival (PFS) was 7.6 months and median overall survival was 23.8 months. The most common treatment-related grade 3-4 adverse events were neutropenia (n=23, 53.4%), thrombocytopenia (n=6, 13.9%), and anemia (n=5, 11.6%). In prespecified exploratory correlative analyses, absence of RTK-RAS pathway genetic alterations (hazard ratio [HR], 6.446; 95% CI, 1.934-21.486; p=0.002) and high PD-1 expression (HR, 0.214; 95% CI, 0.071-0.649; p=0.006) were identified as independent predictors of longer PFS. Conclusions: Doxorubicin plus durvalumab combination therapy exhibited promising efficacy in advanced STS, with acceptable toxicity profile.