Pilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma

PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced >= 1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts. The activity of PD-1 blockade in patients with sarcoma has been modest so far. Here, the authors report the results of a pilot clinical trial to assess the efficacy and safety of bempegaldesleukin, a CD122-preferential interleukin-2 (IL-2) pathway agonist, in combination with the PD1 blockade (nivolumab) in patients with locally advanced or metastatic high-grade sarcoma.

Automated summary

This study investigates the efficacy and safety of bempegaldesleukin in combination with nivolumab for refractory sarcoma, and explores potential predictive biomarkers. The results demonstrate higher response rates in specific subtypes of sarcoma, with correlation to CD8+ T cell infiltrates and PD-1 expression. Additionally, upregulation of immune-related pathways and Hedgehog signaling are associated with improved efficacy and resistance, respectively. Further research is needed to assess the effectiveness of this combination therapy in larger patient cohorts and explore the potential of Hedgehog signaling as a predictive biomarker.