A phase I study of the CSF1R inhibitor vimseltinib in combination with the PD-L1 inhibitor avelumab in patients with advanced sarcoma.

J E Chan, S P D'Angelo, W D Tap, L-X Qin, C R Antonescu, J Erinjeri, P Wong, R Desir, M Duchemin, S Jasnani, M Biniakewitz, V Avutu, M L Keohan, B A Nacev, P Chi, M M Gounder, S Movva, M Bradic, K Seier, E Rosenbaum, S Hwang, M A Dickson, C M Kelly

Journal: ESMO open 2025;10(8):105522

PMID: 40714516

Free Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Sarcomas are frequently infiltrated with immunosuppressive myeloid cells. Vimseltinib is an inhibitor of the colony-stimulating factor 1 receptor kinase and has been shown to decrease tumor-infiltrating myeloid cells in preclinical models. We hypothesized that vimseltinib combined with the Programmed death-ligand 1 (PD-L1) inhibitor avelumab would be safe, tolerable, and clinically effective in patients with advanced sarcoma.

METHODS

This was a phase I study of vimseltinib plus avelumab in patients with unresectable or metastatic sarcoma. The study used a standard 3 + 3 dose-escalation design, followed by dose expansion in patients with select histological subtypes. Vimseltinib was administered daily by mouth in 28-day cycles; avelumab was administered intravenously every 2 weeks. The primary objectives of the dose-escalation and dose-expansion phases were to determine the recommended phase II dose and to estimate the best objective response rate by RECIST version 1.1.

RESULTS

Thirteen patients were treated in the dose-escalation phase, and 19 patients were treated in the dose-expansion phase. The most common treatment-related adverse events were asymptomatic increases in serum levels of amylase, lipase, creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase. One of six patients treated at the highest dose level had a dose-limiting toxicity (grade 4 increase in aspartate aminotransferase). The highest dose level was determined to be the recommended phase II dose. There were no objective responses. The median progression-free survival of patients treated at the recommended phase II dose was 1.55 months (95% confidence interval 1.25-1.78 months). Flow cytometric analysis of peripheral blood mononuclear cells revealed a decrease in myeloid-derived suppressor cells and regulatory T cells after treatment. RNA sequencing of paired tumor samples revealed an increase in tumor-infiltrating T cells and a decrease in macrophages after treatment.

CONCLUSIONS

Vimseltinib plus avelumab was generally safe and well tolerated. This combination had minimal clinical efficacy in our population of heavily pretreated patients with sarcoma.

Address: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, USA. Electronic address: [email protected].; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA.; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA.; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.; Immune Monitoring Facility, Memorial Sloan Kettering Cancer Center, New York, USA.; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.

DOI: 10.1016/j.esmoop.2025.105522