A phase I study of the CSF1R inhibitor vimseltinib in combination with the PD-L1 inhibitor avelumab in patients with advanced sarcoma Journal Article
| Authors: | Rosenbaum, E.; Seier, K.; Bradic, M.; Movva, S.; Kelly, C. M.; Dickson, M. A.; Keohan, M. L.; Gounder, M. M.; Chi, P.; Nacev, B. A.; Chan, J. E.; Avutu, V.; Biniakewitz, M.; Jasnani, S.; Duchemin, M.; Desir, R.; Wong, P.; Erinjeri, J.; Hwang, S.; Antonescu, C. R.; Qin, L. X.; Tap, W. D.; D'Angelo, S. P. |
| Article Title: | A phase I study of the CSF1R inhibitor vimseltinib in combination with the PD-L1 inhibitor avelumab in patients with advanced sarcoma |
| 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. © 2025 The Author(s) |
| Keywords: | sarcoma; immunotherapy; macrophages; pd-1; csf1r |
| Journal Title: | ESMO Open |
| Volume: | 10 |
| Issue: | 8 |
| ISSN: | 2059-7029 |
| Publisher: | European Society for Medical Oncology |
| Date Published: | 2025-08-01 |
| Start Page: | 105522 |
| Language: | English |
| DOI: | 10.1016/j.esmoop.2025.105522 |
| PROVIDER: | scopus |
| PMCID: | PMC12314374 |
| PUBMED: | 40714516 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is E. Rosenbaum -- Source: Scopus |
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