Impact of metronomic trabectedin combined with low-dose cyclophosphamide on sarcoma microenvironment and correlation with clinical outcome: results from the TARMIC study.

Abstract

Soft tissue sarcomas (STS) are diverse mesenchymal tumors with few therapeutic options in advanced stages. Trabectedin has global approval for treating STS patients resistant to anthracycline-based regimens. Recent pre-clinical data suggest that trabectedin's antitumor activity extends beyond tumor cells to influencing the tumor microenvironment (TME), especially affecting tumor-associated macrophages and their pro-tumoral functions. We present the phase I/II results evaluating a combination of metronomic trabectedin and low-dose cyclophosphamide on the TME in patients with advanced sarcomas. 50 patients participated: 20 in phase I and 30 in phase II. Changes in the TME were assessed in 28 patients using sequential tumor samples at baseline and day two of the cycle. Treatment notably decreased CD68 + CD163 + macrophages in biopsies from tumor lesions compared to pre-treatment samples in 9 of the 28 patients after 4 weeks. Baseline CD8 + T cell presence increased in 11 of these patients. In summary, up to 57% of patients exhibited a positive immunological response marked by reduced M2 macrophages or increased CD8 + T cells post-treatment. This positive shift in the TME correlated with improved clinical benefit and progression-free survival. This study offers the first prospective evidence of trabectedin's immunological effect in advanced STS patients, highlighting a relationship between TME modulation and patient outcomes.This study was registered with ClinicalTrial.gov, number NCT02406781.

• Authors: Cheng-Ming Sun, Maud Toulmonde, Mariella Spalato-Ceruso, Florent Peyraud, Alban Bessede, Michèle Kind, Sophie Cousin, Xavier Buy, Jean Palussiere, Antoine Bougouin, Catherine Sautès-Fridman, Hervé Wolf Fridman, Marina Pulido, Antoine Italiano
• Journal: Molecular cancer (Mol Cancer) Vol. 23 Issue 1 Pg. 37 (02 19 2024) ISSN: 1476-4598 [Electronic] England
• PMID: 38374062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2024. The Author(s).

Chemical References

• Trabectedin
• Antineoplastic Agents, Alkylating
• Cyclophosphamide
• Dioxoles

Topics

• Humans
• Trabectedin (therapeutic use)
• Prospective Studies
• Antineoplastic Agents, Alkylating (therapeutic use)
• Sarcoma (drug therapy, pathology)
• Cyclophosphamide (therapeutic use)
• Dioxoles
• Tumor Microenvironment