A new clinical trial offers insight into tackling one of the biggest challenges in soft tissue sarcomas (STS): resistance to immunotherapy due to an immunosuppressive tumor microenvironment (TME). The phase II REGOMUNE study evaluated the combination of regorafenib, a multityrosine kinase inhibitor targeting VEGFR2, and the PD-L1 immune checkpoint blocker avelumab in patients with advanced STS lacking mature tertiary lymphoid structures (mTLS), a characteristic of so-called “cold” tumours.
The trial enrolled 49 patients with mTLS-negative STS, including leiomyosarcoma (45%) and synovial sarcoma (18%). The combination therapy achieved an objective response rate of 11%, with a median progression-free survival of 1.8 months and a median overall survival of 15.1 months.
Although modest in tumor shrinkage, the therapy showed promising biological activity. Immunofluorescence analysis revealed significant increases in CD8+ T cells and B cell infiltration, along with higher PD-1 expression on immune cells, indicating enhanced immune activation. Plasma analysis also showed increased levels of soluble PD-L1 and markers of tryptophan metabolism, both linked to immune regulation.
Common side effects included mild to moderate fatigue, diarrhoea, and hand-foot skin reactions.
The study underscores the complexity of treating cold sarcomas and supports continued exploration of combination therapies to improve outcomes in this difficult-to-treat cancer.
Reference
Toulmonde M et al. Reshaping the tumor microenvironment of cold soft-tissue sarcomas with anti-angiogenics: a phase 2 trial of regorafenib combined with avelumab. Signal Transduction and Targeted Therapy. 2025;10:202.
