Combination therapy in sarcomas and the challenges of heterogeneity

The outcome for patients with advanced sarcomas remains poor with few novel therapies approved over the last 40 years. Doxorubicin remains the cornerstone of first-line therapy either as single agent or in combination (1). It could be argued that the superiority of combination therapy compared to sequential single agent treatment in advanced disease remains unanswered. Doxorubicin and ifosfamide are significantly more effective than single agent doxorubicin in terms of response rate and progression-free survival (PFS), although the combination has considerably more toxicity preventing its routine use in the elderly and those with comorbidities (2). Recently, the combination of doxorubicin and trabectedin has emerged as an effective and well tolerated combination schedule in advanced leiomyosarcomas (3). A major limitation to progress is that our understanding of the underlying biology of most sarcoma subtypes is very limited. Even with a specific subtype, there can be considerable variation in clinical behaviour and response to systemic therapy, but the precise biological reasons for such variation are not currently known.

The introduction of colony stimulating factor 1 receptor (CSF1R) inhibitors in the management of tenosynovial giant cell tumours (TGCT) has revolutionised the management of this disease, with a number of positive Phase 3 trials leading to regulatory approvals (4). However, the role of these agents in sarcomas remains to be defined. Immune checkpoint inhibitors have shown disappointing efficacy in most sarcoma subtypes, with limited durable responses. There is clear evidence of durable benefit in specific sarcomas including alveolar soft part sarcoma, cutaneous angiosarcoma and undifferentiated pleomorphic sarcoma.

With this backdrop, Dr. Rosenbaum and colleagues have performed a Phase 1 trial of the CSF1R inhibitor vimseltinib in combination with the programmed death ligand-1 (PD-L1) inhibitor avelumab (5). The trial had a standard 3+3 dose escalation design and a dose expansion with the recommended Phase 2 dose. They found that the combination was generally safe and well tolerated. However, in this unselected population, efficacy was minimal with no objective responses and a median PFS in the population treated at the recommended Phase 2 dose of 1.55 months.

The hypothesis for assessing this combination is the potential for vimseltinib plus avelumab to enhance immune checkpoint inhibition by reducing tumour associated macrophage (TAM)-mediated immunosuppression. In murine models, combination therapy with CSF1R and checkpoint inhibitors led to dimensional tumour shrinkage and an increase in CD8⁺ T-cell activity. Complementary translational studies in this Phase 1 trial reported decreases in regulatory T cells and myeloid-derived suppressor cells (MDSCs) in peripheral blood consistent with the proposed mechanism of action of the combination. Furthermore, changes in gene expression were observed between paired tumour biopsy specimens, with an increase in tumour-infiltrating T cells and a decrease in macrophage gene expression with treatment. These findings are supportive of the hypothesised mechanism of action, but with this schedule this did not translate to clinical benefit. However, the dose expansion phase was closed early due to slow accrual and therefore interpretation of the negative results should be guarded without sufficient information on efficacy at the recommended dose.

This exploratory Phase 1 trial confirms the safety of combination CSF1R and PD-L1 inhibition in an unselected sarcoma population. This was a heavily pretreated population mainly comprising patients with complex sarcomas such as leiomyosarcoma, pleomorphic sarcoma, undifferentiated and pleomorphic sarcomas. The heterogeneity of advanced sarcomas is a considerable hurdle and suggests that such novel combinations maybe better evaluated in the neoadjuvant setting. This would allow the opportunity to collect data on radiological (with functional imaging) and pathological response as well as translational correlatives. The role of pathological response in sarcomas remains to be defined, but evaluation in clinical trials would provide the ideal opportunity to refine the utility of pathological response in sarcomas (6). Access to the surgical specimen allows a comprehensive analysis of treatment effect both in terms of morphology and molecular changes, including immune modulation by pre-operative therapy.

This trial also illustrates the considerable challenges of performing in research in sarcomas due the bewildering heterogeneity and rarity. In this context, the information from all trials (including negative trials) is valuable and can form the basis of future research. However, in such a complex and heterogeneous group of tumours, there is a compelling rationale to develop trials that incorporate biomarker-patient selection. This is particularly relevant given the number of negative randomised trials in sarcomas over the last few years. The heterogeneity of sarcomas clearly complicates treatment selection and may partly explain the limited efficacy of broad-based immunotherapy approaches observed in unselected sarcoma populations (7). In addition, it could be argued that most sarcomas have an intrinsically “immune cold” microenvironment, and this could also contribute to the negative trial result. Despite the negative results of the current trial, this approach warrants further exploration. Tumour-associated macrophages are increasingly recognized as key mediators of immune evasion, and targeting CSF1R signalling may reprogram these cells to support antitumor immunity, providing a strong mechanistic rationale for combination therapy (8).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0017/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0017/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Tap WD, Wagner AJ, Schöffski P, et al. Effect of Doxorubicin Plus Olaratumab vs Doxorubicin Plus Placebo on Survival in Patients With Advanced Soft Tissue Sarcomas: The ANNOUNCE Randomized Clinical Trial. JAMA 2020;323:1266-76. [Crossref] [PubMed]
2. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014;15:415-23. [Crossref] [PubMed]
3. Pautier P, Italiano A, Piperno-Neumann S, et al. Doxorubicin-Trabectedin with Trabectedin Maintenance in Leiomyosarcoma. N Engl J Med 2024;391:789-99. [Crossref] [PubMed]
4. van der Heijden L, Spierenburg G, Kendal JK, et al. Multimodal management of tenosynovial giant cell tumors (TGCT) in the landscape of new druggable targets. J Surg Oncol 2023;128:478-88. [Crossref] [PubMed]
5. Rosenbaum E, Seier K, Bradic M, et al. A phase I study of the CSF1R inhibitor vimseltinib in combination with the PD-L1 inhibitor avelumab in patients with advanced sarcoma. ESMO Open 2025;10:105522. [Crossref] [PubMed]
6. Wardelmann E, Haas RL, Bovée JV, et al. Evaluation of response after neoadjuvant treatment in soft tissue sarcomas; the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) recommendations for pathological examination and reporting. Eur J Cancer 2016;53:84-95. [Crossref] [PubMed]
7. Serrano C, Bauer S, Blay JY, et al. Guidelines for Next-Generation Sequencing in Sarcoma Diagnosis and Treatment: A Consensus Review. JAMA Oncol 2025;11:1527-37. [Crossref] [PubMed]
8. Recine F, Vanni S, Bongiovanni A, et al. Clinical and translational implications of immunotherapy in sarcomas. Front Immunol 2024;15:1378398. [Crossref] [PubMed]