Reshaping the tumor microenvironment of cold soft-tissue sarcomas with anti-angiogenics: a phase 2 trial of regorafenib combined with avelumab – Nature

Report on the Phase II REGOMUNE Trial: Reshaping the Tumor Microenvironment in Cold Soft-Tissue Sarcomas with Anti-Angiogenics

Abstract

The REGOMUNE study, a phase II clinical trial, investigated the combination of regorafenib, a multityrosine kinase inhibitor targeting VEGFR2, with avelumab, a PD-L1 immune checkpoint inhibitor, in patients with advanced “cold” soft-tissue sarcomas (STS) lacking mature tertiary lymphoid structures (mTLS). The trial enrolled 49 mTLS-negative STS patients, including leiomyosarcoma (45%) and synovial sarcoma (18%). The objective response rate (ORR) was 11.0%, with median progression-free survival (PFS) of 1.8 months and overall survival (OS) of 15.1 months. Treatment was generally well tolerated. Immunological analyses revealed increased infiltration of CD8+ T cells and B cells and elevated PD-1 expression on immune cells, alongside upregulation of soluble PD-L1 and tryptophan consumption. These findings suggest that anti-angiogenic therapy modulates the tumor microenvironment (TME) in cold STS, highlighting the need for complementary strategies to enhance immune cell functionality.

Introduction

Soft-tissue sarcomas (STS) are a heterogeneous group of malignancies with limited response to conventional chemotherapy, underscoring the need for novel therapeutic approaches. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has shown promise in various cancers. However, the immunosuppressive tumor microenvironment (TME) in most STS, especially those lacking mature tertiary lymphoid structures (mTLS), limits the efficacy of ICIs.

Recent molecular insights have identified five sarcoma immune classes based on immune infiltration, with TLS presence correlating with better clinical outcomes and immunotherapy response. Approximately 80% of STS patients have “cold” tumors lacking TLS, representing a major therapeutic challenge.

Preclinical data indicate that targeting abnormal neoangiogenesis via VEGF/VEGFR inhibition can normalize tumor vasculature, promote immune cell infiltration, and enhance tumor immunogenicity. Regorafenib, an approved multikinase inhibitor, has demonstrated immunomodulatory effects and clinical activity in STS. This study hypothesized that combining regorafenib with the PD-L1 inhibitor avelumab could sensitize cold STS tumors to immunotherapy by modulating the TME.

Methods

Study Design and Participants

The REGOMUNE trial is a multi-cohort, single-arm phase II study evaluating regorafenib plus avelumab in various cancers. The STS cohort included adults with histologically confirmed advanced or metastatic STS lacking TLS, ECOG performance status 0–1, measurable disease per RECIST 1.1, and prior systemic therapy. Exclusion criteria included prior treatment with ICIs or regorafenib.

Patients received regorafenib 160 mg daily (3 weeks on, 1 week off) and avelumab 10 mg/kg biweekly starting day 15 of cycle 1. Treatment continued until progression, toxicity, or withdrawal. Dose modifications were permitted for regorafenib based on tolerance. Safety was monitored per CTCAE v5.0. Efficacy was assessed every 8 weeks by blinded central review.

Endpoints and Assessments

• Primary endpoint: 6-month objective response rate (ORR) per modified RECIST 1.1.
• Secondary endpoints: best overall response, progression-free survival (PFS), overall survival (OS), growth modulation index (GMI), safety, and exploratory biomarker analyses.
• Biomarker analyses included multiplex immunofluorescence of tumor biopsies, plasma proteomics, and metabolomics.

Results

Patient Characteristics and Trial Conduct

Fifty patients were enrolled; 43 were evaluable for efficacy. The cohort was heavily pretreated (median two prior lines). After median follow-up of 7.1 months, 84.8% discontinued treatment, primarily due to disease progression.

Efficacy Outcomes

• ORR was 11.0% (95% CI: 4.0%–22.0%), with 4 partial responses observed across various sarcoma subtypes.
• 38.6% achieved stable disease; 50% had progressive disease.
• Median PFS was 1.8 months; 6-month PFS rate was 22.1%.
• Median OS was 15.1 months; 1-year OS rate was 52.4%.
• Responses were durable with median duration of 7.8 months.

Safety Profile

Treatment was generally well tolerated. Common adverse events included fatigue, diarrhea, palmar-plantar erythrodysesthesia, and laboratory abnormalities such as transaminitis and thyroid-stimulating hormone elevation. Dose modifications were frequent but no treatment-related deaths occurred.

Biomarker and Immunological Findings

• Plasma proteomics revealed significant upregulation of soluble PD-L1 and enrichment of immune-related pathways, notably T cell receptor signaling.
• Immune cell estimation indicated increased CD8+ T cells and B cells in plasma post-treatment.
• Metabolomics showed decreased plasma L-tryptophan levels, implicating immune response modulation.
• Multiplex immunofluorescence of paired tumor biopsies demonstrated increased infiltration of CD8+ and CD4+ T cells, B cells, and M2 macrophages, with enhanced PD-1 expression on T cells.
• No induction of tertiary lymphoid structures was observed.

Discussion

This study provides evidence that combining anti-angiogenic therapy with immune checkpoint blockade can modulate the TME in cold STS, enhancing immune cell infiltration and activation markers. Despite these immunological changes, clinical responses were modest, highlighting the complexity of overcoming immune resistance in TLS-negative sarcomas.

Compared to prior studies that did not stratify by immune contexture, this trial focused on the majority of STS patients with cold tumors, emphasizing the importance of TME characterization for personalized therapy. The increase in soluble PD-L1 and tryptophan metabolism suggests mechanisms of immune suppression that may limit therapeutic efficacy.

Safety data confirmed manageable toxicity consistent with known profiles of regorafenib and avelumab. Optimizing dosing strategies for anti-angiogenics to balance efficacy and tolerability remains a critical research area.

Future directions include exploring complementary approaches to induce TLS formation and enhance immune cell functionality, aligning with Sustainable Development Goal (SDG) 3: Good Health and Well-being, by advancing effective cancer therapies. Additionally, the study supports SDG 9: Industry, Innovation, and Infrastructure, through innovative clinical trial designs and biomarker-driven personalized medicine.

Conclusion

The REGOMUNE phase II trial demonstrates that anti-angiogenic therapy combined with PD-L1 blockade can reshape the TME of cold soft-tissue sarcomas, promoting immune infiltration but with limited clinical responses. These findings underscore the need for integrated strategies to overcome immune resistance in STS, contributing to the global effort to improve cancer outcomes and support the United Nations Sustainable Development Goals.

References

1. Spalato-Ceruso, M., Ghazzi, N. E., & Italiano, A. New strategies in soft tissue sarcoma treatment. J. Hematol. Oncol. 17, 761 (2024).
2. Tazzari, M. et al. Molecular determinants of soft tissue sarcoma immunity: targets for immune intervention. Int. J. Mol. Sci. 22, 7518 (2021).
3. Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

1. Sustainable Development Goals (SDGs) Addressed or Connected to the Issues Highlighted in the Article

1. SDG 3: Good Health and Well-being
   • The article focuses on improving treatment for advanced soft-tissue sarcomas (STS), a type of cancer, by exploring novel immunotherapy and anti-angiogenic therapy combinations.
   • It addresses challenges in cancer treatment efficacy and aims to enhance patient survival and quality of life.
2. SDG 9: Industry, Innovation, and Infrastructure
   • The article discusses innovative clinical trial designs (Bayesian adaptive trial) and novel therapeutic strategies combining regorafenib and avelumab.
   • It highlights advances in molecular and immunological understanding to develop personalized medicine approaches.
3. SDG 17: Partnerships for the Goals
   • The study involves multi-institutional collaboration and funding from national cancer institutes and research agencies, demonstrating partnerships in research to achieve health goals.

2. Specific Targets Under Those SDGs Identified Based on the Article’s Content

1. SDG 3: Good Health and Well-being
   • Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
     • The article aims to reduce mortality from cancer (a non-communicable disease) by improving treatment options for STS.
   • Target 3.8: Achieve universal health coverage, including access to quality essential health-care services and access to safe, effective, quality, and affordable essential medicines and vaccines for all.
     • The development of effective immunotherapies and targeted treatments contributes to improving access to quality cancer care.
2. SDG 9: Industry, Innovation, and Infrastructure
   • Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors, including encouraging innovation and substantially increasing the number of research and development workers.
     • The article demonstrates scientific research and innovation in cancer treatment through novel drug combinations and biomarker analyses.
3. SDG 17: Partnerships for the Goals
   • Target 17.6: Enhance North-South, South-South, and triangular regional and international cooperation on and access to science, technology, and innovation.
     • The article reflects international and institutional cooperation in clinical trials and research funding.

3. Indicators Mentioned or Implied in the Article to Measure Progress Towards the Identified Targets

1. Health Outcome Indicators
   • Objective Response Rate (ORR): Percentage of patients showing tumor size reduction (partial response) or stable disease.
   • Progression-Free Survival (PFS): Median time patients survive without disease progression.
   • Overall Survival (OS): Median time patients survive after treatment initiation.
   • Duration of Response: Median time the response to treatment lasts.
   • Adverse Events and Safety Profiles: Frequency and severity of treatment-related side effects.
2. Biomarker and Immunological Indicators
   • Immune Cell Infiltration Levels: Quantification of CD8+ T cells, B cells, CD4+ T cells, and M2 macrophages in tumor microenvironment (TME).
   • Expression Levels of PD-1 and Soluble PD-L1 (sPD-L1): Measured in tumor tissue and plasma to assess immune checkpoint activity.
   • Metabolite Levels: Plasma levels of L-Tryptophan as an indicator of immune response status.
3. Clinical Trial and Research Indicators
   • Bayesian Adaptive Trial Design Metrics: Success probabilities for ORR guiding trial continuation or cessation.
   • Biomarker Analysis Outcomes: Changes in proteomic and metabolomic profiles pre- and post-treatment.

4. Table of SDGs, Targets, and Indicators Relevant to the Article

SDGs	Targets	Indicators
SDG 3: Good Health and Well-being	Target 3.4: Reduce premature mortality from non-communicable diseases through prevention and treatment. Target 3.8: Achieve universal health coverage and access to quality essential health-care services and medicines.	Objective Response Rate (ORR) Progression-Free Survival (PFS) Overall Survival (OS) Duration of Response Adverse Events and Safety Profiles
SDG 9: Industry, Innovation, and Infrastructure	Target 9.5: Enhance scientific research and technological capabilities, encourage innovation.	Use of Bayesian adaptive trial design metrics (success probabilities for ORR) Biomarker and immunological profiling (immune cell infiltration, PD-1/PD-L1 expression) Proteomic and metabolomic analyses
SDG 17: Partnerships for the Goals	Target 17.6: Enhance international cooperation on science, technology, and innovation.	Multi-institutional clinical trial collaboration Funding and resource sharing among national and international research bodies

Source: nature.com