PEMBROSARC combination of MK3475 and metronomic cyclophosphamide (mCP) in patients (pts) with advanced sarcomas a multicentre phase II trial with 3 new combination strategies.

Toulmonde, Maud; Grellety, Thomas; Blay, Jean‐Yves; Cesne, Axel Le; Penel, Nicolas; Piperno‐Neumann, Sophie; Bertucci, François; Chevreau, Christine; Bompas, Emmanuelle; Cousin, Sophie; Sellan-Albert, Sabrina; Pulido, Marina; Bellera, C.; Lortal, Barbara; Mathoulin‐Pélissier, Simone; Italiano, Antoîne

doi:10.1200/jco.2018.36.15_suppl.tps11587

Cited by 5 publications

(4 citation statements)

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“…[37] Through this results, this group is actively evaluating metronomic cyclophosphamide with an IDOinhibitor (epacadostat), TLR4 agonist G100, or EZH2 inhibitor (tazemetostat) in advanced STS. [64] So far, ICI results in the clinic have not been as expected from results from other tumor types. Strategies to potentiate responses, overcome resistance, and better patient-treatment selection are key points for future clinical research.…”

Section: How To Potentiate Immune Checkpoint Inhibitors (Icis) Efficamentioning

confidence: 95%

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma

Wainsztein

Chen

2020

Journal of Immunotherapy and Precision Oncology

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Soft tissue sarcomas (STS) account for less than 1% of adult cancers with a median overall survival of 12 months in the metastatic setting. Although chemotherapy remains the standard of treatment for advanced disease, molecular targeted agents (MTAs) and immunotherapies are under intensive investigation in STS. The success of MTAs comes mainly from antiangiogenic agents in various STS subtypes, from colony-stimulating factor-1 receptor inhibitor in tenosynovial giant cell tumor and neurotrophic tropomyocin receptor kinase (NTRK) inhibitors while others, such as cyclin-dependent kinase (CDK)-4 inhibitors, remain under evaluation. In advanced STS the activity of single-agent immunotherapy was not paradigm-changing as in other tumor types. A better understanding of tumor microenvironment, the immunogenic properties of MTAs, and finding an optimal treatment combination to improve patients outcomes became a central topic of research and discussion. Furthermore, the development and incorporation of transcriptomic profiling-based classification will allow identification, refined patient selection, and guided-treatment assignment. This article reviewed recent advances in STS treatment in MTAs and immunotherapy, strategies to overcome resistance, and outcomes of combination treatments in different STS subtypes. Promising preliminary results from combination strategies have shed light on STS treatment. The increasing understanding of this heterogeneous group of tumors and its microenvironment biology may help develop and guide treatment strategies with MTA and immunotherapies, alone or in combination, in a tailored way based on predictive and validated biomarkers and tumor molecular profiling in this new coming era.

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Section: How To Potentiate Immune Checkpoint Inhibitors (Icis) Efficamentioning

confidence: 95%

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma

Wainsztein

Chen

2020

Journal of Immunotherapy and Precision Oncology

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“…The PEMBROSARC study, a clinical multicohort single arm phase II study, evaluating the role of anti PDL1, Pembrolizumab, associated with metronomic cyclophosphamide in patients with soft tissue sarcoma (STS), have led to disappointed results in terms of 6-month non progression rate (NPR), objective response rate (ORR), progression free survival (PFS), overall survival (OS). The subsequent analysis, evaluating patients selected on the presence of B cells in the immune compartments called tertiary lymphoid structures (TLS), reported an improvement of the results in all of the previous clinical outcomes ( 32 , 33 ). This evidence confirmed significant clinical activity of ICIs in STS which are characterized by the presence of the TLS.…”

Section: Histology-driven Therapeutic Approach: Is There a Role For I...mentioning

confidence: 98%

Clinical and translational implications of immunotherapy in sarcomas

Recine,

Vanni,

Bongiovanni

et al. 2024

Front. Immunol.

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Immunotherapy has emerged as promising treatment in sarcomas, but the high variability in terms of histology, clinical behavior and response to treatments determines a particular challenge for its role in these neoplasms. Tumor immune microenvironment (TiME) of sarcomas reflects the heterogeneity of these tumors originating from mesenchymal cells and encompassing more than 100 histologies. Advances in the understanding of the complexity of TiME have led to an improvement of the immunotherapeutic responsiveness in sarcomas, that at first showed disappointing results. The proposed immune-classification of sarcomas based on the interaction between immune cell populations and tumor cells showed to have a prognostic and potential predictive role for immunotherapies. Several studies have explored the clinical impact of immune therapies in the management of these histotypes leading to controversial results. The presence of Tumor Infiltrating Lymphocytes (TIL) seems to correlate with an improvement in the survival of patients and with a higher responsiveness to immunotherapy. In this context, it is important to consider that also immune-related genes (IRGs) have been demonstrated to have a key role in tumorigenesis and in the building of tumor immune microenvironment. The IRGs landscape in soft tissue and bone sarcomas is characterized by the connection between several tumor-related genes that can assume a potential prognostic and predictive therapeutic role. In this paper, we reviewed the state of art of the principal immune strategies in the management of sarcomas including their clinical and translational relevance.

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“…The immunosuppressive tumour microenvironment and the lack of PD-L1expressing immune cells is therefore implicated in the primary resistance of STS tumours to CPIs and chemotherapy treatment. To address these potential resistance mechanisms, PEMBROSARC is currently assessing the addition of an anti-IDO1, TLR4 agonist or EZH2 inhibitor to the combined pembrolizumab and metronomic cyclophosphamide treatment in advanced STS patients (NCT02406781) [96].…”

Section: Chemotherapy and Radiotherapymentioning

confidence: 99%

Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas

et al. 2022

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Immunotherapy in soft tissue sarcoma (STS) has experienced a surge of interest in the past decade, contributing to an expanding number of therapeutic options for this extremely heterogenous group of rare malignancies. Immune checkpoint inhibitors (CPIs) targeting the PD-1 and CTLA-4 axes have demonstrated promising responses in a select number of STS subtypes, including rarer subtypes, such as alveolar soft part sarcoma, SWI/SNF-deficient sarcomas, clear cell sarcoma, and angiosarcoma. Multiple pan-subtype sarcoma trials have facilitated the study of possible predictive biomarkers of the CPI response. It has also become apparent that certain therapies, when combined with CPIs, can enhance response rates, although the specific mechanisms of this possible synergy remain unconfirmed in STS. In addition to CPIs, several other immune targeting agents, including anti-tumour-associated macrophage and antigen-directed therapies, are now under assessment in STS with promising efficacy in some subtypes. In this article, we review the state of the art in immunotherapy in STS, highlighting the pre-clinical and clinical data available for this promising therapeutic strategy.

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PEMBROSARC combination of MK3475 and metronomic cyclophosphamide (mCP) in patients (pts) with advanced sarcomas a multicentre phase II trial with 3 new combination strategies.

Cited by 5 publications

References 0 publications

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma

When Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma

Clinical and translational implications of immunotherapy in sarcomas

Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas

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