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 4 publications

(3 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 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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“…Based on this, the phase 2 PEMBROSARC trial evaluated the anti-programmed cell death 1 (anti-PD-1) pembrolizumab in combination with alternating cyclophosphamide in 17 patients with OS; only 13.3% of patients had stable disease at 6 months [ 88 ] ; the median progression-free survival was 1.4 months and median overall survival was 5.6 months. This study showed interesting results; for example, none of the three patients with tumor shrinkage had an expression of PD-L1 on sarcoma or immune cells and only 12% of the cases were PD-L1 positive in this study [ 88 ] . One explanation could be the implication of other mechanisms implicated in immune response in OS, such as other members of TME and the tumor survival mechanism [ 89 ] .…”

Section: Tme and Angiogenesismentioning

confidence: 99%

An overview of resistance to chemotherapy in osteosarcoma and future perspectives

García-Ortega¹,

Cabrera-Nieto²,

Caro-Sánchez³

et al. 2022

Cancer Drug Resist

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Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.

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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 4 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

Current Status and Future Directions of Immunotherapies in Soft Tissue Sarcomas

An overview of resistance to chemotherapy in osteosarcoma and future perspectives

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