Title :

Use of pd-1 targeting, macrophage infiltration, and ido pathway activation in sarcomas a phase 2 clinical trial

Author(s) :

Toulmonde, Maud [Auteur]
Penel, Nicolas [Auteur]
METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694
Adam, Julien [Auteur]
Chevreau, Christine [Auteur]
Blay, Jean-Yves [Auteur]
Le Cesne, Axel [Auteur]
Bompas, Emmanuelle [Auteur]
Piperno-Neumann, Sophie [Auteur]
Cousin, Sophie [Auteur]
Grellety, Thomas [Auteur]
Ryckewaert, Thomas [Auteur]
Bessede, Alban [Auteur]
Ghiringhelli, François [Auteur]
Pulido, Marina [Auteur]
Italiano, Antoine [Auteur]

Journal title :

JAMA oncology

Abbreviated title :

JAMA Oncol.

Volume number :

4

Pages :

93-97

Publication date :

2018-01-01

ISSN :

2374-2437

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

There is a strong rationale for treating sarcomas with immunotherapy. To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. This was ...
Show more >There is a strong rationale for treating sarcomas with immunotherapy. To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas. This was an open-label, multicenter, phase 2 study of 4 cohorts of patients with advanced soft-tissue sarcoma (STS), including leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (others), and gastrointestinal stromal tumor (GIST). All patients received 50 mg twice daily cyclophosphamide 1 week on and 1 week off and 200 mg of intravenous pembrolizumab every 3 weeks. Pembrolizumab in combination with metronomic cyclophosphamide. There was a dual primary end point, encompassing both the nonprogression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 for LMS, UPS, and others and 6-month nonprogression for GIST. An objective response rate of 20% and/or a 6-month nonprogression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from patient tumor and plasma samples. Between June 2015 and July 2016, 57 patients were included (median [range] age, 59.5 [18.5-84.0] years; 24 women [42%]); 50 patients were assessable for the efficacy end point. Three patients experienced tumor shrinkage, resulting in a partial response in a single solitary fibrous tumor. The 6-month nonprogression rates were 0%, 0%, 14.3% (95% CI, 1.8%-42.8%) for LMS, UPS, and others, respectively, and 11.1% (95% CI, 2.8%-48.3%) for GIST. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, and anemia. The only patient who experienced partial response was the only one with strong programmed cell death 1 ligand 1-positive staining in immune cell. Strong infiltration by macrophage expressing the inhibitory enzyme indoleamine 2,3-dioxygenase 1 (IDO1) was observed in the majority of cases. Moreover, a significant increase in the kynurenine to tryptophan ratio was observed in patient plasma samples during the study treatment. We found that PD-1 inhibition has limited activity in selected STS and GIST. This may be explained by an immunosuppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. clinicaltrials.gov Identifier: NCT02406781.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
Université de Lille

Collections :

• METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694

Submission date :

2019-12-09T16:49:54Z