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JAMA Oncol. 2018 Jan 1;4(1):93-97. doi: 10.1001/jamaoncol.2017.1617.

Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in Sarcomas: A Phase 2 Clinical Trial.

Author information

1
Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
2
Department of Medical Oncology, Centre Oscar Lambret, Bordeaux, France.
3
Department of Pathology, Gustave Roussy, Villejuif, France.
4
INSERM U981, Villejuif, France.
5
Department of Medical Oncology, Oncopole Toulouse, Toulouse France.
6
Department of Medical Oncology, Centre Leon Berard, Lyon, France.
7
Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.
8
Department of Medical Oncology, Institut de Cancérologie de l'Ouest, Nantes, France.
9
Department of Medical Oncology, Institut Curie, Paris, France.
10
Department of Medical Oncology, Centre Oscar Lambret, Lille, France.
11
Immusmol, Bordeaux, France.
12
INSERM, Dijon, France.
13
Unité de Recherche et d'Epidémiologie Cliniques, Institut Bergonié, Bordeaux, France.
14
INSERM CIC 1401, Bordeaux, France.

Abstract

Importance:

There is a strong rationale for treating sarcomas with immunotherapy.

Objective:

To assess the efficacy and safety of programmed cell death protein 1 (PD-1) targeting in combination with metronomic chemotherapy in sarcomas.

Design, Setting, and Participants:

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.

Intervention or Exposure:

Pembrolizumab in combination with metronomic cyclophosphamide.

Main Outcomes and Measures:

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.

Results:

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.

Conclusions and Relevance:

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.

Trial Registration:

clinicaltrials.gov Identifier: NCT02406781.

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