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Brief Report
June 29, 2017

Use of PD-1 Targeting, Macrophage Infiltration, and IDO Pathway Activation in SarcomasA Phase 2 Clinical Trial

Author Affiliations
  • 1Department of Medical Oncology, Institut Bergonié, Bordeaux, France
  • 2Department of Medical Oncology, Centre Oscar Lambret, Bordeaux, France
  • 3Department of Pathology, Gustave Roussy, Villejuif, France
  • 4INSERM U981, Villejuif, France
  • 5Department of Medical Oncology, Oncopole Toulouse, Toulouse France
  • 6Department of Medical Oncology, Centre Leon Berard, Lyon, France
  • 7Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France
  • 8Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Nantes, France
  • 9Department of Medical Oncology, Institut Curie, Paris, France
  • 10Department of Medical Oncology, Centre Oscar Lambret, Lille, France
  • 11Immusmol, Bordeaux, France
  • 12INSERM, Dijon, France
  • 13Unité de Recherche et d’Epidémiologie Cliniques, Institut Bergonié, Bordeaux, France
  • 14INSERM CIC 1401, Bordeaux, France
JAMA Oncol. Published online June 29, 2017. doi:10.1001/jamaoncol.2017.1617
Key Points

Question  Is programmed cell death protein 1 (PD-1) targeting a relevant strategy for patients with soft-tissue sarcomas (STS)?

Findings  This phase 2 clinical trial assessed the combination of the selective PD-1 inhibitor pembrolizumab in combination with low-dose cyclophosphamide in 4 cohorts of patients with soft-tissue sarcoma (STS). Only 3 of 50 patients assessable for efficacy experienced tumor shrinkage, and analyses of tumor samples showed strong infiltration by M2 macrophages expressing the immunosuppressive enzyme inhibitory enzyme indoleamine 2,3-dioxygenase (IDO).

Meaning  Given the importance of macrophage infiltration and the IDO1/kynurenine pathway in patients with STS, further strategies are warranted to assess the combination of anti–PD-1/programmed cell death 1 ligand 1 with colony-stimulating factor 1 receptor inhibitors and/or IDO inhibitors in patients with selected sarcoma subtypes.


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