PD-1 Inhibitor Therapy Efficacy May Be ‘Limited’ In Soft-Tissue Sarcoma, GIST

Treatment targeting programmed cell death protein 1 may not be a viable strategy for patients with soft-tissue sarcoma or gastrointestinal stromal tumour

medwireNews: Study findings indicate that the immunosuppressive tumour microenvironment of soft-tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST) may limit the role of programmed cell death protein 1 (PD-1) inhibitor therapy in these patients.

The phase II trial assessed the combination of pembrolizumab 200 mg every 3 weeks with metronomic cyclophosphamide (50 mg twice daily on a 1 week on, 1 week off schedule) in 15 patients with leiomyosarcoma (LMS), 16 with undifferentiated pleomorphic sarcoma (UPS), 16 patients with other types of STS and 10 with GIST.

Fifty patients were included in the efficacy analysis; all of the LMS and UPS patients had progressed within 6 months of beginning treatment, with only 14.3% of patients with other STS types and 11.1% of GIST patients meeting the nonprogression endpoint.

Three patients showed tumour shrinkage but just one patient met RECIST criteria for a partial objective response. This individual was the only patient to show a 10% or greater programmed cell death ligand 1 (PD-L1)-positive staining in immune cell analysis, the researchers observe.

Antoine Italiano, from Institut Bergonié in Bordeaux, France, and team also found that the immunosuppressive Enzyme inhibitor indoleamine 2,3-dioxygenase 1 (IDO1) was expressed in immune cells, most commonly Macrophages, in 69%, 73% and 63% of LMS, UPS and GIST patients, respectively, as well as 23% of those with other STS histology.

The ratio of the IDO1 product, kynurenine, to tryptophan in plasma samples increased significantly from baseline, before the first infusion of pembrolizumab, to day 8 of cycle 3. And this increase correlated with a higher density of IDO1 expression at baseline.

In addition, the “vast majority” of tumour samples taken from the STS and GIST patients showed a significantly lower number of tumour-infiltrating CD8-positive effector lymphocytes compared with levels in specimens from 47 non-small-cell lung cancer patients, with a median count of 48 versus 422.

“Given the importance of macrophage infiltration and the IDO1/kynurenine pathway in STS as suggested by our data, further strategies are warranted to assess the combination of anti–PD-1/PD-L1 with therapies targeting these immunological features, such as colony stimulating factor 1 Receptor inhibitors and/or IDO inhibitors in selected sarcoma subtypes”, the researchers write in JAMA Oncology.

Noting that study participants were all heavily pretreated, however, they suggest: “In future sarcoma immunotherapy trials, the greater immune competence and better prognosis of less heavily pretreated patients both argue for considering patients who have not necessarily exhausted all standard treatments.”

Reference

Toulmonde M, Penel N, Adam J, et al. Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas. A phase 2 clinical trial. JAMA Oncol; Advance online publication 29 June 2017. doi:10.1001/jamaoncol.2017.1617

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