A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma

Clin Cancer Res. 2023 Jun 1;29(11):2043-2051. doi: 10.1158/1078-0432.CCR-22-3911.


Purpose: Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes.

Patients and methods: This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1.

Results: Thirty patients were enrolled [60% male; median age 54 years (range, 24-78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%-17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9-26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway-related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline.

Conclusions: Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antibodies, Monoclonal, Humanized
  • Female
  • Humans
  • Leiomyosarcoma* / drug therapy
  • Male
  • Middle Aged
  • Sarcoma* / drug therapy
  • Sarcoma* / genetics
  • Soft Tissue Neoplasms* / drug therapy
  • Tumor Microenvironment


  • pembrolizumab
  • epacadostat
  • Antibodies, Monoclonal, Humanized