A pilot study of Janus kinase 1 (JAK1) inhibitor itacitinib for treatment-refractory sarcomas: Leiomyosarcoma cohort.

Abstract

11546 Background: Sarcomas are a heterogenous group of mesenchymal tumors. Although variable, many sarcoma subtypes have a high proportion of infiltrating macrophages in their immune microenvironment. The JAK/STAT pathway is involved in immune cell regulation and may play a role in tumor immune resistance. Janus kinase 1 (JAK1) shifts tumor associated macrophages (TAM) to an inhibitory M2 phenotype. Inhibition of this pathway could improve anti-tumor immunity. Methods: This is an open-label, single agent, pilot study of the JAK1 inhibitor itacitinib in subjects with metastatic or advanced treatment-refractory sarcomas susceptible to immune infiltration by TAM (NCT03670069). Patients (pts) age 18 and older were enrolled in four cohorts: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS) and related subtypes, synovial sarcoma and myxoid/round cell liposarcoma (MRCL), and chondrosarcoma. Itacitinib was given orally, 300 mg once daily, in a 28-day cycle. Primary endpoint was to assess changes in the macrophage population with itacitinib. Secondary endpoints included objective response rate using RECIST v1.1 criteria, progression free survival (PFS) at 3- and 6- months, and overall survival (OS) at 12-months. Response assessments were performed after cycle 2, and every other cycle thereafter. Research biopsies for pharmacodynamic markers were collected at baseline prior to C1D1 and prior to C3D1. Multiplex immunohistochemistry (mIHC) and transcriptomic analysis using Nanostring were performed on pre-treatment and on-treatment tumor specimens. We report the results from the LMS cohort. Results: 8 pts with LMS enrolled. OS rate at 12 months for the LMS cohort was 100%, median OS for LMS was 23 months. PFS rate at 3 months and 6 months for LMS was 75% and 38%, respectively. No objective responses by RECIST v1.1 were documented. 7/8 (87.5%) of pts with LMS had stable disease as best response. 7/8 LMS pts had paired tumor biopsies pre- and on-treatment. As expected, STAT1 was significantly downregulated in on-treatment whole tumor lysates. Other genes that were significantly downregulated with itacitinib treatment were CCR5, NFKB1, C1QB, CIITA, FCGR3A/B, CXCL10, and MAPKAPK2 . On mIHC, there was a general trend of decreased immune cell tumor infiltration (CD3, CD4, CD8, CD163, FOXP3, CD14, CD206) in on-treatment samples compared to pre-treatment samples, though differences were not statistically significant. Conclusions: Itacitinib demonstrated durable disease control in patients with LMS and warrants further study in this subtype. While our analysis of markers on paired biopsy samples does not suggest that immunotherapy combinations with itacitinib are likely to be successful for LMS, a more thorough analysis will be presented at the meeting as this data may still suggest potent combination therapies. Clinical trial information: NCT03670069 .