Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT

Abstract

Purpose: To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity. Patients and Methods: From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies. Results: Ninety-one patients were treated: TGCT patients (n = 39) had a median treatment duration of 511 days, while other solid tumor patients (n = 52) had a median treatment duration of 56 days. TGCT patients had response rates of 62% (RECIST 1.1) and 56% (TVS) for the full analysis set. PRO assessments for pain showed improvement in patient symptoms, and 76% (19/25) of TGCT tissue biopsy specimens showed evidence of abnormal CSF1 transcripts. Pexidartinib treatment of TGCT resulted in tumor regression and symptomatic benefit in most patients. Pexidartinib toxicity was manageable over the entire study. Conclusions: These results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.

Interactions in CSF1-driven Tenosynovial Giant Cell Tumors

“…In this case 20% of the reads show a splice variant that lacks the exon 6 transmembrane domain (data not shown). The sequences from CSF1 translocations reported by Tap et al (6) also point to the loss of the CSF1 transmembrane domain and cleavage site but also the potential gain of other transmembrane domains from the translocation partners, for example in the translocations involving CD99 and CD101 as fusion partners. The presence of the membrane bound CSF1 could explain the advantage of a dendritic morphology in the neoplastic cells to facilitate interaction with the macrophages and further studies are required to address this issue.…”

“…These cells attract and stimulate a large population of bystander macrophages (3). A number of studies have shown that these tumors react to inhibition of the CSF1 pathway (6)(7)(8)(9)(10)(11)(12)(13)24). To better understand the "landscaping effect" caused by the neoplastic cells on the tumor micro environment we used scRNA-seq and long read RNA-seq.…”

“…Previous studies of the CSF1 fusion pointed to the loss of the 3'-UTR as a possible mechanism for CSF1 upregulation (5,6). The 3'-UTR contains a negative regulatory sequence that would be lost in translocations involving CSF1 (5,6), leading to high levels of expression.…”

“…In this way the neoplastic cells have a “landscaping effect” on their microenvironment that results in the accumulation of large numbers of the non-neoplastic macrophages that form the majority of cells in the tumor (3, 4). Initially, we identified COL6A3 as the fusion partner for CSF1 but others have subsequently identified a range of other translocation partners for CSF1 in TGCT (5, 6). The findings suggested that the chemoattractant and proliferative effect of CSF1 on bystander macrophages could be inhibited by drugs that interfered with the CSF1 pathway.…”

“…The findings suggested that the chemoattractant and proliferative effect of CSF1 on bystander macrophages could be inhibited by drugs that interfered with the CSF1 pathway. Studies using monoclonal antibodies and small molecule inhibitors for the CSF1 pathway have shown a significant clinical effect (6)(7)(8)(9)(10)(11)(12)(13) and a decrease in tumor size as seen by an imaging measurement specifically designed for TGCT (14). It was hypothesized that the CSF1-expressing neoplastic cells might be activated through an autocrine loop by CSF1R expressed on their surface (3).…”