In the context of cancer, evidence suggests that the CSF1R signaling pathway promotes recruitment of M2 macrophages to the tumor microenvironment. This type of TAM facilitates the development of the tumor by secreting proangiogenic and growth factors and suppressing T-cell effector function by releasing immunosuppressive cytokines. Several tumor types have been shown to overexpress the CSF1 ligand; this expression and the presence of CSF1R-positive TAMs in the tumor microenvironment correlate with poor survival.
Diffuse-type tenosynovial giant cell tumor (dt-TGCT), a rare benign tumor that affects the large joints, exemplifies the protumoral role of the CSF1R pathway. These tumors are characterized by overexpression of CSF1 due to chromosomal translocations in the gene (CSF1
) that encodes this protein. As a result of this aberrant CSF1 expression, the bulk of the tumor mass is composed of CSF1R-positive macrophages.1,5-7
Reproducing TAMs Through CSF1R Inhibition
Although there are no FDA-approved anticancer therapies categorized as CSF1R inhibitors, the multitargeted tyrosine kinase inhibitor (TKI) imatinib (Gleevec) has been shown to block CSF1R and demonstrate activity in dt-TGCT, prompting the development of more specific CSF1R inhibitors.8,9
Preclinical study results suggest that this drug class could reprogram TAMs from an M2-like phenotype to a more proinflammatory, antitumor, immunostimulatory phenotype. Treatment with CSF1R inhibitors reduced the number of immunosuppressive TAMs and promoted the production of immunostimulatory cytokines, which resulted in enhanced antitumor immune responses.8,9
Both monoclonal antibodies (mAbs) and small-molecule TKIs targeting CSF1R and the ligand CSF1 have now been developed and are being evaluated in clinical trials (TABLE), although the available clinical data are limited.
Table. Selected Studies Targeting Colony Stimulating Factor Pathway
Frequent overexpression of CSF1 and a need for novel treatment options made dt-TGCT the ideal target in which to test CSF1R inhibitors. Phase I study findings suggest promising antitumor activity for several of these drugs. Emactuzumab, a CSF1R-binding mAb, was evaluated in 28 patients with dt-TGCT and generated partial responses (PRs) in 79% and complete responses (CRs) in 7%, with stable disease (SD) in 11%.10
Although emactuzumab is no longer being evaluated in this clinical setting, it is being tested in non-Hodgkin lymphoma, ovarian cancer, and other solid tumors.
More promising is pexidartinib, a CSFR1 TKI. Forty-one patients with dt-TGCT were enrolled in a phase I dose-escalation trial and an additional 23 were enrolled in an extension study. In the extension study, pexidartinib demonstrated an overall response rate (ORR) of 52%, all PRs, and there was a 30% SD rate. Responses usually occurred within the first 4 months of treatment, and the median duration of response lasted in excess of 8 months.11
This prompted the FDA to award breakthrough therapy status to pexidartinib in this indication. The phase III ENLIVEN trial was subsequently initiated as a 2-part double-blind study in which the efficacy of pexidartinib was compared with placebo.
Although Daiichi Sankyo and Plexxikon reported in 2016 that they had suspended enrollment in the trial as a result of 2 reported cases of nonfatal, serious liver toxicity, evaluation of the 121 patients already enrolled continued to completion. Late last year, the companies reported that the trial had met its primary endpoint of tumor response as measured by tumor size reduction. Publication of full details is eagerly anticipated.12,13
Monotherapy Efficacy Limited
Although CSF1R inhibitors have been evaluated as monotherapy, limited effects on clinical efficacy have been reported thus far. In a phase II study in 38 patients with glioblastoma treated with pexidartinib, 18% of patients experienced SD as best response. There were no PRs or CRs, and there was no significant improvement in 6-month progression-free survival.14
Pexidartinib was also evaluated in a phase I/II trial in 20 heavily pretreated patients with classical Hodgkin lymphoma and demonstrated an ORR of 5%. JNJ-4036527, the development of which has now been halted, showed similar efficacy in this tumor type. Like pexidartinib, ARRY-382 is a CSF1R TKI. In separate phase I studies in patients with advanced solid tumors, both ARRY-382 and emactuzumab demonstrated SD rates of 15% and no objective responses.4
Recently, the CSF1R-targeting mAb AMG 820 was tested in a phase I trial in patients with advanced solid tumors. Participants (N = 25) received AMG 820 intravenously at doses of 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks. Among 15 patients who were evaluable for response, 32% had SD as the best response, including 1 patient each with non–small cell lung cancer, paraganglioma, and a pancreatic neuroendocrine tumor.