Real-World Patient Experience of Pexidartinib for Tenosynovial Giant-Cell Tumor.

BACKGROUND: Pexidartinib (Turalio) is the only systemic therapy approved by the FDA for the treatment of adult patients with symptomatic tenosynovial giant-cell tumor (TGCT) associated with severe morbidity or functional limitations, and not amenable to improvement with surgery. This study assessed patient-reported treatment experiences and symptom improvement among patients receiving pexidartinib. METHODS: A cross-sectional, web-based survey collected data on demographics, disease history, pexidartinib dosing, and symptoms before and after pexidartinib use. RESULTS: Of 288 patients enrolled in the Turalio REMS program in May 2021, 83 completed the survey: mean age was 44.2 years, 62.7% were female, and most common tumor sites were in knee (61%) and ankle (12%). Mean initial dose was 622 mg/day: 29 patients reported reduction from initial dose and 8 had dose reduction after titrating up to a higher dose. At the time of survey completion, median time on pexidartinib was 6.0 months; 22 (26.5%) patients discontinued pexidartinib due to physician suggestion, abnormal laboratory results, side effect, or symptom improvement. Compared with before pexidartinib initiation, most patients reported improvement in overall TGCT symptom (78.3%) and physical function (77.2%) during pexidartinib treatment. Significant improvement was reported during pexidartinib treatment in worst stiffness numeric rating scale (NRS) (3.0 vs. 6.2, P < .05) and worst pain NRS (2.7 vs. 5.7, P < .05). CONCLUSION: Findings from this cross-sectional survey confirmed the benefit of pexidartinib in improving symptoms and functional outcomes among patients with symptomatic TGCTs from the patients' perspective. Future research is warranted to examine the long-term benefit and risk of pexidartinib.

TURALIO® Risk Evaluation and Mitigation Strategy Program (tREMS): 3-year retrospective hepatic safety assessment.

Aim: Hepatic safety data assessment from the TURALIO® (pexidartinib) Risk Evaluation and Mitigation Strategy (tREMS) Program. Methods: Retrospective 3-year assessment (August 2019 to June 2022) of hepatic events from the TURALIO® (pexidartinib) Risk Evaluation and Mitigation Strategy Program. Results: A total of 451 patients, 369 prescribers, 2 wholesalers/distributors and 2 pharmacies were enrolled and certified. Twenty-one (4.7%) patients met the criteria for a hepatic adverse event or laboratory abnormality suggestive of serious and potentially fatal liver injury, all with onset within 2 months of therapy. No new hepatic safety signals were identified. Conclusion: Results are consistent with the phase 3 ENLIVEN trial data. Liver enzyme monitoring, combined with early intervention, including dose modification and discontinuation, conducted in patients treated with pexidartinib mitigate the risk of potential hepatotoxicity.

Safety findings from the 3-year data collected in the TURALIO^® Risk Evaluation and Mitigation Strategy ProgramPexidartinib (TURALIO^®) is an oral drug that is used to treat adults with tenosynovial giant cell tumor (TGCT) that cannot be fixed with surgery. TGCTs are rare, noncancerous tumors that cause pain, stiffness and difficulty moving. Pexidartinib works by blocking a protein that helps these tumors grow. Before pexidartinib, there were no good treatments for TGCT and surgery often could not remove all the tumors, so they would frequently grow back.Pexidartinib was approved in 2019 after a clinical trial showed it worked well in adults with TGCT. However, pexidartinib can sometimes cause serious liver harm for some patients. To handle this risk, a program called the tREMS (TURALIO^® Risk Evaluation and Mitigation Strategy) was established to ensure that pexidartinib is used safely.The tREMS Program teaches doctors, pharmacists and patients about the safe use of pexidartinib and potential liver risks and enrolls patients in a registry to watch their health. Doctors and pharmacies must be certified, and patients need regular liver tests. In the first 3 years, 451 patients and 369 doctors joined the program. Unintended liver issues were found in around 5% of patients, a rate that is about the same as that seen in pexidartinib clinical trials, and no new safety concerns were found. About half of patients with liver issues could reverse them by stopping pexidartinib. No patient had permanent liver damage, needed a transplant or died from liver problems. These results show that the tREMS Program is working well to keep patients with TGCT safe while taking pexidartinib.

Real-world drug utilization and treatment patterns in patients with tenosynovial giant cell tumors in the USA.

Aim: Real-world treatment patterns in tenosynovial giant cell tumor (TGCT) patients remain unknown. Pexidartinib is the only US FDA-approved treatment for TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Objective: To characterize drug utilization and treatment patterns in TGCT patients. Methods: In a retrospective observational study using IQVIA's linked prescription and medical claims databases (2018-2021), TGCT patients were stratified by their earliest systemic therapy claim (pexidartinib [N = 82] or non-FDA-approved systemic therapy [N = 263]). Results: TGCT patients treated with pexidartinib versus non-FDA-approved systemic therapies were predominantly female (61 vs 50.6%) and their median age was 47 and 54 years, respectively. Pexidartinib-treated patients had the highest 12-month probability of remaining on treatment (54%); 34.1% of pexidartinib users had dose reduction after their first claim. Conclusion: This study provides new insights into the unmet need, utilization and treatment patterns of systemic therapies for the treatment of TGCT patients.

Treatment patterns in patients with tenosynovial giant cell tumors in the USAThis database study is the first investigation of how drugs are used to treat patients with tenosynovial giant cell tumor (TGCT) in the real world. We researched adult TGCT patients from IQVIA's prescription and medical claims databases who started treatment with pexidartinib (N = 82) or other non-US FDA-approved systemic therapies (N = 263). The patients included in this analysis were mostly women (61.0 and 50.6%) and their median age was 47 and 54 years for pexidartinib and other non-FDA-approved systemic therapies, respectively. The patients treated with pexidartinib were most likely to remain on treatment (54.0%) at the end of the first year. Most patients (79.3%) started pexidartinib treatment at a total daily dose of 800 mg/day, as per the product label. Only 34.1% of patients had reduced medication dose during follow-up. Of note, this study found that TGCT patients were treated with other systemic therapies which remain unproven to be safe and effective in medical studies of TGCT. Given the unmet need, and with pexidartinib being the only approved systemic treatment in USA, there is an opportunity for the larger population of adult TGCT patients to benefit from its use. Further research is needed to identify barriers for access to pexidartinib and treatment of TGCT patients.

Pexidartinib and Immune Checkpoint Inhibitors Combine to Activate Tumor Immunity in a Murine Colorectal Cancer Model by Depleting M2 Macrophages Differentiated by Cancer-Associated Fibroblasts.

Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.

CYP3A Mediates an Unusual C(sp2)-C(sp3) Bond Cleavage via Ipso-Addition of Oxygen in Drug Metabolism.

Mammalian cytochrome P450 drug-metabolizing enzymes rarely cleave carbon-carbon (C-C) bonds and the mechanisms of such cleavages are largely unknown. We identified two unusual cleavages of non-polar, unstrained C(sp2)-C(sp3) bonds in the FDA-approved tyrosine kinase inhibitor pexidartinib that are mediated by CYP3A4/5, the major human phase I drug metabolizing enzymes. Using a synthetic ketone, we rule out the Baeyer-Villiger oxidation mechanism that is commonly invoked to address P450-mediated C-C bond cleavages. Our studies in 18O2 and H2 18O enriched systems reveal two unusual distinct mechanisms of C-C bond cleavage: one bond is cleaved by CYP3A-mediated ipso-addition of oxygen to a C(sp2) site of N-protected pyridin-2-amines, and the other occurs by a pseudo-retro-aldol reaction after hydroxylation of a C(sp3) site. This is the first report of CYP3A-mediated C-C bond cleavage in drug metabolism via ipso-addition of oxygen mediated mechanism. CYP3A-mediated ipso-addition is also implicated in the regioselective C-C cleavages of several pexidartinib analogs. The regiospecificity of CYP3A-catalyzed oxygen ipso-addition under environmentally friendly conditions may be attractive and inspire biomimetic or P450-engineering methods to address the challenging task of C-C bond cleavages.

Tenosynovial Giant Cell Tumor Observational Platform Project (TOPP) Registry: A 2-Year Analysis of Patient-Reported Outcomes and Treatment Strategies.

BACKGROUND: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies. MATERIAL AND METHODS: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment). RESULTS: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy. CONCLUSION: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088).

Dynamic changes in microglia in the mouse hippocampus during administration and withdrawal of the CSF1R inhibitor PLX3397.

Pexidartinib (PLX3397), a colony-stimulating factor-1 receptor (CSF1R) inhibitor, is currently in phase 1-3 clinical trials as a treatment for a variety of tumours. CSF1R signalling regulates the development, survival and maintenance of microglia, the resident brain innate immune cells. In this study, we examined the effects of PLX3397 in the drinking water of mice on microglia in the hippocampus using ionized calcium-binding adapter molecule 1 (Iba1, a microglial marker) immunocytochemistry. A high concentration of PLX3397 (1 mg/mL) significantly decreased the density of Iba1-immunoreactive cells after 7 days of exposure, but a low concentration of PLX3397 (0.5 mg/mL) did not. In addition, both low and high concentrations of PLX3397 significantly increased the intersection number, total length and maximum length of microglial processes in male mice. PLX3397 administered for 21 days eliminated microglia with 78% efficiency in males and 84% efficiency in females. Significant increases in microglial processes were found after both seven and 21 days of PLX3397 exposure in males, whereas decreases in microglial processes were observed after both 14 and 21 days of exposure in females. After PLX3397 withdrawal following its administration for 14 days in males, the soma size quickly returned to normal levels within a week. However, the microglial density, intersection number and total length of microglial processes after 3 days of recovery stabilized to untreated levels. In summary, these findings provide detailed insight into the dynamic changes in microglial number and morphology in the hippocampus in a dose- and time-dependent manner after PLX3397 treatment and withdrawal.

Cancer therapy with immune checkpoint inhibitor and CSF-1 blockade: A mathematical model.

Immune checkpoint inhibitors (ICIs) introduced in recent years have revolutionized the treatment of many metastatic cancers. However, data suggest that treatment has benefits only in a limited percentage of patients, and that this is due to immune suppression of the tumor microenvironment (TME). Anti-tumor inflammatory macrophages (M1), which are attracted to the TME, are converted by tumor secreted cytokines, such as CSF-1, to pro-tumor anti-inflammatory macrophages (M2), or tumor associated macrophages (TAMs), which block the anti-tumor T cells. In the present paper we develop a mathematical model that represents the interactions among the immune cells and cancer in terms of differential equations. The model can be used to assess treatments of combination therapy of anti-PD-1 with anti-CSF-1. Examples are given in comparing the efficacy among different strategies for anti-CSF-1 dosing in a setup of clinical trials.

Proinflammatory activation of microglia in the cerebellum hyperexcites Purkinje cells to trigger ataxia.

Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.

Pexidartinib hydrochloride exposure induces developmental toxicity and immunotoxicity in zebrafish embryos via activation of Wnt signaling.

Pexidartinib, a macrophage colony-stimulating factor receptor (CSF-1R) inhibitor, is indicated for the treatment of tendon sheath giant cell tumor (TGCT). However, few studies on the toxicity mechanisms of pexidartinib for embryonic development. In this study, the effects of pexidartinib on embryonic development and immunotoxicity in zebrafish were investigated. Zebrafish embryos at 6 h post fertilization (6 hpf) were exposed to 0, 0.5, 1.0, and 1.5 µM concentrations of pexidartinib, respectively. The results showed that different concentrations of pexidartinib induced the shorter body, decreased heart rate, reduced number of immune cells and increase of apoptotic cells. In addition, we also detected the expression of Wnt signaling pathway and inflammation-related genes, and found that these genes expression were significantly upregulated after pexidartinib treatment. To test the effects of embryonic development and immunotoxicity due to hyperactivation of Wnt signaling after pexidartinib treatment, we used IWR-1, Wnt inhibitor, for rescue. Results show that IWR-1 could not only rescue developmental defects and immune cell number, but also downregulate the high expression of Wnt signaling pathway and inflammation-related caused by pexidartinib. Collectively, our results suggest that pexidartinib induces the developmental toxicity and immunotoxicity in zebrafish embryos through hyperactivation of Wnt signaling, providing a certain reference for the new mechanisms of pexidartinib function.

A prospective real-world study of the diffuse-type tenosynovial giant cell tumor patient journey: A 2-year observational analysis.

BACKGROUND AND OBJECTIVES: Diffuse-tenosynovial giant cell tumor (D-TGCT) is a rare, locally aggressive, typically benign neoplasm affecting mainly large joints, representing a wide clinical spectrum. We provide a picture of the treatment journey of D-TGCT patients as a 2-year observational follow-up. METHODS: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study at tertiary sarcoma centers spanning seven European countries and two US sites. Histologically confirmed D-TGCT patients were categorized as either those who remained on initial treatment strategy (determined at baseline visit) or those who changed treatment strategy with specific changes documented (e.g., systemic treatment to surgery) at the 1-year and/or 2-year follow-up visits. RESULTS: A total of 176 patients were assessed, mean diagnosis age was 38.4 (SD ± 14.6) years; most patients had a knee tumor (120/176, 68.2%). For the 2-year observation period, most patients (75.5%) remained on the baseline treatment strategy throughout, 54/79 patients (68.4%) remained no treatment, 30/45 patients (66.7%) remained systemic treatment, 39/39 patients (100%) remained surgery. Those who changed treatment strategy utilized multimodal treatment options. CONCLUSIONS: This is the first prospectively collected analysis to describe D-TGCT patient treatments over an extended follow-up and demonstrates the need for multidisciplinary teams to determine an optimal treatment strategy.

CSF1 receptor inhibition of tenosynovial giant cell tumor using novel disease-specific MRI measures of tumor burden.

Aim: Monitoring treatment of tenosynovial giant cell tumor (TGCT) is complicated by the irregular shape and asymmetrical growth of the tumor. We compared responses to pexidartinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with those by tumor volume score (TVS) and modified RECIST (m-RECIST). Materials & methods: MRIs acquired every two cycles were assessed centrally using RECIST 1.1, m-RECIST and TVS and tissue damage score (TDS). Results: Thirty-one evaluable TGCT patients were treated with pexidartinib. From baseline to last visit, 94% of patients (29/31) showed a decrease in tumor size (median change: -60% [RECIST], -66% [m-RECIST], -79% [TVS]). All methods showed 100% disease control rate. For TDS, improvements were seen in bone erosion (32%), bone marrow edema (58%) and knee effusion (46%). Conclusion: TVS and m-RECIST offer potentially superior alternatives to conventional RECIST for monitoring disease progression and treatment response in TGCT. TDS adds important information about joint damage associated with TGCT.

Turalio risk evaluation and mitigation strategy for treatment of tenosynovial giant cell tumor: framework and experience.

For drugs with enhanced serious safety risks, Risk Evaluation and Mitigation Strategy (REMS) may be required. Pexidartinib is approved for treatment of adult symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Its approval was conditional on its prescription via a mandatory REMS due to serious and potentially fatal liver injury seen in clinical trials. Turalio® REMS aims to mitigate this risk by ensuring provider education on pexidartinib use and required REMS components, prescriber adherence to baseline and periodic monitoring, and enrolling patients in a registry to further assess safe use and acute, chronic and irreversible hepatotoxicity. Through Turalio REMS, benefits of treating patients with pexidartinib may be preserved.

For drugs with serious side effects, specific safety measures may be put in place to manage these serious side effects in the form of Risk Evaluation and Mitigation Strategy (REMS) programs. Pexidartinib (Turalio^®) is approved for treatment of adults who have symptoms of severe tenosynovial giant cell tumor or have limitations in function that do not improve with surgery. Turalio^® has an REMS program because liver injuries that can be serious or fatal were seen in Pexidartinib clinical trials. This program aims to decrease the seriousness of the liver injuries by assuring doctors and pharmacists are educated on how to use the drug, patients are advised of this potential risk and that baseline and periodic monitoring of patients are conducted.

Tenosynovial giant cell tumor-diffuse type, treated with a novel colony-stimulating factor inhibitor, pexidartinib: initial experience with MRI findings in three patients.

Tenosynovial giant cell tumor-diffuse type (diffuse TSGCT) is a benign but locally aggressive proliferative disorder of the synovium. Treatment is usually surgical, although in cases of extensive disease complete synovectomy is not possible and local recurrence rates are high. Pexidartinib (trade name Turalio®), a colony-stimulating factor-1 (CSF-1) inhibitor, was shown in a recent phase III trial to effectively treat diffuse TSGCT and is FDA approved for the treatment of adult patients with symptomatic diffuse TSGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) because of the risk of hepatotoxicity. Magnetic resonance imaging (MRI) is the preferred imaging modality for the diagnosis and surveillance of TSGCT. Here we present three patients with diffuse TSGCT of the knee who underwent multiple MRIs over several years while on pexidartinib. We describe the disease burden and signal characteristics on MRI and correlate with the response reported in the patients' medical records. Given that the use of pexidartinib and other CSF inhibitors is likely to increase, musculoskeletal radiologists should be aware of this novel non-operative treatment and the MRI appearance of diffuse TSGCT during therapy.

Eco-Friendly, Simple, Fast, and Sensitive UPLC-MS/MS Method for Determination of Pexidartinib in Plasma and Its Application to Metabolic Stability.

Pexidartinib is the first drug approved by the U.S. Food and Drug Administration specifically to treat the rare joint tumor tenosynovial giant cell tumor. In the current study, a validated, selective, and sensitive UPLC-MS/MS assay was developed for the quantitative determination of pexidartinib in plasma samples using gifitinib as an internal standard (IS). Pexidartinib and IS were extracted by liquid-liquid extraction using methyl tert-butyl ether and separated on an acquity BEH C18 column kept at 40 °C using a mobile phase of 0.1% formic acid in acetonitrile: 0.1% formic acid in de-ionized water (70:30). The flow rate was 0.25 mL/min. Multiple reaction monitoring (MRM) was operated in electrospray (ESI)-positive mode at the ion transition of 418.06 > 165.0 for the analyte and 447.09 > 128.0 for the IS. FDA guidance for bioanalytical method validation was followed in method validation. The linearity of the established UPLC-MS/MS assay ranged from 0.5 to 1000 ng/mL with r > 0.999 with a limit of quantitation of 0.5 ng/mL. Moreover, the metabolic stability of pexidartinib in liver microsomes was estimated.

Long-term outcomes of pexidartinib in tenosynovial giant cell tumors.

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. RESULTS: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). CONCLUSIONS: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

Pexidartinib Long-Term Hepatic Safety Profile in Patients with Tenosynovial Giant Cell Tumors.

BACKGROUND: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. MATERIALS, AND METHODS: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. RESULTS: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. CONCLUSION: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. IMPLICATIONS FOR PRACTICE: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.

Pexidartinib treatment in Alexander disease model mice reduces macrophage numbers and increases glial fibrillary acidic protein levels, yet has minimal impact on other disease phenotypes.

BACKGROUND: Alexander disease (AxD) is a rare neurodegenerative disorder that is caused by dominant mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament that is primarily expressed by astrocytes. In AxD, mutant GFAP in combination with increased GFAP expression result in astrocyte dysfunction and the accumulation of Rosenthal fibers. A neuroinflammatory environment consisting primarily of macrophage lineage cells has been observed in AxD patients and mouse models. METHODS: To examine if macrophage lineage cells could serve as a therapeutic target in AxD, GFAP knock-in mutant AxD model mice were treated with a colony-stimulating factor 1 receptor (CSF1R) inhibitor, pexidartinib. The effects of pexidartinib treatment on disease phenotypes were assessed. RESULTS: In AxD model mice, pexidartinib administration depleted macrophages in the CNS and caused elevation of GFAP transcript and protein levels with minimal impacts on other phenotypes including body weight, stress response activation, chemokine/cytokine expression, and T cell infiltration. CONCLUSIONS: Together, these results highlight the complicated role that macrophages can play in neurological diseases and do not support the use of pexidartinib as a therapy for AxD.

A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors.

Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).

Tumor-associated macrophages: A promising target for a cancer immunotherapeutic strategy.

Macrophages, a type of myeloid immune cell, play essential roles in fighting against pathogenic invasion and activating T cell-mediated adaptive immune responses. As a major constituent of the tumor microenvironment (TME), macrophages play a complex role in tumorigenesis and tumor progression. They can inhibit tumor growth by releasing proinflammatory cytokines and exerting cytotoxic activities but principally contribute to tumor progression by promoting tumor proliferation, angiogenesis, and metastasis. The tumor-promoting hallmarks of macrophages have aroused widespread interest in targeting tumor-associated macrophages (TAMs) for cancer immunotherapy. Increasing preclinical and clinical studies suggest that TAMs are a promising target for cancer immunotherapy. To date, TAM-targeted therapeutic strategies have mainly been divided into two kinds: inhibiting pro-tumor TAMs and activating anti-tumor TAMs. We reviewed the heterogeneous and plastic characteristics of macrophages in the TME and the feasible strategies to target TAMs in cancer immunotherapy and summarized the complementary effect of TAM-targeted therapy with traditional treatments or other immunotherapies.