Pigmented Villonodular Synovitis Research Articles

Pimicotinib Significantly Improves Outcomes for Patients with Tenosynovial Giant Cell Tumor

Results from the Phase 3 MANEUVER trial (NCT05804045) of pimicotinib (ABSK021), an investigational orally administered, highly selective, and potent small-molecule inhibitor of colony-stimulating factor-1 receptor (CSF-1R) being developed by Abbisko Therapeutics, met its primary endpoint, demonstrating significant improvement in objective response rate (ORR) in patients with tenosynovial giant cell tumor (TGCT). The ORR for pimicotinib at week 25 was 54.0% compared with 3.2% for placebo (p<0.0001).

A phase 4, multicenter, global clinical study to evaluate discontinuation and rechallenge of pexidartinib in patients with tenosynovial giant cell tumor previously treated with pexidartinib.

Pexidartinib is effective in patients with tenosynovial giant cell tumor (TGCT) for whom surgery is not feasible. Durability of response after discontinuation of pexidartinib and the safety and efficacy of restarting pexidartinib have not been previously recorded. This phase 4 study was designed to mimic the real-world experience with pexidartinib to evaluate the effects of discontinuation of and retreatment with pexidartinib in patients with TGCT who previously benefited from the drug. This was a global, multicenter, phase 4 study that enrolled patients with TGCT who were experiencing clinical benefit from pexidartinib in one of four prior phase 1 or phase 3 studies investigating pexidartinib in the disease. Patients could choose to continue pexidartinib at the same dose (the treatment-continuation cohort) or discontinue treatment with the option to restart pexidartinib (the treatment-free/retreatment cohort). Tumor progression determined by Response Evaluation Criteriain Solid Tumors (RECIST) version 1.1, patient-reported outcomes (the Patient-Reported Outcomes Measurement Information System-Physical Function [PROMIS-PF] questionnaire and the EuroQol 5-dimension, 5-level [EQ-5D-5L] visual analog scale), and safety were assessed every 3 months. The primary end point was the proportion of patients in the treatment-free/retreatment cohort who remained treatment-free at month 12 and 24; this did not depend on disease progression. Thirty-two patients were enrolled: 21 chose to enter the treatment-continuation cohort, and 11 entered the treatment-free/retreatment cohort. During the treatment-free period, six of 11 (54.5%) patients in the treatment-free/retreatment cohort had progressive disease (PD) according to RECIST, version 1.1, whereas no patient in the treatment-continuation cohort had disease progression. Over the 24-month study, three of 11 (27.3%) patients in the treatment-free/retreatment cohort restarted treatment because of RECIST version 1.1 PD, symptomatic progression, or both (n=1 each). The probability of remaining treatment-free in the treatment-free/retreatment cohort was 73% (95% confidence interval, 37%-90%). In the treatment-free/retreatment cohort, the median progression-free survival of the treatment-free period was 22.8 months (95% confidence interval, 1.6 months to not estimable). By 6 months of retreatment, all retreated patients achieved new disease stabilization with no new safety concerns; two patients had clinically significant improvements in PROMIS-PF and EQ-5D-5L visual analog scale scores. The mean PROMIS-PF and EQ-5D-5L scores remained stable throughout the study. There was no hepatotoxicity and no new safety signal in either cohort. In this small phase 4 study designed to evaluate outcomes in patients who stopped and restarted pexidartinib, 54.5% of patients who discontinued pexidartinib showed PD, with a median progression-free survival of 22.8 months. Each of the three patients who restarted pexidartinib stopped progressing, and some reported a new gain in physical function. No PD was detected in patients who remained on treatment, and the safety profile did not indicate long-term hepatotoxicity or any new safety concerns. Pexidartinib is a medication for people with tenosynovial giant cell tumor (TGCT) for whom surgery is not recommended. This study examined what happens when patients stop taking pexidartinib (after it has helped them) to see whether it is safe and effective to restart if needed. Thirty-two patients were followed for 2 years: 21 chose to continue pexidartinib and did not experience disease progression, while 11 chose to stop pexidartinib; 54.5% of them had disease progression within 2 years. Three patients who stopped pexidartinib restarted treatment after their tumor size increased or their symptoms worsened. Restarting pexidartinib was safe and effective in these patients.

Is intercalary frozen autograft augmented with intramedullary cement and bridging plates fixation a durable reconstruction?

AimsWe analysed the survival, complications, and function of frozen autograft augmented with intramedullary cement and bridging plates fixation for intercalary bone defect reconstruction in primary bone sarcomas.Patients and MethodsA retrospective cohort study was conducted on 72 patients with primary bone sarcomas (34 males, 38 females) between January 2016 and June 2023. The average age was 22.0 ± 13.6 years (6 to 61 years) and the pathological type included osteosarcoma (55), followed by adamantinoma (5), Ewing’s sarcoma (4), undifferentiated pleomorphic sarcoma (4), chondrosarcoma (3), and malignant tenosynovial giant cell tumor (1). The oncological outcomes included local control, metastasis, progression-free survival and overall survival. The functional outcomes were evaluated by the Musculoskeletal Tumor Society Score (MSTS-93), the Toronto Extremity Salvage Score (TESS), and the motion of the joint.ResultsThe mean follow-up time was 50.0 ± 27.4 months (12 to 99 months). 10 patients died of the disease, 9 patients were alive with disease and 53 patients were alive with no evidence of disease. The average 5-year overall survival of autograft was 85.8% (95% CI, 72.1-93.1%). The average MSTS-93 score was 96% ( 67–100%) and the average TESS score was 98% (74–100%). Twenty-four patients (33.3%) had at least one complication in the follow-up period. The most common complications were nonunion (9.7%, 7/72) and local recurrence (9.7%, 7/72), followed by leg length discrepancy (6.9%, 5/72), infection (5.6%, 4/72), implant failure (4.2%, 3/72), delayed union (2.8%, 2/72), and graft fractures (1.4%, 1/72). Tumor site was an independent risk factor for bone nonunion (OR, 22.23; p = 0.006).ConclusionsWe presented a large technique series for preventing autograft-related complications (especially for autograft fractures) of intercalary frozen autograft reconstruction. This method showed promising functional outcomes and provided durable reconstruction.Level of evidencelevel IV therapeutic study.

Arthroscopic Management of Pigmented Villonodular Synovitis of the Hip: A Systematic Review.

Background/Objectives: Pigmented villonodular synovitis (PVNS) is a benign proliferation of synovial tissue that can cause joint damage. The hip, although less commonly affected than the knee, presents a challenging diagnosis and treatment, with magnetic resonance imaging (MRI) as the gold standard for detection. Surgical excision, arthroscopic or open, is the main treatment approach, but there is no consensus on the best strategy for the hip. The aim of this systematic review is to evaluate the clinical outcomes, complications, and revision rates associated with arthroscopic hip surgery for PVNS. Methods: A systematic review was performed following the PRISMA guidelines. Relevant studies were identified by searching four databases: PubMed, Scopus, Embase, and Medline. Selected articles were evaluated according to the criteria of levels of evidence (LoE). For retrospective studies, the Coleman Methodology Score (mCMS) was used. This systematic review was registered with the International Prospective Register of Systematic Reviews. Results: Six studies satisfied the criteria; these involved 77 patients (48% male, 52% female) with a mean age of 26.4 years and a mean follow-up of 54.3 months. MRI and biopsy confirmed the diagnoses, and arthroscopic synovectomy was the primary treatment. Success rates ranged from 80% to 100%, with a recurrence rate of 7.8%, 1.3% requiring revision surgery, and eight (10.4%) patients in three studies reporting conversion to THA. Complications included mild effusions and residual synovitis. All patients who underwent a subsequent total hip arthroplasty were affected by advanced osteoarthritis. Conclusions: Our systematic review reveals that the use of hip arthroscopy in diagnosing and treating PVNS has shown satisfactory results without increasing the risk of recurrence or complications and can return patients to their former activity levels, provided their preoperative osteochondral status is good and there is early management of PVNS of the hip joint.

Features of Magnetic Resonance Diagnostics of Tenosynovial Giant Cell Tumor (Pigmented Villonodular Synovitis)

Aim. Demonstrate the features of magnetic resonance diagnostics of tenosynovial giant cell tumor.Materials and Methods. Using magnetic resonance imaging, we identified patients with tenosynovial giant cell tumor of the knee joint, describing the diagnostic features and clinical course of diffuse and local forms of the tumor.Results. Specific MRI patterns of tenosynovial giant cell tumor are hemosiderin deposits, villous and nodular growths of the synovium of the knee joint, joint effusion and bone erosion.Conclusion. Тenosynovial giant cell tumor is a rare mesenchymal neoplasm arising from the synovium of joints and tendon sheaths, disabling young able-bodied people. Magnetic resonance imaging, being the “gold” standard for radiological diagnostics, helps to identify specific patterns.

Treatment Modalities for Refractory-Recurrent Tenosynovial Giant Cell Tumor (TGCT): An Update

Background and Objectives: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive, benign neoplasm arising from the synovium of joints, tendon sheaths, and bursa. There are two main subtypes of TGCT: localized-type TGCT(L-TGCT) and diffuse-type TGCT (D-TGCT). While surgical excision is still considered the gold standard of treatment, the high recurrence rate, especially for D-TGCT, may suggest the need for other treatment modalities. Materials and Methods: This study reviews current literature on the current treatment modalities for refractory-relapsed TGCT disease. Results: The gold standard of treatment modality in TGCT remains surgical excision of the tumor nevertheless, the elevated recurrence rate and refractory disease, particularly in D-TGCT indicates and underscores the necessity for additional treatment alternatives. Conclusions: TGCT is a benign tumor with inflammatory features and a potential destructive and aggressive course that can lead to significant morbidity and functional impairment with a high impact on quality of life. Surgical resection remains the gold standard current treatment and the optimal surgical approach depends on the location and extent of the tumor. Systemic therapies have been recently used for relapsed mainly cases.

Vimseltinib versus a placebo in patients with tenosynovial giant cell tumor: a plain language summary of the MOTION phase 3 trial.

This article presents a patient-friendly summary of the MOTION phase 3 clinical trial results, which were published in The Lancet in June 2024.The primary goal of the MOTION trial was to understand if treatment with a drug called vimseltinib shrank tumors more than a placebo in participants with symptomatic tenosynovial giant cell tumor, also known as TGCT, for which surgery was unlikely to provide benefit. A placebo is something that looks like the treatment being studied but does not contain any medicine.The MOTION trial compared the effects of vimseltinib versus a placebo using several different outcomes associated with TGCT. These outcomes included tumor size, active range of motion of the affected joint, and several patient-reported quality-of-life measures including physical function, stiffness, overall health, and pain. The trial showed that more participants treated with vimseltinib experienced significant tumor shrinkage, as defined by a 30% or greater reduction in tumor size, compared with those receiving a placebo. Participants receiving vimseltinib had improved active range of motion, and they reported improved physical function, stiffness, overall health, and pain, regardless of the amount of tumor shrinkage, compared with participants receiving a placebo. Most side effects in participants treated with vimseltinib were not severe and were manageable. Vimseltinib was better at shrinking tumors and improving active range of motion, stiffness, pain, and other health measures than the placebo for participants with TGCT. Vimseltinib has the potential to become a new treatment option for patients with TGCT for whom surgery may not provide benefit.

Unveiling the Role of Radiotherapy in Managing Pigmented Villonodular Synovitis (PVNS): A Unique Case Analysis

Background and Aims: Pigmented villonodular synovitis (PVNS) is an uncommon but aggressive proliferative process affecting the synovium. Diffuse pigmented villonodular synovitis (DPVNS) is a type that affects the whole joint and if left untreated, it can lead to joint destruction and osteoarthritis. Only surgical excision can lead to local recurrences in DPVNS. Postoperative radiotherapy can significantly lower the incidences of local recurrences and improve functional outcomes. Materials and Methods: Here we present a rare case report of a lady with biopsy-proven DPVNS where postoperative radiotherapy was given. Results: At a 48-month follow-up, the patient is free of disease with improved joint function. Discussion: Given the improved local control, low morbidity and remarkable improvement in joint functions, postoperative radiotherapy should be routinely considered in cases of DPVNS if complete excision is doubtful.

Endoscopic En Bloc Resection of Giant Cell Tumor of Tendon Sheath of Anterior Ankle

Giant cell tumor of the tendon sheath (GCTTS) originates from the synovial cells of the tendon sheath. It is one of the most common benign soft-tissue tumors of the foot and ankle affecting the joints, bursae, and tendon sheaths and can behave in a locally aggressive manner. Complete surgical resection with long-term follow-up is the preferred treatment. Because GCTTS is a benign condition, the equilibrium between the quality of the surgical margins and functional preservation should be considered. If more aggressive resection is applied, the outcome may negatively affect quality of life, whereas incomplete resection may lead to recurrence. The purpose of this technical note is to describe the details of endoscopic en bloc resection of GCTTS of the anterior ankle. This endoscopic approach can provide a magnified view of the operative site, allowing accurate surgical assessment to ensure complete resection of the lesion without damage to the adjacent normal structures.

Localized type tenosynovial giant cell tumor with metastases to lungs and pleura: a case report and literature review

BackgroundTenosynovial giant cell tumor is a rare soft tissue tumor of the synovium of joint, bursae, or tendon sheath. It is divided into localized or diffuse types on the basis of the growth pattern. Localized tenosynovial giant cell tumors are usually benign and treated successfully by excision. Diffuse tenosynovial giant cell tumors, in contrast to localized type, can destroy bone and cartilage and are associated with frequent local recurrences and distant metastasis. Localized type tenosynovial giant cell tumors rarely metastasize to distant organs. Here, we report a case of localized tenosynovial giant cell tumor presenting with lung metastases and systematically review literature.Case presentationA 55-year-old Asian male presented with a dry cough, right-sided chest pain and progressive dyspnea for 1 month. At 18 months before this presentation, he had undergone excision of a painless swelling on his right index finger. The swelling recurred within 3 months of excision, and a biopsy was then suggestive of a giant cell tumor. Given the suspicion of a giant cell tumor, a wide excision of the lesion was performed and the excisional biopsy was consistent with a diagnosis of tenosynovial giant cell tumor, localized type. At admission to our hospital, the patient had tachypnoea and absent breath sounds on the right side. A chest radiograph showed a right-sided pleural effusion with a homogenous opacity in the left mid-zone. A contrast-enhanced computed tomography of the chest and abdomen showed right massive pleural effusion and bilateral multiple lobulated heterogeneously enhancing pleural-based masses with areas of internal calcification. Pleural fluid analysis revealed an exudate with no malignant cells on cytology. A lung biopsy showed osteoclast-like giant cells and mononuclear spindle cells with areas of hemorrhage and necrosis, suggesting tenosynovial giant cell tumor metastasis. A final diagnosis of localized type tenosynovial giant cell tumor of the right index finger with metastases to the lungs and pleura was made. The patient passed away after receiving three cycles of denosumab injection owing to progressive disease.ConclusionLung metastasis is extremely rare in patients with localized tenosynovial giant cell tumor. The survival is usually poor in patients with lung metastasis. A close follow-up of patients with localized type tenosynovial giant cell tumor is necessary for early detection of pleuropulmonary complications.

Synovial chondromatosis : Results from the histopathological arthritis register of the German Society for Orthopedic Rheumatology

Synovial chondromatosis, or osteochondromatosis, is arare benign disorder that occurs in joints, tendon sheaths, or bursae, characterized by cartilage proliferations of varying sizes and shapes, often with ossifications. In this study the prevalence, sensitivity, gender predominance, differential diagnoses, and primary localization of synovial chondromatosis are analyzed within the Histopathological Arthritis Registry of the German Society for Orthopedic Rheumatology. All cases of patients diagnosed with "synovial chondromatosis" from the Histopathological Arthritis Registry of the German Society for Orthopedic Rheumatology were retrospectively examined, covering the period from 1 January 2018, to 31 December 2022. Between 1 January 2018, and 31 December 2022, there were 14cases of synovial chondromatosis out of atotal of 13,222 cases in the Histopathological Arthritis Register of the German Society for Orthopedic Rheumatology. The available data include primary localization, and age and gender of the patients. Among the 13,222 cases in the Histopathological Arthritis Register of the German Society for Orthopedic Rheumatology, 14were histopathologically confirmed as synovial chondromatosis. This resulted in aprevalence of 0.1% or 1.13 per 1,000 cases. The correct clinical presumptive diagnosis was made in 5cases, yielding asensitivity of 35.7%, 95% confidence interval (CI) 12.8% to 64.9%. Differential diagnoses for this condition include pigmented villonodular synovitis, tenosynovial giant cell tumor, and chondrosarcoma. Synovial chondromatosis frequently occurs in large joints such as the knee, hip, and the temporomandibular joint. A peak incidence is described in the fifth decade of life. However, the disorder can also occur in children. For the first time, the study was able to provide data for Germany based on alarge sample. Additionally, initial statements regarding the prevalence and sensitivity of synovial chondromatosis could be made. The aim of this work is to raise awareness of this very rare disease to enable faster and more efficient diagnosis. The study also highlights the importance of histopathology in the diagnosis of synovial chondromatosis.

MANEUVER: A Phase III study of pimicotinib to assess efficacy and safety in tenosynovial giant cell tumor patients.

Tenosynovial giant cell tumor (TGCT) is a rare, locally invasive soft tissue tumor arising from the synovium of joints, bursa and tendon sheaths and is associated with the overexpression of the colony-stimulating factor 1 (CSF-1) gene. Pimicotinib is an orally available, highly selective and potent small molecule CSF-1 receptor (CSF-1R) inhibitor with robust efficacy and safety profile in patients with TGCT and is under development in multiple diseases. In an open-label Phase I study in patients with TGCT not amenable to surgery, pimicotinib showed superior efficacy and safety. In this article, we elucidate the rationale and study design of the multi-region Phase III MANEUVER trial (NCT05804045), which is designed to assess the efficacy and safety of pimicotinib in patients with TGCT not amenable to surgical resection in Asia, North America and Europe.

The Use of Radiosynovectomy Using Yttrium-90 as an Adjunct to Mechanical Synovectomy for Pigmented Villonodular Synovitis: How Effective Is This?

Introduction Pigmented villonodular synovitis (PVNS) or giant cell tumour of the tendon sheath (GCTT) is a rare disorder involving the proliferation of the synovium in any joint; however, the knee, hip, and ankle joints are most commonly targeted. The aim of this study is to follow the short-term outcomes of the treatment of patients with PVNS of the knee managed by intra-articular injection of yttrium-90 or radiosynovectomy (RS) aloneand a combination of RS and arthroscopic/open debulking synovectomy. Methods A cohort of eight knees from six patients was included in this study, including three knees treated with combined arthroscopic synovectomy and RS, and five knees treated with RS alone. Patients were asked to complete the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire before attending their three-month follow-up appointment. Their answers were collated and scores were calculated using the designated specific equation. Results Our results demonstrate that although patients in the combined arthroscopic synovectomy and RSarm possess on average higher pain scores and symptoms than those who underwent RSalone, the combined therapy had higher scores in activities of daily living (ADLs), sports and recreation (Sport-Rec), quality of life (QoL), and overall KOOS scores. Conclusion Neoadjuvant arthroscopic mechanical debridement is a safe and quick procedure with minimal side effects, with improved overall KOOS scores.

An extensive infiltrative diffuse tenosynovial giant cell tumor in both compartment of the forearm: A case report

Diffuse tenosynovial giant cell tumors are relatively rare but second most common tumor effecting the synovial containing tissues. The study aim was to present a case involving a 40-year-old male patient with a complaint of a progressively enlarging swelling on the radial side of right wrist. On local examination, there was a bi-lobed swelling 7×9 and 6×5 cm on the dorsolateral and anterolateral aspect of right wrist respectively. Through Hennery’s modified approach tumor was exposed. It was extending from dorsolateral to anteromedial wrist encasing the flexors, extensor and abductor tendons of thumb and radial neurovascular bundle and adjacent wrist and finger flexors. The tumor surrounding the tendons was carefully removed, and carpal tunnel release was performed to address the tingling sensation. The patient managed was having lobulated diffuse type tumor involving the both flexor and extensor compartment. Better outcome, less morbidity and least chance of recurrence can be expected if the tumor had been operated earlier.

1770P Safety, efficacy, and patient-reported outcomes (PROs) with vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT) who received prior anti–colony-stimulating factor 1 (CSF1) therapy: Ongoing phase II study

1770P Safety, efficacy, and patient-reported outcomes (PROs) with vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT) who received prior anti–colony-stimulating factor 1 (CSF1) therapy: Ongoing phase II study

1769P Safety and efficacy with vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT) who received no prior anti–colony-stimulating factor 1 (CSF1) therapy: Ongoing phase II study

1769P Safety and efficacy with vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT) who received no prior anti–colony-stimulating factor 1 (CSF1) therapy: Ongoing phase II study

LBA78 Updated efficacy and safety of vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT): One-year follow-up from the MOTION phase III trial

LBA78 Updated efficacy and safety of vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT): One-year follow-up from the MOTION phase III trial

Thorn-induced Injury of the Knee Mimicking Pigmented Villonodular Synovitis (PVNS): A Case Report

Background and Aims: Plain film radiography is the first imaging modality in the detection of most foreign bodies. However, it is not sensitive for detection of radiolucent objects such as organic material including plant thorns. Case report: Herein, we present the case of a 19-year-old male patient, presenting with an 8-month history of right knee pain and laxity, whose radiographic appearance mimicked that of pigmented villonodular synovitis (PVNS) but was found to have a retained neglected plant thorn in his knee. Upon ultrasound evaluation for image-guided biopsy to confirm the provisional diagnosis of PVNS, he was found to have a retained neglected plant thorn in his knee. Discussion: Plant thorn injuries can present as knee synovitis, as in our case, and should be kept in the differential diagnosis. An ultrasound-guided removal is possible and is a useful minimally invasive procedure.

Chondroid Synoviocytic Neoplasm: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of a Distinctive Tumor of Synoviocytes

Tumors resembling tenosynovial giant cell tumor (TGCT) but additionally forming chondroid matrix are rare and most often involve the temporomandibular joint (TMJ). We studied 21 tumors consisting of synoviocytes (large, eosinophilic mononuclear cells containing hemosiderin) and chondroid matrix to better understand these unusual neoplasms. The tumors occurred in 10 males and 11 females, in the age group of 31 to 80 years (median, 50 years) and involved the TMJ region (16), extremities (4), and spine (1). As in conventional TGCT, all were composed of synoviocytes, small histiocytes, foamy macrophages, siderophages, and osteoclast-like giant cells in variably hyalinized background. Expansile nodules of large, moderately atypical synoviocytes were present, in addition to “chondroblastoma-like,” “chondroma-like,” or “phosphaturic mesenchymal tumor-like” calcified matrix. The synoviocytes expressed clusterin (17/19) and less often desmin (3/15). The tumors were frequently CSF1 positive by chromogenic in situ hybridization (8/13) but at best weakly positive for CSF1 by immunohistochemistry (0/3). Background small histiocytes were CD163 positive (12/12). All were FGF23 negative (0/10). Cells within lacunae showed a synoviocytic phenotype (clusterin positive; S100 protein and ERG negative). RNA-Seq was successful in 13 cases; fusions were present in 7 tumors, including FN1::TEK (5 cases); FN1::PRG4 (2 cases); and MALAT1::FN1, PDGFRA::USP35, and TIMP3::ZCCHC7 (1 case each). Three tumors contained more than 1 fusion (FN1::PRG4 with TIMP3::ZCCHC7, FN1::TEK with FN1::PRG4, and FN1::TEK with MALAT1::FN1). Clinical follow-up (17 patients; median follow-up duration 38 months; range 4-173 months) showed 13 (76%) to be alive without evidence of disease and 4 (24%) to be alive with persistent/recurrent local disease. No metastases or deaths from disease were observed. We conclude that these unusual tumors represent a distinct category of synoviocytic neoplasia, which we term “chondroid synoviocytic neoplasm,” rather than simply ordinary TGCT with cartilage. Despite potentially worrisome morphologic features, they appear to behave in at most a locally aggressive fashion.

CSF1R Inhibition in Patients with Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase I Study of Vimseltinib.

Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. This first-in-human, multicenter, open-label phase I/II study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase II dose, and characterize the pharmacokinetics; exploratory objectives included pharmacodynamics and efficacy. Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were of grade 1/2 severity. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The recommended phase II dose was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7-46.9), and the objective response rate as assessed by independent radiological review using RECIST version 1.1 was 72%. Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT not amenable to surgery.