As New TGCT Therapies Advance, Route, Duration, and Coverage Shape CSF1R Inhibitor Choice

Pexidartinib (Turalio) and vimseltinib (Romvimza) are FDA-approved inhibitors of the colony-stimulating factor 1 receptor (CSF1R) for tenosynovial giant cell tumor (TGCT), a rare tumor that arises in the synovium. Pimicotinib, an oral inhibitor, and emactuzumab, an intravenous (IV) antibody, have each demonstrated objective responses in clinical studies, though not in head-to-head comparisons. With several agents acting on the same pathway, clinicians must weigh dosing format, treatment duration, safety, and access when choosing among them.

In a virtual Case-Based Roundtable event for oncologists across the central US, Seth M. Pollack, MD, director of the sarcoma program at the Lurie Cancer Center and the Steven T. Rosen Professor of Cancer Biology at Northwestern University Feinberg School of Medicine in Chicago, Illinois, reviewed trial data for pimicotinib and emactuzumab and moderated discussion of a patient with recurrent diffuse TGCT. Pollack noted that the toxicity profile of pimicotinib appeared similar to that of vimseltinib and said payer preferences were likely to influence early prescribing.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event. Read part 1.

CASE SUMMARY

Patient Presentation

• A 36-year-old woman
• Chief complaint of right knee swelling, pain, and a "catching" sensation with activity

History

• Ten-month history of progressive right knee swelling and intermittent pain, initially attributed to a sports-related injury
• Symptoms failed to improve with conservative management (rest, nonsteroidal anti-inflammatory drugs, physical therapy) and have gradually worsened, now affecting her ability to exercise and climb stairs
• She denies fever, weight loss, or other systemic symptoms
• No significant past medical history; no family history of similar joint conditions

Physical Exam

• General: Well-appearing, no acute distress
• Right knee: Visible effusion, warmth to palpation, mild tenderness along the joint line; palpable soft-tissue fullness in the suprapatellar region
• Range of motion: Mildly limited flexion (110°) secondary to swelling and discomfort
• Neurovascular: Intact distally
• Gait: Mild antalgic gait favoring the right leg

Diagnostic Workup

• MRI of right knee: diffuse, lobulated synovial proliferation with low-signal foci on T2-weighted sequences consistent with hemosiderin deposition; involvement extends beyond the joint capsule with extra-articular soft-tissue extension
• Biopsy (image-guided): confirms diffuse-type tenosynovial giant cell tumor (D-TGCT)
• Labs: Complete blood count (CBC), comprehensive metabolic panel (CMP), and liver function tests (LFTs) within normal limits

Initial Treatment

• Given the extent of extra-articular extension, the case was reviewed at multidisciplinary sarcoma tumor board and the patient underwent an open synovectomy

Current Status and Assessment

• Timing: 5 months post-synovectomy
• Interval history: Surveillance MRI reveals early recurrence, with disease extension into the posterior compartment, limiting feasibility of a second complete resection without significant functional risk; patient reports recurrent swelling and worsening pain on a visual analog scale (VAS) of 6/10
• Physical exam: Recurrent effusion, warmth, flexion now limited to 100°, palpable synovial thickening
• ECOG performance status: 1
• Labs: normal CBC, CMP, and LFTs—no contraindication to systemic therapy
• Functional impact: Increasing difficulty with work (prolonged standing) and daily activities; sleep disrupted by pain

EVENT RECAP

With a second complete resection judged unfavorable for this patient, the group turned to systemic therapy. Two CSF1R inhibitors, pexidartinib and vimseltinib, are FDA approved for TGCT, and Pollack asked participants how pimicotinib, which he noted was not approved and which he had not yet used, would fit alongside them. In an opening poll, 77.8% of 9 respondents said they treat 0 to 5 patients with TGCT per year, and 66.7% said they were aware of or had used both approved agents.

The phase 3 MANEUVER trial (NCT05804045) randomly assigned 94 adults with TGCT 2:1 to pimicotinib (n = 63) or placebo (n = 31).¹ The overall response rate (ORR) by blinded independent review committee (BIRC) per RECIST v1.1 at week 25 was 54% (95% CI, 41%-67%) with pimicotinib vs 3% (95% CI, 0.1%-17%) with placebo, an absolute difference of 51% (95% CI, 33%-63%; P <.0001). At a median follow-up of 14.3 months, the ORR among patients assigned to pimicotinib was 76.2% (95% CI, 63.8%-86.0%) by RECIST v1.1 and 74.6% (95% CI, 62.1%-84.7%) by tumor volume score, with best overall responses of complete response in 6.3% and partial response in 69.8%. Patients who crossed over from placebo had an ORR of 64.5% at a median of 260 days after switching.

In the longer-term analysis, the most common adverse events were pruritus (60.3%; grade 3 or 4, 3.2%), facial edema (49.2%), rash (38.1%), and periorbital edema (36.5%), and blood creatine phosphokinase was increased in 71.4% (grade 3 or 4, 15.9%). The study reported no evidence of cholestatic hepatotoxicity or drug-induced liver injury.²

Ankit Mangla, MD, of University Hospitals Seidman Cancer Center in Westlake, Ohio, asked how the placebo-controlled trial was conducted in a disease with approved therapies. Pollack said his group did not open MANEUVER because he would not place a patient on placebo, and that the trial reached full enrollment by recruiting globally, including in regions with no approved agent. Pollack said that if pimicotinib is approved, payers may identify preferred agents, and early use would likely favor vimseltinib because clinicians know it better. He expected reimbursement to be the main early barrier.

Emactuzumab was reviewed through its phase 1 dose-escalation and dose-expansion study (NCT01494688) of 63 patients with diffuse TGCT, in which the antibody was given intravenously (IV) on limited-cycle schedules, including 5 doses every 2 weeks and 4 doses every 3 weeks.³ The best ORR on treatment was 71% (45 of 63 patients) with a disease control rate of 98%, and the ORR was 64% (9 of 14 patients assessed) at the optional 2-year follow-up. Pruritus occurred in 70% of patients (grade 3 or higher, 3%), followed by asthenia (62%), face edema (49%), and periorbital edema (43%). Pollack said the efficacy looked similar to that of vimseltinib and pimicotinib, but the studies differed in design and populations, so response rates cannot be compared directly. He added that the randomized phase 3 TANGENT trial (NCT05417789) had completed accrual but that its data were not fully available at that time.

Discussion of emactuzumab centered on its finite course. Mangla said that "if you [can] give it for 5 [cycles] and forget about it," then it might be preferred as first-line therapy as patients tend to prefer a defined stop date. Pollack agreed that many patients would rather stop treatment, but said some would prefer an oral therapy, and cautioned that durability at 3 or 4 years was unknown. Martin Schoen, MD, of Saint Louis University/Veterans Affairs in Clayton, Missouri, pointed out that the 5-year effectiveness of vimseltinib is also not well established, and that institutional incentives sometimes favor prescribing IV antibodies.

On duration, Pollack and Mangla each said they keep patients on vimseltinib for at least 6 months before considering a break, using scans and symptom review to decide. Mangla said this was where the IV schedule looked more appealing, since 5 doses every 3 weeks amounted to about 15 weeks of treatment. Richard Wu, MD, of Ohio State University Cancer Center in Powell, Ohio, said tolerance for particular adverse events and distance from the treatment center could also steer the choice, since infusions are more difficult for patients who live far away. Jinesh Gheeya, MD, of The Ohio State University in Westerville, Ohio, said surgical and local options should be reviewed with the surgical team before starting systemic therapy, which is prolonged for all but the antibody.

Dionisia Quiroga, DO, of The Ohio State University Comprehensive Cancer Center in Powell, Ohio, asked whether pruritus on these agents responds to antihistamines or other drugs. Pollack said he tries antihistamines and, for localized rash, steroid cream, and that pruritus could be a particular problem with emactuzumab if it is approved.

In concluding thoughts, Mangla said he looks forward to the new options and that physicians can now consider both surgical and nonsurgical options. Quiroga said that having agents with different adverse event profiles that can be customized to the patient is beneficial, and in the future it would be exciting to see novel agents with targets other than CSF1R.

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DISCLOSURES: Pollack disclosed consulting work for Attivare, EMD Serono, Bayer, Rain Therapeutics, Deciphera, Boehringer Ingelheim, SpringWorks, Adaptimmune, Ipsen, Daiichi-Sankyo, and Replimmune; payment or honoraria for lectures, presentations, and speaker bureaus from Deciphera and SpringWorks; advisory board membership for SynOx Therapeutic.

REFERENCES

1. Xu H, Niu X, Ravi V, et al. Pimicotinib versus placebo for tenosynovial giant cell tumour (MANEUVER): an international, randomised, placebo-controlled, phase 3 trial. Lancet. 2026;407(10533):1072-1083. doi:10.1016/S0140-6736(25)02602-9

2. Gelderblom H, et al. Extended efficacy and safety from the phase III MANEUVER trial of pimicotinib in patients with tenosynovial giant cell tumour (TGCT). Ann Oncol. 2025;36(suppl 2):S1436-1437. doi:10.1016/j.annonc.2025.08.3301

3. Cassier PA, Italiano A, Gomez-Roca C, et al. Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour. Eur J Cancer. 2020;141:162-170. doi:10.1016/j.ejca.2020.09.038