Adverse Event Burden Tips TKI Selection in Recurrent Diffuse TGCT

Diffuse tenosynovial giant cell tumor (D-TGCT) is locally aggressive and prone to recurrence after surgery, with rates reported as high as 72% for disease involving the knee, the joint most commonly affected. As more patients exhaust the option of repeat resection, oncologists are left choosing between 2 CSF1R-targeted tyrosine kinase inhibitors (TKIs) that each demonstrated clear efficacy over placebo in randomized trials but come with very different long-term burdens.

In a virtual Case-Based Roundtable event for oncologists across the central US, Seth M. Pollack, MD, director of the sarcoma program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and the Steven T. Rosen Professor of Cancer Biology at Northwestern University Feinberg School of Medicine, walked participants through the management of recurrent D-TGCT using a patient case. Pollack noted that once a patient has already given surgery its chance, treatment becomes less about pursuing cure and more about managing a chronic condition.

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CASE SUMMARY

• A 42-year-old man presented with a chief complaint of left knee swelling, stiffness, and pain over several months.
• He had a 1-year history of progressive left knee swelling and stiffness, initially intermittent but now persistent.
• Activity-related pain (VAS 5/10) with occasional episodes of the knee “locking”
• NSAIDs and activity modification tried without meaningful relief
• No history of trauma; no fevers, chills, or weight loss; no relevant family history

Physical Exam​

• General: Well appearing, no acute distress​
• Left knee: Large, boggy effusion; warmth to palpation; palpable synovial thickening along the medial and lateral joint lines​
• Range of motion: Flexion limited to 100°, mild extension lag​
• Neurovascular: Intact distally​
• Gait: Antalgic gait, avoids full weight-bearing on the left leg​

Diagnostic Workup​

• MRI left knee: Diffuse, lobulated synovial proliferation with characteristic low T2 signal (hemosiderin deposition); disease extends circumferentially around the joint with focal extra-articular extension posteriorly​
• Image-guided biopsy: Confirms D-TGCT​
• Laboratory findings within normal limits

Initial Treatment

• Given the diffuse but largely intra-articular distribution of disease, the case was reviewed at a multidisciplinary sarcoma tumor board, and the patient underwent an open total synovectomy​.
• Postoperative recovery was uncomplicated, with initial improvement in swelling and range of motion​.

Current Status and Assessment

• Timing: 6 months postsynovectomy​
• Interval history: Surveillance MRI reveals early recurrence, with re-accumulation of synovial disease along the posterior capsule; patient reports recurrent swelling and pain (VAS 4/10) with mild functional decline​
• Physical exam: Mild-moderate effusion, warmth, flexion limited to 110°​
• ECOG performance status: 1​
• Labs: Normal; no contraindication to systemic therapy​

Multidisciplinary Assessment

• Disease has recurred following surgery, with distribution felt to be poorly suited for a second complete resection without meaningful risk to joint function​.
• Patient is naive to systemic therapy, with normal baseline hepatic function and no comorbidities limiting eligibility​.
• After discussion of risks (including hepatotoxicity monitoring requirements) and benefits, the patient is started on pexidartinib (Turalio), with baseline and scheduled on-treatment liver function test monitoring per risk evaluation and mitigation strategy (REMS) requirements​.

EVENT RECAP

Pollack cited long-term follow-up from the ENLIVEN trial (NCT02371369), in which pexidartinib produced an overall response rate (ORR) of roughly 60% by RECIST criteria at a median follow-up of 31.2 months, rising to roughly 62% when measured by tumor volume score.^1,2 However, the trial also carried meaningful toxicity: about 44% of patients had grade 3 or higher treatment-emergent adverse events, roughly 1 in 5 discontinued treatment because of an adverse event, and about 30% developed alanine transaminase (ALT) elevations 3 times the upper limit of normal or higher. The hepatotoxicity signal, reinforced by a case of liver failure outside the trial, is what prompted the REMS requirement. “So long as patients are managed appropriately and the [liver function tests] are watched, I haven’t heard about any patients having very serious liver problems,” and any issues resolved when the drug was withdrawn, Pollack told the group.

Victoria Wytiaz, MD, described a case from her experience with this regimen: a patient’s aspartate aminotransferase, ALT, and gamma-glutamyl transferase rose to 5 times the upper limit of normal just 14 days after starting pexidartinib. “[It was] alarming how quick they went up, but reassuring how nicely they went down,” Wytiaz said, noting the values normalized after the drug was held with no other intervention needed. Martin Schoen, MD, said that the liver monitoring requirements made it difficult to use pexidartinib in his practice, commenting that “if pexidartinib was third or fourth to market, it would never get approved.”

That difficulty has pushed Schoen and some other participants toward vimseltinib (Romvimza), the CSF1R inhibitor evaluated in the MOTION trial (NCT05059262). “I don’t even have [any patients] on pexidartinib anymore. Everybody’s on vimseltinib,” said Ankit Mangla, MD.

At week 25, vimseltinib produced an ORR of 40% by independent radiological review and 67% by tumor volume score, improving to 48% and 81%, respectively, with 2 or more years of follow-up; patients who crossed over from placebo saw similar gains.^3,4 Vimseltinib’s most common toxicities were periorbital edema, affecting 48% of patients, along with pruritus, edema, and asthenia, and it carries no comparable liver-injury signal, though creatine phosphokinase elevation has been reported.

Mangla acknowledged the difficult in managing the edema. Wytiaz said that most physicians have had to dose reduce or hold with vimseltinib, and very few patients are able to sustain full drug dosing without interruption, but anecdotally, patients receiving a reduced dose have done well and achieved disease responses.

NCCN guidelines list both pexidartinib and vimseltinib as category 1 recommendations for TGCT, whereas imatinib (Gleevec) and nilotinib (Tasigna) remain listed as options for certain circumstances without placebo-controlled evidence behind them;³ Pollack said these could be useful in patients with contraindications to the 2 category 1 options or had to discontinue them.

In polling, 66.7% of participants reporting familiarity with both approved agents. When asked how often they see recurrence after surgery for D-TGCT, the largest share of participants said “somewhat often” (44.4%) or “very often” (33.3%), while only 11.1%, Pollack included, selected “almost always.” Pollack attributed the difference to referral bias, since the cases reaching a sarcoma subspecialist are disproportionately the ones surgery could not resolve. Most participants (88.9%) said they manage D-TGCT primarily in-house rather than referring out, and 44.4% said patients most often reach them at initial diagnosis rather than after a failed surgery or when surgery is no longer an option.

With efficacy roughly comparable between the 2 approved TKIs, the toxicity each patient is willing to monitor for and live with emerged as the deciding factor in recurrent D-TGCT.

Polling results from the live event reflected these practice patterns:

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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. Tap WD, Gelderblom H, Palmerini E, et al. Pexidartinib versus placebo for advanced tenosynovial giant cell tumour (ENLIVEN): a randomised phase 3 trial. Lancet. 2019;394(10197):478-487. doi:10.1016/S0140-6736(19)30764-0

2. Gelderblom H, Wagner AJ, Tap WD, et al. Long-term outcomes of pexidartinib in tenosynovial giant cell tumors. Cancer. 2021;127(6):884-893. doi:10.1002/cncr.33312

3. Gelderblom H, Bhadri V, Stacchiotti S, et al. Vimseltinib versus placebo for tenosynovial giant cell tumour (MOTION): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10445):2709-2719. doi:10.1016/S0140-6736(24)00885-7

4. Bauer S, Bhadri VA, Gelderblom H, et al. Long-term efficacy and safety of vimseltinib in patients (pts) with tenosynovial giant cell tumor (TGCT): 2-year results from the MOTION phase III trial. Ann Oncol. 2025;36(suppl 2):S1342-S1343. doi:10.1016/j.annonc.2025.08.3305

5. NCCN. Clinical Practice Guidelines in Oncology. Soft tissue sarcoma, version 5.2026. Accessed September 9, 2026. https://tinyurl.com/2tha348t