R. Lor Randall, MD, FACS, discusses what’s next for TGCT treatment and the most important developments to come out of 2026 TGCT Master Workshop.
Multidisciplinary approaches, colony-stimulating factor 1 (CSF1) inhibition, monoclonal antibodies, and personalized treatments represented key themes from the 2026 Tenosynovial Giant Cell Tumor (TGCT) Master Workshop, according to R. Lor Randall, MD, FACS.
“The next phase [of research in TGCT] is not simply finding another drug that shrinks the tumor; it's determining which intervention or combination of interventions provide the best long-term function and quality of life for each individual patient,” Randall said in an exclusive interview with OncLive®.
A co-chair of the workshop, Randall provided in-depth insight to what was covered, in addition to previewing and interpreting data for novel CSF1 inhibitors and monoclonal antibodies for the treatment of TGCT.
Randall is the David Linn Endowed Chair for Orthopedic Surgery, chair of the Department of Orthopedic Surgery, and a professor at the University of California Davis Comprehensive Cancer Center in Sacramento.
Randall: One of the real highlights of this year has been the recent opportunity to co-chair the 2026 TGCT Master Workshop in Chicago alongside William D. Tap, MD, of Memorial Sloan Kettering [Cancer Center] and Emanuela Palmerini, MD, from the University of Miami Miller School of Medicine.
Over 2 days, we brought together a remarkable multidisciplinary group that included many of the leading investigators in TGCT, spanning primarily orthopedic oncology and medical oncology. The full team of experts in this area of interest went beyond the medical and orthopedic oncologists to include musculoskeletal radiologists, pathologists, rehabilitation specialists, clinical researchers, sports medicine physicians and researchers, and patient [advocates]. I can't emphasize enough that the breadth of this team approach is important in talking about TGCT.
[TGCT is] not a condition that fits neatly within any given specialty in the area of oncology and our sister specialties. Although [TGCT] is generally classified as a benign neoplasm, the term benign can significantly understate its clinical impact, particularly in the diffuse type of TGCT. The disease can be locally aggressive and produce recurrent swelling, pain, stiffness, bleeding into the joint, cartilage and bone damage, and progressive loss of function. Some patients undergo repeated operations over many years, each operation may provide transient disease control, but repeated surgery can also result in further scarring, stiffness, neurovascular risk, and ultimately joint degeneration. Therefore, the objective is not simply to remove everything visible on an MRI, [the objective is] to control the disease while preserving joint mobility function, gainful employment, and overall quality of life.
Historically, surgery has been essential for the treatment of TGCT, and it's also been the almost exclusive option. The major change in this field came from the understanding of the underlying biology in most TGCTs. A relatively small population of neoplastic cells overexpress CSF1; that signal recruits large numbers of CSF1 receptor–expressing macrophages and other inflammatory cells, which constitute much of the tumor volume. That biological discovery provided us with an understanding of an axis of the CSF1 receptor pathway [CSF1R].
Now, we've moved into a really exciting era in which systemic therapy can produce meaningful tumor reduction and, importantly, clinically relevant improvements in pain, stiffness, range of motion, and physical function. Pexidartinib [Turalio] was the first systemic therapy approved in the United States for the appropriate for patients with TGCT. [Pexidartinib] has established that the pharmacokinetic pharmacological inhibition of the CSF1R can alter the course of disease. Although the risk of potentially serious liver toxicity requires special attention with the use of pexidartinib, monitoring is required. Vimseltinib [Romvimza] subsequently has demonstrated a significant tumor response, and improvements across several functional and patient-reported measures were shown in the randomized phase 3 MOTION trial [NCT05059262].1 Vimseltinib received FDA approval in February 2025 for adults with symptomatic TGCT for whom surgical resection could cause worsening functional limitation or severe morbidity.
The therapeutic landscape [for TGCT] continues to expand. Pimicotinib [ABSK021], another highly selective oral, CSF1 inhibitor, was evaluated in the phase 3 MANEUVER trial [NCT05804045], and the recently published results showed a substantially higher objective response rate [ORR] with pimicotinib than with placebo, in addition to improvements in pain, stiffness, range of motion, physical function, and quality of life measures.2 Longer follow-up has suggested that response rates may deepen with continued treatment. Pimicotinib remains investigational in the United States, but these findings add considerably to the evidence supportive of CSF1 inhibition in TGCT.
At the meeting, we also discussed the monoclonal antibody approaches and emactuzumab. [Emactuzumab] is an intravenously [IV] administered antibody directed against CSF1R, earlier studies have demonstrated high, durable response rates with symptomatic improvement. More recently, the phase 3 TANGENT trial [NCT05417789] reported positive top line results for primary and secondary end points for tumor response with improvement in pain stiffness function, and range of motion compared with placebo.3 One particularly interesting feature of the antibody was that when it is administered, it can be administered as a defined short period of 8 weeks via 5 infusions, rather than indefinitely as an oral. This does require IV administration, but it's nice because you can tell the patient that it's administered for a finite period of time.
Full peer-reviewed phase 3 data [of emactuzumab] will be important before we understand exactly where this strategy could sit in practice.
There's even another investigational monoclonal antibody against CSFR1, AMB-05X. It's been studied both via IV administration and through direct intra-articular injection, particularly in TGCT involving the knee. Local administration is certainly attractive because it may permit concentration of the drug within an infected joint while reducing systemic exposure, but that remains investigational at this point, and we need more efficacy and safety data. However, [agents like AMB-05X] illustrate how treatment may eventually become more individualized and more specific to an anatomic region. With the advancement of the drugs. I will say, what made the workshop so valuable was that we were able to move beyond the basic questions of whether systemic therapy works. [Systemic therapy] clearly can work in appropriately selected patients.
The more difficult questions now concern how we use [systemic therapy in TGCT]. For example: Which patients should undergo surgery first? Which patients are more likely to benefit from systemic treatment because an operation would be excessively morbid or unlikely to provide durable control? Could medical therapy be used before surgery to reduce the extent of an operation in sort of a neoadjuvant way? Could some patients avoid surgery altogether? How long should treatment continue? What about drug holidays? What happens after treatment is interrupted? Could a finite course provide durable disease control? How should we compare an oral therapy taken over a prolonged period with a short course IV antibody infusion, or potentially a locally administered treatment?
We also need to determine how success should be measured. MRI response rate may be important, but tumor size is not the entire story. For a patient, success may mean less pain, greater range of motion, returning to work, returning to activities that are important to them, not needing assistance or assistance devices anymore, sleeping through the night, and even avoiding a joint replacement. Future studies, as some studies are doing now, must integrate imaging with objective functional results and validated patient-reported outcomes.
Another important aspect of the workshop was the candid interaction among academic investigators, treating clinicians, and industry scientists. [TGCT] is a rare disease, and no individual institution can answer all these questions, it takes responsible collaboration across institutions and between academia and industry. This is essential. However, the science must remain rigorous and peer-reviewed. The potential conflicts are transparent, and patients must remain the central objective of any of these sorts of interactions.
I left Chicago optimistic over a relatively short period of time. TGCT has progressed from being an almost exclusively surgical disease to one in which we can begin to develop personalized strategies, integrating active surveillance, systemic treatment, imaging, rehabilitation, and patient-reported outcomes. We also talked about tailoring surgery to do minimally invasive procedures periodically based upon the patient's ambitions for certain activities. The next phase [of research] is not simply finding another drug that shrinks the tumor, it's determining which intervention or combination of interventions provides the best long-term function and quality of life for each individual patient. That is the challenge our group now hopes to address collaboratively with future meetings such as this.
