MANEUVER Trial Underscores Potential Paradigm Shift Toward Targeted Approaches in TGCT

The phase 3 MANEUVER trial (NCT05804045) data demonstrated that selective CSF-1R inhibition with pimicotinib (ABSK021) can produce meaningful radiographic responses and significant functional improvement in patients with tenosynovial giant cell tumor (TGCT), representing a major step forward in integrating targeted therapy into orthopedic oncology care, according to R. Lor Randall, MD, FACS.¹

Long-term results from MANEUVER, which were presented at the 2025 European Society for Medical Oncology Congress, showed that treatment with pimicotinib from baseline (n = 63) produced an overall response rate (ORR) of 76.2% (95% CI, 63.8%-86.0%) per blinded independent review committee (BIRC) by RECIST 1.1; the BIRC-assessed ORR per tumor volume score (TVS) was 74.6% (95% CI, 62.1%-84.7%).¹ The median follow-up was 435 days (range, 78-686; 14.3 months), and the data cutoff date was March 12, 2025. These data supported a new drug application for pimicotinib in TGCT, which was accepted by the FDA on January 13, 2026.²

“We are moving toward a model where tumor biology informs not only survival but how well patients function, and that is a meaningful evolution for our field,” Randall, who serves as the David Linn Endowed Chair for Orthopaedic Surgery, the chair of the Department of Orthopaedic Surgery, and a professor at the University of California Davis Comprehensive Cancer Center in Sacramento, stated in an interview with OncLive®.

In addition to spotlighting the MANEUVER trial, Randall discussed the importance of multidisciplinary, function-focused care and the potential for systemic therapy to shift treatment goals from symptom control to tumor regression or functional restoration in TGCT.

OncLive: What was the clinical impetus for the MANEUVER study?

Randall: Historically, orthopedic oncology has been [primarily] defined by surgery. One of the most important recent developments is that, in select tumors, we are now able to meaningfully alter disease biology and patient function with targeted systemic therapy beyond the operating room. One of the most compelling recent advances comes from TGCT.

To be clear, this is not a high-grade sarcoma—in fact, it is not a sarcoma at all—but it can be a locally super-aggressive, destructive process, particularly to joints, that can lead to associated pain, stiffness, and real functional limitation. The diffuse variant, [which is] distinct from the nodular variant, presents a very difficult therapeutic challenge. Complete surgical resection is often difficult, with high recurrence rates. Repeated operations can lead to progressive joint damage and morbidity, which has created a clear unmet need for systemic therapies to palliate these patients beyond repeated surgeries.

How was MANEUVER designed?

The phase 3 MANEUVER trial was a randomized, double-blind, placebo-controlled study evaluating pimicotinib, a highly selective oral CSF-1R inhibitor, in patients with symptomatic TGCT for whom surgery was not recommended due to anticipated morbidity or functional compromise. The [study] included adults with measurable disease and symptomatic TGCT in cases where surgery was deemed not appropriate or would result in significant functional loss. Patients were [randomly assigned] to pimicotinib vs placebo. The primary end point was ORR at week 25 using RECIST 1.1…; secondary end points included TVS, range of motion, stiffness, pain scores, and patient-reported physical function.

What were the topline results from MANEUVER?

The results were compelling. The ORR at week 25 was 54% in the therapeutic arm vs 3.2% in the placebo arm [P < .0001], and the TVS reduction was concordant and robust. Importantly, patient-centered outcomes, which are critical in studies like this, improved in a clinically meaningful way. There was a significant reduction in pain and stiffness, as well as improvements in range of motion and overall function. These end points are critical in orthopedic oncology, where preserving joint function is central; much of what we are doing is about quality of life as much as life itself.

From a safety standpoint, the adverse effect [AE] profile was consistent with the CSF-1R inhibitor class. Common toxicities included liver enzyme elevations, some edema, and hair color changes, but overall, the drug was considered manageable in this population. Mechanistically, TGCT is driven by the overexpression of CSF-1, leading to the recruitment of macrophages that constitute the bulk of the tumor mass. Inhibiting the CSF-1 receptor disrupts this signaling axis and reduces the tumor-associated macrophage burden, which explains both the radiographic and clinical responses observed.

Why are these findings clinically significant?

These findings build on [data with] prior [systemic] agents such as pexidartinib [Turalio], and more recently, vimseltinib [Romvimza] and suggest a potentially improved therapeutic index with a highly selective CSF-1R inhibitor. This fundamentally changes our treatment paradigm. Instead of viewing these patients as surgical problems with limited options, we can now integrate systemic therapy to downstage disease, improve symptoms, and, in some cases, avoid or even defer surgery. It’s exciting to me as a surgeon as well as an academic oncologist.

If approved, what role do you foresee for pimicotinib in the treatment paradigm and what considerations are most important to keep in mind?

All these decisions need to be made by a multidisciplinary team. It is not the surgeon or the medical oncologist in isolation; in fact, physical therapists and other allied providers are important in the decision-making. Multiple agents are now available, and some patients do very well on current therapies. If it isn’t broken, don’t fix it; the latest and greatest doesn’t mean you should necessarily switch a patient off a prior agent if they are doing well with it, because these drugs are wonderful in certain patients but have AEs in others. As patients are started on treatment, some of these newer agents will be chosen because the specificity and mechanistic biology are getting increasingly refined.

The overall specificity and mechanistic biology is getting more refined with the newer agents. As patients are started on treatment, some of these newer agents will be chosen [over] legacy agents because of that precision. [However…,] if patients are currently on prior agents and they’re tolerating [treatment], keep them on it.

Does the introduction of systemic agents earlier in the paradigm indicate an upcoming shift in treatment goals for TGCT?

Those of us who see enough of these patients are really backing away from up-front surgical management for diffuse TGCT. For nodular TGCT, there is still a role for surgery. Having said that, for advanced, bulky disease, most of us with [substantial] experience are backing away from offering surgery up front. We will still do much of the surveillance and the checkpoints regarding when to [implement] a drug holiday or intervene with surgery in a discretionary way.

Some of these patients are in the prime of their life for the most part, and they want to be active. There may be times where people [who] are weekend warriors or competitive athletes [with a] big event coming up say, “Maybe I should have an arthroscopy to clean that up, because I really want a 3-month window where my disease burden is well controlled.” [In that case], we stop the drug and potentially [recommend] a surgical intervention.

All of this is very nuanced, which brings me back to that fundamental tenet: It needs to be a combined effort from a multidisciplinary team. When patients see a provider about this, the most important question they can ask is, “Are you part of a team that discusses these sorts of cases?”

References

1. Gelderblom H, Ravi V, Martin-Broto J, 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):S1340-S1341. doi:10.1016/j.annonc.2025.08.3301
2. Abbisko Therapeutics announces FDA acceptance of the NDA for pimicotinib for the treatment of tenosynovial giant cell tumor. News release. Abbisko Therapeutics Co Ltd. January 13, 2026. Accessed May 6, 2026. https://www.abbisko.com/newsDetail/234.html
3. Pimicotinib significantly improved outcomes for patients with TGCT in phase III trial. News release. Merck KGaA, Darmstadt, Germany. November 12, 2024. Accessed May 6, 2026. https://www.emdserono.com/us-en/company/news/press-releases/pimicotinib-topline-results-12-11-2024.html