When the tumor shrinks but the burden may persist: redefining therapeutic success in tenosynovial giant cell tumor

Hairong Xu and colleagues (Xu et al. 2026) are to be commended for executing the MANEUVER trial, the first international phase 3 study establishing pimicotinib, a highly selective CSF-1R inhibitor, as a potent therapy for unresectable tenosynovial giant cell tumor (TGCT). With a 54% objective response rate and clinically meaningful improvements in pain, stiffness, and physical function, the data unequivocally support pimicotinib as a new standard for this underserved population. Yet, as oncologists who have witnessed the evolution from surgery to systemic therapy in TGCT, it is worth reflecting on whether current endpoints fully capture the complexity of disease control in this chronic condition.

The MANEUVER trial delivers precisely what the field has sought—a targeted agent with robust efficacy and a manageable safety profile. The 51% absolute difference in objective response rate compared with placebo is striking, particularly given the geographically diverse population that enhances generalizability. However, as pimicotinib moves into clinical practice, several critical questions remain unanswered, each with important implications for long-term disease management.

First, what is the optimal duration of treatment? The MANEUVER protocol allowed continued therapy beyond 24 weeks, and phase 1 data suggest sustained responses with extended dosing. But in a disease affecting young adults (median age 40 years), indefinite CSF-1R inhibition raises concerns about cumulative toxicity, fertility implications, and financial burden. The ENLIVEN and MOTION trials faced similar uncertainties, and real-world data now suggest that some patients achieve durable disease control even after treatment discontinuation (Tap et al. 2019; Gelderblom et al. 2024). Whether some patients maintain functional improvement after treatment withdrawal is an open question, and anecdotal observations suggest this possibility warrants prospective study, as tumor volume reduction may not fully capture the durability of clinical benefit. A randomized phase 2 trial comparing continuous dosing versus symptom-guided intermittent therapy, with co-primary endpoints of quality of life and time to symptom progression, would be valuable to test a “stop-and-go” approach.

Second, does pimicotinib alter the natural history of TGCT, or does it primarily suppress symptoms while the underlying neoplastic clone persists? The biology of TGCT is unique: a small population of CSF1-overexpressing neoplastic cells recruits a massive inflammatory infiltrate that constitutes the bulk of the tumor. CSF-1R inhibition depletes these inflammatory cells, explaining the rapid symptom improvement. However, histopathological studies from preclinical models and post-treatment biopsies suggest that neoplastic cells may persist despite radiographic response, raising the possibility of regrowth upon treatment cessation. This pattern is increasingly recognized with other targeted therapies in indolent malignancies. The MANEUVER protocol’s crossover design and ongoing extension will eventually provide insights, but mechanistic studies examining residual disease architecture after prolonged CSF-1R inhibition are urgently needed to determine whether we are achieving true disease modification or inducing a state of medication-dependent remission.

Third, how do we sequence pimicotinib relative to surgery and other systemic options? The trial enrolled patients with unresectable disease, a designation that can be subjective and surgeon-dependent. As pimicotinib becomes available, some patients initially deemed unresectable may become surgical candidates after tumor downsizing (Stacchiotti et al. 2023). While case series describing such surgical downstaging remain limited, this represents a critical area for future investigation. Conversely, patients with recurrent disease after surgery now face a choice between re-operation, pimicotinib, or, where available, pexidartinib or vimseltinib (Stacchiotti et al. 2023). The absence of head-to-head comparative data leaves clinicians navigating this decision without guidance. Moreover, the cost and accessibility of these agents vary dramatically across regions; while pimicotinib’s once-daily oral dosing and lack of dietary restrictions offer practical advantages, its global availability remains uncertain.

The safety profile of pimicotinib deserves particular attention. The 71% incidence of creatine phosphokinase (CPK) elevation, including 13% grade 3 or 4, mirrors findings with other CSF-1R inhibitors and is generally considered benign and reversible. However, the biological basis of this phenomenon remains poorly understood; it has been hypothesized to reflect altered membrane permeability in activated macrophages or subclinical myocyte injury due to CSF-1R inhibition, but this remains unproven. For young, active patients, even asymptomatic enzyme elevations can trigger unnecessary workups, restrict physical activity, and generate anxiety. Proactive patient education and a clear monitoring algorithm are essential.

The MANEUVER trial powerfully reinforces the argument that patient-reported outcomes should be co-primary endpoints in future TGCT studies. The early and sustained improvements in stiffness, pain, and physical function—observed as early as week 13—suggest that symptom relief precedes radiographic response in many patients. This dissociation between tumor shrinkage and functional improvement challenges the primacy of RECIST-based endpoints in this disease. Future trials should consider integrating volumetric response with validated functional measures, and regulators should embrace this paradigm.

Looking ahead, three research priorities emerge. First, biomarker studies correlating baseline tumor characteristics (e.g., CSF1 expression level, genomic features) with response duration could identify patients suitable for intermittent dosing. Second, prospective registries tracking reproductive outcomes, long-term safety, and quality of life are urgently needed, given the young patient population. Such efforts should include standardized data collection on fertility preservation, pregnancy outcomes, and offspring health. Third, collaborative efforts to harmonize response criteria across trials—incorporating both RECIST and tumor volume score—would facilitate cross-trial comparisons and meta-analyses.

For the practicing oncologist seeing a patient with symptomatic, unresectable TGCT tomorrow, pimicotinib offers a compelling option with high response rates and meaningful functional improvement. However, our conversation with that patient must extend beyond the 24-week trial horizon. We must discuss the uncertainty of treatment duration, the possibility of regrowth upon discontinuation, and the lack of long-term safety data. We must acknowledge that while the tumor may shrink, the disease—and its impact on a young person’s life—may persist. The MANEUVER trial has given us a powerful tool; our task now is to learn how to use it wisely.

Author contributions

Ke QH: Investigation, Resources, Validation, Writing—original draft, Writing—review & editing, Data curation, Supervision, Formal analysis, Conceptualization. Zhou SQ: Writing—review & editing, Conceptualization, Writing—original draft, Formal analysis, Data curation.

Funding

None.

Data availability

No new data were generated or analyzed in support of this commentary. All data discussed are derived from previously published studies cited in the reference list, primarily Xu et al. (2026). The corresponding author may be contacted for inquiries regarding the interpretation of cited data, but no original datasets are associated with this manuscript.

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

We declare no competing interests. All authors had full access to the complete data of the study and took final responsibility for the decision to submit the manuscript for publication. Data and codes are available from the corresponding author upon reasonable request.

Ethical approval

As this article is a commentary on published clinical trial data and does not involve original research with human participants, patient data, or animal subjects, no ethical approval was required.