Efficacy and Safety of CSF1R Inhibitors for Recurrent or Unresectable Tenosynovial Giant Cell Tumor: A Systematic Review and Meta‐Analysis of Phase III Randomized Controlled Trials

Aim Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm driven by overexpression of colony‐stimulating factor 1 (CSF1). We performed a meta‐analysis of the efficacy and safety of CSF1 receptor inhibitors (CSF1Ri) versus placebo in recurrent or unresectable TGCT, defined as symptomatic disease for which surgery would cause worsening functional limitation or severe morbidity. Methods PubMed/MEDLINE, Scopus, Google Scholar, CENTRAL, and the ClinicalTrials.gov registry were searched from inception to March 25, 2026 for phase III randomized controlled trials (RCTs) comparing any CSF1Ri with placebo in adults with histologically confirmed TGCT. The primary outcome was objective response rate (ORR); secondary outcomes were physical function (PROMIS‐PF), range of motion (ROM), pain, health‐related quality of life (EQ‐VAS), and Grade 3 or higher adverse events. Risk of bias (RoB 2) and certainty (GRADE) were assessed; estimates were pooled using random‐effects models (RevMan 5.4.1), with fixed‐effect, Hartung–Knapp–Sidik–Jonkman, risk‐difference, and leave‐one‐out sensitivity analyses. Results Three RCTs were included (ENLIVEN, MOTION, MANEUVER; n = 337), all at low risk of bias. CSF1Ri significantly improved ORR (RR 25.55 [95% CI 6.43–101.52]; risk difference 0.43 [0.36–0.50]), PROMIS‐PF (MD 3.81 [2.28–5.34]), relative ROM (MD 11.43 [6.53–16.34] percentage points), and EQ‐VAS (MD 7.63 [4.03–11.23]) (all I 2 = 0%, p < 0.001), and reduced pain (SMD −1.03 [−1.65 to −0.42]; p = 0.0009; I 2 = 76%). Grade 3 or higher adverse events were more frequent with CSF1Ri (RR 4.08 [2.31–7.21]; p < 0.001; I 2 = 0%). Certainty was high for functional outcomes, moderate for ORR and Grade 3 or higher adverse events, and low for pain. Conclusions In recurrent or unresectable TGCT, CSF1Ri produce clinically meaningful improvements in tumor response, function, and quality of life compared with placebo, at the cost of more frequent severe adverse events, the nature of which differed between trials. The included trials did not compare agents directly, so the relative efficacy and safety of individual CSF1Ri remain uncertain.