Emactuzumab Yields Improved Response Rates in Tenosynovial Giant Cell Tumor

An 8-week course of emactuzumab, an investigational intravenous monoclonal antibody that inhibits colony-stimulating factor 1 receptor (CSF-1R), produced a statistically significant reduction in tumor size vs placebo among patients with tenosynovial giant cell tumor (TGCT), according to the primary analysis of the phase 3 TANGENT trial (NCT05417789) presented at the 2026 European Society for Medical Oncology (ESMO) Congress.

At month 6, the overall response rate (ORR) per RECIST v1.1 criteria, the trial’s primary end point, was 30% (n = 27) in the emactuzumab arm compared with 2% (n = 1) in the placebo arm, for a difference of 28% (95% CI, 16%-39%; P <.001). Most responders in the emactuzumab group (70%) had responded by week 6, the time of the first MRI assessment.

“Emactuzumab demonstrated radiographic and functional efficacy and manageable safety in patients with TGCT and has the potential to be the first short-course, potent treatment option for TGCT,” the investigators wrote in their presentation, which was delivered by Hans Gelderblom, MD, of the chair of the Department of Medical Oncology at Leiden University Medical Center in the Netherlands.

TGCT is a rare, locally aggressive mesenchymal neoplasm of the synovium that can cause debilitating reductions in joint function and range of motion, as well as pain, stiffness, and joint destruction. Tumors arise from a CSF1 gene translocation that leads to overexpression of CSF-1 and chronic inflammation dominated by CSF-1R–expressing macrophages. Although surgery is the standard of care, postsurgical recurrence is common and many tumors are not amenable to resection, and oral tyrosine kinase inhibitors (TKIs) targeting CSF-1R require chronic administration. According to the investigators, emactuzumab is the only short-course treatment in late-stage development for TGCT.

In the global, double-blind, placebo-controlled trial, conducted in 12 countries, adult patients with biopsy-confirmed localized or diffuse TGCT for whom surgical resection would be associated with worsening functional limitations, a high risk of early recurrence or other surgical morbidity, and/or no expected clinical improvement were randomly assigned 2:1 to receive emactuzumab at 1000 mg intravenously every 2 weeks for 5 cycles or matched placebo. Randomization was stratified by prior TKI use, including CSF-1 and CSF-1R inhibitors. Key secondary end points included ORR per tumor volume score (TVS) criteria at month 6 and month 6 changes in physical function, passive range of motion, worst stiffness, worst pain, and quality of life. Patients with progressive disease could receive open label emactuzumab during a follow-up period of 6 to 24 months.

A total of 136 patients were enrolled, including 91 in the emactuzumab arm and 45 in the placebo arm. The mean age was 43 years, 57% of patients were female, and the knee was the most common target tumor location (65%). Overall, 67% of patients had diffuse disease, 65% had undergone at least 1 prior TGCT-related surgery, 13% had undergone 3 or more surgeries, and 29% had received a prior TKI.

By TVS criteria, the ORR at month 6 was 54% with emactuzumab vs 7% with placebo (difference, 48%; 95% CI, 34%-59%; P <.001), with 78% of emactuzumab responders responding by week 6. The best overall response at any point within 6 months in the emactuzumab arm was 44% by RECIST v1.1 and 71% by TVS criteria vs 2% and 7%, respectively, with placebo.

Emactuzumab was also associated with improvements in patient-reported and functional outcomes. At month 6, the least-squares mean change in PROMIS Physical Function TGCT T-score was +4.3 with emactuzumab vs −1.3 with placebo (difference, 5.6; 95% CI, 3.3-7.9; P <.001), and 53% vs 27% of patients, respectively, experienced an improvement of at least 3 points. Passive range of motion improved by 9.9 vs 2.1 (difference, 7.8; 95% CI, 3.2-12.5; P <.001). Differences in both outcomes were statistically significant from week 4, after 2 doses. Worst pain scores declined by 2.5 vs 0.4 (difference, −2.2; 95% CI, −3.0 to −1.4; P <.001), and worst stiffness scores declined by 2.4 vs 0.3 (difference, −2.1; 95% CI, −3.0 to −1.3; P <.001), with significant differences emerging by week 2, after the first infusion. Quality of life per the EQ-5D-5L visual analogue scale showed a numerically greater improvement with emactuzumab (+2.0 vs −0.4), although the difference was not statistically significant (P = .238).

All patients in the emactuzumab arm experienced at least 1 adverse effect (AE) vs 84% of those in the placebo arm, and grade 3 or higher AEs occurred in 53% and 16%, respectively. The most common AEs with emactuzumab included pruritus (76%), periorbital edema (71%), peripheral edema (45%), fatigue (44%), face edema (40%), increased blood creatine phosphokinase (CPK; 31%), and hypertension (25%). Pruritus was predominantly mild or moderate, occurred during dosing, and improved or resolved over time. Increased blood CPK was the most common grade 3 or 4 treatment-related AE, occurring in 24% of patients. Serious AEs occurred in 15% of the emactuzumab arm, and no AEs led to death. No hepatotoxicity signal was observed, and no patients met Hy’s law criteria.

Overall, 75% of patients in the emactuzumab arm received all 5 infusions, and 18% discontinued treatment because of an AE. Most discontinuations were protocol mandated due to asymptomatic elevations in CPK and liver enzymes, which investigators attributed to inhibition of Kupffer cells causing delayed enzyme clearance; this was subsequently addressed through a protocol amendment.

Reference

Gelderblom H, Palmerini E, van de Sande M, et al. Primary analysis of TANGENT: a phase 3 randomised trial evaluating the safety and efficacy of emactuzumab in patients with tenosynovial giant cell tumours. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA89.