The highly selective colony-stimulating factor-1 receptor (CSF-1R) inhibitor pimicotinib demonstrates robust antitumour activity in patients with tenosynovial giant cell tumour (TGCT), yielding meaningful improvements in physical function and symptom burden with a manageable safety profile, according to the international phase III MANEUVER trial.
MANEUVER met its primary endpoint, with the objective response rate (ORR) per BICR (RECIST) assessment at week 25 being 54 percent among patients who received once-daily, oral treatment with pimicotinib vs 3 percent among those who received placebo (absolute difference, 51 percent, 95 percent confidence interval [CI], 33–63; p<0.0001), reported first study author Prof Hairong Xu from Capital Medical University, Beijing, China, and colleagues. [Lancet 2026;407:1072-1083]
In the pimicotinib arm, 52 percent of patients had partial responses, and 2 percent achieved a complete response.
“This effect on tumour reduction was consistent across prespecified subgroups, including age, sex, ECOG performance status, geographical region, disease location, and number of previous surgeries,” Xu and colleagues noted.
ORRs at week 25 assessed by BIRC per tumour volume score were consistent with those based on RECIST: 62 percent with pimicotinib vs 3 percent with placebo (absolute difference, 59 percent, 95 percent CI 41–70; p<0.0001).
Functional, pain outcomes
Compared with those who received placebo, pimicotinib-treated patients showed “early, durable, robust, clinically meaningful, and statistically significant improvements” in all clinical outcome assessments: range of motion (p=0.0003), stiffness (p<0.0001), pain (p<0.0001), and physical function—quality of life domains (p=0.0074), regardless of tumour response.
At week 25, the percentage of patients achieving a decrease in Brief Pain Inventory (BPI) worst pain numerical rating scale (NRS) score of at least 30 percent, without an increase in narcotic analgesic use of at least 30 percent (BPI-30 responders), was 64 percent in the pimicotinib arm vs 16 percent in the placebo arm (absolute difference, 47 percent, 95 percent CI, 27–61; p<0.0001).
Safety profile
“Pimicotinib was associated with mainly mild treatment-emergent adverse events (AEs), including mostly manageable asymptomatic laboratory abnormalities and clinical events, such as pruritus, facial oedema, rash, periorbital oedema, and fatigue,” Xu and colleagues said.
Grade 3 or 4 treatment-emergent AEs occurred in 35 percent of patients treated with pimicotinib, with the most common being blood creatine phosphokinase elevation (13 percent) and increased blood pressure (6 percent). One serious treatment-related AE of increased blood pressure occurred in a pimicotinib-treated patient who had a medical history of hypertension and white-coat syndrome.
Treatment-emergent AEs led to dose reductions in 8 percent of patients, dose interruption in 54 percent, and treatment discontinuations in 2 percent in the pimicotinib arm.
The most common treatment-emergent AEs in the placebo arm were fatigue and arthralgia. None of the patients in this arm experienced a serious treatment-related adverse event.
There were no cases of cholestatic hepatotoxicity, drug-induced liver injury, hypopigmentation of skin or hair, or deaths documented in either treatment arm.
A new option
“Pimicotinib expands treatment options in TGCT and provides an additional, targeted, systemic treatment for patients who are not amenable to surgery,” according to Xu and colleagues.
Currently approved systemic therapies for TGCT include pexidartinib and vimseltinib, which both target CSF-1R. However, pexidartinib has been associated with a potential risk of fatal cholestatic hepatotoxicity, issues with skin or hair hypopigmentation, and the twice-daily dosing regimen with dietary requirements, which could all affect adherence, the authors noted. [https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/211810s009lbl.pdf; Future Oncol 2022;18:1595-1607; Lancet 2019;394:478-487; Oncologist 2025;30:oyaf028]
“There are currently no data directly comparing pimicotinib with pexidartinib or vimseltinib in a global randomized study, in part due to the unavailability of these agents in some regions… [but] the patients treated with pimicotinib in MANEUVER had a higher ORR at week 25 than that reported with pexidartinib in ENLIVEN (39 percent) and with vimseltinib in MOTION (40 percent),” they pointed out. [Lancet 2019;394:478-487; Lancet 2024;403:2709-2719]
Xu and colleagues emphasized that the improvements seen in pain and physical function with pimicotinib “are highly relevant” for this population, whose high symptom burden often impedes routine daily activities and social participation, which can have substantial implications for work and careers.
Additionally, “the diverse patient population (approximately equal China vs non-China sites) suggests that the study findings would be broadly generalizable,” they added.
Treatment protocol
In an accompanying editorial, Dr Jean-Yves Blay from Centre Léon Bérard and Université Claude Bernard, Lyon, France, described the emergence of CSF-1R tyrosine kinase inhibitors such as pimicotinib for treating the rare TGCT as “truly exceptional.” [Lancet 2026;407:1032-1033]
“The results for tyrosine kinase inhibitors provide an opportunity to completely revise the treatment strategy for TGCT, using tyrosine kinase inhibitors to complement or replace surgery, aiming for a reduction in the rate of relapse and long-term improvements in the function and quality of life of these young patients,” wrote Blay.
However, Blay stressed that questions surrounding how to integrate pimicotinib and other CSF-1R tyrosine kinase inhibitors into the multidisciplinary management of TGCT still need to be addressed. It is unclear what the optimal treatment duration is, whether neoadjuvant CSF-1R inhibitors allow for less morbid surgery and fewer relapses, whether it is possible to treat tumours at risk of mutilating or incomplete surgery with tyrosine kinase inhibitors only, and which of these agents should be given first and whether agents should be rotated at relapse, he said.
MANEUVER
MANEUVER was conducted at 40 specialized hospitals across Asia, Europe, and North America and included 94 patients (median age 40 years, 68 percent female, 51 percent Asian) with TGCT and ECOG PS of 0/1. Of these, 45 were from China and 49 were from other countries.
The patients were randomly assigned to receive treatment with either pimicotinib 50 mg once daily (with no food restrictions) (n=63) or matching placebo (n=31). Treatment was administered orally in 28-day cycles for 24 weeks (six cycles).
The median duration of exposure was 169 days in both treatment arms, with a median pimicotinib dose intensity of 94.6 percent.