Background
Phase III MOTION, double-blind randomized placebo-controlled. N=123, locally advanced or recurrent/refractory tenosynovial giant cell tumor (TGCT/PVNS) not amenable to surgery or progressing after prior surgery. Vimseltinib (DCC-3014): highly selective switch-control CSF1R inhibitor, the TGCT driver. NCT04731675.
Interventions and follow up
Arm A: Vimseltinib 30 mg PO twice daily, 5 days on / 2 days off (intermittent) until PD or unacceptable toxicity
Arm B: Matching placebo on the same intermittent schedule
Primary endpoint: ORR by blinded independent central review (RECIST 1.1) at week 25
mFollow up: ~12 mo at primary analysis
Arm B: Matching placebo on the same intermittent schedule
Primary endpoint: ORR by blinded independent central review (RECIST 1.1) at week 25
mFollow up: ~12 mo at primary analysis
Results
ORR (wk 25): 40% vs 0%, P<.001
CR: 7% vs 0%
PR: 33% vs 0%
SD: 55% vs 71%
mDOR: not reached (not estimable)
mPFS: not reached vs not reached; HR significantly favored vimseltinib
Patient-reported outcomes: significant improvement in pain, stiffness, physical function (PROMIS, BPI) vs placebo
CR: 7% vs 0%
PR: 33% vs 0%
SD: 55% vs 71%
mDOR: not reached (not estimable)
mPFS: not reached vs not reached; HR significantly favored vimseltinib
Patient-reported outcomes: significant improvement in pain, stiffness, physical function (PROMIS, BPI) vs placebo
Adverse events
Grade ≥3 AEs: 19% vs 5%
Most common any-grade (vimseltinib vs placebo): periorbital edema 65% vs 3%, face edema 29% vs 0%, limb edema 27% vs 8%, AST/ALT elevations 28% vs 3%
Liver (AST/ALT grade ≥3): 5% vs 0%; no Hy's Law cases of drug-induced liver injury
Discontinuation due to AEs: 6% vs 0%
Most common any-grade (vimseltinib vs placebo): periorbital edema 65% vs 3%, face edema 29% vs 0%, limb edema 27% vs 8%, AST/ALT elevations 28% vs 3%
Liver (AST/ALT grade ≥3): 5% vs 0%; no Hy's Law cases of drug-induced liver injury
Discontinuation due to AEs: 6% vs 0%
Conclusions
Vimseltinib achieved 40% ORR vs 0% placebo in advanced TGCT with significant pain/function improvement. The intermittent 5-on/2-off schedule was designed to reduce hepatotoxicity vs continuous CSF1R inhibition (pexidartinib). Confirms CSF1R inhibition as the dominant strategy for TGCT not amenable to surgery.
Key Limitations
Modest N (123); short 25-wk primary endpoint; mDOR and mPFS not reached (immature durability); no head-to-head vs pexidartinib; long-term hepatic safety needs confirmation.
Clinical Context
Vimseltinib FDA-approved Feb 2025 for symptomatic TGCT not amenable to surgery, without REMS, offering a more favorable hepatic profile than pexidartinib. Surgery remains first-line; CSF1R inhibitors reserved for unresectable/recurrent disease.