ENLIVEN

Background

Phase III ENLIVEN, double-blind randomized placebo-controlled, N=120 (63 pexidartinib, 57 placebo), symptomatic advanced tenosynovial giant cell tumor (TGCT/PVNS) not amenable to surgery without functional-limitation risk. 12 sites USA/Europe/Australia, 2015–2017. TGCT driven by CSF1 overexpression; pexidartinib (PLX3397) oral CSF1R/KIT/FLT3 inhibitor. NCT02371369.

Interventions and follow up

Arm A: Pexidartinib 1000 mg/day (400 AM + 600 PM) PO ×2 wk, then 800 mg/day (400 BID) ×22 wk
Arm B: Matching placebo same schedule; crossover to open-label pexidartinib permitted at week 25
Primary endpoint: ORR at week 25 by blinded independent central review (RECIST + total volume score)
mFollow up: 22.1 mo

Results

ORR (RECIST, wk 25): 39% (24/63) vs 0% (0/57); P<.0001
TVS response rate: 56% vs 0%
Duration of response: 100% of responders maintained response at 1 yr (RECIST)

Adverse events

Hepatotoxicity (cholestatic): serious in 3 (5%), incl 1 requiring liver transplant; grade ≥3 ALT/AST elevation 12% (REMS-restricted distribution)
Other: hair color changes 50%; periorbital edema 29%; fatigue 54%; nausea 44%

Conclusions

Pexidartinib achieved 39% ORR (vs 0% placebo, P<.0001) with durable responses and improved function in TGCT, establishing the first FDA-approved systemic therapy and validating CSF1R inhibition.

Key Limitations

Small N; short 25-wk primary endpoint window; serious hepatotoxicity (incl liver transplant) led to early enrollment halt and mandatory REMS; durable benefit beyond 1 yr less characterized.

Clinical Context

FDA-approved 2019 for symptomatic TGCT not amenable to surgery; distributed under REMS for hepatotoxicity. Surgery remains first-line; systemic CSF1R inhibition reserved for unresectable/recurrent disease. Newer agent vimseltinib (MOTION) offers improved hepatic safety.

References