Final results of ENLIVEN: A global, double-blind, randomized, placebo-controlled, phase 3 study of pexidartinib in advanced tenosynovial giant cell tumor (TGCT).

Abstract

11502 Background: TGCT is a rare neoplasm of the joint/tendon sheath associated with colony-stimulating factor 1 (CSF-1) overexpression. No approved systemic therapy is available. Pexidartinib (Pex), a selective inhibitor of CSF-1 receptor, KIT, and FLT3-ITD, showed promising Phase 1 activity in TGCT. Two severe liver toxicity cases (1 required liver transplant, 1 associated with death) have been observed with Pex across the non-TGCT development program. Methods: Patients (pts) ≥18 yr with symptomatic TGCT, for whom surgery would be associated with potentially worse function or severe morbidity, were randomized (1:1) to Pex or placebo (Pbo) 1000 mg/d x 2 wks then 800 mg/d PO x 22 wks (Part 1). Pts completing Part 1 could continue into an open-label Pex extension (Part 2). The primary endpoint was centrally reviewed overall response rate (ORR) by RECIST at Week 25 for which the study was powered to detect a 25% difference (35% vs 10%). Results: 120 pts were treated, 61/59 on Pex/Pbo. Due to 2 cases of nonfatal, serious hepatic toxicity, the DMC halted enrollment 6 pts short of target and stopped entry of pts on Pbo into Part 2. At the end of Part 1, ORR by RECIST in the ITT population was 39.3% vs 0% (P< 0.0001); after a median 6-mo follow-up (longest 17 mos), no responders have progressed. Secondary endpoints for Pex vs Pbo were ORR by tumor volume score (55.7% vs 0%, P< 0.0001), range of motion (+15.1% vs +6.2%, P =0.0043), PROMIS physical function (+4.06 vs -0.89, P =0.0019), worst stiffness (-2.45 vs -0.28, P <0.0001), and pain response (31.1% vs 15.3%, 1-sided P= 0.032). Hepatic toxicities were more frequent with Pex (AST ≥5X ULN 11.5%, ALT ≥5X ULN 19.7%, total bilirubin ≥2X ULN 4.9%). 8 pts discontinued Pex due to hepatic effects; 4 were serious nonfatal AEs with increased bilirubin, one lasting ~7 mos. Other AEs ≥15% and more common with Pex included hair color changes, vomiting, fatigue, dysgeusia, and periorbital edema. Conclusions: Pex resulted in significantly improved ORR and clinical benefit in terms of functional outcomes. Serious liver toxicity was observed in some pts. Pex may offer a relevant treatment option for select pts. Clinical trial information: NCT02371369.