Pimicotinib in tenosynovial giant cell tumor (TGCT): Efficacy, safety and patient-reported outcomes of phase 3 MANEUVER study.

Abstract

11500 Background: TGCT is a rare, locally aggressive mesenchymal neoplasm, driven by the overproduction of colony-stimulating factor 1 (CSF-1), and is often associated with joint pain, swelling, stiffness and functional impairment. The high rate of recurrence and the significant tumor burden, particularly in the diffuse variant, highlight the necessity for an effective systemic treatment. Pimicotinib (pimi) is an oral, highly selective and potent small-molecule inhibitor of CSF-1 receptor (CSF-1R). We report the results from the double-blind Part 1 of MANEUVER, the first global Phase 3 trial to recruit TGCT patients (pts) from Asia, EU and North America (NA) who were candidates for systemic therapy. Methods: MANEUVER (NCT05804045) is a Phase 3, randomized, double-blind, placebo (pbo)-controlled trial evaluating efficacy and safety of pimi in pts with TGCT. In Part 1, pts received pimi 50 mg QD or pbo (2:1) for 24 weeks. Primary endpoint was objective response rate (ORR) by blinded independent review committee (BIRC) per RECIST v1.1 at Week 25. Key secondary endpoints included ORR by tumor volume score (TVS) and clinical outcome assessments (COAs) at Week 25: mean change from baseline in range of motion (ROM), worst stiffness, Brief Pain Inventory (BPI) worst pain and PROMIS physical function. Safety was also evaluated. Results: At the data cutoff of Sep 23, 2024, all of the planned 94 pts were enrolled (China = 45; EU = 28; NA = 21), with 63 randomized to pimi and 31 to pbo.Median age was 40.0 years (range: 18-69); 68.1% were female; disease location mainly in knee (50.0%), ankle (14.9%) or hip (13.8%). ORR by BIRC per RECIST v1.1 and TVS at Week 25 was significantly higher for pimi vs pbo (54% vs 3.2% and 61.9% vs 3.2%, respectively; both p < 0.0001). Statistically significant and clinically meaningful improvements were observed with pimi vs pbo for all COAs: active ROM (15.64 vs -0.07; p = 0.0003), worst stiffness (-3.00 vs –0.57; p < 0.0001), BPI worst pain (-2.32 vs –0.23; p < 0.0001) and PROMIS physical function (5.63 vs 2.23; p = 0.0074). Significantly more pain responders (BPI-30) were observed with pimi vs pbo (63.5% vs 16.1%; p < 0.0001). Treatment efficacy was consistent across pts from different regions and ethnicities. Most TEAEs were low grade, consistent with the known mechanism of action of CSF-1R inhibitors and led to a low rate of dose reduction (7.9%, 5/63 pts) and treatment discontinuation (1.6%, 1/63 pt). There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. Conclusions: MANEUVER is the first randomized pivotal study in TGCT to demonstrate > 50% ORR by RECIST v1.1 at Week 25 in a diverse, global patient population. Pimi produced statistically significant and clinically meaningful improvements in physical function and symptoms, representing an effective, well-tolerated and convenient daily treatment for patients with TGCT and addressing a critical unmet need. Clinical trial information: NCT05804045 .