Luvometinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: A randomized, double-blind, placebo-controlled, phase 3 trial.

Abstract

3017 Background: Neurofibromatosis type 1 (NF1) related plexiform neurofibromas (PNs) is associated with significant morbidity, including pain, disfigurement and functional impairment. Surgical treatment for PNs may be limited due to tumor size, location and extent. A randomized, double-blind, placebo-controlled, phase 3 trial (NCT05913037) was conducted to evaluate the efficacy and safety of Luvometinib in adults with inoperable NF1 PN causing significant morbidities. Methods: Adults (≥18 yrs) with NF1 and symptomatic, inoperable PNs were randomized in a 2:1 to receive oral Luvometinib (8 mg daily) or placebo in 28-day cycles, stratified by baseline (BL) NRS-11 tumor pain score (≥2 or＜2). An interim analysis was performed at 16 months after the last patient randomization. The primary endpoint was confirmed objective response rate (ORR) by Blinded Independent Review Committe (BIRC) per REiNS criteria. Key secondary endpoints included ORR by the investigator (INV), duration of response (DOR), time to response (TTR) by BIRC and INV, pain severity and safety. Results: 167 adults were randomized to receive luvometinib (n = 112) or placebo (n = 55). As of the data cutoff on Aug 19, 2025, the median follow-up was 19.7 months(range: 1.4-25.5). The confirmed ORR assessed by BIRC was 43.8%（95% CI, 34.4-53.4）with luvometinib, compared with 10.9%（95% CI, 4.1-22.3）with placebo (p＜0.0001). Luvometinib led to a rapid response (median 3.9 months). The median DOR was 15.1 months (95% CI, 14.8-NE), with a 85.2% rate of DOR ≥12 months with luvometinib. A greater proportion of patients with BL overall tumor pain scores ≥2 experienced a reduction in pain score of at least 2 points with luvometinib compared to placebo (81.0% vs. 53.6%). The most common treatment-emergent adverse events (TEAEs) were folliculitis, increased CPK, mouth ulcer, diarrhea. Serious AEs occurred in 14.3% (luvometinib) versus 7.3% (placebo) of pts. TEAEs led to discontinuation was 1.8% in both groups. Conclusions: Our study demonstrated that luvometinib achieved a statistically significant ORR per BIRC compared with placebo, with rapid and durable response, significant reductions in pain severity, and an overall manageable safety profile. These findings suggest that luvometinib may emerge as a new standard treatment for patients with NF1 and symptomatic, inoperable PNs. Clinical trial information: NCT05913037 .