Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibroma (PN): Primary analysis of KOMET (NCT04924608), a phase 3, international, randomized, placebo-controlled study.

3014 Background: No globally approved therapies exist for adults with NF1 and symptomatic, inoperable PN.KOMET is evaluating the efficacy and safety of selumetinib (SELU; ARRY-142886, AZD6244) in adults. Methods: KOMET is an ongoingPhase 3, randomized, double-blind, placebo-controlled trial. Adults (≥18 yrs) with NF1 and symptomatic, inoperable PN were randomized 1:1 to 28-day cycles of oral SELU 25 mg/m 2 BID or placebo (PBO) with crossover to SELU at progression or the end of Cycle (C) 12. Among others, baseline (BL) PAINS-pNF target PN chronic pain intensity score (< 3 or ≥3) was a stratification factor; 70% of patients (pts) were required to have a score ≥3. Primary analyses were conducted after the last pt completed C16 (data cutoff: Aug 5, 2024). The primary endpoint was objective response rate (ORR; confirmed partial/complete response) per ICR REiNS by the end of C16. Key secondary endpoints were change from BL to C12 in PAINS-pNF chronic pain score in pts with a BL score ≥3 and PlexiQoL total score in all randomized pts (SELU vs PBO). A planned sample of 73 pts per arm with a 2-sided 5% alpha Fisher’s exact test had > 99% power to detect the difference between a SELU ORR of 20% and PBO ORR of 0%. Key secondary endpoints were analyzed with a mixed model for repeated measures. Results: Of 145 randomized pts (SELU: 71; PBO: 74), 51.7% were male; median age was 29 yrs (range 18–60). SELU led to a rapid onset of response (median 3.7 mos), with an ORR of 19.7% (95% CI 11.2, 30.9) by C16 vs 5.4% (95% CI 1.5, 13.3) with PBO (p = 0.011). At C12, pts with a BL chronic pain score ≥3 had a greater reduction in pain score with SELU (LS mean −2.0; 95% CI −2.6, −1.4) vs PBO (LS mean −1.3; 95% CI −1.8, −0.7); and clinically meaningful improvement (meaningful score difference −2 points) vs BL, but this was not statistically significant vs PBO (p = 0.070). Reduction in chronic pain intensity was observed with SELU vs PBO in the full analysis set (all pts regardless of BL chronic pain intensity, nominal p = 0.024). Change from BL to C12 in PlexiQoL total score between treatment arms was not statistically significant (LS mean difference −0.1; 95% CI −1.2, 1.1). Adverse events (AEs) in the randomized period were consistent with the known safety profile of SELU. The most common AEs (≥10% of pts) were dermatitis acneiform (59%), increased blood creatine phosphokinase (45%), and diarrhea (42%) with SELU, and COVID-19 (20%), nausea (16%), and fatigue (14%) with PBO. Fourteen pts on SELU and 1 pt on PBO reported CTCAE Grade ≥3 treatment-related AEs; 9 SELU and 5 PBO pts discontinued due to AEs. Conclusions: In the first international, randomized, placebo-controlled trial in adults with NF1-PN, SELU achieved a significant ORR vs PBO (C16), meeting the primary endpoint, and a clinically meaningful reduction in PN-associated chronic pain (C12). Clinical trial information: NCT04924608 .