Final analysis of KOMET (NCT04924608), a phase 3 study of selumetinib in adults with NF1-PN.

Abstract

3110 Background: In 2025 the EMA and FDA expanded the approval of selumetinib (SELU; ARRY-142886, AZD6244) to adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). We report the final exploratory analysis of SELU efficacy and safety from the Phase 3, randomized, double-blind, placebo (PBO)-controlled KOMET trial. Methods: Adults (≥18 yrs) with NF1-PN were randomized 1:1 to 28-day cycles of oral SELU 25 mg/m 2 BID or PBO with crossover to SELU at the end of Cycle (C) 12 or earlier if radiological progression was confirmed by independent central review (ICR). The single-arm objective response rate (ORR) by use of volumetric MRI analysis per ICR REiNS and safety were exploratory endpoints at final DCO (last participant (pt) completed C24; 17 Mar 2025)). Pharmacokinetics (PK) data were collected at steady state C1, Day (D) 8. 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%. Results: Overall, 145 pts (SELU: 71; PBO: 74) were randomized; 66 pts in the PBO group crossed over to SELU treatment for the open-label period (SELU period). In the SELU period, 137 pts were treated; 96 pts (66.2%) (SELU: 45, PBO/SELU: 51) completed the study and were judged by the investigators at DCO to have clinical benefit at study completion and, consequently, continued receiving SELU during the post-trial access program. Median actual exposure to SELU during the SELU period was 554 days and maximum exposure to SELU treatment was 1156 days. The median relative dose intensity of SELU treatment was 99.5%. The ORR in the SELU group (N = 71) was 23.9% (95% CI; 14.6, 35.5). Of the 17 pts who achieved objective response, 10 (58.8%) remained in response for ≥12 months while 5 pts (29.4%) had not yet reached 12 months follow-up from onset of response. Median duration of response was not reached in the SELU group by final analysis. During the SELU period (N = 137), 51 pts (37.2%) had a maximum AE severity of ≥Grade 3 (most frequent were known SELU AEs); ≥1 AEs, possibly related to SELU, were experienced by 127 pts (92.7%); of these, 31 pts (22.6%) had ≥Grade 3 AEs. Serious AEs (SAEs) were experienced by 24 pts (17.5%); 6 pts (4.4%) had SAEs possibly related to SELU. AEs of special interest were experienced by 85 pts (62.0%); increased blood creatine phosphokinase (43.1%), increased ALT/AST (13.9% each), and peripheral edema (13.1%) were the most frequent (≥10% of pts). AEs were manageable; the AE-related discontinuation rate for the trial was 9.5%. At C1 D8, 64 pts who received SELU were included in the PK Analysis Set. Median t max was 1.5 h and geometric mean AUC (0-12) was 2986 h × ng/mL for SELU. Conclusions: In the first international, randomized, PBO-controlled trial in adults with NF1-PN, SELU achieved a sustained and durable, clinically meaningful reduction in PN volume per ICR REiNS. No new safety concerns were identified and AEs were manageable. Clinical trial information: NCT04924608 .