Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (KOMET): a multicentre, international, randomised, placebo-controlled, parallel, double-blind, phase 3 study.

Background: Currently, no worldwide approved therapies exist for adults with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas. The KOMET study aimed to evaluate selumetinib (ARRY-142886, AZD6244) efficacy and safety in this population.

Methods: This ongoing multicentre, international, randomised, placebo-controlled, phase 3, parallel, double-blind trial randomly assigned adults with NF1-plexiform neurofibroma 1:1 to 28-day cycles of oral selumetinib 25 mg/m twice daily, or placebo with crossover to selumetinib at confirmed radiological progression or the end of cycle 12. The primary endpoint was objective response rate (confirmed partial or complete response) established by use of independent central review per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria by cycle 16 (selumetinib vs placebo). This study (KOMET) is registered with ClinicalTrials.gov, NCT04924608 and is ongoing.

Findings: Overall, of 184 participants enrolled, 145 adults were randomly assigned to selumetinib (n=71) or placebo (n=74). Selumetinib led to a rapid response (median 3·7 months), with an objective response rate of 20% (n=14/71; 95% CI 11·2 to 30·9) by cycle 16 versus 5% (n=4/74; 1·5 to 13·3) with placebo (p=0·011). Participants with baseline chronic pain intensity scores of at least 3 had a greater reduction in score at cycle 12 with selumetinib versus placebo (least-squares mean [SE] -2·0 [0·30] -2·6 to -1·4, vs -1·3 [0·29] -1·8 to -0·7; p=0·070), although this did not reach significance; and a clinically meaningful improvement from baseline. Change from baseline to cycle 12 in PlexiQoL total scores between treatment groups was not significant (least-squares mean difference [SE] -0·1 [0·59]; -1·2 to 1·1). Adverse events were consistent with the known selumetinib safety profile.

Interpretation: In the first international, randomised, placebo-controlled trial in adults with NF1-plexiform neurofibromas, selumetinib achieved a significant objective response rate versus placebo. No new safety concerns were identified. The observations of reduction in tumour volume by cycle 16, reduction in chronic and spike pain, reduction in analgesia, and decrease in pain interference over placebo show that selumetinib is effective at treating plexiform neurofibromas in adults with NF1.

Funding: AstraZeneca as part of an alliance between AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck, Rahway, NJ, USA.