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Clinical Trial
. 2025 Jun 21;405(10496):2217-2230.
doi: 10.1016/S0140-6736(25)00986-9. Epub 2025 Jun 2.

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

Alice P Chen  1 , Geraldine O'Sullivan Coyne  2 , Pamela L Wolters  3 , Staci Martin  3 , Said Farschtschi  4 , Ignacio Blanco  5 , Zhongping Chen  6 , Luiz Guilherme Darrigo Jr  7 , Marica Eoli  8 , James R Whittle  9 , Yoshihiro Nishida  10 , Rosa Lamarca  11 , Randolph de la Rosa Rodriguez  12 , Ayo Adeyemi  12 , Idoia Herrero  11 , Nereida Llorente  11 , Scott J Diede  13 , Eva Dombi  3 , Pierre Wolkenstein  14 ; KOMET study investigators
Collaborators, Affiliations
Clinical Trial

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

Alice P Chen et al. Lancet. .

Abstract

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/m2 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.

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Conflict of interest statement

Declaration of interests PLW, SM, and ED receive research support from the Intramural Research Program of the National Institutes of Health and worked on this project as an official duty activity. PLW and SM also received funding from the Neurofibromatosis Therapeutics Acceleration Program for their work on developing and validating the PAINS-pNF and PII-pNF measures. SF has received speaker honoraria from Alexion, AstraZeneca Rare Disease and compensation for advice or lecturing from Alexion, AstraZeneca Rare Disease, and SpringWorks Therapeutics. IB received consultancy fees from Alexion, AstraZeneca Rare Disease and SpringWorks Therapeutics. LDG received consultancy fees from Alexion and AstraZeneca Rare Disease. ME received consultancy fees from Alexion, AstraZeneca Rare Disease. YN received honoraria from Ono, Alexion, AstraZeneca Rare Disease, Daiichi-Sankyo, Hisamitsu, Zimmer-Biomet, and Stryker, and received consulting or advisory role fees from AstraZeneca, Alexion, AstraZeneca Rare Disease, Boehringer, and Seikagaku. RL, RdlRR, AA, IH, and NL are employees of, and own stocks in, Alexion, AstraZeneca Rare Disease. SD is an employee of Merck Sharp & Dohme, a subsidiary Merck, Rahway, NJ, USA and owns stocks in Merck & Rahway, NJ, USA. PW received consultation fees from Alexion, AstraZeneca Rare Disease, AstraZeneca, and SpringWorks Therapeutics.APC received support from AstraZeneca for this study that was paid to the National Cancer Institute.; has received support for attending meetings from the America Association for Cancer Research, AstraZeneca, and Genentech; has a patent pending with Genentech; owns stock in Vanguard Healthcare; declares that the National Cancer Institute has received drugs from AstraZeneca, Genentech, Karyopharma, Pfizer, and Cybrexa, and is Chief Specialty Editor for Precision Medicine Frontiers in Medicine. GO'SC declares support from AstraZeneca for this study paid to the National Cancer Institute. GO'SC declares support from AstraZeneca for this study that was paid to the National Cancer Institute. ZC has received support from AstraZeneca paid to his institution (Sun Yat-sen University Cancer Center) for this study. JRW has received grants paid to his institution from NHMRC, Medical Research Future Fund, Cancer Council Victoria, Anheart therapeutics, Flicker of Hope, and Perpeutual; has received payment or honoraria for lectures, presentations, or speaker bureaus from AnHeart therapeutics, Roche and MSD; has participated on a data safety monitoring board of advisory board for Telix Pharmaceuticals.; and declares an unpaid leadership role in the management committee COGNO and the research advisory committee for the Mark Hughes Foundation.

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