Treatment with selumetinib (Koselugo) has shown a statistically significant and clinically meaningful improvement in objective response rate (ORR) compared to placebo in adult patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN). This was the primary endpoint of the phase 3 KOMET trial (NCT04924608). The data are scheduled to be presented at an upcoming medical meeting and shared with global health authorities, according to Astrazeneca.
Addressing Unmet Needs in Adult NF1 Patients
While selumetinib is already approved for pediatric patients (2 years and older) with NF1 and symptomatic, inoperable PN, approximately 70% of NF1 cases occur in adults, for whom there are currently no approved therapeutic options. The KOMET trial sought to address this significant unmet need.
“With limited options to manage NF1 PN in adults, many patients experience functional impairment and symptoms, which can substantially impact their lives,” said Ignacio Blanco Guillermo, MD, PhD, chairman of the Genetic Counseling and Clinical Genetics Program at the Germans Trias i Pujol University Hospital, chairman of the Spanish National Reference Center for Adult Patients with Neurofibromatosis, and principal investigator of the KOMET trial. “These clinically meaningful data show [selumetinib] has the potential to make a positive impact in patient care by reducing the size of plexiform neurofibromas.”
KOMET Trial Design and Results
The KOMET trial was a global, randomized, double-blind, placebo-controlled, multicenter trial that enrolled 145 patients at least 18 years of age with NF1 featuring symptomatic, inoperable PN across 13 countries in North America, Asia, Australia, South America, and Europe. Patients were randomized 1:1 to receive selumetinib or placebo for twelve 28-day cycles. Key inclusion criteria included having at least one inoperable target PN measurable via volumetric MRI, a chronic target PN pain score documented for a minimum period during screening, stable chronic PN pain medication use, and adequate organ and bone marrow function. After 12 cycles, patients in the placebo arm crossed over to receive selumetinib for 12 additional cycles, and those in the experimental arm also received the agent for an additional 12 cycles. Patients completing both treatment periods could participate in a long-term extension.
The primary endpoint was independent review committee–assessed ORR by cycle 16. Secondary endpoints included change in chronic target PN pain intensity, duration of response, progression-free survival, time to progression, time to response, target PN volume, physical functioning, and health-related quality of life. Safety and pharmacokinetics were also assessed.
The safety profile of selumetinib was consistent with prior data reported for the agent in pediatric and adolescent patients, and no new safety signals were observed.
Implications for NF1 Treatment
“Adults with NF1 are in critical need of treatment options to help manage symptomatic, inoperable plexiform neurofibromas,” said Scot Ebbinghaus, MD, vice president of Global Clinical Development at Merck Research Laboratories. “These positive results from the phase 3 KOMET trial demonstrate the potential to expand the use of [selumetinib] beyond pediatric patients to also treat adult patients living with this rare and challenging genetic condition.”
