Selumetinib Boosts ORR in NF1 With Inoperable Plexiform Neurofibroma

Treatment with selumetinib (Koselugo) led to a statistically significant and clinically meaningful improvement in objective response rate (ORR) compared with placebo in adult patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN), meeting the primary end point of the phase 3 KOMET trial (NCT04924608).¹

Data will be presented at an upcoming medical meeting and shared with global health authorities, according to an announcement from Astrazeneca.

In 2020, the FDA approved selumetinib for the treatment of pediatric patients 2 years of age and older with NF1 who have symptomatic, inoperable PN.² However, approximately 70% of cases of NF1 are seen in adults, and no therapeutic options are currently approved for the treatment of adult patients.¹

“With limited options to manage NF1 PN in adults, many patients experience functional impairment and symptoms, which can substantially impact their lives,” 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, stated in a news release. “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 was a global, randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients at least 18 years of age with NF1 featuring symptomatic, inoperable PN.³ Patients were required to have at least 1 inoperable target PN that was measurable via volumetric MRI. Other key inclusion criteria consisted of a chronic target PN pain score documented for minimum period during screening, stable chronic PN pain medication use, and adequate organ and bone marrow function.

Key exclusion criteria included confirmed or suspected malignant glioma or malignant peripheral nerve sheath tumor; a history of other malignancies, except for those treated with curative-intent therapy with no known active disease for at least 5 years; clinically significant cardiovascular disease; ophthalmological conditions; and prior exposure to MEK inhibitors.

Patients (n = 145) were enrolled across 13 countries in North America, Asia, Australia, South America, and Europe, and they were randomly assigned 1:1 to receive selumetinib or placebo for 12 28-day cycles.¹ After 12 cycles of treatment, 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 who completed both treatment periods had the option to participate in a long-term extension, where they could continue receiving selumetinib.

Independent review committee–assessed ORR by cycle 16 served as the trial’s primary end point.¹ Secondary end points 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.³ Safety and pharmacokinetics were other end points.

Regarding safety, the profile of selumetinib was consistent with prior data reported for the agent in pediatric and adolescent patients, and no new safety signals were observed.¹

“Adults with NF1 are in critical need of treatment options to help manage symptomatic, inoperable plexiform neurofibromas,” Scot Ebbinghaus, MD, vice president of Global Clinical Development at Merck Research Laboratories, added in a news release. “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.”

References

1. Koselugo showed statistically significant and clinically meaningful objective response rate vs. placebo in adults with neurofibromatosis type 1 in global KOMET phase III trial. News release. Astrazeneca. November 12, 2024. Accessed November 12, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/komet-phase-iii-trial-met-primary-endpoint.html
2. Koselugo. Alexion. January 2024. Accessed November 12, 2024. https://alexion.com/Documents/koselugo_uspi.pdf
3. Efficacy and safety of selumetinib in adults with NF1 who Have symptomatic, inoperable plexiform neurofibromas (KOMET). ClinicalTrials.gov. Updated September 19, 2024. Accessed November 12, 2024. https://clinicaltrials.gov/study/NCT04924608