Koselugo Demonstrates Clinically Meaningful Improvement in Adults with Symptomatic, Inoperable Plexiform Neurofibromas

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Data from the Phase III KOMET trial demonstrated that Koselugo (selumetinib; Alexion, AstraZeneca Rare Disease, and Merck), an oral MEK inhibitor targeting neurofibromatosis type 1 (NF1), demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR) compared to placebo in adults with symptomatic, inoperable plexiform neurofibromas (PN). According to Merck, the data will be shared with regulatory authorities and presented at an upcoming medical meeting.¹

“With limited options to manage NF1 plexiform neurofibromas in adults, many patients experience functional impairment and symptoms, which can substantially impact their lives. These clinically meaningful data show Koselugo has the potential to make a positive impact in patient care by reducing the size of plexiform neurofibromas,” KOMET trial principal investigator Ignacio Blanco Guillermo, MD, PhD, chairman, genetic counseling and clinical genetics program, Germans Trias i Pujol University Hospital, chairman, Spanish National Reference Center for Adult Patients with Neurofibromatosis, said in a press release.

The global randomized, double-blind, placebo-controlled, multi-center KOMET trial evaluated the efficacy and safety of Koselugo in adults with NF1 who have symptomatic, inoperable PNs. As part of the trial, 145 patients were enrolled from 13 countries across the United States, Asia, Australia, South America, and Europe, with participants’ baseline characteristics—including gender and distribution of PNs—reflective of the global adult NF1 patient population. All patients were randomly assigned in a 1:1 ratio to receive Koselugo or placebo for twelve 28-day cycles. The primary endpoint of the study was confirmed ORR by cycle 16 as determined by independent central review per response evaluation in neurofibromatosis and schwannomatosis criteria.

ORR was defined as the percentage of patients with at least a 20% reduction in tumor volume by cycle 16. After 12 cycles, patients on placebo were switched to Koselugo, with patients already on Koselugo staying on the treatment for an additional 12 cycles. Patients who had the opportunity to complete both treatment periods with 24 cycles of treatment had the option to participate in a long-term extension period and continue to receive it.

Adverse events associated with Koselugo included cardiomyopathy, ocular toxicity, gastrointestinal toxicity, skin toxicity, increased creatinine phosphokinase, increased levels of vitamin E, risk of bleeding, and embryo-fetal toxicity. The safety profile of Koselugo was found to be consistent with previously observed findings in clinical trials among children and adolescents, with no new safety signals identified.¹

“These promising results demonstrate that Koselugo, the first and only approved targeted therapy for certain children with NF1 plexiform neurofibromas, now has the potential to benefit adult patients for whom there are no approved targeted therapies. As the largest and only global placebo-controlled Phase 3 trial in adults with NF1 plexiform neurofibromas, KOMET reinforces our leadership in advancing potential treatment options for people living with this debilitating disease. We look forward to sharing these findings with regulatory authorities,” said Marc Dunoyer, CEO, Alexion, in the press release.

According to a study published in The National Library of Medicine, PNs occur in 30% to 50% of patients with NF1.²

“Adults with NF1 are in critical need of treatment options to help manage symptomatic, inoperable plexiform neurofibromas. These positive results from the Phase III KOMET trial demonstrate the potential to expand the use of Koselugo beyond pediatric patients to also treat adult patients living with this rare and challenging genetic condition,” said Scot Ebbinghaus, VP, global clinical development, Merck Research Laboratories, in the press release.

References

1. KOSELUGO® (selumetinib) Showed Significant and Clinically Meaningful Improvement in Objective Response Rate Versus Placebo in Adults With Neurofibromatosis Type 1 who Have Symptomatic, Inoperable Plexiform Neurofibromas in Global Phase 3 KOMET Trial. Merck. November 12, 2024. Accessed November 13, 2024. https://www.merck.com/news/koselugo-selumetinib-showed-significant-and-clinically-meaningful-improvement-in-objective-response-rate-versus-placebo-in-adults-with-neurofibromatosis-type-1-who-have-symptomatic-inoperable/

2. Impact of neurofibromatosis type 1 with plexiform neurofibromas on the health-related quality of life and work productivity of adult patients and caregivers in the UK: a cross-sectional survey. NLM. Accessed November 13, 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC10666383/#:~:text=Background,and%20caregivers%20of%20paediatric%20patients.