Positive high-level results of COMET Phase III trial of oral Koselugo (selumetinib) in adults with neurofibromatosis type 1 – AstraZeneca

Positive high-level results of KOMET, the largest, global randomised double-blind placebo-controlled multicentre Phase III trial in adults with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN), showed that Koselugo (selumetinib), an oral, selective MEK inhibitor, met its primary endpoint, demonstrating a statistically significant and clinically meaningful objective response rate (ORR) versus placebo in these adult patients.

NF1  is a rare, progressive, genetic condition that is caused by a spontaneous or inherited mutation in the NF1 gene. NF1 is associated with a variety of symptoms, including soft lumps on and under the skin (cutaneous neurofibromas) and, in 30-50% of patients, tumours develop on the nerve sheaths (PNs). These PNs can cause clinical issues such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment and bladder or bowel dysfunction. PNs begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years..

Prof. Ignacio Blanco Guillermo, MD, PhD, Chairman of the Genetic Counselling and Clinical Genetics Programme at the Germans Trias i Pujol University Hospital, Chairman of the Spanish National Reference Centre for Adult Patients with Neurofibromatosis and Principal Investigator of the KOMET trial, said: “With limited options to manage NF1 PN 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.”

Marc Dunoyer, Chief Executive Officer, Alexion, AstraZeneca Rare Disease, said: “These promising results demonstrate that Koselugo, the first and only approved targeted therapy for certain children with NF1 PN, 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 III trial in adults with NF1 PN, 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.”

In the trial, ORR was defined as the percentage of patients with confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumour volume) by cycle 16 (28 days per cycle) as determined by independent central review (ICR) per response evaluation in neurofibromatosis and schwannomatosis (REiNS) criteria.

The safety profile of Koselugo in this study was consistent with that observed in clinical trials among children and adolescents. No new safety signals were identified.

Alexion, AstraZeneca Rare Disease will share these data with regulatory authorities and present at a forthcoming medical meeting. AstraZeneca and MSD are jointly developing and commercialising Koselugo globally.

KOMET; KOMET is a global Phase III randomised, double-blind, placebo-controlled, multicentre trial designed to evaluate the efficacy and safety of Koselugo in adults with NF1 who have symptomatic, inoperable PNs. The trial enrolled 145 adults from 13 countries across North America, South America, Europe, Asia and Australia, with participants’ baseline characteristics, including gender and distribution of PNs, reflective of the global adult NF1 patient population. Patients were enrolled and randomised to receive Koselugo or placebo (1:1) for 12 28-day cycles. Participants were required to have diagnosis of NF1, at least one symptomatic, inoperable PN measurable by volumetric MRI analysis, chronic PN pain score documented during screening, adequate organ and marrow function and stable chronic PN pain medication use at enrolment.

The primary endpoint is confirmed ORR by cycle 16 as assessed by ICR. ORR is defined as the percentage of patients with confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumour volume). After 12 cycles, patients on placebo were switched to Koselugo and patients on Koselugo remained on treatment for an additional 12 cycles. Patients who had the opportunity to complete 24 cycles of treatment have the option to participate in a long-term extension period and continue to receive Koselugo