Koselugo (selumetinib) has met its primary endpoint in the Phase III KOMET trial, demonstrating a statistically significant and clinically meaningful objective response rate (ORR) compared to placebo in adult patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN). The KOMET trial is the largest global, randomized, double-blind, placebo-controlled study in this patient population, potentially paving the way for the first approved targeted therapy for adults with NF1 PN.
Addressing Unmet Needs in Adult NF1 Patients
NF1 is a rare genetic condition affecting approximately 1.7 million individuals worldwide, with about 70% being adults. In 30-50% of these patients, tumors develop on the nerve sheaths, leading to disfigurement, motor dysfunction, pain, and other debilitating symptoms. Currently, there are no approved treatments specifically for adults with NF1 PN, leaving many to endure multiple surgeries and a diminished quality of life.
"With limited options to manage NF1 PN in adults, many patients experience functional impairment and symptoms, which can substantially impact their lives," said Prof. Ignacio Blanco Guillermo, MD, PhD, Principal Investigator of the KOMET trial. "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 Details and Results
The KOMET trial enrolled 145 adults with NF1 from 13 countries. Participants were randomized to receive either Koselugo or placebo for 12 cycles (28 days per cycle). The primary endpoint was the confirmed ORR by cycle 16, as determined by independent central review (ICR) using Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria. ORR was defined as the percentage of patients with a confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumor volume).
The safety profile of Koselugo in the KOMET trial was consistent with previous studies in children and adolescents, with no new safety signals identified. After 12 cycles, patients on placebo were switched to Koselugo, and those on Koselugo continued treatment for an additional 12 cycles, with an option to participate in a long-term extension period.
Mechanism of Action and Regulatory Status
Koselugo (selumetinib) is an oral, selective MEK inhibitor that blocks MEK1 and MEK2 enzymes, which are involved in stimulating cell growth. In NF1, these enzymes are overactive, causing unregulated tumor cell growth and the formation of plexiform neurofibromas. By inhibiting these enzymes, Koselugo slows down tumor growth.
Koselugo is already approved in the US, EU, Japan, China, and other countries for the treatment of certain pediatric patients with NF1 who have symptomatic, inoperable PNs. The KOMET trial results could expand its use to adult patients, offering a much-needed treatment option.
Future Steps
Alexion, AstraZeneca Rare Disease, will share the KOMET trial data with regulatory authorities and present the findings at an upcoming medical meeting. AstraZeneca and MSD are jointly developing and commercializing Koselugo globally.
