AstraZeneca's Koselugo (selumetinib) has met its primary endpoint in the KOMET Phase III trial, demonstrating a statistically significant and clinically meaningful improvement in objective response rate (ORR) in adult patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PNs). The global, randomized, double-blind, placebo-controlled trial involved 145 adults across North America, South America, Europe, Asia, and Australia.
The KOMET trial compared Koselugo to placebo over 12 28-day cycles, with ORR assessed by independent central review (ICR) at cycle 16. ORR was defined as the percentage of patients with confirmed complete response (disappearance of PNs) or partial response (at least 20% reduction in tumor volume). Patients enrolled had a confirmed diagnosis of NF1, at least one symptomatic, inoperable PN measurable by volumetric MRI analysis, and documented chronic PN pain.
Detailed Trial Design and Patient Population
The KOMET trial enrolled 145 adults with NF1 from 13 countries. Participants were randomized 1:1 to receive either Koselugo or placebo for 12 cycles. Baseline characteristics, including gender and distribution of PNs, were reflective of the global adult NF1 patient population. After 12 cycles, patients on placebo were switched to Koselugo, and those on Koselugo continued treatment for an additional 12 cycles. Patients completing 24 cycles could opt into a long-term extension period.
Understanding NF1 and Plexiform Neurofibromas
NF1 is a rare, progressive, genetic condition caused by a mutation in the NF1 gene. It affects approximately 1 in 3,000 people worldwide. Between 30% and 50% of individuals with NF1 develop PNs, which are tumors on the nerve sheaths that can cause disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment, and bladder or bowel dysfunction. PNs typically begin in early childhood and can reduce life expectancy by up to 15 years.
Koselugo Mechanism of Action
Koselugo (selumetinib) is a kinase inhibitor that blocks MEK1 and MEK2 enzymes, which are involved in stimulating cell growth. In NF1, these enzymes are overactive, leading to unregulated growth of tumor cells and the formation of PNs. By inhibiting these enzymes, Koselugo slows down the growth of tumor cells and, consequently, PN growth.
Previous Approvals and Strategic Collaboration
Koselugo is already approved in the US, EU, Japan, China, and other countries for treating certain pediatric patients with NF1 who have symptomatic, inoperable PNs. It also holds Orphan Drug Designation in multiple regions. The development and commercialization of Koselugo are part of a strategic collaboration between AstraZeneca and Merck & Co., Inc. (MSD outside the US and Canada), which also includes the PARP inhibitor Lynparza (olaparib).
