Recently, the open label II of AstraZeneca targeted anticancer drug Koselugo (selumetinib) for the treatment of symptomatic, unresectable plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1) The results of the SPRINT Stratum 1 trial (NCT01362803) were published online in the New England Journal of Medicine (NEJM). The article title is: Selumetinib in Children with Inoperable Plexiform Neurofibromas.
NF1 is a genetic disease of the nervous system that causes tumors to grow on nerves. These tumors (plexiform neurofibroma) can grow anywhere on the body, including the face, limbs, around the spine, and areas in the body that may affect organs . The most common neurofibromatosis-related symptoms include disfigurement, motor dysfunction, and pain. Data from the SPRINT Stratum 1 trial shows that Koselugo treatment has significant clinical benefits for patients, which can continue to reduce tumor volume, relieve pain, improve daily function and overall health-related quality of life.
Koselugo is a novel oral kinase inhibitor that was approved by the US FDA in mid-April this year. It is used for pediatric patients with neurofibromatosis type 1 (NF1) aged 2 years or older to treat NF1-related symptomatic and inoperable plex Neurofibromatosis (PN). It is worth mentioning that Koselugo is the first drug approved by the US FDA to treat NF1. Previously, Koselugo was awarded the orphan drug qualification (ODD) and breakthrough drug qualification (BTD) for the treatment of NF1. Koselugo is a kinase inhibitor, meaning it acts through key enzymes, thereby preventing the growth of tumor cells.
Plexus neurofibroma (PN) (Image source: cancerworld.info)
NF1 is a rare disease that is debilitating, progressive, and often causes disfigurement. This disease usually starts early in life and is caused by mutations or defects in specific genes. NF1 is usually diagnosed early in childhood. NF1 occurs in about one in 3,000 babies and is characterized by changes in skin color (pigmentation), nerve and bone damage, and the risk of developing benign and malignant tumors throughout life. 30% to 50% of patients with NF1 have one or more plexiform neurofibromas (PN). The main treatment for PN is surgical resection. Unfortunately, due to the location or volume of these tumors, many patients are not suitable for surgery. In addition, NP usually recurs after optimal surgical resection and therefore represents an important area where medical needs are not met.
The SPRINT Stratum 1 trial was sponsored by the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP). The trial enrolled 50 pediatric patients (median age 10.2 years, range: 3.5-17.4). These children had NF1 And inoperable PN (defined as PN that cannot be completely removed but does not pose a serious risk to the patient). The most common neurofibromatosis-related symptoms are disfigurement (44 cases), motor dysfunction (33 cases), and pain (26 cases). In the trial, patients took Koselugo 25 mg / m2 (approved recommended dose) twice daily until the condition deteriorated or unacceptable adverse reactions occurred. During the trial period, the patient's tumor volume changes and tumor-related disease symptoms were routinely evaluated, and the overall response rate (ORR) was determined, which was defined as: 3-6 months by MRI confirmed complete or partial remission (PN tumor volume reduction ≥ 20%).
Data published on NEJM shows that as of March 29, 2019, 35 of 50 patients had confirmed remission, that is, the total remission rate (ORR) of Koselugo twice daily oral monotherapy was 70% (n = 35 / 50), all patients have partial remission (PR). Of the 35 patients with confirmed remission, 28 (80%) showed sustained remission (remission duration ≥ 1 year). In addition,
The trial also evaluated the impact of Koselugo on other clinical outcomes, including changes in PN-related defects, symptoms, and functional impairment. Despite the small sample size of patients assessing each PN-related morbidity (such as defects, pain, strength and mobility problems, airway compression, visual impairment, and bladder or bowel dysfunction), PN-related deficiencies, symptoms, and function during treatment The damage also showed improvement.
Specifically: After 1 year of treatment, the patient ’s reported tumor pain intensity score decreased by an average of 2 points, which is considered to have clinically significant improvement. In addition, the daily functions (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) and strength (56%) and range of motion (38%) in children ’s reports and parents ’reports In the outcome, an improvement in clinical significance was also observed.
At a 3-year follow-up, the progression-free survival rate of the disease in the Koselugo treatment group was 84%, compared with 15% in the natural history control group. During the trial, 5 patients discontinued treatment due to possible toxic effects related to Koselugo, and 6 patients deteriorated. The most common toxic reactions are nausea, vomiting, diarrhea, asymptomatic increase in creatine phosphokinase levels, acne-like rash, paronychia.
Koselugo's active pharmaceutical ingredient is selumetinib, which is an oral, potent and selective MEK1 / 2 kinase inhibitor. The NF1 gene encodes neurofibromin (neurofibromin), which negatively regulates the RAS / MAPK pathway and helps control cell growth, differentiation, and survival. Mutations in the NF1 gene may cause the RAS / RAF / MEK / ERK signaling pathway to become unregulated, which may cause cells to grow, divide, and replicate in an uncontrolled manner, and may cause tumor growth. Selumetinib potentially inhibits tumor growth by inhibiting the MEK enzyme in this pathway. Currently, selumetinib is being evaluated in clinical studies as a monotherapy and in combination with other therapies for the treatment of multiple tumor types.
selumetinib was discovered by Array BioPharma, and AstraZeneca was authorized in 2003 to obtain exclusive global rights to the compound. In July 2018, AstraZeneca and Merck reached a strategic cooperation in oncology to jointly develop and commercialize selumetinib and PARP inhibitor Lynparza globally. Currently, both parties are conducting a phase I / II clinical study, SPRINT, to explore the potential benefits of selumetinib in pediatric patients with inoperable NF1-related plexiform neurofibromas (PN).
Neurofibromatosis type 1 (NF1) is an incurable genetic disease with an incidence of about 3,000 to 4,000 in infants. The disease is caused by a spontaneous mutation or genetic mutation in the NF1 gene and is associated with many symptoms, including soft clumps (subcutaneous neurofibromas) on the skin surface and in the skin, skin pigmentation (coffee milk plaques), in Benign nerve sheath tumors (plexiform neurofibromas [PN]) can also be caused in 20% -50% of patients. These plexiform neurofibromas (PN) can cause pain, motor dysfunction, and disfigurement.
People with NF1 may experience many other complications, such as learning difficulties, twisting and bending of the spine, hypertension and epilepsy. NF1 also increases a person's risk of other cancers, including malignant brain and peripheral nerve sheath tumors and leukemia. Symptoms of the disease start early in childhood and vary greatly in severity, which can reduce life expectancy by as much as 15 years.