Selumetinib (Koselugo®; AstraZeneca and Merck & Co.), an inhibitor of mitogen-activated protein kinases 1 and 2 (MEK1/2), increases the potential for successful tumor reduction in patients and could benefit over 2.5 million pediatric patients, 2 years of age and older, living with Neurofibromatosis Type 1 (NF1) and Symptomatic, Inoperable Plexiform Neurofibromas (PN).
The FDA approved selumetinib for use in patients with inoperable plexiform neurofibromas, a common manifestation in the disease neurofibromatosis type one (NF1). The approval is, according to the Children’s Tumor Foundation, a major milestone for patients living with neurofibromatosis (NF), also known as Von Recklinghausen’s disease (VRD) a genetic disorder that causes tumors to grow on nerves throughout the body.
Incidence and manifestation
The disease, a debilitating autosomal dominant tumor predisposition, disorder, affects 1 in 3,000 to 4,000 people of all populations equally, is an . In approximately 50% of all cases, the disease is a familial (inherited) disease. The remainder of the disease is the result of de novo (sporadic) mutations 
De novo mutations in the NF1 gene, located at chromosome 17q11.2, leading to Neurofibromatosis Type 1 or NF1, occur primarily in paternally derived chromosomes and the likelihood of de novo disease has been known to increase with advanced paternal age.  One of the characteristics of the disease is its high mutation rate of 1 x 10(-4) per gamete per generation.
Neurofibromin, the protein product encoded by the NF1 gene, is produced by multiple cell types, including nerve cells and specialized cells called oligodendrocytes and Schwann cells that surround nerves and express by a variety of tissues including the kidney, spleen, and thymus. It belongs to a family of guanosine triphosphate hydrolase or GTPase-activating proteins (GAPs) that stimulate intrinsic GTPase activity and negatively regulates in the Ras pathway activity by accelerating hydrolysis of Ras-bound guanosine triphosphate (GTP) in the ras p21 family (also known as 21 kD rat sarcoma viral oncogene homologs).
Ras activates a number of signaling pathways that include the stem cell factor (SCF)/c-kit signaling, mechanistic target of rapamycin (mTOR), and the mitogen-activated protein kinase (MAPK) pathways.
Overall, mutations in the NF1 gene result in loss of production or reduced function of Neurofibromin, causing a variety of clinical findings, including NF1-associated tumors.
Manifestations of NF1 vary extremely within the same family and from one family to another. Even within the same family the expression of the disease (i.e., the severity of and specific manifestations of the disorder) varies among affected individuals.
The disease is often characterized by multiple cafe au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris Lisch nodules. Learning disabilities are also well-known and frequently observed characteristic. Less common, but potentially more serious, is the development of plexiform neurofibromas, optic and other central nervous system gliomas, malignant peripheral nerve sheath tumors, vasculopathy, and osseous lesions.
Patients with a germline inactivation of the NF1 gene have a higher change of developing both benign and malignant tumors through acquired inactivation of the functioning NF1 allele. While most incidences include benign neurofibroma, these patients have an 8% –13% lifetime risk of developing malignant peripheral nerve sheath tumor (MPNST) 
In addition, patients may also be diagnosed with gliomas, predominantly low-grade pilocytic astrocytomas (a slow-growing benign brain tumor that arises from astrocytes, the supportive cells in the nervous system) that occur mainly in the optic pathways and brainstem but may arise elsewhere in the brain and spinal cord.  Phaeochromocytoma (a rare tumor of adrenal gland tissue which results in the release of too much epinephrine and norepinephrine, hormones that control heart rate, metabolism, and blood pressure), gastrointestinal stromal tumors (GIST), myeloproliferative disease (i.e., juvenile myelomonocytic leukemia), myelodysplastic syndrome, osteosarcoma and rhabdomyosarcoma have also been diagnosed in patients with NF1
Overall, patients with NF1 have an increased relative risk for a variety of cancers outside the nervous system. For example, a study published in the British Journal of Cancer confirmed that these patients have a higher risk for gastrointestinal neoplasms, thyroid, bone, ovary and lung tumors, breast cancer in women under 50, melanoma and non-Hodgkin’s lymphoma. 
Based on the increased risk, patients diagnosed with NF1 have an 8- to 15-year shortened lifespan compared to the general population.
First-ever treatment for NF1
Selumetinib is the first-ever approved treatment for NF and represents the potential for the development of additional treatment options for all NF patients.
The approval of selumetinib follows comprehensive clinical testing in patients at the National Cancer Institute (NCI), a division of the National Institutes of Health (NIH). In those clinical trials, over 70% of NF patients with inoperable plexiform neurofibromas saw tumor size reduction anywhere from 20% – 60% in size. In addition to both visible and actual tumor reduction, patients reported higher-quality physical function, reduced pain, improved mobility, and enhanced emotional and psychological status.
The first use of MEK inhibitors as a potential treatment for NF tumors came from early-stage discoveries by Children’s Tumor Foundation (CTF)-funded researchers, who showed that MEK inhibitors could significantly affect NF tumor size. Positive early clinical results were first reported at CTF’s annual scientific NF Conference in 2015, as well as in subsequent publications in the New England Journal of Medicine in 2016 and 2020.
Collaborative efforts among the NCI, the NIH, the NFRP-CDMRP (Neurofibromatosis Research Program of the Congressionally Directed Medical Research Programs), NTAP (Neurofibromatosis Therapeutic Acceleration Program), and CTF ensured that this ‘MEK Story’ proceeded expeditiously through proactive and strategic coordination, guaranteeing efficient use of donor/investor funding, including from the federal government.
Inclusion of patients
One of the remarkable hallmarks of the drug’s path to approval has been the inclusion of patients throughout the process, including the first-ever ‘NF listening session’ held at the FDA in 2019.
The FDA approval of selumetinib is based on positive results from the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP)-sponsored Phase II SPRINT Stratum 1 trial coordinated by the NCI’s Center for Cancer Research, Pediatric Oncology Branch.
The SPRINT Phase I/II trial was designed to evaluate the objective response rate and impact on patient-reported and functional outcomes in paediatric patients with NF1-related inoperable PNs treated with selumetinib monotherapy. Results, published in The New England Journal of Medicine showed an overall response rate (ORR) of 66% [95% CI: 51, 79] in pediatric patients with NF1 and symptomatic, inoperable PN (n=33/50 patients) when treated with selumetinib as a twice-daily oral monotherapy. ORR is defined as the percentage of patients with confirmed complete or partial response of at least 20% tumor volume reduction. Of the 33 patients, all patients were confirmed partial response.
Serious adverse reactions can occur with selumetinib, including cardiomyopathy, ocular toxicity, gastrointestinal toxicity, skin toxicity, increased creatinine phosphokinase (CPK), increased vitamin E levels and risk of bleeding, and fetal harm. Based on the type and severity of the adverse reaction, treatment with selumetinib may need to be interrupted, reduced and/or discontinued.
The most common adverse reactions (ARs) (reported in ≥40% of patients) included: vomiting (82%), rash (80%), abdominal pain (76%), diarrhea (70%), nausea (66%), dry skin (60%), fatigue (56%), musculoskeletal pain (58%), pyrexia (56%), rash acneiform (50%), stomatitis (50%), headache (48%), paronychia (48%), and pruritus (46%). The most common grade ≥ 3 ARs were diarrhea (16%), pyrexia (8%), vomiting (6%), rash (6%), paronychia (6%), acneiform rash (4%), dermatitis (4%), nausea (2%), headache (2%), skin infection (2%), and hematuria (2%). Permanent discontinuation due to an adverse reaction occurred in 12% of patients who received selumetinib.
Dose interruptions and dose reductions due to an adverse reaction occurred in 80% and 24% of patients who received selumetinib, respectively.
“For the first time, patients and families impacted by this incurable genetic condition have an approved medicine to treat the resulting plexiform neurofibromas. I would like to thank our research partners, the NCI, the Neurofibromatosis Therapeutic Acceleration Program (NTAP), the Children’s Tumor Foundation (CTF), the NF1 patient community and, most importantly, the children, parents and doctors who participated in the SPRINT clinical trial program,” noted Dave Fredrickson, executive vice president, oncology business unit, AstraZeneca
“We are so excited for the entire NF community today! This announcement from the FDA about Koselugo (selumetinib) is a tremendous step towards our ultimate dream – approved treatments for all forms of neurofibromatosis,” said Annette Bakker, Ph.D., President of the Children’s Tumor Foundation.
“We believe that FDA approval of this treatment helps not only a subset of NF1 patients, it opens the door to increased interest in all forms of NF by pharmaceutical companies. We are already experiencing it – the number of companies interested in NF1, NF2, and schwannomatosis is growing rapidly,” she added.
“Previously, there were no medicines approved for this disease. This approval [of selumetinib] has the potential to change how symptomatic, inoperable NF1 plexiform neurofibromas are treated and provides new hope to these patients,” Roy Baynes, MD, Ph.D.,senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories,
Brigitte C. Widemann, M.D., principal investigator of the SPRINT clinical trial and chief, National Cancer Institute Pediatric Oncology Branch, said, “Selumetinib has made a difference for many children in this trial. This is an important treatment advance for patients and their families.”
Many other MEK inhibitors are also now in a clinical trial, including mirdametinib (formerly PD-0325901) from SpringWorks Therapeutics, a company which the Children’s Tumor Foundation helped spin-off from Pfizer.
MEK 1/2 Inhibitor Selumetinib (AZD6244 Hydrogen Sulfate) in Adults With Neurofibromatosis Type 1 (NF1) and Inoperable Plexiform Neurofibromas – NCT02407405
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