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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Selumetinib is being developed by AstraZeneca and MSD under a global license agreement, and was granted orphan drug designation by the FDA and EU in 2018, and breakthrough therapy designation by the FDA in early 2019. In late 2019 the FDA accepted a New Drug Application (NDA) and granted priority review for selumetinib for the treatment of pediatric patients aged three years and older with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PNs). Neurofibromatosis is a genetic disorder that typically causes non-malignant tumors to grow on nerve fibers throughout the body which can be painful, disabling, and disfiguring. Most tumors of this type are inoperable, although some patients do undergo surgical procedures which may have to be repeated. NF1 can also cause a number of other health-related issues including deafness, blindness, learning disabilities, bone abnormalities, and sometimes other types of cancers.
Malignant Melanoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Targeted therapies and immunotherapy have also been investigated in metastatic uveal melanoma. Responses are seen but have proven less durable than in cutaneous melanoma. Three MEK inhibitors have been evaluated either alone or in combination; selumetinib with or without dacarbazine,35,36 trametinib,37 and binimetinib with pan kinase C inhibitor sotrastaurin. Across these studies results were disappointing with response rates from 0 to 14% and progression-free survival 3.1 to 16 weeks. The most encouraging activity was seen with selumetinib which was compared to investigators choice of temozolomide or dacarbazine in a randomized phase II trial of 101 patients. Patients treated with selumetinib had significantly higher response rate (14% vs. 0%) and longer progression-free survival compared to temozolomide (15.9 weeks vs. 7 weeks). Overall survival was also longer with selumetinib (11.1 vs. 9.1 months) although this was not statistically significant.35 However the phase III randomized double-blind SUMIT trial of selumetinib or placebo in combination with dacarbazine failed to show any benefit for the addition of selumetinib.36 Other trials of MEK inhibitors are underway including in combination with paclitaxel and with AKT inhibitors.
Pediatric Spinal Tumors
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Rajiv R. Iyer, Nir Shimony, Mohammad Hassan A. Noureldine, Eric Bouffet, George I. Jallo
In recent years, there has been growing interest in the implementation of MEK inhibitors (MAPK kinase inhibitors) as a potential treatment for plexiform neurofibromas, with good response and tumor progression control.51 Recently, the use of selumetinib (investigational MEK 1/2 inhibitor licensed by AstraZeneca from Array BioPharma Inc. in 2003) for NF1-related plexiform neurofibromas was approved by the US Food and Drug Administration, since it has been shown to be effective in shrinking this subgroup of tumors.52 MEK inhibitors, and selumetinib in particular, has promising antitumor activity in children with low-grade gliomas, since it was shown to cause a response in 40% of low-grade glioma associated with NF1.52,53
Plexiform neurofibroma: shedding light on the investigational agents in clinical trials
Published in Expert Opinion on Investigational Drugs, 2022
Simge Acar, Amy E. Armstrong, Angela C. Hirbe
Within the class of MEKi, selumetinib is the only drug with FDA approval which is limited to the pediatric population to date. Current studies will need to be completed to determine the true benefit within the adult population. While there is excitement regarding positive clinical trial findings leading to the FDA approval of selumetinib, questions still remain in terms of understanding how to best use this drug or other MEKi and replication of study findings to the real-world setting. It is also undecided as to the best timing to start MEKi and duration of treatment. Intermittent dosing of selumetinib is additionally being explored in ongoing clinical trials. Another potential use of this drug class is in the neoadjuvant setting with the goal of making a resection less morbid or in adjuvant setting following surgical debulking to determine if MEKi could reduce the risk of recurrent tumor growth. Additionally, different MEKi have not been compared to one another, so it remains to be determined if one drug in this class is superior.
Characteristics, treatment patterns, healthcare resource use, and costs among pediatric patients diagnosed with neurofibromatosis type 1 and plexiform neurofibromas: a retrospective database analysis of a medicaid population
Published in Current Medical Research and Opinion, 2021
Xiaoqin Yang, Kaushal Desai, Neha Agrawal, Kirti Mirchandani, Sagnik Chatterjee, Eric Sarpong, Shuvayu Sen
Clinical management of patients with NF1-related PNs consists of surveillance of disease progression and palliative care for symptoms, including, when possible, surgical excision of tumors8. However, because of their invasive nature, complete removal of PNs is generally impossible1,16,17, and tumors tend to regrow18. Ongoing clinical trials are examining the efficacy of targeted therapies, that is, drugs targeted to the specific cellular signaling pathways that are disrupted by the NF1 mutation19,20, with the goal of slowing or stopping the growth of PNs. Only recently has one of these therapies, selumetinib, been approved for use in pediatric patients with symptomatic, inoperable PNs21.
An evaluation of selumetinib for the treatment of neurofibromatosis type 1-associated symptomatic, inoperable plexiform neurofibromas
Published in Expert Review of Precision Medicine and Drug Development, 2021
Laura K. Metrock, Mina Lobbous, Bruce Korf
Pharmacokinetic studies were completed in phase 1 and 2 trials of children and young adults with NF1-associated PNs. In the phase 1 study, selumetinib was administered twice daily in a continuous dosing cycle (28 day cycles) with the dose calculated based on body-surface area. The maximum tolerated dose was 25 mg/m2. The pharmacokinetics of selumetinib in the plasma were evaluated during cycle 1 with blood samples drawn on day 1 prior to the first dose of the drug, then at 0.5, 1, 2, 3, 5, 8, 10–12, 24 and 30–36 hours after administration of the first dose as well as on day 27 prior to the morning dose. Concentrations of selumetinib and N-desmethyl selumetinib, the active metabolite, were analyzed. In the trial, selumetinib was absorbed rapidly and selumetinib drug exposures increased with increasing dose but were less than dose-proportional. Selumetinib concentration exceeded those of N-desmethyl at all time points studied. These findings were similar to pharmacokinetic studies done in the DhhCre;Nfl/fl/fl genetically engineered mouse model of neurofibroma [14].