Nirogacestat and its potential impact on desmoid tumor.

IF 0.9 Q4 ONCOLOGY
Samia Rohail, Areeba Fareed, Muskaan Asim Taimuri, Alishba Adnan
{"title":"Nirogacestat and its potential impact on desmoid tumor.","authors":"Samia Rohail, Areeba Fareed, Muskaan Asim Taimuri, Alishba Adnan","doi":"10.1177/20363613231182485","DOIUrl":null,"url":null,"abstract":"Desmoid tumors (DT) are rare, benign, and invasive soft tissue tumors affecting 3–5 people in one million each year. Also known as desmoid fibromatosis, they present usually in the second and fourth decade of life, with an unpredictable prognosis and a risk of significant impairment in quality of life. According to estimates there are 1000 to 1650 new diagnoses in the United States each year. Habitually, these tumors are found in the abdomen, arms, and legs, however, they can affect vital organs as well. Desmoid tumors do not metastasize but painful disfigurement and problems in functioning due to local, aggressive growth can occur. Since desmoid tumors lack the ability to metastasize, local control using surgery and radiation has traditionally been the mainstay of therapy for these tumors. However, recurrence rate is very high, especially after surgery and in rare cases, it can be fatal. Therefore, the need for effective treatment is undeniable. The Food and Drug Administration (FDA) recently awarded Nirogacestat’s new drug application (NDA) for the treatment of adult patients with desmoid tumours a priority evaluation. The FDA has also given desmoid tumours in adult patients Fast Track and Breakthrough Therapy classifications. Nirogacestat is an oral, specific, small-molecule gamma secretase inhibitor that works by cleaving a variety of transmembrane protein complexes, including Notch, which may be involved in pathways that support the development of desmoid tumours. Inhibition of γ-secretase preserves membrane-bound B-cell maturation antigen (BCMA) and increases target density by reducing the levels of soluble BCMA, thus serving as a decoy receptor for BCMA-targeted therapy. The ability of Nirogacestat to potentiate the activity of BCMA-targeted therapy has been observed in preclinical models of multiple myeloma. A DeFi study, the largest and most rigorous randomized controlled trial was conducted in which 142 patients with advanced desmoid tumors were recruited. Patients were randomized to receive either Nirogacestat 150 mg or placebo twice daily in cycles of 28 days until they developed symptoms on radiologic imaging. The results showed a statistically significant improvement in progression of survival in patients randomized to Nirogacestat compared to placebo, with an average 71% reduction in risk of disease advancement. Participants taking Nirogacestat improved by 41% in their response within 5.6 months, compared to 8% in a longer period of 11.1 months by the placebo group. However, treatment was stopped due to ovarian dysfunction, which is defined by investigator-reported events of amenorrhea, premature menopause, menopause, and ovarian failure and was seen in 75% of women of childbearing potential receiving Nirogacestat. Nirogacestat demonstrated a manageable safety profile in DeFi studies, with 95% of all treatment-emergent adverse events. Therefore, treatment should be individualized for each patient to optimize tumor control and improve symptom burden, including impact on pain, physical function and overall quality of life. It may become the standard of care for patients with desmoid tumors who require systemic treatment despite the high rate of ovarian failure as it has a moderate safety profile. Nevertheless, the potential risks associated with the drug must be carefully monitored to ensure its safety for patients. Nirogacestat may enhance patients’ quality of life and offer hope to individuals who are suffering from the condition. The FDA’s approval of Nirogacestat represents an","PeriodicalId":46078,"journal":{"name":"Rare Tumors","volume":null,"pages":null},"PeriodicalIF":0.9000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f0/ed/10.1177_20363613231182485.PMC10265347.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Rare Tumors","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1177/20363613231182485","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Desmoid tumors (DT) are rare, benign, and invasive soft tissue tumors affecting 3–5 people in one million each year. Also known as desmoid fibromatosis, they present usually in the second and fourth decade of life, with an unpredictable prognosis and a risk of significant impairment in quality of life. According to estimates there are 1000 to 1650 new diagnoses in the United States each year. Habitually, these tumors are found in the abdomen, arms, and legs, however, they can affect vital organs as well. Desmoid tumors do not metastasize but painful disfigurement and problems in functioning due to local, aggressive growth can occur. Since desmoid tumors lack the ability to metastasize, local control using surgery and radiation has traditionally been the mainstay of therapy for these tumors. However, recurrence rate is very high, especially after surgery and in rare cases, it can be fatal. Therefore, the need for effective treatment is undeniable. The Food and Drug Administration (FDA) recently awarded Nirogacestat’s new drug application (NDA) for the treatment of adult patients with desmoid tumours a priority evaluation. The FDA has also given desmoid tumours in adult patients Fast Track and Breakthrough Therapy classifications. Nirogacestat is an oral, specific, small-molecule gamma secretase inhibitor that works by cleaving a variety of transmembrane protein complexes, including Notch, which may be involved in pathways that support the development of desmoid tumours. Inhibition of γ-secretase preserves membrane-bound B-cell maturation antigen (BCMA) and increases target density by reducing the levels of soluble BCMA, thus serving as a decoy receptor for BCMA-targeted therapy. The ability of Nirogacestat to potentiate the activity of BCMA-targeted therapy has been observed in preclinical models of multiple myeloma. A DeFi study, the largest and most rigorous randomized controlled trial was conducted in which 142 patients with advanced desmoid tumors were recruited. Patients were randomized to receive either Nirogacestat 150 mg or placebo twice daily in cycles of 28 days until they developed symptoms on radiologic imaging. The results showed a statistically significant improvement in progression of survival in patients randomized to Nirogacestat compared to placebo, with an average 71% reduction in risk of disease advancement. Participants taking Nirogacestat improved by 41% in their response within 5.6 months, compared to 8% in a longer period of 11.1 months by the placebo group. However, treatment was stopped due to ovarian dysfunction, which is defined by investigator-reported events of amenorrhea, premature menopause, menopause, and ovarian failure and was seen in 75% of women of childbearing potential receiving Nirogacestat. Nirogacestat demonstrated a manageable safety profile in DeFi studies, with 95% of all treatment-emergent adverse events. Therefore, treatment should be individualized for each patient to optimize tumor control and improve symptom burden, including impact on pain, physical function and overall quality of life. It may become the standard of care for patients with desmoid tumors who require systemic treatment despite the high rate of ovarian failure as it has a moderate safety profile. Nevertheless, the potential risks associated with the drug must be carefully monitored to ensure its safety for patients. Nirogacestat may enhance patients’ quality of life and offer hope to individuals who are suffering from the condition. The FDA’s approval of Nirogacestat represents an
硝加司他及其对硬纤维瘤的潜在影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Rare Tumors
Rare Tumors ONCOLOGY-
CiteScore
1.50
自引率
0.00%
发文量
15
审稿时长
15 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信