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SpringWorks Therapeutics Announces Data to Be Presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting

SpringWorks Therapeutics Announces Data to Be Presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting

SpringWorks Therapeutics宣佈將在2024年美國臨床腫瘤學會(ASCO)年會上公佈數據
GlobeNewswire ·  05/24 05:13

– Results from pivotal Phase 2b ReNeu trial of mirdametinib in patients with NF1-PN to be presented in an oral presentation –

— 米達美替尼針對 NF1-PN 患者的關鍵 2b 期 ReneU 試驗的結果將以口頭陳述方式公佈 —

– Additional data and analyses from Phase 3 DeFi trial of OGSIVEO (nirogacestat) highlighting consistent safety and efficacy across subgroups of adults with desmoid tumors also being presented in oral and poster sessions –

— 來自OGSIVEO(nirogacestat)3期DeFi試驗的更多數據和分析,這些數據和分析突顯了硬結腫瘤亞組成年人群中始終如一的安全性和有效性,這些數據和分析也將在口頭和海報會議上公佈—

STAMFORD, Conn., May  23, 2024  (GLOBE NEWSWIRE) -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a commercial-stage biopharmaceutical company focused on severe rare diseases and cancer, today announced that four abstracts from the company's portfolio will be presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting being held May 31 to June 4, 2024.

康涅狄格州斯坦福,2024年5月23日(GLOBE NEWSWIRE)——專注於嚴重罕見疾病和癌症的商業階段生物製藥公司SpringWorks Therapeutics, Inc.(納斯達克股票代碼:SWTX)今天宣佈,將在2024年5月31日至6月4日舉行的2024年美國臨床腫瘤學會(ASCO)年會上公佈該公司投資組合的四份摘要。

Data from the pivotal Phase 2b ReNeu trial evaluating mirdametinib, an investigational MEK inhibitor, in adults and children with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) will be presented in an oral presentation. ReNeu is the largest multicenter trial conducted to date in patients with NF1-PN, a condition in which tumors can grow aggressively along peripheral nerves and lead to pain, disfigurement and other morbidities. In the ReNeu trial, mirdametinib treatment demonstrated deep and sustained tumor volume reductions, and improvement in pain and health-related quality of life across both the adult and pediatric cohorts.

評估在研MEK抑制劑mirdametinib的關鍵性2b期ReneU試驗的數據將以口頭形式呈報,該試驗評估了MEK抑制劑mirdametinib在成人和兒童中的1型神經纖維瘤病相關叢狀神經纖維瘤(NF1-PN)。ReneU 是迄今爲止針對 NF1-PN 患者進行的最大規模的多中心試驗,在這種疾病中,腫瘤會沿着周圍神經大量生長,並導致疼痛、毀容和其他發病率。在ReneU試驗中,米達美替尼的治療顯示,成人和兒童隊列的腫瘤體積可大幅持續減少,疼痛和與健康相關的生活質量得到改善。

In addition, three new data sets from the pivotal Phase 3 DeFi trial of nirogacestat in adults with desmoid tumors will be presented at ASCO. Monitoring ovarian function in oncology studies and the onset and resolution of ovarian toxicity for desmoid tumor patients treated with nirogacestat in the DeFi trial will be discussed in an oral presentation. Investigators will also present two posters that include post hoc analyses from the DeFi trial in high-risk patient populations, which reinforce the efficacy and safety of nirogacestat in adults with desmoid tumors across various clinical characteristics.

此外,將在ASCO上公佈針對成年硬纖維瘤的nirogacestat的關鍵性3期DeFi試驗的三個新數據集。將在口頭陳述中討論腫瘤學研究中的卵巢功能監測以及在DeFi試驗中使用nirogacestat治療的硬結腫瘤患者的卵巢毒性的發病和消退。研究人員還將展示兩張海報,其中包括針對高危患者群體的DeFi試驗的後期分析,這些分析加強了nirogacestat對成年硬纖維瘤患者的療效和安全性,涵蓋各種臨床特徵。

"We are very pleased to present important data at this year's ASCO annual meeting, including positive results from our pivotal Phase 2b ReNeu trial of mirdametinib in NF1-PN, which showed significant objective response rates confirmed by blinded independent central review, deep responses, as well as a manageable and tolerable safety profile in both adult and pediatric patients. These data are the foundation of our NDA, which we are on track to submit to the FDA by the end of the second quarter, and we believe provide compelling evidence of differentiation and potentially transformative benefit for patients with this devastating disease," said Jim Cassidy, M.D., Ph.D., Chief Medical Officer of SpringWorks. "In addition, new data and analyses from our Phase 3 DeFi trial further reinforce the robust efficacy and manageable safety profile of OGSIVEO across subgroups of adults with desmoid tumors who require systemic treatment."

“我們很高興在今年的ASCO年會上公佈重要數據,包括我們在NF1-PN 中對米達美替尼的關鍵性2b ReneU試驗的積極結果,該試驗顯示了顯著的客觀緩解率,得到了盲目獨立中心審查的證實,深度反應以及成人和兒童患者的可控和可耐受的安全性。SpringWorks首席醫學官吉姆·卡西迪醫學博士、博士吉姆·卡西迪說,這些數據是我們保密協議的基礎,我們有望在第二季度末之前將其提交給美國食品藥品管理局,我們相信這些數據爲這種毀滅性疾病的患者提供了差異化並可能帶來變革性益處的令人信服的證據。“此外,我們的3期DeFi試驗的新數據和分析進一步強化了OGSIVEO在需要全身治療的硬狀腫瘤成年亞組中的強大療效和可管理的安全性。”

Rapid Oral Presentations at the 2024 ASCO Annual Meeting

在 2024 年 ASCO 年會上進行快速口頭演講

ReNeu: A pivotal phase 2b trial of mirdametinib in children and adults with neurofibromatosis type 1 (NF1)-associated symptomatic inoperable plexiform neurofibroma (PN)
Abstract #: 3016
Date and Time: June 3, 8:00 - 9:30 a.m. CDT (9:00 – 10:30 a.m. EDT)

ReneU:一項米達美替尼的關鍵性2b期試驗,用於患有1型神經纖維瘤病(NF1)相關症狀性無法手術的叢狀神經纖維瘤(PN)的兒童和成人
摘要編號:3016
日期和時間:中部夏令時間 6 月 3 日上午 8:00-9:30(美國東部夏令時間上午 9:00 — 10:30)

As previously reported, results from the pivotal Phase 2b ReNeu trial (NCT03962543) demonstrated a statistically significant confirmed objective response rate (ORR), the primary endpoint of the study, as well as deep and sustained reduction in tumor volume and significant improvement in key secondary patient-reported outcome measures in both adults and children with NF1-PN. The data being presented at ASCO include:

正如先前報道的那樣,關鍵的2b期ReneU試驗(NCT03962543)的結果顯示,經證實的客觀緩解率(ORR)是該研究的主要終點,腫瘤體積持續大幅減少,患者報告的關鍵次要預後指標也得到顯著改善,NF1-PN 成人和兒童報告的關鍵次要結局指標均有顯著改善。在ASCO上提供的數據包括:

  • As of the data cutoff of September 20, 2023, mirdametinib treatment resulted in a confirmed ORR of 41% (24/58; P<0.001) in adults and 52% (29/56; P<0.001) in children, as assessed by blinded independent central review (BICR). Two additional adult patients and one additional pediatric patient had a confirmed partial response in the long-term follow-up phase.

  • Tumor volume reductions were deep and durable over the course of the study. Median (range) best change in tumor volume from baseline was -41% (-90% to 13%) in adults and -42% (-91% to 48%) in children. Among study participants with a confirmed objective response on mirdametinib, 62% of adults and 52% of children achieved a >50% reduction in tumor volume.

  • The median treatment duration for both adults and children was 22 months; the median (range) time to onset of response was 7.8 months (4 to 19 months) in adult patients and 7.9 months (4 to 19 months) in pediatric patients; the median duration of response was not reached in either group.

  • Both adult and pediatric patients experienced improvement in patient-reported pain and patient-reported (adult) or patient- or parent proxy-reported (children) health-related quality of life (HRQoL) at the pre-specified Cycle 13 assessment. Least square (LS) mean change from baseline at Cycle 13 in worst tumor pain (assessed by Numeric Rating Scale-11) was -1.3 (P<0.001) in adults and -0.8 (P=0.003) in children. LS mean change from baseline at Cycle 13 in HRQoL was 3.9 in adults (P=0.018) and 4.0 (P=0.096) as self-reported in children; parent-proxy reported LS mean change in HRQoL in children was 5.6 (P=0.005).

  • Mirdametinib was generally well tolerated in the ReNeu trial, with most adverse events (AEs) being Grade 1 or 2. Among all study participants, 21% of adults and 9% of children discontinued the study due to treatment-related adverse events (TRAEs), and dose reductions due to TRAEs were 17% in adults and 12% in children.

  • The most frequently reported TRAEs affecting >20% of adult participants were dermatitis acneiform, diarrhea, nausea, vomiting, and fatigue. The most frequently reported TRAEs affecting ≥20% of pediatric participants were dermatitis acneiform, diarrhea, paronychia (infection of the tissue adjacent to a fingernail or toenail), nausea, decrease in ejection fraction (asymptomatic), and increase in blood creatinine phosphokinase (asymptomatic).

  • 根據盲人獨立中心審查(BICR)的評估,截至2023年9月20日的數據截止日期,米達美替尼治療證實的成人ORR爲41%(24/58;P

  • 在研究過程中,腫瘤體積的減少是深刻而持久的。成人腫瘤體積與基線相比的最佳變化中位數(範圍)爲-41%(-90%至13%),兒童爲-42%(-91%至48%)。在經證實對米達美替尼有客觀反應的研究參與者中,62%的成人和52%的兒童腫瘤體積減少了超過50%。

  • 成人和兒童的中位治療持續時間均爲22個月;成人患者出現反應的中位時間(範圍)爲7.8個月(4至19個月),兒科患者爲7.9個月(4至19個月);兩組均未達到中位緩解持續時間。

  • 在預先指定的第13週期評估中,成人和兒童患者報告的疼痛和患者報告(成人)或患者或父母代理報告的健康相關生活質量(HRQoL)均有所改善。成人最嚴重腫瘤疼痛(按數字評級量表11評估)與基線相比的最小平方(LS)平均變化爲-1.3(P

  • 在ReneU試驗中,米達美替尼的耐受性總體良好,大多數不良事件(AE)爲1級或2級。在所有研究參與者中,有21%的成人和9%的兒童因治療相關不良事件(TRAE)停止了研究,成人因traEs而減少的劑量爲17%,兒童爲12%。

  • 最常報告的影響超過 20% 的成年參與者的TRAE是痤瘡樣皮炎、腹瀉、噁心、嘔吐和疲勞。最常報告的影響≥20%的兒科參與者的TRAE是痤瘡樣皮炎、腹瀉、甲溝炎(指甲或腳趾甲附近組織感染)、噁心、射血分數降低(無症狀)和血肌酐磷酸激酶升高(無症狀)。

"ReNeu is the largest multicenter NF1-PN trial conducted to date and prospectively used blinded independent central review to confirm target tumor response in NF1-PN patients," said Christopher L. Moertel, M.D., Medical Director of the Pediatric Neuro-Oncology and Neurofibromatosis Program and Kenneth and Betty Jayne Dahlberg Professor of Pediatrics at the University of Minnesota School of Medicine and lead investigator of the ReNeu trial. "The potentially unprecedented depth of response and significant reduction in pain and other quality of life measures across the pediatric and adult cohorts in the ReNeu study, coupled with the manageable safety profile, support the potential for mirdametinib to become an important and much needed treatment for patients with NF1-PN, particularly adults who currently do not have an approved treatment option."

兒科神經腫瘤學和神經纖維瘤病項目醫學主任、明尼蘇達大學醫學院肯尼思和貝蒂·傑恩·達爾伯格兒科教授、ReneU試驗首席研究員克里斯托弗·莫爾特爾醫學博士說:“ReneU是迄今爲止規模最大的多中心 NF1-PN 試驗,預計將使用盲獨立中心審查來確認 NF1-PN 患者的靶腫瘤反應。”“在ReneU研究中,針對兒童和成人群體的反應深度可能前所未有,疼痛和其他生活質量的顯著減輕,再加上可控的安全性,支持了米達美替尼有可能成爲 NF1-PN 患者,尤其是目前尚無批准治療選擇的成年人的重要且急需的治療方法。”

Monitoring ovarian function in oncology trials: Results and insights from the DeFi phase 3 trial of nirogacestat in desmoid tumor
Abstract #: 11520
Date and Time: May 31, 2:45 - 4:15 p.m. CDT (3:45 – 5:15 p.m. EDT)

腫瘤學試驗中的卵巢功能監測:DeFi nirogacestat 3期硬纖維瘤試驗的結果和見解
摘要編號:11520
日期和時間:中部夏令時間 5 月 31 日下午 2:45-4:15(美國東部時間下午 3:45 — 5:15)

Results and insights from the DeFi trial (NCT03785964) on monitoring ovarian function in oncology studies will be presented at ASCO. In the DeFi trial, ovarian toxicity (OT) was reported in 75% (27 of 36) of females of reproductive potential (FORP) receiving nirogacestat and 0% (0 of 37) of FORP patients receiving placebo. In a post hoc analysis, resolution of OT was reported by investigators in 78% (21 of 27) of FORP patients, assessed by reproductive hormone values (FSH, LH, AMH, progesterone and estradiol) or perimenopausal symptoms (e.g., menstrual irregularity) or both. Investigators reported OT resolution among all patients (11/11) who were off treatment for any reason, with a median time to resolution of 76 days. Among patients who remained on nirogacestat, 71% (10/14) of patients experienced resolution of OT according to investigators, with a median time to resolution of 171 days.

在腫瘤學研究中監測卵巢功能的DeFi試驗(NCT03785964)的結果和見解將在ASCO上公佈。在DeFi試驗中,75%(36人中有27人)接受尼羅加司他治療的具有生殖潛能的女性(FORP)和接受安慰劑的FORP患者中有0%(37例中有0例)報告了卵巢毒性(OT)。在一項事後分析中,根據生殖激素值(促卵泡激素、LH、AMH、孕酮和雌二醇)或圍絕經期症狀(例如月經不調)或兩者兼而有之的評估,研究人員報告了78%(27例中的21例)的FORP患者OT的消退。研究人員報告了所有因任何原因停止治療的患者(11/11)的OT消退,平均緩解時間爲76天。研究人員稱,在繼續服用尼羅加司他的患者中,有71%(10/14)的患者經歷了OT的消退,中位緩解時間爲171天。

"Historically, ovarian toxicity has rarely been systematically assessed in cancer clinical trials. And when collected, data have not always been gathered with the goal of counseling future patients clearly in mind. The DeFi trial developed one of the most comprehensive assessments of ovarian function in an oncology clinical trial to date. This timely and important ASCO presentation will review best practices for evaluating a drug's effect on ovarian function for future cancer trials, using the DeFi trial as an example," said Elizabeth Loggers, M.D., Ph.D., Associate Professor, Clinical Research Division, sarcoma expert and Medical Director, Supportive and Palliative Care, Fred Hutchinson Cancer Center, and Associate Clinical Professor of Medicine, University of Washington. "In this case, our ability to confirm resolution of ovarian toxicity in most DeFi participants, including all who discontinued nirogacestat for any reason, is possible because DeFi observed ASCO's recommendations to assess ovarian function through both clinical measures and biomarkers, even beyond the end of a trial, if necessary, to better characterize the temporality and nature of resolution."

“從歷史上看,癌症臨床試驗中很少系統地評估卵巢毒性。而且,在收集數據時,並不總是爲了明確爲未來的患者提供諮詢而收集的。DeFi試驗開發了迄今爲止腫瘤學臨床試驗中最全面的卵巢功能評估之一。這份及時而重要的ASCO演講將以DeFi試驗爲例,回顧評估藥物對卵巢功能影響的最佳實踐,以未來癌症試驗爲例。” 華盛頓大學臨床研究部副教授、肉瘤專家兼Fred Hutchinson癌症中心支持和姑息治療醫學主任、臨床醫學副教授Elizabeth Loggers說。“在這種情況下,我們能夠確認大多數DeFi參與者的卵巢毒性消失,包括所有出於任何原因停用nirogacestat的人,是可能的,因爲DeFi觀察了ASCO的建議,即通過臨床措施和生物標誌物評估卵巢功能,必要時甚至在試驗結束之後,也可以更好地描述解除的時間和性質。”

Poster Presentations at the 2024 ASCO Annual Meeting

2024 年 ASCO 年會上的海報演講

Efficacy of nirogacestat in patients with poor prognostic factors for desmoid tumors: Analyses from the randomized phase 3 DeFi trial
Abstract #: 11556
Date and Time: June 1, 1:30 - 4:30 p.m. CDT (2:30 – 5:30 p.m. EDT)

nirogacestat對預後不良的硬纖維瘤患者的療效:來自隨機3期DeFi試驗的分析
摘要編號:11556
日期和時間:中部夏令時間 6 月 1 日下午 1:30-4:30(美國東部時間下午 2:30 — 5:30)

A post hoc analysis of the DeFi trial was conducted to assess the effect of nirogacestat in subgroups of patients with desmoid tumors who have risk factors associated with poor prognosis (i.e., larger tumor size, younger age, CTNNB1 gene mutation, and presence of pain at baseline). Nirogacestat demonstrated consistent improvements in progression-free survival (PFS) and ORR versus placebo in patients with these poor prognostic factors. These results were consistent with the overall DeFi patient population and suggest that nirogacestat can provide clinically meaningful benefit in patients with characteristics that have been historically associated with poor prognosis.

對DeFi試驗進行了事後分析,以評估nirogacestat對具有與預後不佳(即腫瘤體積較大、年齡較小、CTNNB1 基因突變以及基線時存在疼痛)相關的危險因素的硬結腫瘤患者亞組的影響。對於預後不佳的患者,Nirogacestat顯示無進展存活率(PFS)和ORR與安慰劑相比持續改善。這些結果與整個DeFi患者群體一致,表明nirogacestat可以爲具有歷史上與預後不佳相關的特徵的患者提供具有臨床意義的益處。

Efficacy and safety of nirogacestat in patients with desmoid tumor and adenomatous polyposis coli (APC) mutation: phase 3 DeFi analyses
Abstract #: 11558
Date and Time: June 1, 1:30 - 4:30 p.m. CDT (2:30 – 5:30 p.m. EDT)

nirogacestat對硬結瘤和腺瘤性息肉病(APC)突變患者的療效和安全性:3期DeFi分析
摘要編號:11558
日期和時間:中部夏令時間 6 月 1 日下午 1:30-4:30(美國東部時間下午 2:30 — 5:30)

A post hoc analysis of the DeFi trial was conducted to assess the effects of nirogacestat in desmoid tumor patients with APC mutations, which are associated with more aggressive desmoid tumor behavior and poor prognosis. Of the 142 patients in the DeFi trial intent-to-treat population, 29 had identified APC mutations (nirogacestat, N=13; placebo, N=16). Results of the analysis demonstrated improvements in PFS, ORR and patient-reported outcomes, including pain, desmoid tumor-specific symptom burden, role and physical functioning, and overall quality of life in this subgroup of patients. Reductions in tumor size, volume, and T2 hyperintensity were also observed with nirogacestat compared with placebo in desmoid tumor patients with identified APC mutations. These efficacy results, as well as the safety results in this subgroup, were consistent with the overall DeFi trial population, and suggest that nirogacestat can provide clinically meaningful benefits in the challenging population of patients with progressing desmoid tumors and APC mutations.

對DeFi試驗進行了事後分析,以評估nirogacestat對APC突變的硬結腫瘤患者的影響,APC突變與更具侵略性的硬結腫瘤行爲和預後不佳有關。在DeFi試驗意向治療人群中的142名患者中,有29人發現了APC突變(nirogacestat,N=13;安慰劑,N=16)。分析結果顯示,該亞組患者的PFS、ORR和患者報告的預後都有所改善,包括疼痛、硬狀腫瘤特異性症狀負擔、角色和身體機能以及整體生活質量。與安慰劑相比,在已確定APC突變的硬狀腫瘤患者中,使用nirogacestat還觀察到腫瘤大小、體積和T2超強度減小。這些療效結果以及該子組中的安全性結果與整個DeFi試驗人群一致,並表明nirogacestat可以爲具有挑戰性的硬質腫瘤進展和APC突變患者群體提供具有臨床意義的益處。

About the ReNeu Trial

關於 ReneU 試用版

ReNeu (NCT03962543) is an ongoing, multi-center, open-label Phase 2b trial evaluating the efficacy, safety, and tolerability of mirdametinib in patients two years of age and older with an inoperable NF1-associated PN causing significant morbidity. The study enrolled 114 patients to receive mirdametinib at a dose of 2 mg/m2 twice daily (maximum dose of 4 mg twice daily) without regard to food. Mirdametinib was administered orally in a 3-week on, 1-week off dosing schedule as either a capsule or dispersible tablet. The primary endpoint is confirmed objective response rate defined as ≥ 20% reduction in target tumor volume as measured by MRI and assessed by blinded independent central review. Secondary endpoints include safety and tolerability, duration of response, and changes from baseline in patient reported outcomes to Cycle 13.

ReneU(NCT03962543)是一項正在進行的多中心、開放標籤的2b期試驗,評估了米達替尼對兩歲及以上患有NF1相關PN無法手術導致嚴重發病率的患者的療效、安全性和耐受性。該研究招收了114名患者接受米達美替尼,劑量爲2 mg/m2,每日兩次(最大劑量爲4 mg,每日兩次),不考慮食物。米達美替尼以膠囊或分散片劑的形式口服給藥,開服期爲3周,休息1周。主要終點是經證實的客觀緩解率,定義爲通過磁共振成像測量和盲目獨立中心審查評估的靶腫瘤體積減少≥20%。次要終點包括安全性和耐受性、反應持續時間以及從基線患者報告結果到第 13 週期的變化。

About NF1-PN

關於 NF1-PN

Neurofibromatosis type 1 (NF1) is a rare genetic disorder that arises from mutations in the NF1 gene, which encodes for neurofibromin, a key suppressor of the MAPK pathway.1,2 NF1 is the most common form of neurofibromatosis, with an estimated global birth incidence of approximately 1 in 2,500 individuals, and approximately 100,000 patients living with NF1 in the United States.3,4 The clinical course of NF1 is heterogeneous and manifests in a variety of symptoms across numerous organ systems, including abnormal pigmentation, skeletal deformities, tumor growth and neurological complications, such as cognitive impairment.5 Patients with NF1 have an eight to 15-year mean reduction in their life expectancy compared to the general population.2

1 型神經纖維瘤病 (NF1) 是一種罕見的遺傳性疾病,源於 NF1 基因的突變,該基因編碼神經纖維蛋白,這是 MAPK 通路的關鍵抑制劑。1,2 NF1 是最常見的神經纖維瘤病形式,估計全球出生發病率約爲 2,500 人中就有 1 例,美國約有 100,000 名神經纖維瘤病患者。3,4 臨床病程 1型神經纖維瘤病是異質性的,表現爲多個器官系統的各種症狀,包括異常色素沉着、骨骼畸形、腫瘤生長和神經系統併發症,例如認知障礙。5 與普通人群相比,1型神經纖維瘤病患者的預期壽命平均縮短了八到十五年。2

NF1 patients have approximately a 30-50% lifetime risk of developing plexiform neurofibromas, or PN, which are tumors that grow in an infiltrative pattern along the peripheral nerve sheath and that can cause severe disfigurement, pain and functional impairment; in rare cases, NF1-PN may be fatal.6,7 Patients with NF1-PN can also experience additional manifestations, including neurocognitive deficits and developmental delays. NF1-PNs are most often diagnosed in the first two decades of life.6 These tumors can be aggressive and are associated with clinically significant morbidities; typically, they grow more rapidly during childhood.8,9

NF1 患者終身患叢狀神經纖維瘤或 PN 的風險約爲 30-50%,叢狀神經纖維瘤是沿着周圍神經鞘浸潤生長的腫瘤,可導致嚴重的毀容、疼痛和功能障礙;在極少數情況下,NF1-PN 可能致命。6,7 NF1-PN 患者還可能出現其他表現,包括神經認知缺陷和發育遲緩。NF1-PNS 最常在生命的頭二十年被診斷出來。6 這些腫瘤可能具有侵襲性,並與臨床上顯著的發病率有關;通常,它們在童年時期的生長速度更快。8,9

Surgical removal of these tumors is challenging due to the infiltrative tumor growth pattern along nerves and can lead to permanent nerve damage and disfigurement.10 MEK inhibitors have emerged as a validated class of treatment for NF1-PN.11

由於腫瘤沿神經的浸潤性生長模式,手術切除這些腫瘤具有挑戰性,並可能導致永久性神經損傷和毀容。10 MEK抑制劑已成爲NF1-PN.11的有效治療類別

About Mirdametinib

關於米達美替尼

Mirdametinib is a potent, oral, allosteric small molecule MEK inhibitor in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. Mirdametinib is an investigational drug for which safety and efficacy have not been established.

Mirdametinib 是一種有效的口服變構小分子 MEK 抑制劑,正在開發中,可用作 1 型神經纖維瘤病相關叢狀神經纖維瘤(NF1-PN)和低度神經膠質瘤(LGG)的單一療法,以及用於治療生物標誌物定義的幾種轉移性實體瘤的聯合療法。米達美替尼是一種研究藥物,其安全性和有效性尚未確定。

Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and that plays a central role in multiple oncology and rare disease indications when genetically altered.

米達美替尼旨在抑制在MAPK途徑中佔據關鍵位置的MEK1和MEK2。MAPK通路是調節細胞生長和存活的關鍵信號網絡,在基因改變後,它在多種腫瘤學和罕見疾病適應症中起着核心作用。

The FDA and the European Commission have granted Orphan Drug designation for mirdametinib for the treatment of NF1. The FDA has also granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity and Rare Pediatric Disease designation for the treatment of NF1.

美國食品藥品管理局和歐盟委員會已授予用於治療1型神經纖維瘤病的米達美替尼的孤兒藥資格。美國食品和藥物管理局還授予快速通道稱號,用於治療 2 歲以上、正在進展或導致嚴重發病的 NF1-PN 患者,並授予罕見兒科疾病認證,用於治療 NF1。

SpringWorks expects to complete the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for mirdametinib in children and adults with NF1-PN in the second quarter of 2024. The Company also plans to file a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for mirdametinib for the treatment of children and adults with NF1-PN in the second half of 2024.

SpringWorks預計將在2024年第二季度完成向美國食品藥品監督管理局(FDA)滾動提交米達替尼用於患有 NF1-PN 的兒童和成人的新藥申請(NDA)。該公司還計劃在2024年下半年向歐洲藥品管理局(EMA)提交用於治療 NF1-PN 兒童和成人的米達美替尼的上市許可申請(MAA)。

About the DeFi Trial

關於 DeFi 試用

DeFi (NCT03785964) is a global, randomized (1:1), double-blind, placebo-controlled Phase 3 trial evaluating the efficacy, safety and tolerability of nirogacestat in adult patients with progressing desmoid tumors. The double-blind phase of the study randomized 142 patients (nirogacestat, n=70; placebo n=72) to receive 150 mg of nirogacestat or placebo twice daily. Key eligibility criteria included tumor progression by ≥20% as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) within 12 months prior to screening. The primary endpoint was progression-free survival, as assessed by blinded independent central review, or death by any cause. Secondary and exploratory endpoints include safety and tolerability measures, objective response rate (ORR), duration of response, changes in tumor volume assessed by magnetic resonance imaging (MRI), and changes in patient-reported outcomes (PROs). DeFi includes an open-label extension phase, which is ongoing.

DeFi(NCT03785964)是一項全球性、隨機(1:1)、雙盲、安慰劑對照的3期試驗,評估了nirogacestat對進展性硬纖維瘤的成年患者的療效、安全性和耐受性。該研究的雙盲階段隨機抽取了142名患者(nirogacestat,n = 70;安慰劑n = 72),每天兩次接受150毫克的尼羅加司他或安慰劑。關鍵資格標準包括篩查前12個月內,根據實體瘤反應評估標準(RECIST 1.1)測量,腫瘤進展≥20%。根據盲人獨立中心審查的評估,主要終點是無進展存活率或任何原因導致的死亡。次要和探索性終點包括安全性和耐受性測量、客觀反應率 (ORR)、反應持續時間、磁共振成像 (MRI) 評估的腫瘤體積變化以及患者報告結果 (PROs) 的變化。DeFi 包括開放標籤擴展階段,該階段正在進行中。

About Desmoid Tumors

關於 Desmoid 腫瘤

Desmoid tumors (sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis) are rare, aggressive, locally invasive tumors of the soft tissues that can be serious, debilitating, and, in rare cases when vital structures are impacted, life-threatening.12,13

硬質腫瘤(有時稱爲侵襲性纖維瘤病或硬狀纖維瘤病)是罕見的、侵襲性的局部侵襲性軟組織腫瘤,可能嚴重、使人衰弱,在極少數情況下,當重要結構受到影響時,還會危及生命。12,13

Desmoid tumors are most commonly diagnosed in patients between the ages of 20 and 44 years, with a two-to-three times higher prevalence in females.14,15 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.15,18,19

Desmoid 腫瘤最常見於 20 至 44 歲的患者,女性的患病率要高出兩到三倍。14,15 據估計,美國每年診斷出1,000-1,650例新發病例。15,18,19

Although they do not metastasize, desmoid tumors are associated with recurrence rates of up to 77% after surgical resection.14,16,17 Desmoid tumor experts and treatment guidelines now recommend systemic therapies as first-line intervention instead of surgery for most tumor locations requiring treatment.17

儘管硬質腫瘤沒有轉移,但手術切除後的複發率高達77%。14,16,17 Desmoid腫瘤專家和治療指南現在建議將全身療法作爲一線干預措施而不是手術,用於大多數需要治療的腫瘤部位。17

About OGSIVEO (nirogacestat)

關於 OGSIVEO(nirogacestat)

OGSIVEO (nirogacestat) is an oral, selective, small molecule gamma secretase inhibitor approved in the United States for the treatment of adult patients with progressing desmoid tumors who require systemic treatment.

OGSIVEO(nirogacestat)是一種口服、選擇性、小分子 gamma 分泌酶抑制劑,在美國獲批,用於治療需要全身治療的進展性硬狀腫瘤的成年患者。

OGSIVEO is not approved for the treatment of any other indication in the United States, or for any indication in any other jurisdiction by any other health authority.

OGSIVEO 在美國未獲批准用於任何其他適應症的治療,也未獲任何其他衛生機構批准用於任何其他司法管轄區的任何適應症。

SpringWorks is also evaluating nirogacestat as a potential treatment for patients with ovarian granulosa cell tumors and for patients with multiple myeloma as part of several B-cell maturation agent (BCMA) combination therapy regimens in collaboration with leaders in industry and academia.

SpringWorks還評估了nirogacestat作爲卵巢顆粒細胞腫瘤患者和多發性骨髓瘤患者的潛在治療方法,這是與業界和學術界領導者合作的幾種B細胞成熟劑(BCMA)聯合治療方案的一部分。

IMPORTANT SAFETY INFORMATION

重要的安全信息

WARNINGS AND PRECAUTIONS

警告和注意事項

  • Diarrhea: Diarrhea, sometimes severe, can occur in patients treated with OGSIVEO. Diarrhea occurred in 84% of patients treated with OGSIVEO, and included Grade 3 events in 16% of patients. Median time to first diarrhea event was 9 days (range: 2 to 434 days). Monitor patients and manage using antidiarrheal medications. Modify dose as recommended.

  • Ovarian Toxicity: Female reproductive function and fertility may be impaired in patients treated with OGSIVEO. Impact on fertility may depend on factors like duration of therapy and state of gonadal function at time of treatment. Long-term effects of OGSIVEO on fertility have not been established. Advise patients on the potential risks for ovarian toxicity before initiating treatment. Monitor patients for changes in menstrual cycle regularity or the development of symptoms of estrogen deficiency, including hot flashes, night sweats, and vaginal dryness.

  • Hepatotoxicity: ALT or AST elevations occurred in 30% and 33% of patients, respectively. Grade 3 ALT or AST elevations (>5 × ULN) occurred in 6% and 2.9% of patients. Monitor liver function tests regularly and modify dose as recommended.

  • Non-Melanoma Skin Cancers: New cutaneous squamous cell carcinoma and basal cell carcinoma occurred in 2.9% and 1.4% of patients, respectively. Perform dermatologic evaluations prior to initiation of OGSIVEO and routinely during treatment.

  • Electrolyte Abnormalities: Decreased phosphate (65%) and potassium (22%) occurred in OGSIVEO-treated patients. Phosphate <2 mg/dL occurred in 20% of patients. Grade 3 decreased potassium occurred in 1.4% of patients. Monitor phosphate and potassium levels regularly and supplement as necessary. Modify dose as recommended.

  • Embryo-Fetal Toxicity: OGSIVEO can cause fetal harm when administered to pregnant women. Oral administration of nirogacestat to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity and death at maternal exposures below human exposure at the recommended dose of 150 mg twice daily. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during treatment with OGSIVEO and for 1 week after the last dose.

  • 腹瀉:接受OGSIVEO治療的患者可能會出現腹瀉,有時很嚴重。在接受OGSIVEO治療的患者中,有84%出現腹瀉,16%的患者出現了3級腹瀉。首次腹瀉事件的中位時間爲 9 天(範圍:2 至 434 天)。監測患者並管理止瀉藥物的使用。根據建議修改劑量。

  • 卵巢毒性:在接受OGSIVEO治療的患者中,女性生殖功能和生育能力可能會受到損害。對生育能力的影響可能取決於治療時間和治療時性腺功能狀態等因素。OGSIVEO對生育率的長期影響尚未確定。在開始治療之前,建議患者有關卵巢毒性的潛在風險。監測患者月經週期規律的變化或雌激素缺乏症狀的發展,包括潮熱、盜汗和****乾燥。

  • 肝毒性:分別有30%和33%的患者出現ALT或AST升高。6% 和 2.9% 的患者出現了 3 級 ALT 或 AST 升高(>5 × ULN)。定期監測肝功能檢查並根據建議修改劑量。

  • 非黑色素瘤皮膚癌:2.9%和1.4%的患者分別出現新的皮膚鱗狀細胞癌和基底細胞癌。在開始使用OGSIVEO之前進行皮膚病學評估,並在治療期間定期進行皮膚病學評估。

  • 電解質異常:接受Ogsiveo治療的患者出現磷酸鹽(65%)和鉀(22%)的減少。20% 的患者出現磷酸鹽

  • 胚胎-胎兒毒性:OGSIVEO 在給孕婦服用時會對胎兒造成傷害。在器官發生期間向懷孕的大鼠口服尼羅加司他會導致胚胎-胎兒毒性,如果母體暴露量低於人體暴露量,建議劑量爲150 mg,每天兩次,則會導致胚胎-胎兒毒性並死亡。告知孕婦對胎兒的潛在風險。建議具有生殖潛力的女性和男性在OGSIVEO治療期間以及最後一次服藥後的1周內使用有效的避孕措施。

ADVERSE REACTIONS

不良反應

  • The most common (≥15%) adverse reactions were diarrhea (84%), ovarian toxicity (75% in the 36 females of reproductive potential), rash (68%), nausea (54%), fatigue (54%), stomatitis (39%), headache (30%), abdominal pain (22%), cough (20%), alopecia (19%), upper respiratory tract infection (17%), and dyspnea (16%).

  • Serious adverse reactions occurred in 20% of patients who received OGSIVEO. Serious adverse reactions occurring in ≥2% of patients were ovarian toxicity (4%).

  • The most common laboratory abnormalities (≥15%) were decreased phosphate, increased urine glucose, increased urine protein, increased AST, increased ALT, and decreased potassium.

  • 最常見(≥ 15%)的不良反應是腹瀉(84%)、卵巢毒性(36名具有生殖潛力的女性中有75%)、皮疹(68%)、噁心(54%)、疲勞(54%)、口炎(39%)、頭痛(30%)、腹痛(22%)、咳嗽(20%)、脫髮(19%)、上呼吸道感染(17%)和呼吸困難 (16%)。

  • 在接受OGSIVEO治療的患者中,有20%出現嚴重的不良反應。≥ 2% 的患者發生的嚴重不良反應爲卵巢毒性(4%)。

  • 最常見的實驗室異常(≥ 15%)是磷酸鹽降低、尿糖升高、尿蛋白升高、AST 升高、ALT 升高和鉀降低。

DRUG INTERACTIONS

藥物相互作用

  • CYP3A Inhibitors and Inducers: Avoid concomitant use with strong or moderate CYP3A inhibitors (including grapefruit products, Seville oranges, and starfruit) and strong or moderate CYP3A inducers.

  • Gastric Acid Reducing Agents: Avoid concomitant use with proton pump inhibitors and H2 blockers. If concomitant use cannot be avoided, OGSIVEO can be staggered with antacids (e.g., administer OGSIVEO 2 hours before or 2 hours after antacid use).

  • Consult the full Prescribing Information prior to and during treatment for important drug interactions.

  • CYP3A 抑制劑和誘導劑:避免與強度或中度 CYP3A 抑制劑(包括葡萄柚產品、塞維利亞橙子和楊桃)以及強度或中度 CYP3A 誘導劑同時使用。

  • 胃酸還原劑:避免與質子泵抑制劑和 H2 阻滯劑同時使用。如果無法避免同時使用,OGSIVEO 可以錯開使用抗酸劑(例如,在抗酸劑使用前 2 小時或抗酸劑使用後 2 小時給藥 OGSIVEO)。

  • 在治療之前和治療期間,請查閱完整的處方信息,了解重要的藥物相互作用。

USE IN SPECIFIC POPULATIONS

在特定人群中使用

  • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with OGSIVEO and for 1 week after the last dose.

  • 由於母乳餵養的兒童可能會出現嚴重的不良反應,建議女性在使用OGSIVEO治療期間和最後一次給藥後的1周內不要進行母乳餵養。

To report suspected adverse reactions, contact SpringWorks Therapeutics at 1-888-400-SWTX (1-888-400-7989) or FDA at 1-800-FDA-1088 or .

要報告疑似不良反應,請致電 1-888-400-SWTX(1-888-400-7989)與 SpringWorks Therapeutics 聯繫,或致電 1-800-FDA-1088 或。

Please see full U.S. Prescribing Information for OGSIVEO for more information.

有關更多信息,請參閱OGSIVEO的完整美國處方信息。

References

參考文獻

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  9. Nguyen R, Dombi E, Widemann B, et al. Growth dynamics of plexiform neurofibromas: a retrospective cohort study of 201 patients with neurofibromatosis 1. Orphanet J Rare Dis. 2012;7(1):75. doi:10.1186/1750-1172-7-75.

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  19. 美國商務部。新聞博客。2022年1月1日,美國人口估計爲332,403,650人。已於 2023 年 11 月 24 日訪問。

譯文內容由第三人軟體翻譯。


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