背景:纤维瘤很少见,当地的侵略性,高度复发的软组织肿瘤,没有批准的治疗。
方法:我们进行了第三阶段,国际,双盲,随机化,根据实体瘤的反应评估标准,在患有进行性硬纤维瘤的成人中进行尼罗加塞坦的安慰剂对照试验,1.1版。患者以1:1的比例分配,每天两次口服γ-分泌酶抑制剂nirogacestat(150mg)或安慰剂。主要终点是无进展生存期。
结果:从2019年5月到2020年8月,共有70名患者被分配接受nirogacestat,72名患者被分配接受安慰剂。与安慰剂相比,Nirogacestat具有显着的无进展生存获益(疾病进展或死亡的风险比,0.29;95%置信区间,0.15至0.55;P<0.001);nirogacestat在2年无事件发生的可能性为76%,安慰剂为44%。在预设的亚组中,无进展生存期的组间差异是一致的。有客观反应的患者百分比使用尼罗加塞坦明显高于安慰剂(41%vs.8%;P<0.001),中位反应时间为5.6个月和11.1个月,完全缓解的患者百分比分别为7%和0%,分别。次要患者报告结果的显著组间差异,包括疼痛,症状负担,身体或角色功能,和健康相关的生活质量,观察到(P≤0.01)。nirogacestat的常见不良事件包括腹泻(84%的患者),恶心(54%),疲劳(51%),低磷酸盐血症(42%),和斑丘疹(32%);95%的不良事件为1级或2级.在接受nirogacestat的育龄妇女中,36人中有27人(75%)出现与卵巢功能障碍一致的不良事件,20名女性(74%)。
结论:Nirogacestat与无进展生存期的显著获益相关,客观反应,疼痛,症状负担,身体机能,角色功能,和健康相关的生活质量与成人进行性硬纤维瘤。nirogacestat的不良事件频繁发生,但大多为低等级。(由SpringWorksTherapeutics资助;DeFiClinicalTrials.gov编号,NCT03785964。).
BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments.
METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival.
RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%).
CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).