Harari Sergio, Elia Davide, Caminati Antonella, Geginat Jens, Luisi Francesca, Pelosi Giuseppe, Specchia Claudia, Torre Olga, Trevisan Roberta, Vasco Chiara, Zompatori Maurizio, Cassandro Roberto
Division of Pulmonary and Respiratory Intermediate Care Unit, MultiMedica IRCCS, Milan, Italy; Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
Division of Pulmonary and Respiratory Intermediate Care Unit, MultiMedica IRCCS, Milan, Italy.
Lancet Respir Med. 2024 Dec;12(12):967-974. doi: 10.1016/S2213-2600(24)00217-0. Epub 2024 Oct 25.
Lymphangioleiomyomatosis is an ultra-rare disease mainly affecting women of childbearing age. The MILES trial showed the efficacy of sirolimus, an mTOR inhibitor, in stabilising lung function in patients with lymphangioleiomyomatosis. Drug toxicity and development of resistance are potential limitations of therapy with sirolimus. Nintedanib is a multikinase inhibitor that inhibits PDGFR, which is active in human and murine lymphangioleiomyomatosis lesions. We aimed to investigate the activity and safety of nintedanib in patients with lymphangioleiomyomatosis.
This phase 2, open-label, single-arm study was conducted at MultiMedica IRCCS, a national referral university centre for rare pulmonary diseases in Milan, Italy. Eligible participants were aged 18 years and older and had sporadic or tuberous sclerosis complex-associated lymphangioleiomyomatosis with progressive pulmonary function decline in the past year despite treatment with sirolimus or treatment naive. Patients received nintedanib 150 mg orally twice per day, with a possible reduction to 100 mg twice per day in case of side-effects or hepatoxicity, for 12 months, followed by a period of 12 additional months without study treatment. The primary endpoint was the change in FEV (FEV slope in L) over 12 months. This study is registered with ClinicalTrials.gov, NCT03062943.
From Oct 14, 2016, to Dec 13, 2019, 35 female patients (mean age 50 years [SD 11]) entered the study, 30 of whom were eligible and received nintedanib. After 12 months, 22 patients completed the treatment, 19 of whom also completed the 12 months of follow-up. FEV remained stable after one year of treatment (predicted mean difference 0·001 L [95% CI -0·063 to 0·066]; p=0·97). During the 12 months off treatment, a slight decline in FEV was observed (predicted mean difference -0·076 L [95% CI -0·149 to -0·004]; p=0·040). The most frequent adverse events were nausea (15 [50%] patients), diarrhoea (eight [26%]), and abdominal pain (two [7%]). No serious adverse events were observed during the treatment period.
Our findings suggest that nintedanib did not improve FEV, but that the treatment was generally well tolerated. These results might support nintedanib as a second-line therapy in patients not controlled by standard treatment with mTOR inhibitors. Further investigation, such as a non-inferiority trial comparing nintedanib and sirolimus could help to better clarify the role of this drug as a potential alternative treatment.
Boehringer-Ingelheim.
淋巴管平滑肌瘤病是一种极为罕见的疾病，主要影响育龄期女性。MILES试验显示，mTOR抑制剂西罗莫司在稳定淋巴管平滑肌瘤病患者肺功能方面具有疗效。药物毒性和耐药性的产生是西罗莫司治疗的潜在局限性。尼达尼布是一种多激酶抑制剂，可抑制在人类和鼠类淋巴管平滑肌瘤病病变中具有活性的血小板衍生生长因子受体（PDGFR）。我们旨在研究尼达尼布在淋巴管平滑肌瘤病患者中的活性和安全性。
这项2期开放标签单臂研究在意大利米兰的MultiMedica IRCCS进行，该中心是一家全国罕见肺病转诊大学中心。符合条件的参与者年龄在18岁及以上，患有散发性或结节性硬化症相关的淋巴管平滑肌瘤病，尽管接受了西罗莫司治疗或未接受过治疗，但在过去一年中肺功能仍进行性下降。患者每天口服两次尼达尼布150 mg，若出现副作用或肝毒性，剂量可能减至每天两次100 mg，持续12个月，随后再有12个月不进行研究治疗。主要终点是12个月内第1秒用力呼气容积（FEV，以升为单位的FEV斜率）的变化。本研究已在ClinicalTrials.gov注册，注册号为NCT03062943。
从2016年10月14日至2019年12月13日，35名女性患者（平均年龄50岁[标准差11]）进入研究，其中30名符合条件并接受了尼达尼布治疗。12个月后，22名患者完成治疗，其中19名也完成了12个月的随访。治疗一年后FEV保持稳定（预测平均差异0.001升[95%置信区间-0.063至0.066]；p = 0.97）。在停药的12个月期间，观察到FEV略有下降（预测平均差异-0.076升[95%置信区间-0.149至-0.004]；p = 0.040）。最常见的不良事件是恶心（15例[50%]患者）、腹泻（8例[26%]）和腹痛（2例[7%]）。治疗期间未观察到严重不良事件。
我们的研究结果表明，尼达尼布并未改善FEV，但该治疗总体耐受性良好。这些结果可能支持将尼达尼布作为mTOR抑制剂标准治疗无法控制的患者的二线治疗药物。进一步的研究，如比较尼达尼布和西罗莫司的非劣效性试验，可能有助于更好地阐明这种药物作为潜在替代治疗的作用。
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