Verstovsek Srdan, Gerds Aaron T, Vannucchi Alessandro M, Al-Ali Haifa Kathrin, Lavie David, Kuykendall Andrew T, Grosicki Sebastian, Iurlo Alessandra, Goh Yeow Tee, Lazaroiu Mihaela C, Egyed Miklos, Fox Maria Laura, McLornan Donal, Perkins Andrew, Yoon Sung-Soo, Gupta Vikas, Kiladjian Jean-Jacques, Granacher Nikki, Lee Sung-Eun, Ocroteala Luminita, Passamonti Francesco, Harrison Claire N, Klencke Barbara J, Ro Sunhee, Donahue Rafe, Kawashima Jun, Mesa Ruben
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
Lancet. 2023 Jan 28;401(10373):269-280. doi: 10.1016/S0140-6736(22)02036-0.
Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.
MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting.
195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).
Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.
Sierra Oncology.
已获批用于治疗骨髓纤维化的 Janus 激酶（JAK）抑制剂可改善脾脏状况和症状，但对贫血无显著改善作用。莫美替尼是一种一流的激活素 A 受体 1 型以及 JAK1 和 JAK2 抑制剂，已在骨髓纤维化患者中显示出对症状、脾脏和贫血的有益效果。我们旨在确认莫美替尼与活性对照药达那唑相比，在接受过 JAK 抑制剂治疗、有症状、合并贫血且为中危或高危骨髓纤维化患者中的差异化临床获益。
MOMENTUM 是一项国际、双盲、随机、对照的 3 期研究，在全球 21 个国家的 107 个地点招募患者。符合条件的患者年龄在 18 岁及以上，确诊为原发性骨髓纤维化、真性红细胞增多症后骨髓纤维化或原发性血小板增多症后骨髓纤维化。患者按 2:1 随机分组，接受莫美替尼（每日口服 200 mg 一次）加达那唑安慰剂（即莫美替尼组）或达那唑（每日口服 300 mg 两次）加莫美替尼安慰剂（即达那唑组），按总症状评分（TSS；<22 与≥22）、脾脏大小（<12 cm 与≥12 cm）、随机分组前 8 周输注的红细胞或全血单位数（0 单位与 1 - 4 单位与≥5 单位）以及研究地点进行分层。主要终点是第 24 周时骨髓纤维化症状评估表（MFSAF）TSS 缓解率（定义为在第 24 周结束前紧接的 28 天内，平均 MFSAF TSS 较基线降低≥50%）。MOMENTUM 在 ClinicalTrials.gov 注册，编号为 NCT04173494，处于活跃状态但未招募患者。
195 名患者被随机分配至莫美替尼组（130 名[67%]）或达那唑组（65 名[33%]），并在 2020 年 4 月 24 日至 2021 年 12 月 3 日的 24 周随机治疗期内接受研究治疗。莫美替尼组报告 TSS 降低 50%或更多的患者比例显著高于达那唑组（130 名中的 32 名[25%]对 65 名中的 6 名[9%]；比例差异 16%[95%CI 6 - 26]，p = 0·0095）。莫美替尼和达那唑最常见的 3 级或更高等级治疗中出现的不良事件通过实验室检查值为血液学异常：贫血（130 名中的 79 名[6 / 1]对 65 名中的 49 名[75%]）和血小板减少（36 名[28%]对 17 名[26%]）。莫美替尼和达那唑最常见的非血液学 3 级或更高等级治疗中出现的不良事件是急性肾损伤（130 名中的 4 名[3%]对 65 名中的 6 名[9%]）和肺炎（3 名[2%]对 6 名[9%]）。
与达那唑相比，莫美替尼治疗可使骨髓纤维化相关症状、贫血指标和脾脏反应在临床上得到显著改善，且安全性良好。这些发现支持未来将莫美替尼用作骨髓纤维化患者，尤其是贫血患者的有效治疗药物。
Sierra Oncology。
