背景:Magrolimab是一种阻断CD47的单克隆抗体,在癌细胞上过度表达“不要吃我”信号,导致肿瘤吞噬作用,并与阿扎胞苷协同作用。在HRMDS患者中,目前的标准护理阿扎胞苷存在高度未满足的需求。
目的:报告最终安全性/耐受性和疗效数据。
方法:Ph1b马格列单抗+阿扎胞苷试验(NCT03248479)。
方法:95例未经治疗的HRMDS患者(中度,高,或根据修订的国际预后评分系统[IPSS-R],风险非常高)。
方法:MagrolimabIV1-mg/kg(引发)然后30-mg/kg增加QW/Q2W(维持)。阿扎胞苷75mg/m2IV/SC第1-7天(每个28天周期)。
方法:主要终点是安全性/耐受性和完全缓解(CR)率。
结果:年龄中位数为69岁[范围,28-91y]).IPSS-R风险中等,高,或者非常高的27%,52%,21%的病人,分别。治疗相关MDS,TP53突变,22%的人报告了低风险的细胞遗传学,26%,62%的病人,分别。周期的中位数为6(范围,1-27).最常见的治疗引起的不良事件(TEAE)包括便秘(68%),血小板减少症(55%),贫血(52%),中性粒细胞减少症(47%),恶心(46%),腹泻(43%)。最常见的3/4级TEAE包括贫血(47%),中性粒细胞减少症(46%),血小板减少症(46%),白细胞计数下降(30%)。6例患者因AE停止治疗。60天死亡率为2%。第一次给药后样本的基线血红蛋白变化中位数为-0.7g/dL(范围,-3.1至2.4g/dL)。CR和客观反应(OR)率分别为33%和75%;基线细胞遗传学异常的OR可评估患者中有31%具有细胞遗传学CR。到第一个OR的中值时间,CR的持续时间,OR的持续时间,无进展生存期分别为1.9、11.1、9.8和11.6个月,分别。12个月和24个月总生存率(OS)分别为75%和52%,分别;在17.1个月的随访中,未达到中位OS.在TP53突变患者中观察到良好的结局(n=25;CR率,40%;OS中位数,16.3个月)和野生型TP53(n=61;CR率,31%;OS中位数,没有达到)。
结论:Magrolimab+阿扎胞苷的耐受性良好,在未经治疗的HRMDS患者中具有有希望的疗效,包括TP53突变和野生型疾病。一项关于马格罗利马/安慰剂+阿扎胞苷的Ph3试验(ENHANCE;NCT04313881)正在进行中。
BACKGROUND: Magrolimab is a monoclonal antibody blocking CD47, a \"don\'t eat me\" signal overexpressed on cancer cells, which leads to tumor phagocytosis and is synergistic with azacitidine. A high unmet need exists to build on current standard-of-care azacitidine in patients with HR MDS.
OBJECTIVE: Report final safety/tolerability and efficacy data.
METHODS: Ph1b
trial of magrolimab+azacitidine (NCT03248479).
METHODS: 95 patients with untreated HR MDS (intermediate, high, or very-high risk per the Revised International Prognostic Scoring System [IPSS-R]).
METHODS: Magrolimab IV 1-mg/kg (priming) then 30-mg/kg ramp-up QW/Q2W (maintenance). Azacitidine 75 mg/m2 IV/SC days 1-7 (each 28-day cycle).
METHODS: Primary endpoints were safety/tolerability and complete remission (CR) rate.
RESULTS: Median age was 69y [range, 28-91y]). IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21% of patients, respectively. Therapy-related MDS, TP53 mutation, and poor-risk cytogenetics were reported in 22%, 26%, and 62% of patients, respectively. Median number of cycles was 6 (range, 1-27). The most common treatment-emergent adverse events (TEAEs) included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (43%). The most common grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and white blood cell count decreased (30%). Six patients discontinued treatment due to AEs. The 60-day mortality rate was 2%. Median hemoglobin change from baseline at first post dose sample was -0.7 g/dL (range, -3.1 to 2.4 g/dL). CR and objective response (OR) rates were 33% and 75%; 31% of OR-evaluable patients with baseline abnormal cytogenetics had cytogenetic CR. Median time to first OR, duration of CR, duration of OR, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. 12- and 24-month overall survival (OS) rates were 75% and 52%, respectively; median OS was not reached with 17.1 months of follow-up. Favorable outcomes were observed in patients with TP53 mutation (n=25; CR rate, 40%; median OS, 16.3 months) and wild-type TP53 (n=61; CR rate, 31%; median OS, not reached).
CONCLUSIONS: Magrolimab+azacitidine was well tolerated, with promising efficacy in patients with untreated HR MDS, including those with TP53-mutated and -wild-type disease. A Ph3
trial of magrolimab/placebo+azacitidine (ENHANCE; NCT04313881) is ongoing.