A PhaseIISingle Arm Pilot Study of theCHK1Inhibitor Prexasertib (LY2606368) inBRCAWild-Type, AdvancedTriple-NegativeBreast Cancer
A PhaseIISingle Arm Pilot Study of theCHK1Inhibitor Prexasertib (LY2606368) inBRCAWild-Type, AdvancedTriple-NegativeBreast Cancer
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DOI：
10.1634/theoncologist.2020-0491
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发表时间：
2020-06-24
期刊：
影响因子：
5.8
通讯作者：
Lee, Jung-Min
中科院分区：
文献类型：
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作者：
Gatti-Mays, Margaret E.;Karzai, Fatima H.;Lee, Jung-Min
经验教训Prexasertib单药治疗在BRCA野生型、复发性三阴性乳腺癌中表现出适度的活性，突出了联合治疗策略的未满足需求。中性粒细胞减少、贫血和血小板减少是使用prexasertib时常见的，但可通过支持性治疗措施进行管理。应考虑预防性使用粒细胞集落刺激因子，以避免剂量减少或治疗延迟。药效学研究表明，prexasertib治疗诱导外周免疫细胞DNA损伤。细胞周期检查点激酶1（CHK 1）是p53功能障碍的肿瘤（如三阴性乳腺癌（TNBC））中主要的G2/M细胞周期调节因子。我们假设第二代CHK 1抑制剂prexasertib将在散发性TNBC中产生临床活性。方法该单臂II期试验评估了转移性/复发性TNBC患者接受105 mg/m2 IV每2周一次的prexasertib治疗。主要终点为总缓解率（ORR）。结果9例患者均为BRCAwt，既往至少接受过一次治疗。观察到1例部分缓解（PR）（ORR为11.1%）。4例患者病情稳定。中位无进展生存期（PFS）为86天（范围17 - 159天）。3/4级治疗相关不良事件包括无发热性中性粒细胞减少（n= 8; 88.9%）、贫血（n= 3; 33.3%）和血小板减少（n= 1; 11.1%）。药效学研究显示，prexasertib治疗诱导外周免疫细胞DNA损伤，并显示活化/复苏的CD 8 T细胞减少;然而，1例PR患者显示T细胞恢复的证据。结论Prexasertib单药治疗BRCAwt TNBC的临床疗效中等。需要进一步研究prexasertib与其他药物的联合用药。
Lessons LearnedMonotherapy with prexasertib demonstrated modest activity inBRCAwild-type, recurrent triple-negative breast cancer, highlighting the unmet need for combination treatment strategies. Neutropenia, anemia, and thrombocytopenia are common with the use of prexasertib but are manageable with supportive care measures. Prophylactic use of granulocyte colony stimulating factor should be considered to avoid dose reductions or treatment delays. Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells. Background Cell cycle checkpoint kinase 1 (CHK1) is a major G2/M cell cycle regulator in tumors with p53 dysfunction, such as triple-negative breast cancer (TNBC). We hypothesized the second-generation CHK1 inhibitor, prexasertib, would yield clinical activity in sporadic TNBC. Methods This single arm, phase II trial evaluated prexasertib at 105 mg/m(2)IV every 2 weeks in patients with metastatic/recurrent TNBC. The primary endpoint was overall response rate (ORR). Results All nine patients enrolled were germlineBRCAwild-type (BRCAwt) and had at least one prior treatment. One partial response (PR) was observed (ORR of 11.1%). Four patients experienced stable disease. The median progression-free survival (PFS) was 86 days (range 17 to 159 days). Grade 3/4 treatment-related adverse events included afebrile neutropenia (n= 8; 88.9%), anemia (n= 3; 33.3%), and thrombocytopenia (n= 1; 11.1%). Pharmacodynamic studies showed prexasertib treatment induced DNA damage in peripheral immune cells and demonstrated a decrease in activated/reinvigorated CD8 T cells; however, the one patient with a PR showed evidence of T-cell recovery. Conclusion Prexasertib monotherapy had modest clinical efficacy inBRCAwt TNBC. Further studies of prexasertib in combination with other agents are needed.