Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors
Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors
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DOI：
10.1200/jco.19.02404
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发表时间：
2020-09-20
影响因子：
45.3
通讯作者：
de Bono, Johann S.
中科院分区：
文献类型：
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作者：
Yap, Timothy A.;O'Carrigan, Brent;de Bono, Johann S.
临床前研究表明，ATR抑制可以利用合成致死性（例如，在具有通过ATM损失受损的补偿性DNA损伤反应的癌细胞中）作为单一疗法和与DNA损伤药物如卡铂组合。（每周一次或两次）并与卡铂联合（21天周期中第1天使用卡铂，第2天和第9天使用M6620）。主要目标是安全性，耐受性和最大耐受剂量;次要目标包括药代动力学和抗肿瘤活性;探索性目标包括在定时配对肿瘤biopsies.Results药效学40例患者入组; 17接受M6620单药治疗，这是安全的，耐受性良好。推荐的II期剂量（RP 2D）每周一次或每周两次给药为240 mg/m（2）。1例携带分子畸变（包括ATM丢失和ARID 1A突变）的转移性结直肠癌患者达到了RECISTv1.1完全缓解并维持了该缓解，末次评估时无进展生存期为29个月。23例患者接受M6620联合卡铂治疗，在较高剂量下出现基于机制的血液学毒性，需要延迟给药和减量。联合治疗的RP 2D为M6620 90 mg/m2，卡铂AUC 5。1例晚期生殖系BRCA 1卵巢癌患者实现了RECISTv1.1部分缓解和妇科癌症组间CA 125缓解，尽管是铂类难治性和PARP抑制剂耐药。另外15例患者的最佳缓解为RECISTv1.1疾病稳定。药代动力学与剂量成比例，并超过临床前有效水平。药效学研究表明，实质性抑制磷酸化CHK 1，下游ATRsubstrate.CONCLUSION据我们所知，这是第一个ATR抑制剂作为单一疗法，并与卡铂。M6620耐受性良好，观察到靶向结合和初步抗肿瘤反应。(C)2020年美国临床肿瘤学会
PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin.PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies.RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m(2). A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m(2) with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate.CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed. (C) 2020 by American Society of Clinical Oncology