DKK1是DKN-01治疗反复性子宫内膜癌妇女预测性生物标志物：一项2期篮子研究的结果。
DKK1 is a predictive biomarker for response to DKN-01: Results of a phase 2 basket study in women with recurrent endometrial carcinoma.
发表日期：2023 Mar 29
作者：
Rebecca Arend, Jhalak Dholakia, Cesar Castro, Ursula Matulonis, Erika Hamilton, Camille Gunderson Jackson, Kristopher LyBarger, Howard M Goodman, Linda R Duska, Haider Mahdi, Adam C ElNaggar, Michael H Kagey, Amy Liu, Diane Piper, Lisa M Barroilhet, William Bradley, Jasgit Sachdev, Cynthia A Sirard, David M O'Malley, Michael Birrer
来源：
GYNECOLOGIC ONCOLOGY
摘要：
Dickkopf-1 (DKK1) 是一种促进肿瘤生长、转移、血管生成和免疫抑制的 Wnt 信号调节因子，通过调节先天免疫系统来实现这些功能。DKK1 在妇科癌症中过度表达，并且与生存期缩短有关。DKN-01 是一种具有 DKK1 中和作用的人源化单克隆抗体，可为具有 DKK1 过表达或 Wnt 基因改变的肿瘤患者提供临床益处。我们在子宫内膜癌 (EC) 和铂类耐药/难治性上皮性卵巢癌患者中进行了一个开放标签、2 阶段设计的篮型研究。DKN-01 以单药或与周报紫杉醇联用的方式进行给药，根据研究者的自主选择。所有患者在入组前进行了 NGS 检测；肿瘤组织经过 RNAscope 预处理和第一疗程后进行了 DKK1 表达检测。至少有 50% 的患者需要直接或间接具有 Wnt 信号异常。本文报告了来自 EC 总体人群和 DKK1 表达的结果。DKN-01 单药和与紫杉醇联用治疗对高 DKK1 表达肿瘤患者的治疗效果优于低表达肿瘤患者。DKN-01 单药组中，客观缓解率 [ORR] 分别为 25.0% 对比 0%; 疾病控制率 [DCR] 分别为 62.5% 对比 6.7%; 中位无进展生存期 [PFS] 分别为 4.3 对比 1.8 个月，中位总生存期 [OS] 分别为 11.0 对比 8.2 个月。同样，DKN-01 与紫杉醇联用治疗在高 DKK1 表达肿瘤患者中展现出更高的临床活性，DCR 分别为 55% 对比 44%; 中位 PFS 分别为 5.4 对比 1.8 个月; OS 分别为 19.1 对比 10.1 个月。Wnt 激活突变与更高的 DKK1 表达相关。DKN-01 作为单药或与紫杉醇联用治疗都被良好地耐受。总体而言，数据证明了一种耐受性良好的药物 DKN-01 在表达高的肿瘤 DKK1 的 EC 患者中展现出了有希望的临床活性，这往往与 Wnt 激活突变的存在有关。未来的发展将重点关注在使用 DKN-01 与免疫疗法联合治疗表达高的 EC 患者中。Copyright © 2023 Elsevier Inc. All rights reserved.
Dickkopf-1 (DKK1) is a Wnt signaling modulator promoting tumor growth, metastasis, angiogenesis, and immunosuppression by regulating innate immunity. DKK1 is over-expressed in gynecologic cancers and is associated with shortened survival. DKN-01 is a humanized monoclonal antibody with DKK1 neutralizing activity that may provide clinical benefit to patients whose tumors have overexpression of DKK1 or Wnt genetic alterations.We conducted an open-label, Phase 2 basket study with 2-stage design in patients with endometrial carcinoma (EC) and platinum-resistant/refractory epithelial ovarian cancer. DKN-01 was administered either as monotherapy or in combination with weekly paclitaxel at investigator's discretion. All patients underwent NGS testing prior to enrollment; tumor tissue was also tested for DKK1 expression by RNAscope pre-treatment and after cycle 1 if available. At least 50% of patients were required to have a Wnt signaling alteration either directly or tangentially. This publication reports results from the EC population overall and by DKK1-expression.DKN-01 monotherapy and in combination with paclitaxel was more effective in patients with high DKK1-expressing tumors compared to low-expressing tumors. DKN-01 monotherapy demonstrated an objective response rate [ORR] of 25.0% vs. 0%; disease control rate [DCR] of 62.5% vs. 6.7%; median progression-free survival [PFS] was 4.3 vs. 1.8 months, and overall survival [OS] was 11.0 vs. 8.2 months in DKK1-high vs DKK1-low patients. Similarly, DKN-01 in combination with paclitaxel demonstrated greater clinical activity in patients with DKK1-high tumors compared to DKK1-low tumors: DCR was 55% vs. 44%; median PFS was 5.4 vs. 1.8 months; and OS was 19.1 vs. 10.1 months. Wnt activating mutations correlated with higher DKK1 expression. DKN-01 was well tolerated as a monotherapy and in combination with paclitaxel.Collectively, data demonstrates promising clinical activity of a well-tolerated drug, DKN-01, in EC patients with high tumoral DKK1 expression which frequently corresponded to the presence of a Wnt activating mutation. Future development will focus on using DKN-01 in DKK1-high EC patients in combination with immunotherapy.Copyright © 2023 Elsevier Inc. All rights reserved.