Therapeutic combinations targeting innate and adaptive immunity and predictive biomarkers of response in esophagogastric cancer (EGC) are needed. We assessed safety and clinical utility of DKN-01 (a novel DKK1-neutralizing IgG4 antibody) combined with pembrolizumab and retrospectively determined DKK1 tumoral expression as a biomarker. Patients with advanced EGC received intravenous DKN-01 (150 or 300 mg) on days 1 and 15 with pembrolizumab 200 mg on day 1 in 21-day cycles. Clinical response was assessed by RECIST v1.1. Association of tumoral DKK1 mRNA expression ( H -score: high ≥ upper-tertile, low < upper-tertile) with response was assessed with PD-L1 levels as a covariate. Sixty-three patients received DKN-01 150 mg ( n = 2) or 300 mg ( n = 61) plus pembrolizumab. Common adverse events were fatigue, anemia, blood alkaline phosphatase elevation, aspartate aminotransferase elevation, and hyponatremia. Among evaluable anti-PD-1/PD-L1-naïve patients receiving DKN-01 300 mg and pembrolizumab, objective response rate (ORR) was 11.4% (5/44) and 18.5% (5/27) in patients with gastroesophageal junction or gastric cancer (GEJ/GC). Among response-evaluable anti-PD-1/PD-L1-naïve patients with GEJ/GC and known tumoral DKK1 expression, ORR was 50% in DKK1-high and 0% in DKK1-low patients, median PFS was 22.1 vs. 5.9 weeks (HR, 0.24; 95% CI, 0.08–0.67), respectively, and median OS was 31.6 weeks vs. 17.4 weeks (HR, 0.41; 95% CI, 0.16–1.07), respectively. Association of DKK1 expression with PFS was independent of PD-L1 expression (adjusted HR, 0.21; 95% CI, 0.06–0.69). DKN-01 combined with pembrolizumab was well tolerated with no new safety signals. Antitumor activity was enriched in anti-PD-1/PD-L1-naïve patients with GEJ/GC whose tumors expressed high DKK1.

中文翻译：

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抗 DKK1 抗体 DKN-01 联合派姆单抗治疗晚期食管胃癌的 Ib 期研究的安全性、有效性和生物标志物结果

需要针对先天免疫和适应性免疫的治疗组合以及食管胃癌 (EGC) 反应的预测性生物标志物。我们评估了 DKN-01（一种新型 DKK1 中和 IgG4 抗体）联合派姆单抗的安全性和临床效用，并回顾性确定了 DKK1 肿瘤表达作为生物标志物。晚期 EGC 患者在第 1 天和第 15 天接受静脉注射 DKN-01（150 或 300 mg），并在第 1 天接受 pembrolizumab 200 mg，周期为 21 天。临床反应由 RECIST v1.1 评估。肿瘤 DKK1 mRNA 表达（H 评分：高 ≥ 上三分位数，低 < 上三分位数）与反应的关联以 PD-L1 水平作为协变量进行评估。63 名患者接受 DKN-01 150 毫克（n = 2）或 300 毫克（n = 61）加帕博利珠单抗。常见的不良事件是疲劳、贫血、血碱性磷酸酶升高、谷草转氨酶升高和低钠血症。在接受 DKN-01 300 mg 和 pembrolizumab 的可评估抗 PD-1/PD-L1 初治患者中，胃食管交界处患者的客观缓解率 (ORR) 分别为 11.4% (5/44) 和 18.5% (5/27)或胃癌 (GEJ/GC)。在具有 GEJ/GC 和已知肿瘤 DKK1 表达的可评估抗 PD-1/PD-L1 初治患者中，ORR 在 DKK1-high 患者中为 50%，在 DKK1-low 患者中为 0%，中位 PFS 为 22.1 vs. 5.9周（HR，0.24；95% CI，0.08-0.67），中位 OS 分别为 31.6 周和 17.4 周（HR，0.41；95% CI，0.16-1.07）。DKK1 表达与 PFS 的关联独立于 PD-L1 表达（调整后的 HR，0.21；95% CI，0.06–0.69）。DKN-01 联合 pembrolizumab 耐受性良好，没有新的安全信号。