Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers.
Safety, Efficacy, and Biomarker Results from a Phase Ib Study of the Anti-DKK1 Antibody DKN-01 in Combination with Pembrolizumab in Advanced Esophagogastric Cancers.
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DOI：
10.1158/1535-7163.mct-21-0273
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发表时间：
2021-11
影响因子：
5.7
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中科院分区：
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需要靶向先天性和适应性免疫的治疗组合以及食管胃癌（EGC）中反应的预测生物标志物。我们评估了DKN-01（一种新型DKK 1中和IgG 4抗体）与帕博利珠单抗联合使用的安全性和临床实用性，并回顾性地确定了DKK 1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），第1天接受帕博利珠单抗200 mg，21天为一个周期。通过RECIST v1.1评估临床应答。以PD-L1水平作为协变量，评估肿瘤DKK 1 mRNA表达（H评分：高≥上三分位数，低<上三分位数）与缓解的相关性。63例患者接受DKN-01 150 mg（n = 2）或300 mg（n = 61）加派姆单抗。常见的不良事件是疲劳、贫血、血碱性磷酸酶升高、天冬氨酸转氨酶升高和低钠血症。在接受DKN-01 300 mg和帕博利珠单抗治疗的可评价抗PD-1/PD-L1初治患者中，胃食管连接部或胃癌（GEJ/GC）患者的客观缓解率（ORR）分别为11.4%（5/44）和18.5%（5/27）。在具有GEJ/GC和已知肿瘤DKK 1表达的缓解可评价抗PD-1/PD-L1初治患者中，DKK 1高表达患者的ORR为50%，DKK 1低表达患者的ORR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vs. 17.4周（HR，0.41; 95% CI，0.16-1.07）。DKK 1表达与PFS的相关性与PD-L1表达无关（校正HR，0.21; 95% CI，0.06-0.69）。DKN-01联合帕博利珠单抗耐受性良好，无新的安全性信号。抗肿瘤活性在抗PD-1/PD-L1初治GEJ/GC患者中富集，这些患者的肿瘤表达高DKK 1。
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.