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
| العنوان: | 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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| المؤلفون: | John H. Strickler, Johanna C. Bendell, Samuel J. Klempner, James B. Rottman, Michael H. Kagey, Stacey Stein, Girish S. Naik, Marya F. Chaney, Victoria M. Villaflor, Laura LaNiel Tenner, Cynthia A. Sirard |
| المصدر: | Molecular Cancer Therapeutics. 20:2240-2249 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Esophageal Neoplasms, Mrna expression, Programmed Cell Death 1 Receptor, Pembrolizumab, Antibodies, Monoclonal, Humanized, Stomach Neoplasms, Esophagogastric cancer, Internal medicine, Biomarkers, Tumor, medicine, Humans, Aged, Predictive biomarker, Aged, 80 and over, biology, business.industry, Middle Aged, Acquired immune system, DKK1, biology.protein, Biomarker (medicine), Female, Antibody, business |
| الوصف: | 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. |
| تدمد: | 1538-8514 1535-7163 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d57089086b532fd1a3579ca7fe1a764cTest https://doi.org/10.1158/1535-7163.mct-21-0273Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d57089086b532fd1a3579ca7fe1a764c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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