A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors

作者：Todd Michael Bauer, Kathleen N. Moore, Janet Sue Rader, Fiona A. Simpkins, Alain C. Mita, Joseph Thaddeus Beck, Lowell L. Hart, Quincy Siu-Chung Chu, Amit M. Oza, Anna V. Tinker, Esteban Rodrigo Imedio, Sanjeev Kumar, Ganesh M. Mugundu, Suzanne C. Jenkins, Juliann Chmielecki, Suzanne Fields Jones, David Robert Spigel, Siqing Fu · 发表于：Targeted Oncology · 年份：2023 · DOI：10.1007/s11523-023-00965-7 · 被引用次数：35 · 研究领域：Insect Resistance and Genetics、Biochemical and Molecular Research、Protein Kinase Regulation and GTPase Signaling

BACKGROUND: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. OBJECTIVE: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. PATIENTS AND METHODS: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle. RESULTS: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7...