Efficacy and safety of abemaciclib alone and with PI3K / mTOR inhibitor LY3023414 or galunisertib versus chemotherapy in previously treated metastatic pancreatic adenocarcinoma: A randomized controlled trial

作者：E. Gabriela Chiorean, Vincent J. Picozzi, Chung‐Pin Li, Marc Peeters, Joan Maurel, Jaswinder Singh, Talia Golan, Jean‐Frédéric Blanc, Sonya C. Chapman, Anwar M. Hussain, Erica L. Johnston, Howard S. Höchster · 发表于：Cancer Medicine · 年份：2023 · DOI：10.1002/cam4.6621 · 被引用次数：20 · 研究领域：Advanced Breast Cancer Therapies、Pancreatic and Hepatic Oncology Research、Peptidase Inhibition and Analysis

BACKGROUND: Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This study evaluated safety and efficacy of abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, as monotherapy or in combination with PI3K/mTOR dual inhibitor LY3023414 or TGFβ inhibitor galunisertib versus standard of care (SOC) chemotherapy in patients with pretreated metastatic PDAC. METHODS: This Phase 2 open-label study enrolled patients with metastatic PDAC who progressed after 1-2 prior therapies. Patients were enrolled in a safety lead-in (abemaciclib plus galunisertib) followed by a 2-stage randomized design. Stage 1 randomization was planned 1:1:1:1 for abemaciclib, abemaciclib plus LY3023414, abemaciclib plus galunisertib, or SOC gemcitabine or capecitabine. Advancing to Stage 2 required a disease control rate (DCR) difference ≥0 in abemaciclib-containing arms versus SOC. Primary objectives for Stages 1 and 2 were DCR and progression-free survival (PFS), respectively. Secondary objectives included response rate, overall survival, safety, and pharmacokinetics. RESULTS: One hundred and six patients were enrolled. Abemaciclib plus galunisertib did not advance to Stage 1 for reasons unrelated to safety or efficacy. Stage 1 DCR was 15.2% with abemaciclib monotherapy, 12.1% with abemaciclib plus LY3023414, and 36.4% with SOC. Median PFS was 1.7 months (95% CI: 1.4-1.8), 1.8 months (95% CI: 1.3-1.9), and 3.3 months (95% CI: 1.1-5.7), respectively. No a...