Journal Article

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

Hochster, Howard S., Peeters, Marc, Picozzi, Vincent, Chapman, Sonya C., Golan, Talia, Blanc, Jean‐Frédéric, Singh, Jaswinder, Li, Chung‐Pin, Maurel, Joan, Hussain, Anwar M., Johnston, Erica L., Chiorean, E. Gabriela

2023

Overview

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 arms advanced to Stage 2. No new safety signals were identified. Conclusion In patients with pretreated metastatic PDAC, abemaciclib‐based therapy did not improve DCRs or PFS compared with SOC chemotherapy. No treatment arms advanced to Stage 2. Abemaciclib remains investigational in patients with PDAC. Pancreatic ductal adenocarcinomas (PDAC) are characterized by frequent cell cycle pathways aberrations. This phase 2 randomized study for refractory metastatic PDAC patients showed that the CDK4/6 inhibitor abemaciclib, alone or in combination with the PI3K/mTOR LY3023414, does not improve disease control or progression‐free survival compared to standard chemotherapy.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: 1-Phosphatidylinositol 3-kinase / Abemaciclib / Adenocarcinoma / Adenocarcinoma - drug therapy / Adenocarcinoma - etiology / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics / Breast cancer / Cancer therapies / Cell cycle / Chemotherapy / Cyclin-dependent kinase / Cyclin-dependent kinase 4 / Cyclin-dependent kinases / Disease control / Gemcitabine / Growth factors / Humans / Kinases / Metabolites / Metastases / Metastasis / metastatic pancreatic cancer / Mutation / Oncology / Pancreas / Pancreatic cancer / Pancreatic Neoplasms / Pancreatic Neoplasms - pathology / Pharmacokinetics / Phosphatidylinositol 3-Kinases / PI3K/mTOR / Quinolones - therapeutic use / Safety / second‐line therapy / TGFβ / third‐line therapy / TOR protein / TOR Serine-Threonine Kinases