Journal Article

Safety and activity of the TGFβ receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer

Benhadji, Karim A, Calvo, Emiliano, Oh, Do-Youn, Hollebecque, Antoine, Man, Michael, Lanasa, Mark C, Gueorguieva, Ivelina, Avsar, Emin, Garcia-Carbonero, Rocio, Merz, Valeria, Borazanci, Erkut, Zhao, Yumin, Varghese, Anna, Gandhi, Leena, Macarulla, Teresa, Melisi, Davide, Zecchetto, Camilla, Estrem, Shawn T, Guba, Susan C

2021

Overview

BackgroundWe assessed the safety, efficacy, and pharmacokinetics of the transforming growth factor beta (TGFβ) receptor inhibitor galunisertib co-administered with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab in recurrent/refractory metastatic pancreatic cancer previously treated with ≤2 systemic regimens.MethodsThis was a two-part, single-arm, multinational, phase Ib study. In a dose-finding phase, escalating oral doses of galunisertib were co-administered on days 1–14 with fixed-dose intravenous durvalumab 1500 mg on day 1 every 4 weeks (Q4W), followed by an expansion cohort phase.ResultsThe galunisertib recommended phase II dose (RP2D) when co-administered with durvalumab 1500 mg Q4W was 150 mg two times per day. No dose-limiting toxicities were recorded. Among 32 patients treated with galunisertib RP2D, 1 patient had partial response, 7 had stable disease, 15 had objective progressive disease, and 9 were not evaluable. Disease control rate was 25.0%. Median overall survival and progression-free survival were 5.72 months (95% CI: 4.01 to 8.38) and 1.87 months (95% CI: 1.58 to 3.09), respectively. Pharmacokinetic profiles for combination therapy were comparable to those published for each drug. There was no association between potential biomarkers and treatment outcomes.ConclusionGalunisertib 150 mg two times per day co-administered with durvalumab 1500 mg Q4W was tolerable. Clinical activity was limited. Studying this combination in patients in an earlier line of treatment or selected for predictive biomarkers of TGFβ inhibition might be a more suitable approach.Trial registration numberClinicalTrials.gov identifier: NCT02734160.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adult / Aged / Aged, 80 and over / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - pharmacokinetics / Antibodies, Monoclonal - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / B7-H1 Antigen - antagonists & inhibitors / B7-H1 Antigen - metabolism / Biomarkers / Cancer / Cancer therapies / Clinical/Translational Cancer Immunotherapy / Disease Progression / Drug dosages / Europe / Female / Hematology / Humans / Immune Checkpoint Inhibitors - adverse effects / Immune Checkpoint Inhibitors - pharmacokinetics / Immune Checkpoint Inhibitors - therapeutic use / Immunotherapy / Kinases / Male / Metastasis / Middle Aged / Monoclonal antibodies / Neoplasm Metastasis / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - mortality / Pancreatic Neoplasms - pathology / Patients / Pharmacokinetics / Progression-Free Survival / Protein Kinase Inhibitors - adverse effects / Protein Kinase Inhibitors - pharmacokinetics / Protein Kinase Inhibitors - therapeutic use / Pyrazoles - adverse effects / Pyrazoles - pharmacokinetics / Pyrazoles - therapeutic use / Quinolines - adverse effects / Quinolines - pharmacokinetics / Quinolines - therapeutic use / Receptor, Transforming Growth Factor-beta Type I - antagonists & inhibitors / Receptor, Transforming Growth Factor-beta Type I - metabolism / Republic of Korea / Signal Transduction / Targeted cancer therapy / Time Factors / Tumors / United States