| Autor: |
David G. DeNardo, Brett H. Herzog, William G. Hawkins, Olivia Aranha, Lee Ratner, Nikolaos A. Trikalinos, Mojun Zhu, Harry H. Yoon, Feng Gao, Mina Abdiannia, Abhi Acharya, Nicholas Boice, Benjamin Tan, Katrina Pedersen, Savannah J. Bogner, John Herndon, Jad I. Belle, Marcus Breden, Amberly Brown, Albert C. Lockhart, Rama Suresh, Robert McWilliams, Kian-Huat Lim, Andrea Wang-Gillam |
| Rok vydání: |
2023 |
| Popis: |
Purpose:Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse model. Defactinib is a highly potent oral FAK inhibitor that has a tolerable safety profile.Patients and Methods:We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a recommended phase II dose (RP2D). In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had stable disease (SD) after at least 4 months of standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and posttreatment tumor biopsies were performed to evaluate tumor immunity.Results:The triple drug combination was well-tolerated, with no dose-limiting toxicities. Among 20 treated patients with refractory PDAC, the disease control rate (DCR) was 80%, with one partial response (PR) and 15 SDs, and the median progression-free survival (PFS) and overall survival (OS) were 3.6 and 7.8 months, respectively. Among 10 evaluable patients in the maintenance cohort, DCR was 70% with one PR and six SDs. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS on study treatment were 5.0 and 8.3 months, respectively.Conclusions:The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated and safe, had promising preliminary efficacy, and showed biomarker activity in infiltrative T lymphocytes. Efficacy of this strategy may require incorporation of more potent chemotherapy in future studies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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