Search

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.

Supplemental Table 2 Patient demographics

This article gives a brief introduction to the MacArthur Competence Assessment Tool-Treatment (MacCAT-T) and critically examines its theoretical presuppositions. On the basis of empirical, methodological and ethical critique it is emphasised that the cognitive bias that underlies the MacCAT-T assessment needs to be modified. On the one hand it has to be admitted that the operationalisation of competence in terms of value-free categories, e.g. rational decision abilities, guarantees objectivity to a great extent; but on the other hand it bears severe problems. Firstly, the cognitive focus is in itself a normative convention in the process of anthropological value-attribution. Secondly, it misses the complexity of the decision process in real life. It is therefore suggested that values, emotions and other biographic and context specific aspects should be considered when interpreting the cognitive standards according to the MacArthur model. To fill the gap between cognitive and non-cognitive approaches the phenomenological theory of personal constructs is briefly introduced. In conclusion some main demands for further research to develop a multi-step model of competence assessment are outlined.