Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors: A Phase 1b/2a Nonrandomized Clinical Trial.

IMPORTANCE: Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors. OBJECTIVE: To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. DESIGN, SETTING, AND PARTICIPANTS: A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020. INTERVENTIONS: Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal. MAIN OUTCOMES AND MEASURES: Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA. RESULTS: A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. CONCLUSIONS AND RELEVANCE: In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02401815.

Prosocial deficits in behavioral variant frontotemporal dementia relate to reward network atrophy.

INTRODUCTION: Empathy and shared feelings of reward motivate individuals to share resources with others when material gain is not at stake. Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease that affects emotion- and reward-relevant neural systems. Although there is diminished empathy and altered reward processing in bvFTD, how the disease impacts prosocial behavior is less well understood. METHODS: A total of 74 participants (20 bvFTD, 15 Alzheimer's disease [AD], and 39 healthy controls) participated in this study. Inspired by token-based paradigms from animal studies, we developed a novel task to measure prosocial giving (the "Giving Game"). On each trial of the Giving Game, participants decided how much money to offer to the experimenter, and prosocial giving was the total amount that participants gave to the experimenter when it cost them nothing to give. Voxel-based morphometry was then used to identify brain regions that were associated with prosocial giving. RESULTS: Prosocial giving was lower in bvFTD than in healthy controls; prosocial giving in AD did not differ significantly from either of the other groups. Whereas lower prosocial giving was associated with atrophy in the right pulvinar nucleus of the thalamus, greater prosocial giving was associated with atrophy in the left ventral striatum. CONCLUSION: These findings suggest that simple acts of generosity deteriorate in bvFTD due to lateralized atrophy in reward-relevant neural systems that promote shared feelings of positive affect.

Metacognition in the behavioral variant of frontotemporal dementia and Alzheimer's disease.

OBJECTIVE: Impaired self-awareness is characteristic of nearly all dementias, including Alzheimer's disease (AD), but the deficit is most severe in the behavioral variant of frontotemporal dementia (bvFTD). The prominence of frontal pathology in bvFTD suggests that failure of online monitoring, the process by which individuals monitor their own cognitive processing in real time, is an important contributor. Metacognitive research offers several approaches to measure self-assessment, some more and others less sensitive to online monitoring. The goal of this study was to assess metacognition in bvFTD using several approaches, and to compare the results with those in AD. METHOD: We examined metacognition in 12 patients with bvFTD, 14 with AD, and 35 healthy controls using feeling of knowing (FOK), ease of learning (EOL), judgment of learning (JOL), and retrospective confidence rating (CR) tasks, as well as response to feedback about performance. RESULTS: BvFTD and AD were both impaired at FOK compared with controls, although AD showed some sparing. Both groups were similarly impaired at CR and neither group was impaired at JOL after accounting for memory performance. Most striking, bvFTD patients failed to appropriately adjust their predictions about future memory performance even after receiving explicit feedback that they had performed worse than they expected. CONCLUSIONS: Both bvFTD and AD show deficits in online monitoring, although the deficit appears more severe in bvFTD. The insensitivity of bvFTD patients to overt feedback may point to unique mechanisms, possibly frontally mediated, that add to their severe lack of self-awareness.

Deficits in self-awareness impact the diagnosis of asymptomatic neurocognitive impairment in HIV.

A recent national survey of HIV(+) adults noted that nearly three-quarters of cognitively impaired individuals are categorized as having asymptomatic neurocognitive impairment (ANI), lacking documented compromise of everyday function. The clinical impact and long-term consequences of ANI are unknown and the importance of this asymptomatic diagnosis has raised concerns in clinical care settings where competing priorities often exist. In this study, we conducted structured tests of everyday functioning in a sample of HIV(+) subjects over 60 years of age and asked subjects to rate their performance relative to peers. We demonstrate that individuals with neuropsychological testing impairment often lack self-awareness of functional performance deficits. Specifically, ANI subjects rated functional performance similar to that of HIV-negative control subjects, despite noted deficits in objective measures of function. These findings have important implications for use of self-report of function in the diagnosis of HIV-associated neurocognitive disorders (HAND), likely underestimating symptomatic impairment.

Distinct neuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer's disease and behavioral variant frontotemporal dementia.

Figure copy is the most common method of visual spatial assessment in dementia evaluations, but performance on this test may be multifactorial. We examined the neuroanatomical substrates of figure copy performance in 46 patients with Alzheimer's disease (AD) and 48 patients with the behavioral variant of Frontotemporal dementia (bvFTD). A group of 94 neurologically healthy controls were studied for comparison. In AD, poor figure copy correlated significantly with right parietal cortex volumes but not with right dorsolateral prefrontal cortex volumes, whereas in bvFTD, figure copy performance correlated significantly with right dorsolateral prefrontal cortex volumes and there was only a trend with right parietal cortex volumes. The cognitive processes associated with figure copy performance also differed by diagnostic group such that figure copy was associated with spatial perception and attention in AD and with spatial planning and working memory in bvFTD. Spatial planning accounted for unique variance in the figure copy performance of bvFTD even after accounting for spatial perception, attention, and working memory. These results suggest that figure copy performance in AD and bvFTD is not anatomically specific and is differentially impacted by bottom-up and top-down aspects of visual spatial processing. Alternative methods of visual spatial assessment for dementia evaluations are proposed.

Neuroanatomical correlates of cognitive self-appraisal in neurodegenerative disease.

Self-appraisal is a critical cognitive function, which helps us to choose tasks based on an accurate assessment of our abilities. The neural mechanisms of self-appraisal are incompletely understood, although a growing body of literature suggests that several frontal and subcortical regions are important for self-related processing. Anosognosia, or lack of awareness of one's deficits, is common in neurodegenerative dementias, offering an important window onto the brain systems involved in self-appraisal. We examined the neuroanatomical basis of self-appraisal in a mixed group of 39 individuals, including 35 with cognitive impairment due to one of several probable neurodegenerative diseases, using voxel-based morphometry and an objective, neuropsychologically-based measure of self-appraisal accuracy. Self-appraisal accuracy was correlated with tissue content in the right ventromedial prefrontal cortex (vmPFC). We hypothesize that emotional/physiological processing carried out by vmPFC is an important factor mediating self-appraisal accuracy in dementia.

Standardised measurement of self-awareness deficits in FTD and AD.

BACKGROUND: Diminished ability to perceive one's own impairments, whether cognitive or social, is common in dementia, in particular frontotemporal dementia (FTD), where 'lack of insight' is listed as a core diagnostic feature. Yet, there is no currently accepted method for measuring insight in dementia. The most commonly used methods, which involve comparing patients' opinions of their level of impairment with the opinions of care givers or close family members, are subjective and require the participation of a knowledgeable informant. Here, the authors introduce a new method that allows objective quantification of an individual's awareness of their cognitive abilities and relies upon objective bedside testing. METHODS: The authors administered several tests of everyday, real-world functions to patients with FTD (n=10) and Alzheimer's disease (AD, n=10) and to control subjects (n=10). Prior to the tasks, participants were asked to predict their performance using a percentile-based rating system. They were also asked to estimate their performance after task completion. Differences between their self-rated and actual performances were calculated. RESULTS: Whereas the control group showed very little discrepancy between pretest predictions, post-task estimates and actual performance (mean difference of 3.9 percentile points for prediction/3.0 percentile points for post-task estimate), both patient groups overpredicted and overestimated their performance, with a significantly greater discrepancy for FTD (49.0/54.3 percentile points) than AD (27.2/28.3 percentile points). DISCUSSION: Failures of insight and self-awareness of cognitive dysfunction can be objectively measured in dementia without the assistance of an informant, which will facilitate further study of this key component of higher cognitive functioning.