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Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC9974829 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC9974829 | ||
References | PMC9974829 | |||
Subject terms | CORTEX | Task shielding is an important executive control demand in dual-task performance enabling the segregation of stimulus–response translation processes in each task to minimize between-task interference. Although neuroimaging studies have shown activity in left dorsolateral prefrontal cortex (dlPFC) during various multitasking performances, the specific role of dlPFC in task shielding, and whether non-invasive brain stimulation (NIBS) may facilitate task shielding remains unclear. We therefore applied a single-blind, crossover sham-controlled design in which 34 participants performed a dual-task experiment with either anodal transcranial direct current stimulation (atDCS, 1 mA, 20 min) or sham tDCS (1 mA, 30 s) over left dlPFC. Task shielding was assessed by the backward-crosstalk effect, indicating the extent of between-task interference in dual tasks. Between-task interference was largest at high temporal overlap between tasks, i.e., at short stimulus onset asynchrony (SOA). Most importantly, in these conditions of highest multitasking demands, atDCS compared to sham stimulation significantly reduced between-task interference in error rates. These findings extend previous neuroimaging evidence and support modulation of successful task shielding through a conventional tDCS setup with anodal electrode over the left dlPFC. Moreover, our results demonstrate that NIBS can improve shielding of the prioritized task processing, especially in conditions of highest vulnerability to between-task interference.Open Access funding enabled and organized by Projekt DEAL. | PMC10105771 | |
Introduction | CORTEX | Multitasking is required in a variety of contexts in modern life, ranging from multimedia use to vehicle operation and scheduling of complex task sequences in an emergency room. Yet, performing even two simple cognitive tasks at the same time often results in between-task interference, e.g., when the engagement in an additional task impacts the processing of a prioritized task. Executive control processes, subsumed under the term task shielding serve to reduce this between-task interference by ensuring the correct binding of task-specific stimulus codes to respective response codes in each task to minimize the risk of response reversals and/or confusionRecent functional neuroimaging studies confirm a close link between dual-task performance and neural activity in brain regions associated with executive control, such as the dorsolateral prefrontal cortex (dlPFC, e.g.,Non-invasive brain stimulation techniques (NIBS), such as transcranial direct current stimulation (tDCS), have been applied to improve dual-task performance (e.g.,Studies focusing on improving executive control in dual tasks with tDCS have supported the claim that the dlPFC plays a central role in dual-task performance, especially when high demands on executive functioning are required (e.g.,In the present study, we aimed to test whether the application of atDCS over the left dlPFC can improve task shielding. We used a dual-task paradigm, in which both tasks were presented in close temporal proximity and shared processing similarities to give rise to crosstalk between the two tasks. Effective task shielding can be inferred from the size of the so-called backward crosstalk effect (BCE) that reflects to which extent Task 1 processing is affected by simultaneous Task 2 processing. Importantly, the smaller this backward crosstalk onto Task 1 performance, the more effective is task shielding and interference control | PMC10105771 | |
Methods | PMC10105771 | |||
Participants | thirty-four | Forty-one participants signed up for participation in the experiment. Data sets of seven participants were not usable for analyses because of technical problems during recording (one participant), not completing both sessions (four participants), difficulties following task instructions, and obvious signs of disinterest in participation (two participants). The final sample consisted of thirty-four healthy participants (27 females; mean age: 22.4 years [ | PMC10105771 | |
Study overview | The study was conducted as a single-blind, crossover, sham-controlled trial. Each participant completed two sessions on separate days, with an average of 7 days between the two sessions. They received either atDCS or sham tDCS with the order of stimulation conditions being counterbalanced, i.e., half of the participants received atDCS, whereas the other half received sham tDCS for their first session. Each session lasted for about 60 min, including the tDCS setup. | PMC10105771 | ||
Materials and methods | PMC10105771 | |||
Behavioral task | The dual task consisted of a visual discrimination task (Task 1) and an auditory discrimination task (Task 2), which were performed in close succession. In order to increase processing similarities between the two tasks as the basis for crosstalkStimuli were presented in Arial font (font size 30) and in white on a black background with a viewing distance of approximately 60 cm. S1 was responded to with the left middle and index finger pressing the 'a' and 's' keys, respectively. Task 2 consisted of easy to discriminate auditory stimuli (S2), i.e., a high or low tone of 900 and 300 Hz, presented via a loudspeaker. Responses to S2 were provided by pressing the 'k' and 'l' keys using the right index and middle finger, respectively. Half of the participants responded to H and high tones with both index fingers and T and low tones with both middle fingers. The other half of the participants received the reversed assignment. Stimulus presentation and data recording were realized on a Pentium I computer with a Windows 10 platform using E-prime software (Version 3)The participants were instructed to respond first as fast and accurately as possible to S1 and only subsequently as fast and accurately as possible to S2. Each trial began with an 800 ms fixation period, in which a plus sign was presented in the center of the screen, followed by the onset of the visual S1. After a variable stimulus onset asynchrony (SOA) of 40, 130, or 300 ms, the auditory S2 was presented for 150 ms. S1 remained on screen for a maximum of 2500 ms (plus SOA duration) or until responses to both tasks were given. In the case of erroneous responses or wrong order, error feedback ("Falsch" or "Falsche Reihenfolge," respectively) was presented for 500 ms. The next trial started after a blank screen was presented for a random inter-trial-interval (ITI) between 0 and 1000 ms. Figure Trial procedure of the study. After the fixation sign, the visual stimulus for Task 1 (H or T) was presented. The auditory stimulus for Task 2 (high or low tone, represented by the speaker symbol) was delivered after one of three stimulus onset asynchronies (SOA, 40, 130, 300 ms). In the case of an erroneous response, feedback (i.e., “Falsch,” German for wrong) was presented.In each session, the experiment started with 12 dual-task trials to instruct stimulus–response mappings, followed by one practice block and eight experimental blocks consisting of 72 trials each. The 72 trials consisted of 36 compatible and incompatible trials. Of the 36 trials, in each compatibility condition, the three SOAs were presented 12 times each. That is, each combination of 2(S1) × 2(S2) × 3(SOA) was presented six times per block. The practice block was excluded from the analysis. Thus, 576 trials per session were considered for analysis. | PMC10105771 | ||
Stimulation protocol | SimNibs | Stimulation was delivered (NeuroConn DCStimulator Plus; neuroCare Grouo GmbH, Munich, Germany) using two saline-soaked surface sponge electrodes over the left dlPFC (anode, centered over F3, 10–20 EEG system, size: 5 × 7 cmDemonstration of the electrode placement and simulation of electric field distribution of applied stimulation parameters on MNI head/brain with SimNibs (simnibs.org, Version 3)Both atDCS and sham tDCS started with a 10-s ramp on and ended with a 10-s ramp off. In atDCS, the stimulation started with the first experimental block and lasted until 20 min—through the first half of the experiment blocks, while the second half of the experiment was not stimulated (see Fig. Experimental design. Illustration of atDCS and sham tDCS, which were realized in two sessions, separated approximately by 7 days. (In the sham tDCS, the stimulation duration was 30 s, including 20 s of ramping | PMC10105771 | |
Design | A 2 (Stimulation condition: atDCS, sham tDCS) × 2 (Compatibility: compatible, incompatible) × 3 (SOA: 40, 130, 300 ms) repeated measures single-blind, crossover, sham-controlled design was applied. Because BCEs take effect in Task 1 performance | PMC10105771 | ||
Analysis | The practice block of each session was not considered for analyses. Before RT analyses, erroneous trials in either Task 1 or Task 2 were removed. Further, all trials with RT1 < 200 ms and RT1 > 2000 ms and RT2 < 200 ms, and RT2 > 2500 ms were considered outliers and were not included in the analysis. This led to a removal of 0.6% of trials. A repeated measures ANOVA with the within-subject factors 2 (Stimulation condition: atDCS, sham tDCS) × 2 (Compatibility: compatible, incompatible) × 3 (SOA: 40, 130, 300 ms) was applied on mean RTs and PEs (see Tables RT1 (in ms) as a function of Stimulation condition (atDCS vs. sham tDCS), SOA (40 vs. 130 vs. 300 ms), Compatibility (compatible vs. incompatible).Standard errors of the mean are presented in parentheses.PE2 as a function of Stimulation condition (atDCS vs. sham tDCS), SOA (40 vs. 130 vs. 300 ms), Compatibility (compatible vs. incompatible).Standard errors of the mean are presented in parentheses.RT2 (in ms) as a function of Stimulation condition (atDCS vs. sham tDCS), SOA (40 vs. 130 vs. 300 ms), Compatibility (compatible vs. incompatible).Standard errors of the mean are presented in parentheses.The percentage error in Task 1 (PE1) for compatible and incompatible trials across SOA (in ms), for atDCS and sham tDCS. Error bars represent standard error of the mean. * | PMC10105771 | ||
Results | PMC10105771 | |||
PE1 | Participants made more errors in Task 1 when the Task 2 response was incompatible (Importantly, the application of atDCS modulated the BCE as compared to sham tDCS across the three SOAs, as indicated by the significant three-way interaction between Stimulation condition, SOA, and Compatibility, To test for potential effects of stimulation condition order (i.e., atDCS first vs. sham first), an analysis with stimulation order as an additional between-subject factor was conducted. However, no significant main effect or interaction with stimulation order was observed, all | PMC10105771 | ||
RT1 | Participants responded faster in compatible trials (There was also a significant main effect of SOA, | PMC10105771 | ||
PE2 | Mean PE2 is summarized in Table | PMC10105771 | ||
RT2 | Mean correct RT2 is summarized in Table | PMC10105771 | ||
General tDCS effects | itching, fatigue, pain | HEAT, SIDE EFFECT | The frequency and severity of reported side effects (i.e., itching, pain, burning, heat, metallic taste, and fatigue) were assessed for the last experimental session. None of the participants reported metallic taste as a side effect in atDCS or sham tDCS. Two-sided Fisher exact tests revealed no association between the frequency of reported side effects and type of stimulation (atDCS and sham tDCS), all Severity ratings of experienced side effects after the last experimental session. | PMC10105771 |
Discussion | The present study investigated whether modulation of excitability in the left-lateralized executive control network, as modulated by a prefrontal tDCS setup with anode over left dlPFC, facilitated the executive control function of prioritized task shielding in dual tasking. Results demonstrated that atDCS, as compared to sham tDCS, reduced crosstalk between the two tasks indicating improved task shielding. Importantly, improved task shielding was observed in conditions of highest dual-task demands, i.e., the largest temporal overlap between the two tasks.More precisely, in the condition of sham tDCS, crosstalk was stronger the more simultaneously both tasks were being processed. The close temporal proximity of stimuli at high temporal task overlap allows for more simultaneous task-component processing, which typically increases crosstalk between tasks. With less temporal task overlap, crosstalk typically declines. Thus, our findings in the sham tDCS condition mirror the usual result pattern obtained in dual-task research without any brain stimulation (e.g.,The findings of the present interventional approach, therefore, extend previous imaging studies suggesting a significant role of the dlPFC in task shielding (e.g.,Based on the present observations, we can only speculate how the modulation of the underlying executive control network by atDCS over left dlPFC facilitates processes of task shielding. One way of interpreting our results would be that atDCS could have aided conflict resolution by biasing the signals needed for Task 1 prioritized processing. Recent neuroimaging studies, for example, have shown a conflict-related attentional biasing in favor of task-relevant stimulus dimensions in single tasksAlternatively, tDCS-induced facilitation of task shielding may be directly related to enhanced processing efficiency rather than conflict resolution. That is, neural accounts to explain training effects on cognitive task performance postulate that training can lead to more efficient processing of the already engaged neural circuitsSuch an assumed benefit in neural efficiency, however, did not show up in the present RT measures, as the effects of improved task shielding under atDCS were found in error rates only. A selective impact of tDCS on error rates is not uncommon and has been reported frequentlyIn contrast to the error rates, RT results showed an increase of RT1 with longer SOAs. In dual-task paradigms with mostly short SOAs, participants tend to execute both responses at the same time, which leads to a typical strategic Task 1 response deferment with increasing SOAWhile the present results demonstrate that atDCS over the dlPFC improves task shielding in conditions of high between-task interference, further research combining functional neuroimaging and brain stimulation techniques may be informative to which extent facilitated task shielding is a consequence of tDCS-modulated activity and/or functional connectivity in underlying brain networks. In addition, the present effects of tDCS on task shielding were assessed across all experimental blocks, i.e., during and immediately after stimulation | PMC10105771 | ||
Limitations | The present study used a conventional tDCS setup as applied in previous studies that reported successful tDCS-related dual-task performance benefitsIn addition, to potentially increase blinding efficacy, a double-blind design might be taken into consideration. We carefully implemented certain protocols to standardize testing across all participants, such as written instructions, and minimized interactions with participants | PMC10105771 | ||
Acknowledgements | We thank Josefin Fruck and Hannah Pünjer for their assistance in data collection. | PMC10105771 | ||
Author contributions | D.M., D.A., R.F. conceived and designed the experiment, D.M. analyzed the data under the supervision of R.F., D.M. and R.F. wrote the manuscript, D.A. and A.F. edited, and revised the manuscript. D.M. prepared Figs. | PMC10105771 | ||
Funding | Open Access funding enabled and organized by Projekt DEAL. | PMC10105771 | ||
Data availability | The datasets generated during the current study are available in the PsychArchives repository, 10.23668/psycharchives.8155. | PMC10105771 | ||
Competing interests | The authors declare no competing interests. | PMC10105771 | ||
References | PMC10105771 | |||
Background | Rates of advance directive (AD) completion in the United Kingdom are lower than in the United States and other western European countries, which is especially concerning in light of the COVID-19 pandemic. UK residents typically complete an advance decision to refuse care (ADRT), whereas US versions of ADs present a more neutral choice between comfort-oriented or life-prolonging care. The purpose of this study is to test whether this framing affects decision making for end-of-life care and if this is affected by exposure to information about the COVID-19 pandemic. | PMC10196681 | ||
Methods | In an online experiment, 801 UK-based respondents were randomly allocated to document their preferences for end-of-life care in a 2 (US AD or UK ADRT) by 2 (presence or absence of COVID-19 prime) between-subjects factorial design. | PMC10196681 | ||
Results | Most (74.8%) of participants across all conditions chose comfort-oriented care. However, framing comfort care as a refusal of treatment made respondents significantly less likely to choose it (65.4% v. 84.1%, | PMC10196681 | ||
Conclusions | The UK ADRT significantly reduced the proportion of participants choosing comfort-oriented care, an effect that was heightened in the presence of information about COVID-19. This suggests the current way end-of-life care wishes are documented in the United Kingdom could affect people’s choices in a way that does not align with their preferences, especially in the context of the COVID-19 pandemic. | PMC10196681 | ||
Highlights | deaths, death, infections, infectious disease | INFECTIOUS DISEASE, VIRUS, INFECTIONS | Participants completing an AD framed as an advance decision to refuse treatment were significantly less likely to choose comfort-oriented care than participants completing an AD with a neutral choice between comfort-oriented and life-prolonging care.Exposure to a COVID-19 prime had an interactive effect on documented preferences in the refusal of treatment condition, with these participants even less likely to choose comfort-oriented care.Policy makers and organizations that design templates for advance care planning, particularly in the time of the COVID-19 pandemic, should be aware how the framing of these forms can influence decisions.Evidence suggests that people who have documented their wishes for end-of-life care experience a better quality of death. Specifically, people who have completed advance decisions (ADs) are more likely to receive their preferred care and less likely to die in hospital, and there are fewer communication issues with their surrogate decision makers.While there are cultural and contextual differences between the United States and the United Kingdom that could affect decisions around end-of-life care,While the AD presents a neutral choice between comfort and life-prolonging care, UK citizens are given the option to complete an advance decision to refuse treatment (ADRT). In other words, comfort care is framed as having no treatment at all. It seems likely this framing could have an impact on how people perceive it: studies have shown that patients will accept a treatment that has no chance of improving their condition when the other option is watchful waiting—particularly when the latter is described as “doing nothing.”These decisions have not only become increasingly relevant in light of the COVID-19 pandemic but could also be influenced by exposure to news about infections, hospitalizations, and deaths. Increased mortality salience following deadly disasters has been linked to an increase in risk-seeking behavior,It seems unlikely that all but 4% of the UK population would prefer life-prolonging care, given statistics from previous studies and culturally similar countries. For example, one study found that 65% of respondents in England would choose improving the quality of their life over extending it as the priority for their treatment if they were diagnosed with a serious illness.The aim of this study is, first, to measure the effect of different form templates on decisions about end-of-life care, comparing the US AD with the UK ADRT. In the United States, standard AD forms give a free choice between prioritizing comfort or life-prolonging care. The ADRT form commonly used in the United Kingdom, however, only gives the option of comfort care for anyone completing the form. This study is the first of its kind to experimentally examine the effect of positioning comfort care as refusing treatment in the UK frame, relative to presenting the choices more neutrally in the US frame.The second aim of the study is to identify what, if any, effect priming participants to think about the COVID-19 pandemic has on these choices. The data collection was undertaken in September 2020, between the United Kingdom’s peaks of COVID-19 cases and before the first vaccines were distributed, meaning the threat of the virus was still very salient and real. Therefore, at the beginning of each form template, we add a second manipulation to include (or not) a prime with information about COVID-19.We hypothesized that most participants in all conditions would choose comfort care over life-prolonging care in line with previous research (hypothesis 1). However, we also hypothesized that participants in the UK condition would be more likely to choose life-prolonging care than participants in the US condition, due to the negative framing of comfort care as refusal of treatment (hypothesis 2). As a result of the increase in mortality salience from reflecting on the pandemic, we predicted that participants exposed to a COVID-19 prime before completing the form would be more likely to choose life-prolonging care than comfort care (hypothesis 3). Finally, we hypothesized there would be an interaction between framing and priming, with participants in the UK frame and COVID-19 prime condition even more likely to choose life-prolonging care (hypothesis 4). This is because we predicted that the UK framing of life-prolonging care as accepting treatment would be perceived as the default option, while the threat of infectious disease from the COVID-19 prime would lead to increased conformity to that norm. | PMC10196681 |
Methods | EVENT | A preregistered online randomized experiment was conducted in which participants documented their preferences for end-of-life care, in the event of being unable to communicate their wishes ( | PMC10196681 | |
UK condition | PMC10196681 | |||
US condition |
Following completion of the form, participants were asked additional questions about attitudes toward and experiences of health care, their concerns and experiences with COVID-19, and demographic information such as age, sex, education, and ethnicity. | PMC10196681 | ||
Outcomes | death, dementia | CORONAVIRUS, DISEASE, SECONDARY | The primary outcome is whether participants choose comfort care or life-prolonging care, in 3 domains: 1) as the overall preference for their care, 2) in the case of 4 specific illnesses (being diagnosed with dementia, a brain injury, a disease of the CNS, and other terminal illnesses), and 3) in the case of 5 specific treatments (CPR, admission to the ICU, mechanical ventilation, kidney dialysis, and feeding tube insertion). The 4 conditions are based on the Compassion in Dying living will template,There are also several secondary outcomes and control variables. First, a behavioral measure recorded whether participants clicked on a link to the AD page on the NHS website after completing the form. Second, questions were asked about relevant experiences and attitudes, such as their current health, access to private health insurance, being admitted to an ICU, the death of a loved one, and preferences for decision making with a doctor. Third, questions about coronavirus itself were included: concerns about contracting it and getting seriously ill, worries about loved ones getting seriously ill, whether the participant or any of their loved ones had had it, and how severe those cases were. Finally, demographic information was collected, including age, gender, ethnicity, religion, and education, as it is possible these factors could also influence end-of-life decisions. | PMC10196681 |
Power Calculation | REGRESSION | The necessary sample size to detect a minimum effect size of 0.3 (a small to medium minimum effect size), with 0.80 power and a standard 0.05 alpha error probability, was calculated using G*Power for a Wilcoxon-Mann-Whitney nonparametric test and a logistic regression. The sample size per group was between 160 and 184, so, to be conservative, the study aimed to recruit 200 participants per group, with 800 in total. | PMC10196681 | |
Statistical Analyses | REGRESSIONS | Data were analysed using Wilcoxon-Mann-Whitney nonparametric tests for differences-in-proportions. Further analysis was performed using logistic regressions to determine the main effects of country frame and prime, their interactive effects, and control for additional variables such as age, gender, and ethnicity. To account for multiple hypotheses testing, a Bonferroni-corrected significance level of 0.005 was used for all analyses. Analysis was conducted using Stata 17.0. | PMC10196681 | |
Results | PMC10196681 | |||
Participants | A total of 801 UK resident participants were recruited through Prolific Academic, of whom 60.6% were female, with an average age of 34.08 ± 13.1 y (ranging from 18 to 80 y). Ethnicity was predominantly White at 84.1%, 8.5% Asian, 2.5% Black, 3.9% mixed race, and 1% other. Participant Characteristics by Experimental Condition | PMC10196681 | ||
Exploratory Analysis for Overall Goal of Care | REGRESSION, REGRESSIONS | The logistic regressions with control variables also highlighted further findings for which explicit hypotheses were not included in the preregistration. In particular, older respondents, respondents for whom religion was important, or respondents who were very worried about COVID-19 were more likely to choose comfort for their care. There were no significant effects of gender or ethnicity on end-of-life preferences.Given the strong influence of age on patient preferences, a subgroup analysis was performed, separating participants above and below the median age and repeating the logistic regression models (see | PMC10196681 | |
Correlations between Choices | Decisions for the overall goal of care, specific illnesses, and specific medical treatments were all highly correlated. Between specific illnesses, these ranged from | PMC10196681 | ||
Documenting End-of-Life Decisions | The self-reported likelihood of formally documenting end-of-life preferences in the near future did not significantly differ across conditions. In the US condition, 35.8% of participants stated they were likely or very likely to do so, compared with 36.6% in the UK condition (z = 1.33, For the behavioral measure, only 24 participants (just under 3%) clicked on the link for more information about Advance Decisions. This was lowest in the UK*COVID-19 prime condition, in which only 1.5% of participants clicked on the link. In the other conditions, this number ranged from 3.4 to 3.6%. Again, there was no main effect of country (z = 0.81, | PMC10196681 | ||
Discussion | cancer, AD | CANCER, VIRUS | This study is the first of its kind to experimentally examine the difference between a US-style AD, in which the choice between comfort and life-prolonging care is presented neutrally, and the ADRT used in the United Kingdom, where comfort care is framed as refusing treatment. This was combined with a COVID-19 prime, to reflect the effect the global pandemic might have had on end-of-life care choices. At the time the data were collected in September 2020, COVID-19 cases in the United Kingdom were rising, new restrictions were being announced, and the vaccination program was still months away. As a result, the risk of catching the virus and becoming seriously ill from it would have been very salient when participants were completing this task.In all conditions, most of our UK-based participants selected comfort care for their overall preference for care and also in the case of their preferences for specific diagnoses. However, this was significantly influenced by the framing of the form participants filled out. As hypothesized, the UK ADRT frame had a significant effect on participants’ choices: framing comfort as refusing treatment significantly reduced the number of participants choosing comfort care, compared with participants who were given a more neutral choice under the US frame. Interestingly, the COVID-19 prime affected only participants given the UK-style form and only for the first question about the overall preferences for their care: respondents in the UK condition and primed with COVID-19 were more likely to choose life-prolonging care. There was no effect on participants in the US condition. This suggests that the effect is not due to a general mortality salience, as this would have had a similar effect in the US frame. Instead, it could be due to an increased desire to conform to standard care as part of the UK manipulation, as the UK frame explicitly stated that standard care focuses on prolonging life. Interestingly, this interaction effect was not observed for the other 4 specific illnesses. One possible explanation to reconcile these findings may be related to the behavioral immune system theoryFor specific treatments, the effect of the country frame also disappeared. Furthermore, while most participants preferred comfort overall, when faced with the types of treatments that would usually be considered aggressive for the end of life, the majority chose to accept them. As no additional information was provided about these treatments, it might be due to a lack of knowledge about what they entail or the likely outcome. This is very likely, given the nonclinical sample, and reports of similar misconceptions during the height of the pandemic, such as patients asking if they could still walk around while on a ventilator.While the country frame (and to a lesser extent, the COVID-19 prime) had some influence on what people chose to prioritize for their end-of-life care, it did not affect their self-reported likelihood to document their preferences in the near future. In both the UK and US conditions, slightly more than one-third of participants indicated they were likely or very likely to do so. This is a positive finding, as one concern about the framing of the ADRT is that it could deter people from making advance care plans at all. However, self-reported likelihood might not necessarily reflect whether people actually go on to write an AD, and only 3% of participants clicked on the link for more information, which is in line with statistics on UK completion rates.In the exploratory analysis of the additional variables collected, several had a significant influence on the choice between comfort or life-prolonging care. Increases in the age of the participants was linked to an increase in choosing comfort care, which is consistent with previous research on the treatment choices of cancer patients.It is important to note that, although the different framing did influence participants’ choices, the country frame, COVID-19 prime, and the interaction between the two account for only 5% of the variance in their preferences for end-of-life care. This rises to just 9% when factors such as age, gender, and ethnicity are included, which suggests that there are more explanatory variables to be identified in future work.This study has also 2 important limitations that may limit its generalizability. The first is the sample itself, which was not fully representative of the UK population and may therefore limit the generalizability of the findings. The participants were more likely to be younger, female, nonreligious, and more educated compared with the general population. In particular, age had a significant impact on participants’ choices, but with only 5.6% of the total sample aged 60 y or older, it was not possible to observe the effects of the experimental conditions on this subgroup in isolation. Moreover, the overwhelming preference for comfort-oriented care is surprising given most participants (71.2%) were younger than 40 y. Previous work has demonstrated that younger people are more likely to choose life-prolonging care,The second limitation is the design of the form that participants filled out. The order in which the questions were presented was not randomized, which could have influenced the way participants answered them. If participants had reflected on specific illnesses or medical treatments before stating their overall goal of care, it might have changed their preferences. Furthermore, to keep the 2 forms as similar as possible, the final design of the UK-style ADRT was quite different from the typical form template. This is because the form is designed only for those who wish to refuse treatment; there is no option for life-prolonging care. If participants were given the choice to simply fill in the form or not, which would be more reflective of real-life decision making, there could have been a very different outcome. However, this would have made the results from the 2 conditions less useful to compare. Clearly, completing an AD is not the same as choosing comfort care, so it is important to separate these 2 constructs in future studies. The participants were also never explicitly asked if they understood refusal of care to mean they would receive no treatment at all, and instead their choice of life-prolonging care is used as a proxy for this. This needs to be examined in more detail.Even with these limitations, these findings have important implications for public policy with regard to documenting preferences for end-of-life care. The percentage of UK residents with an AD is far lower than many comparable Western countries, and it is likely that this disparity is driven in part by the way the question is frequently asked. Instead of comfort care being framed as an equal choice for treatment, it is instead framed as refusing treatment altogether. Just as patients tend to prefer taking action to doing nothing, | PMC10196681 |
Conclusions | This study is the first of its kind to experimentally examine the effect of framing comfort care as a refusal of treatment on people’s choices between comfort or life-prolonging care. While the majority of participants still chose comfort care and personal preferences played a role, this framing made people significantly more likely to choose life-prolonging care. This could have important policy implications, as it may be a factor explaining the unusually low rates of ADRT completion in the United Kingdom. This effect was exacerbated by priming participants to think about COVID-19, which suggests that living through a pandemic could paradoxically make people less likely to engage with advance care planning. If this is the case, it is crucial to find ways to better engage people in this area, particularly during health crises. While the effect of the UK frame also influenced choices for specific illnesses, the effect disappeared and preferences reversed when it came to specific treatments; participants in all conditions were more likely to accept aggressive treatments than to refuse. However, there are some important limitations of the study, particularly that the sample was not representative of the UK population in pertinent ways, such as education, religion, and especially age. Future work must be conducted with a more representative sample to explore how patients make decisions about their treatment and what influences the decisions of clinicians about their patients’ care. | PMC10196681 | ||
Supplemental Material | PMC10196681 | |||
References | PMC10196681 | |||
Supplementary Information | ICH, FIP | FIP | The first-in-patient (FIP) starting dose for oncology agents should be reasonably safe and provide potential therapeutic benefit to the patient. For late-stage oncology patients, this dose is often based on the ICH S9 guidance, which was developed primarily based on experience with cytotoxic chemotherapeutic agents using the rodent STDThe online version contains supplementary material available at 10.1007/s00280-023-04570-3. | PMC10638197 |
Keywords | PMC10638197 | |||
Introduction | cancer, FIP, ICH | MALIGNANCIES, CANCER, FIP | The first-in-patient (FIP) nonclinical safety package is designed to enable an initial risk assessment of the drug candidate, identify appropriate clinical safety monitoring, and define the recommended starting dose (RSD) for the FIP clinical trial. The FIP trial for oncology agents is generally conducted in patients with advanced malignancies, which necessitates careful selection of the RSD to be sufficiently safe, while also potentially providing therapeutic benefit to late-stage cancer patients with limited therapeutic options that enrolled in these trials. Therefore, an optimal balance between safety and clinical benefit is desired, such that the number of patients in initial and subsequent cohorts exposed to potential sub-optimal therapeutic doses of the investigational agent is minimized [Currently, the RSD approach for small molecule oncology agents is detailed in the International Council for Harmonisation (ICH) S9 guidance [Selection of starting dose for clinical trials depends on population (healthy volunteers or patients) and mechanism of action. Prior scientific publications have reviewed the potential approaches to determine the FIP starting dose, with authors generally focusing on the previously described toxicology-based STDA review of 59 approved small molecule oncology MTAs [Since the FIP starting dose for oncology therapeutics is now based on the ICH S9 guidance (or similar guidance from [ | PMC10638197 |
Methods | dose-limiting, toxicities, FIP | STD, FIP | An IQ DruSafe Working Group was formed to evaluate an alternative approach to setting starting doses in oncology FIP clinical studies. The scope was small molecule marketed MTA oncology drugs or those in clinical development that had reached an MTD/RP2D. A database was created capturing 50 fields of information for each of the 92 anonymized compounds provided by 12 pharmaceutical companies (AbbVie, AstraZeneca, Amgen, Boehringer Ingelheim, Bristol Meyers Squibb, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, and Pfizer). An additional 9 fields of data were collected for the alternative starting dose scenario exercise, for a total of 5428 data points. The information collected related to the compound attributes, and nonclinical and clinical safety data. These included general target class, nonclinical toxicology species, and toxicology or clinical study information. Nonclinical and clinical information included doses, exposures (AUC), dose-limiting target toxicities, NOAEL, STD | PMC10638197 |
Results | PMC10638197 | |||
Overview | ICH | The companies were asked to characterize the target class for the compound (Table Target class*Other (With regard to the MTA nonclinical toxicology FIP-enabling packages, 74% were conducted after the implementation of ICH S9. The dosing route was oral in 86% of cases for both nonclinical and clinical studies. The majority of nonclinical dosing regimens were daily for 4 weeks (75% of rodent and 74% of non-rodent studies), corresponding to continuous daily clinical dosing (59%). The distribution of compounds that identified a NOAEL, STD10, or HNSTD is summarized in Table Distribution of NOAEL, STD10, and HNSTD for submitted compounds | PMC10638197 | |
Analysis of nonclinical NOAEL | toxicity, ICH | SECONDARY | The determination of a NOAEL in toxicology studies conducted to support the clinical dosing of new drugs to oncology patients is not a required endpoint in ICH S9 [When assessing criteria for justifying the starting dose in clinical studies, it is important to understand species sensitivity to the compound with the more sensitive species most often being used. In preparing to conduct the analysis for using the alternative NOAEL approach, the submitted products were evaluated for how often a NOAEL was determined or justified in both the rodent and non-rodent toxicity studies. Using the criteria outlined for assessing an alternative NOAEL-based starting dose, 66 (72%) of the products were suitable for the exercise.There were 26 products that did not meet the criteria for the NOAEL-based starting dose assessment (Table Primary and secondary DLTs preventing NOAEL determination in animals and patient DLTs for these compounds | PMC10638197 |
Discussion | NOAEL-based, toxicity, cancer, toxicities, ICH, FIP | CANCER, FIP | The primary goal of selecting a FIP starting dose for cancer patients should be to define a safe dose level that is sufficiently high to potentially result in clinical benefit and to enable rapid identification of the RP2D [Similarly, Le Tourneau et al. reviewed the Scopus abstract database for FIP trials of MTAs in cancer patients and concluded the derivation of the starting dose was safe but was based on diverse practices using a variety of nonclinical toxicological parameters (e.g., MTD, TDL, LD10, NOAEL). This analysis showed that starting doses for MTAs were based on rodent and non-rodent data in similar proportions, and overall, starting doses selected using a toxicity-based method did not exceed the human MTD in 96% of clinical trials reviewed. A median of five dose levels was required from the starting dose to the clinical MTD, which is a similar number of cohorts reported by Mittapalli [The analysis performed in this paper provides an opportunity to review the optimal starting dose algorithm(s) to enable a reduction in the number of cancer patients starting clinical trials at sub-optimal therapeutic doses and to minimize the number of dose escalation steps and time needed to reach MTD or RP2D. An analysis of 92 small molecule oncology compounds from 12 pharmaceutical companies showed that in more than half of cases the approach used was more conservative than the ICH S9 guideline dictates. In some cases, a less aggressive starting dose was justified based on the data. However, it was rare for starting doses to be significantly more aggressive than the guideline.Our analysis demonstrates that a less conservative approach to starting dose selection, such as basing the FIP dose on the nonclinical NOAEL without a safety factor, would generally be safe and would reduce the number of dose levels tested in the clinic. To encourage sponsors to be more aggressive in starting dose selection for small molecule oncology therapeutics, thereby reducing the number of patients treated at sub-efficacious dose levels and accelerating drugs to approval, we encourage sponsors to propose and discuss with regulatory agencies using this alternative NOAEL-based method to justify higher starting doses when the data supports it as outlined in Fig. Proposed decision tree for justifying starting dose for FIP oncology studiesIn the majority of cases evaluated (82%), the NOAEL-based alternative starting dose would have been safe. The number increases to 93% when evaluating those that originally used the HNSTD or STD10 approach. The reasons for not using the HNSTD or STD10 approach vary, but one common alternative is the use of MABEL. The MABEL is typically applied to immune-oncology agents, mostly those with agonist activity, for which the pharmacological activity is of great safety concern and the translation from nonclinical to clinical safety has lower confidence [Of the 12 (18%) cases where the NOAEL-based alternative starting dose would have exceeded the MTD/RP2D, nonclinical toxicities would have been monitorable in all but one instance. Of these 12 cases, only 3 used HNSTD or STD10 to select the actual starting dose. Others used MABEL, NOAEL with safety factors, or pharmacokinetic/pharmacodynamic modeling. Of the 12 cases, 8 NOAEL-based alternative starting doses were within two–threefold of the clinical MTD/RP2D. Those within twofold of the RP2D would not likely have resulted in significant toxicity as this is within a typical single cohort escalation. Those within threefold might be a slightly more, but possibly acceptable, risk of causing toxicity. Of the remaining 4 cases with NOAEL-based starting doses between 4.5- and 20-fold the MTD/RP2D, 2 were IO agents using IT delivery, one of which did not determine the clinical MTD (implying RP2D was not based on tolerability). IT delivery is often limited by the maximum feasible dose determined by formulation or delivery volume restrictions. In the other 2 cases, both with a NOAEL-based alternative starting dose sixfold the MTD/RP2D, 1 used a NOAEL-based approach with a 50-fold safety factor, implying heightened safety concern, while the other used a LOAEL-based approach with a sixfold safety factor. It should be noted that in the latter case, the actual starting dose was not only the same as the NOAEL-based alternative but was not tolerated and the RP2D was 1/5 the starting dose. Therefore, these 4 cases would not be likely candidates for the NOAEL-based alternative method.Extensive analysis of translation from nonclinical toxicology studies to clinical findings have been previously published [The decision tree (Fig. In conclusion, retrospective analysis of previously determined starting doses for oncology therapeutics clearly indicate more aggressive starting dose selection should be considered to reduce the use of sub-therapeutic dose levels in oncology patients, and accelerate patient access to effective drugs [ | PMC10638197 |
Acknowledgements | The database was developed under the auspices of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), a not-for-profit organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators and the broader research and development community. DruSafe is a Leadership Group of the IQ Consortium with the mission to advance nonclinical safety sciences and impact the global regulatory environment. We would like to thank the following biopharmaceutical companies and their scientists that contributed to the IQ Consortium database design and/or data collection: Abbvie (Sherry Ralston), AstraZeneca, Amgen (Katsu Ishida), Boehringer Ingelheim (Florian Colbatzky), Bristol Meyers Squibb, Eisai, Eli Lilly, Gilead (Carrie McMahon), GlaxoSmithKline, Janssen (Manisha Sonee), Merck (Danuta Herzyk), Novartis (Li Li), Pfizer, and UCB. Also, thanks to James Vergis for managing the database at the IQ Consortium. | PMC10638197 | ||
Data availability | The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10638197 | ||
Declarations | PMC10638197 | |||
Conflict of interest | On behalf of all authors, the corresponding author states that there is no conflict of interest. | PMC10638197 | ||
References | PMC10638197 | |||
Purpose: | mRCC, P., Cancer | METASTATIC RENAL CELL CARCINOMA, CANCER | Current address for P. Iruku: Cone Health Cancer Center, Greensboro, North Carolina; and current address for M. Amirault, Massachusetts General Hospital, Boston, Massachusetts.
Immune checkpoint inhibitor and VEGFR inhibitor combinations are effective treatments for patients with metastatic renal cell carcinoma (mRCC). This phase I/II clinical trial evaluated the safety and efficacy of pembrolizumab and cabozantinib in patients with mRCC. | PMC10249509 |
Experimental Design: | non-clear, clear-cell | ONCOLOGY, DISEASE | Eligible patients had mRCC with clear-cell or non-clear cell histology, adequate organ function, Eastern Cooperative Oncology Group 0–1 performance status, and no prior exposure to pembrolizumab or cabozantinib. The primary endpoint was objective response rate (ORR) at the recommended phase II dose (RP2D). Secondary endpoints included safety, disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). | PMC10249509 |
Results: | nausea, diarrhea, fatigue, encephalopathy, dysgeusia, weight loss, anorexia | HYPOPHOSPHATEMIA, ADVERSE EVENTS, ENCEPHALOPATHY, SYNDROME, HYPERTENSION, ANOREXIA | Forty-five patients were enrolled. A total of 40 patients were treated at the RP2D of pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily, 38 of which were evaluable for response. The ORR was 65.8% [95% confidence interval (CI), 49.9–78.8] for all evaluable patients [78.6% as first-line therapy, 58.3% as second-line therapy]. The DCR was 97.4% (95% CI, 86.5–99.9). Median DoR was 8.3 months (interquartile range, 4.6–15.1). At a median follow-up of 23.54 months, the median PFS was 10.45 months (95% CI, 6.25–14.63) and median OS was 30.81 months (95% CI, 24.2–not reached). The most common grade 1 and/or 2 treatment-related adverse events (TRAE) were diarrhea, anorexia, dysgeusia, weight loss, and nausea. The most common grade 3 and/or 4 TRAEs were hypertension, hypophosphatemia, alanine transaminase elevation, diarrhea, and fatigue. There was one grade 5 TRAE of reversible posterior encephalopathy syndrome related to cabozantinib. | PMC10249509 |
Conclusions: | toxicity | Pembrolizumab and cabozantinib treatment in patients with mRCC demonstrated encouraging preliminary efficacy and a manageable toxicity profile comparable with other available checkpoint inhibitor-tyrosine kinase inhibitor combinations. | PMC10249509 | |
Trial Registration: | ClinicalTrials.gov Identifier: NCT03149822 | PMC10249509 | ||
Significance: | This study evaluated the safety and effectiveness of the combination of pembrolizumab and cabozantinib in patients with mRCC. The safety profile was manageable. The combination showed promising activity with an objective response rate of 65.8%, median PFS of 10.45 months, and median OS of 30.81 months. | PMC10249509 | ||
Introduction | Kidney cancer, cancer | KIDNEY CANCER, DISEASE, CANCER | Kidney cancer is an important cancer worldwide with an estimated 431,000 new cases globally and 81,800 new cases in the United States with a 5-year survival of 13% for stage IV disease (Pembrolizumab, a potent and highly selective humanized monoclonal anti-PD-1 antibody, has demonstrated survival benefit in combination with the VEGFR TKIs axitinib and lenvatinib in the 1 L setting (In this phase I/II, open-label study, we evaluated the safety, tolerability, and antitumor activity of pembrolizumab and cabozantinib in patients with mRCC. | PMC10249509 |
Materials and Methods | PMC10249509 | |||
Patient Eligibility | pneumonitis, RPLS, toxicities, clear-cell RCC, non-clear, RCC, autoimmune disease | ADVERSE EVENT, PNEUMONITIS, IMMUNODEFICIENCY, REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME, WOUND DEHISCENCE, ONCOLOGY, OSTEONECROSIS OF THE JAW, AUTOIMMUNE DISEASE, RCC | Eligible patients had histologically confirmed, locally advanced, recurrent, or mRCC. Patients with clear-cell RCC (ccRCC) or non-clear cell RCC (nccRCC) were included. Key inclusion criteria were Eastern Cooperative Oncology Group 0–1 performance status, adequate organ function, and resolution of prior treatment-related toxicities to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade 1 or less. Key exclusion criteria were prior treatment with pembrolizumab or cabozantinib; prior anticancer mAb therapy within 4 weeks and prior anticancer targeted small-molecule therapy within 2 weeks of day 1 of study treatment; active autoimmune disease requiring systemic treatment in the past 2 years, diagnosis of immunodeficiency, current systemic steroid therapy equivalent to ≥10 mg/day of prednisone; history of osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome (RPLS), pneumonitis, or wound dehiscence within 6 months of study; or uncontrolled or significant intercurrent cardiovascular, gastrointestinal, or pulmonary disorders. There was no requirement or limit on the number of prior anticancer therapies. | PMC10249509 |
Study Design and Treatment | Phase I dose escalation was done using a standard 3 + 3 design. Phase II dose expansion was done using a Simon two-stage design (The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. The protocol was approved by the Institutional Review Board and all patients provided written informed consent prior to study procedures. | PMC10249509 | ||
Study Endpoints | toxicities, tumor, DLT | DISEASE, BONE METASTASES, TUMOR | The primary endpoint of the overall study was objective response rate (ORR) in patients treated at the RP2D of pembrolizumab and cabozantinib. Secondary endpoints included dose-limiting toxicities (DLT), MTD, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of treatment, time to response, and duration of response (DoR). Exploratory endpoints included PD-L1 status of archival tumor samples and serum bone turnover markers in patients with bone metastases. | PMC10249509 |
Antitumor Activity Assessments | Tumor | TUMOR | Tumor assessments were performed at baseline and every 9 weeks on study. Tumor responses were evaluated based on investigator assessment per RECIST 1.1 ( | PMC10249509 |
Safety Assessments | DLT was defined as any treatment-related AE (TRAE) grade 3 or higher that occurred during the 21-day DLT assessment window. Any dose-escalation patient who did not complete the DLT period for any reason other than a DLT was replaced by an additional patient at that same dose level. DLT-evaluable patients were required to have received the planned cycle 2 dose of pembrolizumab within 7 days of the planned administration date and to have taken 75% or more of the planned doses of cabozantinib in cycle 1. The MTD was defined as the highest dose level with no more than 1 DLT reported in 6 DLT-evaluable subjects. The RP2D of cabozantinib was selected on the basis of the clinical data, not exceeding the MTD. If <2/6 subjects experience a DLT at 60 mg daily during dose escalation, then 60 mg daily would be considered the RP2D.AEs were recorded throughout the study and during the follow-up period and graded according to NCI CTCAE Version 4.0 ( | PMC10249509 | ||
Exploratory Assessments | tumor | TUMOR | PD-L1 testing was performed on archival tumor tissues by Discovery Life Sciences (formerly QualTek Molecular Laboratories) using a previously validated IHC assay for PD-L1 using the Merck & Co., Inc proprietary mouse mAb clone 22C3 for the testing of formalin-fixed, paraffin-embedded tissues ( | PMC10249509 |
Statistical Analysis | PD, death | DISEASE | The planned enrollment was estimated to be 6–9 evaluable patients in phase I and 20–38 evaluable patients in phase II. For the primary endpoint of ORR, a Simon two-stage design was used to test the null hypothesis that ORR ≤ 0.20 versus the alternative that ORR ≥ 0.50. After enrollment of 20 evaluable patients in the first stage, the trial would be terminated if 2 or fewer patients respond. If the trial continues to the second stage, a total of 38 patients would be studied. Patients from the phase I dose escalation who were treated at the RP2D were included in the efficacy assessments in Simon stage 1 of the phase II dose expansion.The ORR, along with a 95% confidence interval (CI), was estimated. The PFS and OS survival curves and medians were estimated using the Kaplan–Meier method and reported with the corresponding two-sided 95% Brookmeyer–Crowley CI, from the on-treatment date to progressive disease (PD), death, or data cut-off date. All statistical analyses were performed by an independent statistician to ensure unbiased data review and conducted on R version 4.1.0, R Core Team (2021). | PMC10249509 |
Data Availability Statement | Source data generated in this study are not publicly available due to compromise of patient privacy. Derived data supporting the findings of this study may be available from the corresponding author upon request. | PMC10249509 | ||
Results | PMC10249509 | |||
Patients | toxicity | ONCOLOGY, RCC | Between October 2017 and August 2020, 45 patients were enrolled (8 patients in phase I and 37 patients in phase II) across five sites within the University of Colorado/UCHealth system. A total of 40 patients were treated at the RP2D and were evaluable for PFS and OS, and 38 patients were evaluable for response (CONSORT diagram and patient disposition. DLT, dose-limiting toxicity; RP2D, recommended phase II dose; P, pembrolizumab; C, cabozantinib.Baseline characteristicsAbbreviations: CPI, checkpoint inhibitor; ECOG, Eastern Cooperative Oncology Group performance status; IMDC, International Metastatic RCC Database Consortium; IQR, interquartile range; VEGFRi, vascular endothelial growth factor receptor inhibitor. | PMC10249509 |
MTD and DLT Evaluation | Eight patients were enrolled in phase I [5 patients in the first cohort of pembrolizumab 200 mg and cabozantinib 40 mg (2 were not evaluable for DLT due to missing ≥25% of the planned cabozantinib doses in cycle 1, not related to TRAE) and 3 patients in the second cohort of pembrolizumab 200 mg and cabozantinib 60 mg]. There were no DLTs observed. The MTD and RP2D were determined to be pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally daily. | PMC10249509 | ||
Safety | RPLS | REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME, ADVERSE EVENT | The most common TRAEs in all 45 patients are reported in TRAEs in ≥10% of patients and all grade ≥3Abbreviations: AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; No., number of patients; RPLS, reversible posterior leukoencephalopathy syndrome.
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Efficacy | PD, tumor, clear-cell renal cell carcinoma, non-clear cell renal cell carcinoma | EVENTS, TUMOR, BEST | Thirty-eight patients were evaluable for tumor response at the RP2D (pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally daily). The ORR was 65.8% (25/38 patients, 95% CI, 49.9–78.8) with 1 CR, 24 PR, 12 SD, 1 PD. The ORR was 78.6% (11/14) in evaluable patients who received study treatment as 1 L therapy and 58.3% (14/24) among patients who received it as second- or subsequent-line therapy. By type or prior therapy, the ORR was 37.5% in patients who had previously received VEGF/R inhibitor only, 62.5% in patients with prior CPI only, 75% in patients who had received both VEGF/R inhibitor and CPI (either in combination or sequentially), and 78.6% in patients who had received no prior therapy (Best response by RECIST in evaluable patients treated at RP2D (pembrolizumab 200 mg i.v. every 3 weeks and cabozantinib 60 mg orally once daily).Abbreviations: ccRCC, clear-cell renal cell carcinoma; nccRCC, non-clear cell renal cell carcinoma.Clinical activity of pembrolizumab and cabozantinib. All 40 patients treated at the RP2D were included in the survival analyses. There were 33 PFS events and 16 OS events. The median PFS was 10.45 months (95% CI, 6.25–14.63; Kaplan–Meier curves of PFS ( | PMC10249509 |
Exploratory Studies | PD, tumor, MPS | TUMOR, BONE METASTASES | There were 44 samples of archival tissue available for PD-L1 testing, 40 of which (90.9%) were interpretable and four samples which did not have tumor in the specimen. Of the 40 evaluable samples, 32 (80.0%) had PD-L1 tumor MPS ≥ 1. The ORR was 69% in patients with PD-L1–positive samples and 50% in patients with PD-L1–negative samples. The median MPS of patients with an objective response was 2.5 (range, 0–100) as compared with 10 (range, 0–85) in patients without a treatment response. Two patients with PD had MPS of 20 and 70. The patient with CR had MPS 40.Twenty-three of 26 patients with bone metastases had bone turnover markers collected at baseline. Very few patients had elevated bone turnover markers at baseline: 1 for beta-cross-linked C-terminal telopeptide (β-CTX; 4.3%), 3 for BS-ALP (13.0%), and 3 for P1NP (13.0%). The ORR in patients with bone metastases was 38.5%. At the time of the first on-treatment scans at 9 weeks, P1NP had decreased in all patients regardless of treatment response. Among patients with PD (2 patients) or a PR (6 patients) who had bone turnover markers collected at baseline and at 9 weeks, change in β-CTX and BS-ALP was concordant with radiographic response in 71.4% and 62.5% patients, respectively. | PMC10249509 |
Discussion | tumor, RCC | TUMOR, BONE METASTASES, RCC | We conducted this phase I/II study of pembrolizumab and cabozantinib beginning in 2017, prior to the FDA approvals of combination CPI-TKI therapies including pembrolizumab and axitinib in 2019, and nivolumab and cabozantinib and pembrolizumab and lenvatinib in 2021. In our study, the primary endpoint of ORR for all patients treated at the RP2D was met, with ORR 65.8%. The ORR was 73.3% among 1 L patients and 56% among 2 L patients. These results are better than historical results from cabozantinib alone (33% in 1 L and 21% in 2 L+; refs. The safety profile of pembrolizumab plus cabozantinib was manageable and generally consistent with AEs reported with other CPI-TKI combinations. As with the phase I nivolumab and cabozantinib study (Our exploratory analyses included PD-L1 tumor testing in all patients with archival tissue and bone turnover markers in patients with bone metastases at baseline. In contrast to previously seen responses to pembrolizumab in advanced RCC with positive PD-L1 expression ( | PMC10249509 |
Limitations | tumors | TUMORS | Inherent to small phase I/II studies, the main limitations of this clinical trial include small number of patients, single-arm design with no comparator treatment arm, and absence of randomization. Another limitation is the heterogeneity of the patients included in this study. Because of demonstrated activity of cabozantinib in both ccRCC and nccRCC, we included patients with both histologic subtypes. This may have diluted out the true ORR of this combination in ccRCC tumors alone. However, although numbers of patients with nccRCC were small and no formal conclusions can be made, a response rate of 50% (3/6) gave us insight into potential activity of this CPI-TKI combination in nccRCC. These results are consistent with those of the phase II KEYNOTE-B61 study of 147 untreated patients with metastatic nccRCC which showed promising results of ORR 47.6%, DCR 79.3%, 6-month PFS 72.3%, 6-month OS 87.8% (Our study was initially designed with historical comparisons with single-agent cabozantinib. As cabozantinib monotherapy has approval in both 1 L and ≥2 L settings for mRCC, we also included patients regardless of line of therapy. As ORR is expected to be highest with 1 L and lower with 2 L therapies, combining these cohorts could have overestimated the response in the 2 L setting and underestimated the response in the 1 L setting. What we observed was ORR of 65.8% in all response-evaluable patients, ORR 73.3% (11/15 patients) in 1 L and ORR 56% (14/25 patients) in the 2 L setting, which is similar to the reported ORR with other combinations in 1 L or 2 L settings, and higher when compared with cabozantinib alone in these settings. | PMC10249509 |
Conclusions | toxicity | The combination of pembrolizumab and cabozantinib treatment in patients with mRCC demonstrated encouraging preliminary efficacy that is comparable with other available CPI-TKI combinations with a manageable toxicity profile. Further prospective evaluation of pembrolizumab and cabozantinib is warranted, especially in the 2 L treatment setting and in patients with nccRCC. | PMC10249509 | |
Supplementary Material | clear cell renal cell carcinoma | CLEAR CELL RENAL CELL CARCINOMA, EVALUABLE, BEST | Supplemental Figure S1: Kaplan-Meier curves of (A) progression-free survival (PFS) and (B) overall survival (OS) for patients with clear cell renal cell carcinoma histology (N=34). Vertical lines show censored patientsClick here for additional data file.Best Response by RECIST in Evaluable Patients Treated at RP2D (Pembrolizumab 200 mg IV Q3W and Cabozantinib 60 mg PO QD) by Prior TherapyClick here for additional data file.Best Response by RECIST in Evaluable Patients Treated at the Pembrolizumab 200 mg IV Q3W and Cabozantinib 40 mg PO QD CohortClick here for additional data file. | PMC10249509 |
Acknowledgments | Cancer | ONCOLOGY, CANCER | We are grateful to the patients who participated in this study, their caretakers, and families. In addition, we thank the study coordinators, nurses, and pharmacy teams at all the study sites, the University of Colorado Cancer Center Cancer Clinical Trials Office, and Oncology Clinical Research Support Team.
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Authors’ Disclosures | OnQuality, Cancer | ONCOLOGY, CANCER, MOORE | E.R. Kessler reports grants from Merck during the conduct of the study; grants from Bristol Myers Squibb, Seattle Genetics, Eli Lily, and AstraZeneca outside the submitted work. J. Moore reports other from Merck outside the submitted work. T.W. Flaig reports other from MERCK and Exelixis during the conduct of the study; other from Aurora Oncology outside the submitted work; in addition, T.W. Flaig has a patent to 2 patents in early stage bladder detection and treatment issued and licensed. E.T. Lam reports grants and other from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.; grants from NCI (HHS – NIH) Cancer Center Support Grant P30CA046934, Colorado Cancer Foundation, and NIH/NCI Paul Calabresi Award for Clinical Oncology Research 5K12CA086913 during the conduct of the study; grants and personal fees from Calithera Biosciences and Exelixis; grants from Advaxis, Amgen, Argos Therapeutics, Arrowhead Pharmaceuticals, Astellas Pharma, Bristol-Myers Squibb, Constellation Pharmaceuticals, Decibel Therapeutics, Forma Therapeutics, Peloton Therapeutics, Harpoon Therapeutics, OnQuality Pharmaceuticals, Pfizer, Phosplatin Therapeutics, and Genentech/Roche outside the submitted work. No disclosures were reported by the other authors. | PMC10249509 |
Role of the Funder/Sponsor | Cancer | CANCER | This was an investigator-initiated study coordinated by the University of Colorado Cancer Center (sponsor) and E.T. Lam (principal investigator) who were responsible for administering the study and coordinating the subsites involved in the study. The funder did not have a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation or decision to submit the article. The funder has reviewed and approved of the article for publication. | PMC10249509 |
Authors’ Contributions | PMC10249509 | |||
References | PMC10249509 | |||
Background | death | DISEASE PROGRESSION, COVID-19 INFECTION | The COMET-ICE trial demonstrated that sotrovimab clinically and statistically significantly reduces the risk of all-cause > 24-h hospitalization or death due to any cause among patients with COVID-19 at high risk of disease progression. Patient-reported outcomes are important to capture symptom burden of COVID-19 and assess treatment effectiveness. This study investigated symptoms and their impact over the acute phase of COVID-19 infection among patients on sotrovimab versus placebo. | PMC10499766 |
Methods | obesity, asthma, chronic kidney disease, diabetes | OBESITY, DISEASE PROGRESSION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CONGESTIVE HEART FAILURE, ASTHMA, DIABETES | Randomized (1:1), double-blind, multicenter, placebo-controlled, phase 2/3 study in 57 centers across five countries. Participants were non-hospitalized patients with symptomatic, mild-to-moderate COVID-19 and ≥ 1 baseline risk factor for disease progression (aged ≥ 55 years or ≥ 1 of the following: diabetes requiring medication, obesity, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate-to-severe asthma). An intravenous infusion of sotrovimab 500 mg or placebo was administered on Day 1. The FLU-PRO Plus questionnaire was administered once-daily with 24-h recall from Day 1–21, and at Day 29. Intensity and duration of COVID-19 symptoms were determined from area under the curve (AUC) and mean change in total and individual domain scores through Days 7, 14, and 21. Time to symptom alleviation was assessed. | PMC10499766 |
Results | In total, 1057 patients were randomized to sotrovimab (n = 528) or placebo (n = 529). At Day 7, mean decrease in FLU-PRO Plus total score (measured by AUC) was statistically significantly greater for patients on sotrovimab (–3.05 [95% confidence interval (CI) –3.27 to –2.83]) than placebo (–1.98 [95% CI –2.20 to –1.76]; difference –1.07 [95% CI –1.38 to –0.76]; | PMC10499766 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s41687-023-00621-8. | PMC10499766 | ||
Keywords | PMC10499766 | |||
Introduction | SARS | SEVERE ACUTE RESPIRATORY SYNDROME | Sotrovimab is an Fc-engineered pan-sarbecovirus human monoclonal antibody, which was developed for the treatment of COVID-19 from a parental antibody isolated from a survivor of the severe acute respiratory syndrome (SARS) outbreak in 2003 [The Globally, COVID-19 is associated with significant clinical, public health and economic burden, leading to missed school and work to recover from illness [In COMET-ICE, the FLU-PRO Plus questionnaire was used to assess symptoms and impacts of COVID-19, along with the Short Form-12 (SF-12) Hybrid questionnaire (SF-12 plus the full SF-36 domains of vitality and physical role) to measure self-reported functional health and wellbeing, and the validated, patient-reported Work Productivity and Activity Impairment (WPAI) tool to quantitively assess absenteeism, presenteeism, work productivity loss, and activity impairment. Here we report the results for these PRO assessments in the COMET-ICE trial up to Day 29. | PMC10499766 |
Methods | COMET-ICE was a randomized, double-blind, multicenter, placebo-controlled phase 2/3 study, involving 57 centers across five countries (CONSORT-PRO checklist available in Additional file The COMET-ICE study was conducted in accordance with the principles of the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice guidelines, and applicable laws and regulations. Written informed consent was provided by all patients prior to study entry. | PMC10499766 | ||
PRO measurements | fatigue, throat, cough, gastrointestinal, body/systemic, and sense., taste and smell assessments, loss of smell or taste | DISEASE | Questionnaires were administered using an electronic device where possible. A paper PRO option was used in instances where logistical or technical difficulties in using electronic PROs were experienced. FLU-PRO Plus was completed once-daily with a 24-h recall, from Day 1 through Day 21, and then at Day 29, Week 8, and Week 12. Data through Day 29 are reported in this manuscript.COVID-19 symptoms were assessed across the 32 FLU-PRO Plus items and predominantly scored on a five-point severity scale (higher scores indicating more severe symptoms). Severity and duration of symptoms were quantified using the averaged change from baseline in FLU-PRO Plus score (as measured by area under the curve [AUC]) through Day 7, and through Day 14 and Day 21. FLU-PRO Plus total score did not include taste and smell assessments (i.e., sense domain) and these were instead accounted for as a separate binary score; individual domains were nose, throat, eyes, chest/respiratory, gastrointestinal, body/systemic, and sense.Subgroup analyses by symptom severity at baseline were performed for the FLU-PRO Plus endpoints among patients with ≥ 2 symptoms of moderate/higher intensity and those with < 2 symptoms of moderate/higher intensity.Time to sustained (≥ 48 h) symptom alleviation (i.e., responder definition), was measured by the FLU-PRO Plus over the first 21 days. Sustained (≥ 48 h) symptom resolution was defined as the absence of the majority of core symptoms of COVID-19 except for cough and fatigue items scoring no more than “Somewhat” in severity, but loss of smell or taste allowed; this definition was developed in line with the U.S. Food and Drug Administration (FDA) draft guidance [Health-related quality of life was measured by the SF-12 Hybrid, an established measure of health-related quality of life which has demonstrated validity in many disease areas [ | PMC10499766 |
Statistical analysis | SECONDARY | Change in FLU-PRO Plus total score (AUC) through Day 7 was a secondary trial endpoint, formally tested with an alpha level of 5% (two-sided) after adjustment for multiplicity using a pre-specified testing hierarchy (Fig. S1 in Additional file Subgroup analyses by symptom severity were adjusted for treatment, baseline value, age group, duration of symptoms group, sex, and region, along with a treatment by subgroup interaction term.Missing data, which were mostly due to challenges with electronic questionnaire software, failure to complete paper questionnaires, or lost-to-follow-up data, were imputed using a modified last-observation carried forward approach for the final assessment only (i.e., Day 7, Day 14, or Day 21). If a FLU-PRO score was missing, the last non-missing, post-baseline score from that week (i.e., Day 2–6 for missing Day 7, Day 8–13 for missing Day 14, and Day 15–20 for missing Day 21) was carried forward as the Day 7/14/21 score. If no non-missing score was available, no score was imputed and the AUC was not calculated.Time to sustained (≥ 48 h) symptom alleviation was analyzed using the Kaplan–Meier methods and a log-rank test stratified by region, duration of symptoms group, age group, and sex.For the exploratory endpoints of WPAI and SF-12 Hybrid, mean change in scores were summarized and no formal statistical analysis was conducted. | PMC10499766 |
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