Oliceridine as a Novel Selective mu-receptor G-protein Pathway Modulator: A Narrative review

Objective: To review the literature on equianalgesic efficacy and better safety(less respiratory depression and gastrointestinal dysfunction) of oliceridine versus opioid analgesic in moderate to severe postoperative pain. Methodology: A comprehensive literature search was conducted in PubMed (January 2021 to March 2021) using keywords as ‘oliceridine’, ‘ligand biased mu receptor agonist’, ‘acute postoperative pain’, ‘conventional opioids’ and ‘morphine’. All English language full text pre-clinical and clinical research articles were searched. In addition, other data source was from ClinicalTrial. Gov. Data Synthesis: Oliceridine is a novel selective µ (mu)-receptor G-protein pathway modulator. G protein biased mu receptor agonists are a new class of opioids exhibiting analgesic properties at par to morphine with less respiratory depressant properties. Oliceridine a first-in-class intravenous (IV) analgesic has received the US FDA approval in August 2020, for management of moderate to severe acute pain in adults. The drug can be administered in cases where the pain is severe enough to require an intravenous opioid and when alternative treatments become inadequate. Oliceridine is an opioid agonist with a rapid onset of action within two to five minutes, was administered via clinician-administered bolus dosing, patient-controlled analgesia (PCA), or a combination of the two. Bolus dosing was initiated at 1 to 2 mg, with supplemental doses of 1 to 3 mg every one to three hours, as needed, based on individual patient need and previous response to oliceridine in management of acute post-operative pain. If oliceridine was administered via PCA, the loading dose was 1.5 mg, the demand dose was 0.5 mg, and the lockout interval (repeat dose)was six minutes. The clinically relevant concentration range of 0 to 35 ng/ml. It is indicated for short-term use only & limited to hospitals or other controlled clinical settings. Oliceridine requires no dosage adjustments in patients with renal impairment as well as in patient with significant medical complications. Therefore, opioids that bias towards G-protein and away from β arrestin signaling should produce analgesia with reduced side effects.

Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies

A proportion of patients with lung cancer experience long-term clinical benefit with immune checkpoint inhibitors (ICIs). However, most patients develop disease progression during treatment or after treatment discontinuation. Definitions of immune resistance are heterogeneous according to different clinical and biologic features. Primary resistance and acquired resistance, related to tumor-intrinsic and tumor-extrinsic mechanisms, are identified according to previous response patterns and timing of occurrence. The clinical resistance patterns determine differential clinical approaches. To date, several combination therapies are under development to delay or prevent the occurrence of resistance to ICIs, including the blockade of immune coinhibitory signals, the activation of those with costimulatory functions, the modulation of the tumor microenvironment, and the targeting T-cell priming. Tailoring the specific treatments with distinctive biologic resistance mechanisms would be ideal to improve the design and results of clinical trial. In this review, we reviewed the available evidence on immune resistance mechanisms, clinical definitions, and management of resistance to ICIs in lung cancer. We also reviewed data on novel strategies under investigation in this setting.

Frailty and Depression in Late Life: A High-Risk Comorbidity with Distinctive Clinical Presentation and Poor Antidepressant Response

Background Investigate the longitudinal relationship between physical frailty, the clinical representation of accelerated biological aging, and antidepressant medication response in older adults with depressive illness. Methods An 8-week randomized placebo-controlled trial (escitalopram or duloxetine) followed by 10-months of open antidepressant medication treatment (augmentation, switch strategies) was conducted in an outpatient research clinic. 121 adults age > 60 years with Major Depressive (MDD) or Persistent Depressive Disorders and a 24-item Hamilton Rating Scale for Depression (HRSD) > 16 were enrolled. Primary measures assessed serially over 12-months include response (50% reduction from baseline HRSD score), remission (HRSD score < 10), and frailty (non/intermediate frail [0-2 deficits] vs frail [> 3 deficits]); latent class analysis was used to classify longitudinal frailty trajectories. Results A 2-class model best fit the data, identifying a consistently-low frailty-risk (63% of the sample) and consistently-high frailty-risk (37% of the sample) trajectory. Response and remission rates (P’s<.002) for adults in the high-risk frailty class were at least 21 percentage-points worse than those in the low-risk class over 12-months. Furthermore, subsequent frailty was associated with previous frailty (P’s < .01) but not previous response or remission (P’s > .10). Conclusions Antidepressant medication is poorly effective for MDD occurring in the context of frailty in older adults. Furthermore, even when an antidepressant response is achieved, this response does little to improve their frailty. These data suggest that standard psychiatric assessment of depressed older adults should include frailty measures and that novel therapeutic strategies to address comorbid frailty and depression are needed.

Asciminib in Real-Life Clinical Practice, Safety and Efficacy Profile in Chronic Myeloid Leukemia Pretreated Patients

Introduction: asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that potently inhibits aberrant kinase activity of the BCR-ABL1 oncoprotein via allosteric binding. asciminib has shown high efficacy profile in heavily pretreated Chronic Myeloid Leukemia (CML) patients with an adequate safety profile in phase I and III clinical trials. However, data from the use of asciminib in real life setting are still scarce. Methods: We gathered real-life retrospective data from 49 patients with BCR-ABL1 positive CML treated with asciminib (mean dose: 40 mg twice daily) between October 2018 and July 2021 at 33 institutions. The indication of asciminib was made according to the criterion of the attending physician and the drug was granted by Novartis under a controlled access program. Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % IS in all centers. Treatment responses were calculated with the patients at risk at each specific time points. For the event free survival (EFS), the events were treatment discontinuation due to any reason, progression or death. Data collection followed the local regulations for observational studies. Results: Median time on asciminib was 11,69 months for the entire cohort. Patients' characteristics are displayed on Table 1. Most patients were heavily pretreated with at least 3 prior TKI lines in 45 patients (91,83%), 18 of them receiving prior Ponatinib. Switch to asciminib occurred due to intolerance in 32 patients and due to resistance in the remaining 17. Fifteen patients (30,61%) harbored mutations in BCR-ABL1 (3 with a T315 mutation). Regarding efficacy (Table 2), probability of reaching or maintaining previous responses were 94%, 45% and 21% for complete hematological response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR), respectively. Considering probabilities of improving previous response, rates were 40%, 42% and 33% for the same parameters. Probabilities to obtain CCyR and MMR in resistant and intolerant patients were 29% (4/14) vs 55% (6/11) and 27% (4/15) vs 52% (11/21), respectively. Amid the patients previously treated with Ponatinib, probabilities of reaching or maintaining previous response were 53% (9/17) and 35% (6/17) for CCyR and MMR respectively, and 30% (3/10), 23% (3/13) displayed improvement of response. Regarding responses in patients with mutations, 39% (5/13) achieved or maintained CCyR and 31% (4/13) MMR; whereas 20% (2/10) and 18% (2/11) improved such responses. Of the three patients with T315I mutation, one discontinued due to progression to advanced stages, and the rest maintained the previous response. With a median follow-up of 11,69 months, the estimated EFS was 80% (figure 1). In terms of safety (Table 3), the most frequent extra-hematological adverse events (AE) were: fatigue (16,2%), joint pain (13,5%) and nausea (8,1%), most of them grade 1-2. Grade 3-4 AE were observed in 10% of patient (fatigue (2), cholestasis enzyme elevation (1), hypertension (1), pancreatitis (1) and pericardial effusion (1)). Thrombocytopenia was shown as the most frequent AE (16,3%), with 6% of patients suffering from grade 3-4. Dose reduction was required in 15 patients (30,6%). After a median follow up of 51 weeks, 73,5% of the patients remained on treatment. Only fourteen patients discontinued treatment due to progression or loss of efficacy, whereas 6% of patients discontinuing treatment due to intolerance. Conclusions: The results presented are in line with the data obtained in clinical trials, positioning asciminib as a potential safe and efficacious treatment for CML patients with failure to several TKI lines. Figure 1 Figure 1. Disclosures Sanchez-Guijo: Novartis: Consultancy, Honoraria, Research Funding; Celgene/Bristol-Myers-Squibb,: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Garcia Gutierrez: BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding.

Performance Errors Influence Voluntary Task Choices

Humans adjust their behavior after they committed an error, but it is unclear whether and how error commissions influence voluntary task choices. In the present article, we review different accounts on effects of errors in the previous trial (transient error effects) and overall error probabilities (sustained error effects) on behavioral adaptation. Based on this review, we derived five statistical models how errors might influence voluntary task choices. We analyzed the data of three experiments in which participants voluntarily selected one of two tasks before each trial whereby task difficulty, and concomitantly error probability, increased successively for the selected/performed tasks. Model comparison suggested that choice behavior was best explained by a combination of error probability of the performed task, error probability of the alternative task, and whether the previous response was correct or incorrect. The results revealed that participants were most likely to switch tasks in situations where the error probability of the performed task was high, the error probability of the alternative task was low, and after an error on the previous trial. We conclude that task selection processes are influenced by transient and sustained error effects.

Efficacy of selpercatinib after prior systemic therapy in patients with RET mutant medullary thyroid cancer.

6074 Background: Selpercatinib is a first-in-class, CNS active, highly selective, and potent RET kinase inhibitor which has demonstrated durable antitumor activity in patients (pts) with RET altered thyroid cancer and is approved in multiple countries for the treatment of RET fusion+ lung or thyroid cancers. As response rates to cancer therapy usually decline on subsequent lines of therapy, the efficacy of selpercatinib was examined in the context of the last prior therapy received before trial enrollment. Methods: Pts with RET mutant medullary thyroid cancer (MTC) previously treated with multikinase inhibitors (cabozantinib and/or vandetanib) were enrolled in the global LIBRETTO-001 trial (NCT03157128). This post-hoc exploratory intrapatient analysis, based on March 30, 2020 data cutoff date, was performed to compare the retrospective physician-reported objective response rate (ORR) from the last systemic therapy prior to enrollment, as reported in pts case reports, to ORR by independent review committee per RECIST 1.1 with selpercatinib treatment, with each patient serving as his/her own control. Results: Efficacy-evaluable pts, 64% male, 90% white with a median age of 58 years, received prior therapy for MTC (n = 143). Pts had a median of 2 (range 1-8) prior systemic regimens. The ORR on selpercatinib (69%) was markedly higher than for the last prior therapy (10%) received before enrollment. ORR improvements with selpercatinib were observed regardless of prior therapy: cabozantinib (66% vs 14%) or vandetanib (71% vs 12%). Fewer pts had progressive disease as their best overall response with selpercatinib (2/143; 1.4%) compared to last prior therapy (33/143; 23.1%). Notably selpercatinib achieved 62% ORR in pts that did not respond to their previous line of therapy prior to enrolment. This shift from non-responder to responder on selpercatinib therapy was consistent regardless of prior cabozantinib or vandetanib treatment, where pts achieved 57% and 61% ORR respectively when subsequently treated with selpercatinib. In contrast, only 3% of patients did not respond to selpercatinib after a previous response to the immediate prior therapy. Similarly, 5% and 2% of patients were non-responders on selpercatinib after a prior response with cabozantinib and vandetanib therapy respectively. Conclusions: Prior to selpercatinib, response with previous multikinase therapy was rare. By contrast, selpercatinib demonstrated robust efficacy regardless of response to or specific prior therapy in pts with RET mutant MTC. Clinical trial information: NCT03157128.

Liquid biopsy-driven anti-EGFR rechallenge in patients with metastatic colorectal cancer.

3577 Background: The rechallenge with EGFR inhibitors represents an emerging strategy for anti-EGFR pre-treated patients with RAS wild type colorectal cancer (CRC). Unfortunately definitive selection criteria for anti-EGFR rechallenge in this setting are lacking. Very recently RAS wild type status on circulating tumor DNA (ct-DNA) at the time of rechallenge along with already known clinical criteria emerged as a potential watershed for this strategy. In the present study we explored liquid biopsy-driven anti-EGFR rechallenge strategy in the clinical practice for patients with metastatic colorectal cancer. Methods: Ct-DNA from RAS and BRAF wild type metastatic CRC patients previously treated with an anti-EGFR containing therapy was analyzed for RAS/BRAF mutations with the aim to evaluate the rechallenge strategy with anti-EGFR. The ct-DNA was analyzed for RAS-BRAF mutations using pyro-sequencing (PyroMark Q24 MDx Workstation) and nucleotide sequencing (Genetic Analyzer ABI3130) assays. Real-time PCR (Idylla) and droplet digital PCR (QX200 System) were performed to confirm the RAS-BRAF mutation status. Several clinical variables including previous response to anti EGFR containing therapy, tumor sidedness and anti-EGFR free interval were evaluated in relation to outcome. Tumor response evaluation was performed according to RECIST 1.1. Differences between categorical variables were evaluated using the Fisher’s exact test. Survival probability over time was estimated by the Kaplan–Meier method. Significant differences in the probability of survival between the strata were evaluated by log-rank test. Results: Twenty patients were included in the study. All patients were tested for RAS-BRAF mutations in ct-DNA. Fourteen patients (70%) showed a RAS-BRAF WT molecular profile, six patients (30%) showed a KRAS mutation. All the patients with ct-DNA RAS-BRAF WT profile underwent rechallenge with anti-EGFR. In details 11 patients (78.6%) underwent irinotecan+ cetuximab treatment, whereas 3 patients (21.4%) underwent panitumumab monotherapy. As for the outcome results to the rechallenge strategy, the median OS was 7 months (95% CI 5.0 to 13.0), the median PFS was 3 months (95% CI 2.0 to 6.0), the ORR was 27.3% with a DCR of 54.5%. Among the clinical variables evaluated as putative predictive/prognostic factors, previous response to anti-EGFR treatment was related to a not statistically significant improved OS (12 months vs 5 months HR:0.19 p: 0.06) and to a statistically significant improved ORR (75% vs 0% p:0.03). Conclusions: The rechallenge strategy with anti-EGFR confirmed to be feasible in clinical practice. The clinical outcome resulted consistent with the literature data. In addition to the molecular selection through the analysis of ct-DNA for RAS, previous response to anti EGFR treatment is confirmed as a prospective selection criteria for this therapeutic option.

Memory Effects as a Source of Bias in Repeated Survey Measurement

A key advantage of longitudinal data collections is the ability to measure change over time by repeatedly asking the same questions to the same respondents. Estimations based on such longitudinal data, as well as other designs that incorporate repetitions of the same questions, generally rely on the assumption that at each point of data collection, respondents answer the questions independently of their previous responses. This assumption implies that respondents either do not remember their previous responses, or that they at least do not use this information in forming their later responses. This is a strong assumption, given that data collections are becoming more and more frequent, giving respondents less time to forget earlier responses. If respondents do, however, remember both being asked the same question and their previous response, they may be influenced by this information. This form of bias is known as a memory effect. In this chapter, we conceptualize the potential role of respondents’ memory when answering survey questions and propose a model of the cognitive response process that takes potential memory effects into account. This is supplemented with the literature on the cognitive response process, the sparse existing research on memory effects, as well as adjacent literature on dependent interviewing and question order effects. We conclude the chapter by identifying gaps in this literature and highlighting areas that require additional research to further our understanding of memory effects in longitudinal survey research.

A rational model of people's inferences about others' preferences based on response times

There's a difference between someone instantaneously saying "Yes!" when you ask them on a date compared to "...yes." Psychologists and economists have long studied how people can infer preferences from others' choices. However, these models have tended to focus on what people choose and not how long it takes them to make a choice. We present a rational model for inferring preferences from response times, using a Drift Diffusion Model to characterize how preferences influence response time and Bayesian inference to invert this relationship. We test our model's predictions for three experimental questions. Matching model predictions, participants inferred that a decision-maker preferred a chosen item more if the decision-maker spent longer deliberating (Experiment 1), participants predicted a decision-maker's choice in a novel comparison based on inferring the decision-maker's relative preferences from previous response times and choices (Experiment 2), and participants could incorporate information about a decision-maker's mental state of cautious or careless (Experiments 3, 4A, and 4B).

The Yin-yang of Serial Dependence Effects: Every Response is both an Attraction to the Prior Response and a Repulsion from the Prior Stimulus

Visual perceptual decisions can be altered by recent experience. In the “serial dependence” effect, participants’ responses to visual stimuli appear to be biased toward (i.e., attracted to) recently encountered stimuli. Fischer and Whitney (2014) proposed that serial dependence reflects a “continuity field” that promotes visual stability by biasing perception toward the recent past. However, when participants are relatively accurate on the prior trial, there is no discernible difference between attraction to the prior stimulus and attraction to the prior response. To tease apart these alternative explanations of the attraction effect, we developed two complementary analysis techniques that rely on participants’ naturally occurring errors on a trial-by-trial basis, identifying any effect of the prior stimulus and, separately, any effect of the prior response (i.e., each effect could be attractive, repulsive, or absent). Applying these techniques to serial dependence data from a new experiment and four previously published studies, including Fischer and Whitney’s, we found that serial dependencies reflect an attraction to the previous response and repulsion from the previous stimulus, with these effects cancelling each other to different degrees for different experiments. In no case did we find evidence of an attraction to the prior stimulus. These results are consistent with literatures that predate the serial dependence effect: Attraction to prior responses is routinely observed in a wide variety of paradigms and repulsion from prior stimuli is ubiquitous, such as in the tilt aftereffect.