Speed/Accuracy Trade-Off between the Habitual and the Goal-Directed Processes

Instrumental responses are hypothesized to be of two kinds: habitual and goal-directed, mediated by the sensorimotor and the associative cortico-basal ganglia circuits, respectively. The existence of the two heterogeneous associative learning mechanisms can be hypothesized to arise from the comparative advantages that they have at different stages of learning. In this paper, we assume that the goal-directed system is behaviourally flexible, but slow in choice selection. The habitual system, in contrast, is fast in responding, but inflexible in adapting its behavioural strategy to new conditions. Based on these assumptions and using the computational theory of reinforcement learning, we propose a normative model for arbitration between the two processes that makes an approximately optimal balance between search-time and accuracy in decision making. Behaviourally, the model can explain experimental evidence on behavioural sensitivity to outcome at the early stages of learning, but insensitivity at the later stages. It also explains that when two choices with equal incentive values are available concurrently, the behaviour remains outcome-sensitive, even after extensive training. Moreover, the model can explain choice reaction time variations during the course of learning, as well as the experimental observation that as the number of choices increases, the reaction time also increases. Neurobiologically, by assuming that phasic and tonic activities of midbrain dopamine neurons carry the reward prediction error and the average reward signals used by the model, respectively, the model predicts that whereas phasic dopamine indirectly affects behaviour through reinforcing stimulus-response associations, tonic dopamine can directly affect behaviour through manipulating the competition between the habitual and the goal-directed systems and thus, affect reaction time

OA11.04 Volrustomig + platinum doublet chemotherapy (CTx) in first-line non-small cell lung cancer (NSCLC): Phase 1b trial update

Introduction: Volrustomig, a novel PD-1/CTLA-4 bispecific antibody, has shown robust pharmacodynamic effect and clinical promise in multiple advanced solid tumors (Tran, AACR 2022; Albiges, ASCO 2022; Voss, ESMO 2023), and especially in PD-L1-negative first-line (1L) NSCLC (Ahn, ESMO 2022). PD-L1-negative NSCLC is a disease segment of key unmet need, with limited benefit gained from addition of anti-PD-(L)1 therapy alone to CTx, and where anti-PD-(L)1/anti-CTLA-4 therapy + CTx has previously shown clinical potential (Paz-Ares, Lancet Oncol 2021; Johnson, JCO 2023). Here we report updated results from patients with 1L advanced NSCLC treated with volrustomig 750mg + CTx in a global Phase 1b study. Methods: Patients with 1L advanced NSCLC were treated with volrustomig 750mg + CTx Q3W based on histology: 120 nonsquamous (Nsq) NSCLC patients enrolled over two different time periods (Cohort 1A: n=66; Cohort 1B: n=54) and 20 squamous (Sq) NSCLC patients (Cohort 2). The primary endpoint was objective response rate (ORR) in the Nsq cohorts and safety in the Sq cohort. Secondary endpoints included safety, tolerability, and disease control rate (DCR). Exploratory endpoints included receptor occupancy and pharmacodynamic biomarkers of CTLA-4 blockade. Results: Among 140 patients enrolled, 89 had PD-L1 tumor cell expression (TC) \u3c1% NSCLC (63.6%), reflecting the unmet need and previously seen benefit of CTLA-4 inhibition in this population; median age was 68.0 years, 73.6% were males, 67.9% with ECOG performance status 1, 15.7% with liver metastases, and 15% with brain metastases. Efficacy outcomes are shown in the Table. Nearly all patients achieved disease control. Among evaluable patients with PD-L1 TC \u3c1%, ORR in the Nsq (n=78) and Sq (n=10) cohorts was 42.3% and 50.0%, respectively. Median number of cycles was 6 (range 1-39); 97.1% and 75.7% of patients experienced all-grade and grade 3/4 treatment-related adverse events (AE), respectively. Seven treatment-related deaths occurred (two of which were volrustomig-related immune-related AEs): 6 in Cohort 1A, 0 in Cohort 1B, 1 in Cohort 2. Clinical peripheral T cell flow cytometry, TCR sequencing, and single-cell sequencing demonstrated greater T cell proliferation and memory T cell activation with volrustomig 750mg + CTx versus anti-PD1 + CTx. Conclusions: Volrustomig 750mg + CTx demonstrates robust PD-1/CTLA-4 blockade, manageable safety, and promising efficacy in 1L advanced NSCLC, especially in patients with PD-L1 TC \u3c1%. The ongoing phase 3 EVOLVE-Lung02 trial (NCT05984277) is evaluating volrustomig + CTx for metastatic NSCLC with PD-L1 TC \u3c50%. [Formula presented] Keywords: NSCLC, immunotherapy, chemotherap

OA11.04 Volrustomig + platinum doublet chemotherapy (CTx) in first-line non-small cell lung cancer (NSCLC): Phase 1b trial update

Introduction: Volrustomig, a novel PD-1/CTLA-4 bispecific antibody, has shown robust pharmacodynamic effect and clinical promise in multiple advanced solid tumors (Tran, AACR 2022; Albiges, ASCO 2022; Voss, ESMO 2023), and especially in PD-L1-negative first-line (1L) NSCLC (Ahn, ESMO 2022). PD-L1-negative NSCLC is a disease segment of key unmet need, with limited benefit gained from addition of anti-PD-(L)1 therapy alone to CTx, and where anti-PD-(L)1/anti-CTLA-4 therapy + CTx has previously shown clinical potential (Paz-Ares, Lancet Oncol 2021; Johnson, JCO 2023). Here we report updated results from patients with 1L advanced NSCLC treated with volrustomig 750mg + CTx in a global Phase 1b study. Methods: Patients with 1L advanced NSCLC were treated with volrustomig 750mg + CTx Q3W based on histology: 120 nonsquamous (Nsq) NSCLC patients enrolled over two different time periods (Cohort 1A: n=66; Cohort 1B: n=54) and 20 squamous (Sq) NSCLC patients (Cohort 2). The primary endpoint was objective response rate (ORR) in the Nsq cohorts and safety in the Sq cohort. Secondary endpoints included safety, tolerability, and disease control rate (DCR). Exploratory endpoints included receptor occupancy and pharmacodynamic biomarkers of CTLA-4 blockade. Results: Among 140 patients enrolled, 89 had PD-L1 tumor cell expression (TC) \u3c1% NSCLC (63.6%), reflecting the unmet need and previously seen benefit of CTLA-4 inhibition in this population; median age was 68.0 years, 73.6% were males, 67.9% with ECOG performance status 1, 15.7% with liver metastases, and 15% with brain metastases. Efficacy outcomes are shown in the Table. Nearly all patients achieved disease control. Among evaluable patients with PD-L1 TC \u3c1%, ORR in the Nsq (n=78) and Sq (n=10) cohorts was 42.3% and 50.0%, respectively. Median number of cycles was 6 (range 1-39); 97.1% and 75.7% of patients experienced all-grade and grade 3/4 treatment-related adverse events (AE), respectively. Seven treatment-related deaths occurred (two of which were volrustomig-related immune-related AEs): 6 in Cohort 1A, 0 in Cohort 1B, 1 in Cohort 2. Clinical peripheral T cell flow cytometry, TCR sequencing, and single-cell sequencing demonstrated greater T cell proliferation and memory T cell activation with volrustomig 750mg + CTx versus anti-PD1 + CTx. Conclusions: Volrustomig 750mg + CTx demonstrates robust PD-1/CTLA-4 blockade, manageable safety, and promising efficacy in 1L advanced NSCLC, especially in patients with PD-L1 TC \u3c1%. The ongoing phase 3 EVOLVE-Lung02 trial (NCT05984277) is evaluating volrustomig + CTx for metastatic NSCLC with PD-L1 TC \u3c50%. [Formula presented] Keywords: NSCLC, immunotherapy, chemotherap

MET: a promising anticancer therapeutic target.

The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors--including identification of predictive biomarkers--as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy

The detour paradigm in animal cognition

In this paper, we review one of the oldest paradigms used in animal cognition: the detour paradigm. The paradigm presents the subject with a situation where a direct route to the goal is blocked and a detour must be made to reach it. Often being an ecologically valid and a versatile tool, the detour paradigm has been used to study diverse cognitive skills like insight, social learning, inhibitory control and route planning. Due to the relative ease of administrating detour tasks, the paradigm has lately been used in large-scale comparative studies in order to investigate the evolution of inhibitory control. Here we review the detour paradigm and some of its cognitive requirements, we identify various ecological and contextual factors that might affect detour performance, we also discuss developmental and neurological underpinnings of detour behaviors, and we suggest some methodological approaches to make species comparisons more robust