Wendy Hayes's research while affiliated with Bristol-Myers Squibb and other places

Introduction: We aimed to define a baseline radiomic signature associated with overall survival (OS) using baseline computed-tomography (CT) images obtained from patients with non-small cell lung cancer (NSCLC) treated with nivolumab or chemotherapy. Methods: The radiomics signature was developed in patients with NSCLC treated with nivolumab in CheckMate 017, 026, and 063. Nivolumab-treated patients were pooled and randomized to training, calibration, or validation sets using a 2:1:1 ratio. From baseline CT images, volume of tumor lesions was semi-automatically segmented, and 38 radiomic variables depicting tumor phenotype were extracted. Association between the radiomics signature and OS was assessed in the nivolumab-treated (validation set) and chemotherapy-treated (test set) patients in these studies. Results: A baseline radiomic signature was identified using CT images obtained from 758 patients. The radiomic signature used a combination of imaging variables (spatial correlation, tumor volume in the liver, and tumor volume in mediastinal lymph nodes) to output a continuous value, ranging from 0 to 1 (from most to least favorable estimated OS). Given a threshold of 0.55, the sensitivity and specificity of the radiomic signature for predicting 3-month OS were 86% and 77.8%, respectively. The signature was identified in the training set of patients treated with nivolumab and was significantly associated (p < 0.0001) with OS in patients treated with nivolumab or chemotherapy. Conclusions: The radiomic signature provides an early readout of the anticipated OS in patients with NSCLC treated with nivolumab or chemotherapy. This could provide important prognostic information and may support risk stratification in clinical trials.

Background: Treatments for nonalcoholic steatohepatitis (NASH) are urgently needed. Hepatic fat fraction and shear stiffness quantified by magnetic resonance imaging (MRI-HFF) and magnetic resonance elastography (MRE-SS), respectively, are biomarkers for hepatic steatosis and fibrosis. Purpose: This study assessed the longitudinal effects of fibroblast growth factor 21 variant (polyethylene glycol [PEG]-FGF21v) on MRI-HFF and MRE-SS in a NASH mouse model. Study type: Preclinical. Animal model: This study included a choline-deficient, amino acid-defined, high-fat diet (CDAHFD) model and 6-week-old, male C57BL/6J mice (N = 78). Field strength/sequence: This study was performed using: 3T: gradient-echo two-point Dixon and spin-echo (SE) echo-planar imaging elastography (200 Hz) and 7T: SE two-point Dixon and SE elastography (200 Hz). Assessment: MRI and MRE were performed before control diet (CD) or CDAHFD (BD), before PEG-FGF21v dosing (baseline), and after PEG-FGF21v treatment (WK4/8). Regions of interest for MRI-HFF and MRE-SS were delineated by J.L. and H.T. (>5 years of experience each). Fibrosis and steatosis were measured histologically after picrosirius red and H&E staining. Alkaline phosphatase, alanine transaminase, bile acids, and triglycerides (TGs) were measured. Statistical tests: Two-tailed Dunnett's tests were used for statistical analysis; untreated CDAHFD or baseline was used for comparisons. Imaging and histology/biochemistry data were determined using Spearman correlations. Bayesian posterior distributions for MRE-SS at WK8, posterior means, and 95% credible intervals were presented. Results: CDAHFD significantly increased baseline MRI-HFF (3T: 21.97% ± 0.29%; 7T: 40.12% ± 0.35%) and MRE-SS (3T: 1.25 ± 0.02; 7T: 1.78 ± 0.06 kPa) vs. CD (3T: 3.45% ± 0.7%; 7T: 12.06% ± 1.4% and 3T: 1.01 ± 0.02; 7T: 0.89 ± 0.06 kPa). At 7T, PEG-FGF21v significantly decreased MRI-HFF (WK4: 28.97% ± 1.22%; WK8: 20.93% ± 1.15%) and MRE-SS (WK4: 1.57 ± 0.04; WK8: 1.36 ± 0.05 kPa) vs. untreated (WK4: 36.36% ± 0.62%; WK8: 30.58% ± 0.81% and WK4: 2.03 ± 0.06; WK8: 2.01 ± 0.04 kPa); 3T trends were similar. WK8 SS posterior mean percent attenuation ratios (RDI ) were -68% (-90%, -44%; 3T) and -64% (-78%, -52%; 7T). MRI-HFF was significantly correlated with H&E (3T, r = 0.93; 7T, r = 0.94) and TGs (both, r = 0.92). Data conclusions: MRI-HFF and MRE-SS showed PEG-FGF21v effects on hepatic steatosis and fibrosis across 3 and 7T, consistent with histological and biochemical data. Level of evidence: 1 TECHNICAL EFFICACY STAGE: 2.

Programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors target the important molecular interplay between PD-1 and PD-L1, a key pathway contributing to immune evasion in the tumor microenvironment (TME). Long-term clinical benefit has been observed in patients receiving PD-(L)1 inhibitors, alone and in combination with other treatments, across multiple tumor types. PD-L1 expression has been associated with response to immune checkpoint inhibitors, and treatment strategies are often guided by immunohistochemistry-based diagnostic tests assessing expression of PD-L1. However, challenges related to the implementation, interpretation, and clinical utility of PD-L1 diagnostic tests have led to an increasing number of preclinical and clinical studies exploring interrogation of the TME by real-time imaging of PD-(L)1 expression by positron emission tomography (PET). PET imaging utilizes radiolabeled molecules to non-invasively assess PD-(L)1 expression spatially and temporally. Several PD-(L)1 PET tracers have been tested in preclinical and clinical studies, with clinical trials in progress to assess their use in a number of cancer types. This review will showcase the development of PD-(L)1 PET tracers from preclinical studies through to clinical use, and will explore the opportunities in drug development and possible future clinical implementation.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease characterized by worsening dyspnea and lung function and has a median survival of 2–3 years. Forced vital capacity (FVC) is the primary endpoint used most commonly in IPF clinical trials as it is the best surrogate for mortality. This study assessed quantitative scores from high-resolution computed tomography (HRCT) developed by machine learning as a secondary efficacy endpoint in a 26-week phase II study of BMS-986020 – an LPA 1 receptor antagonist – in patients with IPF. Methods HRCT scans from 96% (137/142) of randomized subjects were utilized. Quantitative lung fibrosis (QLF) scores were calculated from the HRCT images. QLF improvement was defined as ⩾2% reduction in QLF score from baseline to week 26. Results In the placebo arm, 5% of patients demonstrated an improvement in QLF score at week 26 compared with 15% and 27% of patients in the BMS-986020 600 mg once daily (QD) and twice daily (BID) arms, respectively [ versus placebo: p = 0.08 (600 mg QD); p = 0.0098 (600 mg BID)]. Significant correlations were found between changes in QLF and changes in percent predicted FVC, diffusing capacity for carbon monoxide (DLCO), and shortness of breath at week 26 ( ρ = −0.41, ρ = −0.22, and ρ = 0.27, respectively; all p < 0.01). Conclusions This study demonstrated the utility of quantitative HRCT as an efficacy endpoint for IPF in a double-blind, placebo-controlled clinical trial setting. The reviews of this paper are available via the supplemental material section.

Blocking the interaction of the immune checkpoint molecules programmed cell death protein-1 (PD-1) and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression positron emission tomography (PET) imaging may potentially allow for a better prediction of response to PD-1 targeted therapies. Imaging of PD-L1 expression is feasible by PET with the Adnectin protein 18F-BMS-986192. However, radiofluorination of proteins, such as BMS-986192 remains complex and labelling yields are low. The goal of this study was therefore the development and preclinical evaluation of a 68Ga-labeled Adnectin protein (68Ga- BMS-986192) to facilitate clinical trials. Methods:68Ga-labeling of DOTA-conjugated Adnectin (BXA-206362) was carried out in NaOAc-buffer at pH 5.5 (50°C, 15min). In vitro stability in human serum at 37°C was analyzed using Radio-thin layer chromatography (Radio-TLC) and Radio-high performance liquid chromatography (Radio-HPLC). PD-L1 binding assays were performed using the transduced PD-L1 expressing lymphoma cell line U-698-M and wild-type U-698-M cells as negative control. Immunohistochemical staining studies, biodistribution and small animal PET studies of 68Ga-BMS-986192 were carried out using PD-L1-positive and negative U-698-M-bearing NSG mice. Results:68Ga-BMS-986192 was obtained with quantitative radiochemical yields (RCYs) >97% and with high radiochemical purity (RCP). In vitro stability in human serum was ≥ 95% after 4h of incubation. High and specific binding of 68Ga-BMS-986192 to human PD-L1-expressing cancer cells was confirmed, which closely correlates with the respective PD-L1 expression level determined by flow cytometry and IHC staining. In vivo, 68Ga-BMS-986192 uptake was high in PD-L1+ tumors (9.0±2.1%ID/g at 1hp.i.) and kidneys (56.9±9.2% ID/g at 1hp.i.) with negligible uptake in other tissues. PD-L1 negative tumors demonstrated only background uptake of radioactivity (0.6±0.1% ID/g). Co-injection of an excess of unlabelled Adnectin reduced tumor uptake of PD-L1 by more than 80%. Conclusion:68Ga-BMS-986192 enables easy radiosynthesis and shows excellent in vitro and in vivo PD-L1 targeting characteristics. The high tumor uptake combined with low background accumulation at early imaging time points demonstrate the feasibility of 68Ga-BMS-986192 for imaging of PD-L1 expression in tumors and is encouraging for further clinical applications of PD-L1 ligands.

Purpose: Usig stadard-of-care CT images obtaied from patiets with a diagosis of o–small cell lug cacer (NSCLC), we defied radiomics sigatures predictig the sesitivity of tumors to ivolumab, docetaxel, ad gefitiib. Experimetal Desig: Data were collected prospectively ad aalyzed retrospectively across multiceter cliical trials [ivolumab, = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, = 50, CheckMate017; gefitiib, = 46, (NCT00588445)]. Patiets were radomized to traiig or validatio cohorts usig either a 4:1 ratio (ivolumab: 72T:20V) or a 2:1 ratio (docetaxel: 32T:18V; gefitiib: 31T:15V) to esure a adequate sample size i the validatio set. Radiomics sigatures were derived from quatitative aalysis of early tumor chages from baselie to first o-treatmet assessmet. For each patiet, 1,160 radiomics features were extracted from the largest measurable lug lesio. Tumors were classified as treatmet sesitive or isesitive; referece stadard was media progressio-free survival (NCT01642004, NCT01721759) or surgery (NCT00588445). Machie learig was implemeted to select up to four features to develop a radiomics sigature i the traiig datasets ad applied to each patiet i the validatio datasets to classify treatmet sesitivity. Results: The radiomics sigatures predicted treatmet sesitivity i the validatio dataset of each study group with AUC (95 cofidece iterval): ivolumab, 0.77 (0.55–1.00); docetaxel, 0.67 (0.37–0.96); ad gefitiib, 0.82 (0.53–0.97). Usig serial radiographic measuremets, the magitude of expoetial icrease i sigature features decipherig tumor volume, ivasio of tumor boudaries, or tumor spatial heterogeeity was associated with shorter overall survival. Coclusios: Radiomics sigatures predicted tumor sesitivity to treatmet i patiets with NSCLC, offerig a approach that could ehace cliical decisio-makig to cotiue systemic therapies ad forecast overall survival.

The aim of this work was to quantify the uptake of 18F-BMS-986192, a programmed cell death ligand 1 (PD-L1) adnectin PET tracer, in patients with non-small cell lung cancer. To this end, plasma input kinetic modeling of dynamic tumor uptake data with online arterial blood sampling was performed. In addition, the accuracy of simplified uptake metrics such as SUV was investigated. Methods: Data from a study with 18F-BMS-986192 in patients with advanced-stage non-small cell lung cancer eligible for nivolumab treatment were used if a dynamic scan was available and lesions were present in the field of view of the dynamic scan. After injection of 18F-BMS-986192, a 60-min dynamic PET/CT scan was started, followed by a 30-min whole-body PET/CT scan. Continuous arterial and discrete arterial and venous blood sampling were performed to determine a plasma input function. Tumor time-activity curves were fitted by several plasma input kinetic models. Simplified uptake parameters included tumor-to-blood ratio as well as several SUV measures. Results: Twenty-two tumors in 9 patients were analyzed. The arterial plasma input single-tissue reversible compartment model with fitted blood volume fraction seems to be the most preferred model as it best fitted 11 of 18 tumor time-activity curves. The distribution volume (V T ) ranged from 0.4 to 4.8 mL⋅cm-3 Similar values were obtained with an image-derived input function. From the simplified measures, SUV normalized for body weight at 50 and 67 min after injection correlated best with V T , with an R2 of more than 0.9. Conclusion: A single-tissue reversible model can be used to quantify tumor uptake of the PD-L1 PET tracer 18F-BMS-986192. SUV at 60 min after injection, normalized for body weight, is an accurate simplified parameter for uptake assessment of baseline studies. To assess its predictive value for response evaluation during programmed cell death protein 1 or PD-L1 immune checkpoint inhibition, further validation of SUV against V T based on an image-derived input function is recommended.

139 Background: PD-(L)1 immunotherapy is effective in multiple tumors, including NSCLC and melanoma, but tumor PD-L1 IHC correlates only moderately with treatment outcome. This study aims to assess 1) safety of ¹⁸ F-BMS-986192 ( ¹⁸ F-PD-L1) in human, 2) PD-L1 quantification in tumors using ¹⁸ F-PD-L1 PET, 3) PD-L1 PET correlation with IHC and treatment outcome, and 4) intra and inter subject tracer uptake variability. Methods: Pts with NSCLC (N = 10) and melanoma (N = 3) were included. At baseline, pts received a static or multiphase dynamic whole body PET scan after injecting 200 MBq ¹⁸ F-BMS-986192. For NSCLC pts, (1) SUV(max, peak and mean) were measured for each delineable tumor (N = 32, 1-7 tumors/pt), (2) PD-L1 IHC (28.8 assay) was performed on the biopsy, and (3) response to Nivolumab therapy assessed by RECIST 1.1. Intra and inter subject variability and intraclass correlation were calculated using SUVs of all assessed tumors. Equal variance for PD-L1 status was evaluated by a Levene’s test. Four (3 female) pts underwent dosimetry study (ICRP 60). Results: No AEs related to radiotracer was observed. Dosimetry study demonstrated whole body exposure of 30 mGy at dose > 1400 MBq. Biodistribution among pts is comparable. PD-L1 IHC from 13 biopsied lesions were evaluated, 5 < 1%, 4 ≥1%, and 4 ≥50%. Tumor tracer uptake was measured in NSCLC pts and categorized by PDL-1 IHC as ≥50% or < 50%. Clinical trial information: 2015-004760-11. Tumor SUVs did not correlate with RECIST 1.1 assessment. Lesion heterogeneity was reflected in both inter and intra pt variability (CVinter = 41%, CVintra = 53%, ICC = 0.41 for SUVpeak). Levene’s test showed no significance in variability between the two PD-L1 categories. Conclusions: PET-imaging with ¹⁸ F-BMS-986192 is safe and feasible in pts with NSCLC and melanoma. Pts with higher PD-L1 PET SUV have higher PD-L1 by IHC. Intra pt variability is similar to inter pt variability. With limited number of pts, no clear correlation of PET PD-L1 and tumor response is observed. A prospective study with this tracer is underway to further investigate ¹⁸ F-BMS-986192 in understanding of PD-L1 expression.[Table: see text]

Major depressive disorder is a leading cause of disability globally. Improvements in the efficacy of antidepressant therapy are needed as a high proportion (>40%) of individuals with major depressive disorder fail to respond adequately to current treatments. The non-selective N-methyl-D-aspartate receptor channel blocker, (±)-ketamine, has been reported to produce a rapid and long-lasting antidepressant response in treatment-resistant major depressive disorder patients, which provides a unique opportunity for investigation of mechanisms that mediate its therapeutic effect. Efforts have also focused on the development of selective N-methyl-D-aspartate receptor subtype 2B antagonists which may retain antidepressant activity but have lower potential for dissociative/psychotomimetic effects. In the present study, we examined the central nervous system effects of acute, intravenous administration of (±)-ketamine or the N-methyl-D-aspartate receptor subtype 2B antagonist, traxoprodil, in awake rats using pharmacological magnetic resonance imaging. The study contained five treatment groups: vehicle, 3 mg/kg (±)-ketamine, and three doses of traxoprodil (0.3 mg/kg, 5 mg/kg, and 15 mg/kg). Non-linear model fitting was performed on the temporal hemodynamic pharmacological magnetic resonance imaging data to generate brain activation maps as well as regional responses based on blood oxygen level dependent signal changes for group analysis. Traxoprodil at 5 mg/kg and 15 mg/kg produced a dose-dependent pharmacological magnetic resonance imaging signal in rat forebrain regions with both doses achieving >80% N-methyl-D-aspartate receptor subtype 2B occupancy determined by ex vivo [³H]Ro 25-6981 binding. The middle dose of traxoprodil (5 mg/kg) generated region-specific activations in medial prefrontal cortex, ventral orbital cortex, and anterior cingulate cortex whereas the high dose (15 mg/kg) produced a widespread pharmacological magnetic resonance imaging response in both cortical and subcortical brain regions which was similar to that produced by (±)-ketamine (3 mg/kg, intravenous).