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Simple Summary: T cell receptor fusion constructs (TRuC-Ts) represent a promising next-generation T cell therapy for solid tumors. To enhance their development, improved patient selection is essential. A pilot study was conducted to evaluate the feasibility and performance of a predictive model for treatment responses in mesothelioma patients, leveraging radiomics and machine learning. Radiomics and delta-radiomics (Δradiomics) features from CT scans were analyzed for reproducibility and informativeness, identifying key features for training a random forest classifier. The model achieved an accuracy of 0.75–0.9 in predicting pleural tumor responses, supporting the design of future studies involving 250–400 tumors. This study demonstrated the reproducibility and effectiveness of radiomics/Δradiomics in relation to tumor localization, emphasizing the need for multiple tumor models to create an integrated patient model. These findings provide a foundation for combining tumor-specific models into a unified approach, improving patient selection for TRuC-T therapy in mesothelioma patients. Background/Objectives: T cell receptor fusion constructs (TRuCs), a next generation engineered T cell therapy, hold great promise. To accelerate the clinical development of these therapies, improving patient selection is a crucial pathway forward. Methods: We retrospectively analyzed 23 mesothelioma patients (85 target tumors) treated in a phase 1/2 single arm clinical trial (NCT03907852). Five imaging sites were involved, the settings for the evaluations were Blinded Independent Central Reviews (BICRs) with double reads. The reproducibility of 3416 radiomics and delta-radiomics (Δradiomics) was assessed. The univariate analysis evaluated correlations at the target tumor level with (1) tumor diameter response; (2) tumor volume response, according to the Quantitative Imaging Biomarker Alliance; and (3) the mean standard uptake value (SUV) response, as defined by the positron emission tomography response criteria in solid tumors (PERCISTs). A random forest model predicted the response of the target pleural tumors. Results: Tumor anatomical distribution was 55.3%, 17.6%, 14.1%, and 10.6% in the pleura, lymph nodes, peritoneum, and soft tissues, respectively. Radiomics/Δradiomics reproducibility differed across tumor localizations. Radiomics were more reproducible than Δradiomics. In the univariate analysis, none of the radiomics/Δradiomics correlated with any response criteria. With an accuracy ranging from 0.75 to 0.9, three radiomics/Δradiomics were able to predict the response of target pleural tumors. Pivotal studies will require a sample size of 250 to 400 tumors. Conclusions: The prediction of responding target pleural tumors can be achieved using a machine learning-based radiomics/Δradiomics analysis. Tumor-specific reproducibility and the average values indicated that using tumor models to create an effective patient model would require combining several target tumor models. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer treatment has dramatically evolved in the past decade, but some pitfalls of image interpretation have been introduced in parallel, such as pseudo-progressions. These challenges could be made more evident with blinded independent central reviews, as readers are often blinded to patient clinical symptoms and outcomes. The aim of this study was to analyze a pool of lung trials that used RECIST 1.1, document the proportion of reader discrepancies and the reader performance through monitoring procedures, and provide suggestions for the reduction of read inconsistency. This study provides benchmarks for the reader discordance rate in novel lung cancer therapeutic trials that will help to trigger corrective actions such as initial reader training and follow-up re-training. Background: Double reads in blinded independent central reviews (BICRs) are recommended to control the quality of trials but they are prone to discordances. We analyzed inter-reader discordances in a pool of lung cancer trials using RECIST 1.1. Methods: We analyzed six lung cancer BICR trials that included 1833 patients (10,684 time points) involving 17 radiologists. We analyzed the rate of discrepancy of each trial at the time-point and patient levels as well as testing inter-trial differences. The analysis of adjudication made it possible to compute the readers' endorsement rates, the root causes of adjudications, and the proportions of "errors" versus "medically justifiable differences". Results: The trials had significantly different discrepancy rates both at the time-point (average = 34.3%) and patient (average = 59.2%) levels. When considering only discrepancies for progressive disease, homogeneous discrepancy rates were found with an average of 32.9%, while readers' endorsement rates ranged between 27.7% and 77.8%. Major causes of adjudication were different per trial, with medically justifiable differences being the most common, triggering 74.2% of total adjudications. Conclusions: We provide baseline performances for monitoring reader performance in trials with double reads. Intelligent reading system implementation along with appropriate reader training and monitoring are solutions that could mitigate a large portion of the commonly encountered reading errors. [ABSTRACT FROM AUTHOR]