Towards AI-Assisted Clinical Trial Matching: Practical Considerations, Multicenter Evaluation, and Real-World Deployment

Clinical trials are essential for advancing cancer care and drug development, but many fail because of insufficient patient enrollment. While there is growing interest in using AI to support patient recruitment, existing systems largely perform eligibility assessment alone and have rarely been evaluated in real-world oncology workflows. Here we present TrialGPT 2.0, an AI-assisted clinical trial recommendation system designed for real-world deployment. Rather than asking only whether a patient may qualify, the system also assesses which trials warrant further consideration given the patient's current clinical needs and local workflow priorities, and provides structured, inspectable explanations for expert review. Importantly, we evaluated TrialGPT 2.0 retrospectively and prospectively across multiple oncology-focused settings, spanning government, academic cancer-center, patient-advocacy, and NIH referral workflows. In retrospective multicenter cohorts comprising 288 cases, TrialGPT 2.0 retrieved at least one clinician-recommended trial in its top 10 recommendations for approximately 91% of cases while reducing clinician screening time by 55.0%. In a six-month prospective evaluation embedded in an active precision oncology tumor board, TrialGPT 2.0 contributed additional trial opportunities missed by the routine workflow, expanding patient access to clinical trial participation by 90.9%. To support scientific reproducibility, we also introduce NIH-TrialBench, a clinician-authored dataset comprising 126 diverse synthetic patient vignettes and matching scenarios from 11 NIH Institutes and Centers. Together, these results support the value of AI to assist clinical trial matching by improving clinician efficiency and identifying frequently overlooked trial opportunities, ultimately helping to expand and accelerate accrual to cancer trials.

From Analytics to Tumor Boards: An Evidence-Linked Multi-Agent Workflow for Oncology Feature Extraction

Clinically relevant oncology information is distributed across heterogeneous, longitudinal documentation, creating substantial abstraction burden and requiring accurate attribution across specimens, tumors, biomarkers, and time points, while manual cancer-registry abstraction can require 27.2 minutes per case, highlighting the need for scalable methods that preserve clinical context while converting documentation into structured data. We evaluate an oncology information-extraction workflow in which OncoLens supplies multi-source, oncology-aware document selection, aggregation, and normalization from integrated EHRs, while the NimbleMind Multi-Agent System (nMAS) is a configurable oncology information-extraction workflow that extracts clinically relevant structured fields from fragmented oncology documentation. The extraction task uses a clinician-informed schema of 328 attributes spanning report metadata, diagnosis, staging, and cancer-type-specific information. nMAS separates clinician-defined field specifications from model execution and combines complexity-aware extraction, report-level consolidation, and source-grounded validation. The retrospective evaluation included 230 de-identified oncology documents from 40 patients and 418 clinician-reviewed document-field pairs containing 1,126 non-empty reference values. Evaluation focused on fields identified by clinicians as present in the source documents rather than exhaustively annotating all 328 schema fields. nMAS achieved a rank-weighted value-level precision of 82.6%, recall of 87.5%, and F1 of 85.0%, compared with an F1 of 66.4% for an independently implemented UMA-style MiniMax M2.5 comparator. These findings support the feasibility of using a configurable, source-grounded extraction workflow to convert fragmented oncology documentation into reusable structured data.

A Multimodal Foundation Model for Longitudinal Patient Representation and Scalable Insight Generation in Oncology

Precision oncology necessitates a longitudinal model of patient state that captures cancer evolution and treatment over time, integrating multimodal observations. We introduce the oFM, a foundation model developed on a real-world oncology cohort of 1.67 million cancer patients that integrates clinical trajectories with DNA, RNA, and H&E pathology. Patient-level partitions were reserved for training, validation, and testing, with over one million patients used for training. The oFM encodes daily clinical and molecular episodes and, along with pathology images, integrates them over time to produce a patient state embedding. We evaluate frozen oFM embeddings against expert-curated clinical and molecular baseline features. In prognostic benchmarks, the oFM improved AUC for treatment response, progression-free survival, and overall survival (0.774 vs. 0.563 for overall survival). Across 11 comparative-treatment cohorts, the oFM embeddings achieved a three-fold higher pooled and scale-normalized treatment-benefit AUTOC than baseline features with improved benefit ranking in 9 of 11 cohorts, and provided stronger prognostic discrimination within both treatment arms. We also evaluated a mechanism discovery framework that interprets downstream models built on oFM embeddings by linking their predicted outcomes to clinically and biologically grounded mechanisms through an evidence-grounded temporal graph, enabling evaluation in clinical and drug-development applications.

Dissecting Neuro-Symbolic Quality Assurance for Synthetic Oncology Data Generation

Synthetic clinical data generation with large language models addresses the scarcity that limits cancer staging research, but oncology hallucinations are categorically harmful: one clinically impossible staging assignment contaminates every downstream model trained on it. Neuro-symbolic pipelines validate during generation, yet the contribution of individual quality-assurance components remains unclear. We report three controlled studies isolating gate necessity, constraint attribution, and retrieval conditionality, holding generation protocol, diversity thresholds, and fine-tuning hyperparameters constant across adapter conditions. The symbolic gate enforces schema completeness, ontology coverage against the Systematized Nomenclature of Medicine, and staging-logic consistency under American Joint Committee on Cancer eighth-edition rules. Ungated, 29.9% of records contain schema failures and 20.1% contain clinically invalid staging. Schema validation is the load-bearing filter: within the fully gated corpus it rejects 148 of 512 records, ontology grounding a further 24, and staging-logic validation none---the only generator producing logic violations is already excluded on schema, making clinical-logic validation a generator-conditional safeguard rather than the dominant filter. Retrieval augmentation is strongly model-dependent: it improves gate compliance for one generator by 12.5 percentage points, has no measurable effect for a second, and collapses output in a third. Across gated configurations ontology density is largely unchanged, indicating that symbolic validation improves clinical validity rather than vocabulary richness. Symbolic gating therefore buys corpus validity but no commensurate gain on real lung-cancer notes in this study; retrieval should be evaluated per model, and ontology density should not be reported as a proxy for corpus quality.

MultiSigBERT: Beyond Survival Analysis through Multimodal and Sequential Modeling in Oncology

Machine learning has become an essential component of modern healthcare, where the integration of heterogeneous data sources offers unprecedented opportunities to improve clinical decision-making. Electronic Health Records (EHR) contain complementary information -- including narrative clinical reports, numerical measurements, and structured variables -- yet most survival models remain limited to a single modality or fail to exploit the temporal nature of patient trajectories. We propose MultiSigBERT, a unified framework for multimodal sequential survival modeling in oncology based on path signature representations. Here, narrative medical reports (free-text) are converted into sentence embeddings by extracting and averaging contextual word embeddings. These representations are then compressed via modality-specific PCA and concatenated with structured covariates to form joint temporal trajectories which are then encoded using the Signature transform, a tool from Rough Paths theory that efficiently captures higher-order temporal interactions across modalities without supervision needed. The computed Signature features are finally incorporated as high dimensional features into a LASSO-regularized Cox model to estimate individualized risk scores. The performance of our novel MultiSigBERT pipeline is illustrated on the analysis of a real-world oncology cohort from the Léon Bérard Center, comprising over 120,000 medical reports and structured records from more than 2,500 patients. The model achieves a concordance index of 0.743 (sd 0.029) on an independent test set, demonstrating the benefit of jointly modeling multimodal temporal dynamics together with patient-level geometric structure for survival prediction.

Learning Clinical-Trial Strategy: Offline Policy Training for Decision Agents

Clinical development is sequential decision-making under uncertainty, where a sponsor must plan a portfolio of experiments from heterogeneous evidence. We study this setting by framing oncology clinical development as an offline decision-making problem in which an agent predicts the next six-month trial portfolio of an oncology drug program from information available at the decision date. To support this, we construct a temporal dataset that combines 31.7k heterogeneous public data records, including trial registries, regulatory reviews, sponsor filings, utilization data, and epidemiology, into 881 offline decision episodes across 45 historical programs. We compare four offline objectives: behavioral cloning, reward-weighted behavioral cloning, learned-reward training, and value-based implicit Q-learning against four frontier LLM agents that share a common date-gated retrieval scaffold across held-out drug, sponsor, drug-class, and temporal splits. Models trained offline outperform the non-fine-tuned baselines, particularly in the post-August 2025 contamination-clean holdout. Reward-weighted behavioral cloning performs the best, obtaining 46.2% indication F1 and 14.2% strict F1 against 25.0% and 2.1%, respectively, for the best-performing tool agent on each metric. These results suggest that structured offline learning can teach agents to plan clinical experiments.

Value-Monotonicity Matters: A Concordance Loss for Deep Survival Prediction

Deep survival models are evaluated almost exclusively by the concordance index (C-index), yet they are commonly trained using likelihood objectives such as the Cox partial likelihood, discrete-time negative log-likelihood, and DeepHit likelihood. This mismatch is usually considered acceptable because the C-index can be recomputed on validation data during training. However, for end-to-end training of high-capacity encoders on small, heavily censored oncology cohorts, frequent C-index evaluation is computationally expensive, making the loss value itself an important signal for monitoring, early stopping, and model selection. We show that likelihood losses are unreliable for this purpose and propose a value-monotone concordance loss. We prove that every strictly proper survival likelihood admits directions where the loss decreases while the C-index remains unchanged, causing the loss value to decouple from ranking performance. We then study a sigmoid concordance loss (SCL), whose value approximates one minus the C-index up to a temperature term, ensuring that lower loss corresponds to higher C-index during optimization. The loss is architecture agnostic and reduces to a convex survival ranking support vector machine for linear models. Across eighteen datasets from four modalities using a unified five-fold cross-validation protocol, SCL achieves discrimination comparable to standard likelihood losses and is the best or within one standard deviation of the best C-index. Unlike likelihood losses, SCL maintains a strong correlation between loss value and C-index during training, with rank correlations of 0.96 to 0.99 compared with -0.03 to 0.53 for likelihood losses. Calibration measured by the integrated Brier score is comparable. SCL provides a value-monotone optimization objective whose value can serve as a reliable surrogate for the C-index during expensive end-to-end training.

The Large Cancer Assistant (LCA): A Model-Agnostic Orchestration Framework for Scalable Clinical Decision Support in Oncology

- Objective: Multimodal deep learning models in oncology are currently limited by monolithic designs that rigidly couple data ingestion, clinical routing, and artificial intelligence (AI) inference. To address this inflexibility, we propose the Large Cancer Assistant (LCA), a model-agnostic, post-hoc orchestration framework designed for scalable clinical decision support. - Methods: The LCA is mathematically formalized as a 7-tuple architecture grounded in the principle of Algorithmic Impermeability, ensuring the orchestration logic remains strictly independent of underlying black-box AI models. We introduce the Entry Theory, leveraging Geometric Deep Learning (GDL) to standardize multimodal patient data along distinct structural and medical axes. The system dynamically orchestrates data via a Cancer Switching Module and intentionally isolates the core AI execution from volatile hospital IT infrastructures by outputting a Standardized Intermediate Payload (SIP). - Results: A Proof of Concept (PoC) validated the orchestration logic across four technical scenarios. The framework executed a nominal flow with negligible orchestration overhead. It empirically demonstrated algorithmic impermeability by maintaining an invariant routing projection during AI model swaps, and it validated strict failure-safety by achieving a 100\% recall rate in generating targeted Supplementary Data Requests (SDR) under injected data anomalies. Multi-protocol execution capability was also successfully verified. - Conclusion: By structurally decoupling multimodal ingestion from feature inference, the LCA provides a highly adaptable and modular orchestration foundation. The SIP establishes a clear architectural boundary, natively setting the stage for downstream Electronic Medical Record (EMR) interoperability as an independent future paradigm.

OncoSynth: Synthetic data generation for treatment effect estimation in oncology

In oncology, access to patient-level data is often restricted. Synthetic data provides an alternative for analyzing treatment effectiveness, but existing methods for synthetic data generation fail to preserve the causal relationships between covariates, treatments, and outcomes, thereby leading to biased estimates of treatment effects. Here, we introduce OncoSynth, a generative, causally-aware machine learning framework designed to produce synthetic cohorts that enable accurate estimation of population- and patient-level treatment effects. OncoSynth uses a diffusion-based sequential approach to model how covariates influence treatment assignment and how treatment affects survival. We evaluate OncoSynth using large lung (N = 37,128) and breast cancer (N = 17,046) cohorts. Our results show that OncoSynth generates high-fidelity synthetic patient cohorts that preserve real-world patient, treatment, and outcome distributions. Notably, OncoSynth improves treatment effect estimation over existing approaches, by reducing population-level treatment effect error by up to 66%, and patient-level treatment effect error by up to 58%. Thereby, OncoSynth supports reliable evidence generation for precision oncology in settings where data sharing is restricted.

Diagnosis, Bad Planning & Reasoning. Treatment, SCOPE -- Planning for Hybrid Querying over Clinical Trial Data

We study clinical trial table reasoning, where answers are not directly stored in visible cells but must be reasoned from semantic understanding through normalization, classification, extraction, or lightweight domain reasoning. Motivated by the observation that current LLM approaches often suffer from "bad reasoning" under implicit planning assumptions, we focus on settings in which the model must recover implicit attributes such as therapy type, added agents, endpoint roles, or follow-up status from partially observed clinical-trial tables. We propose SCOPE (Structured Clinical hybrid Planning for Evidence retrieval in clinical trials), a multi-LLM planner-based framework that decomposes the task into row selection, structured planning, and execution. The planner makes the source field, reasoning rules, and output constraints explicit before answer generation, reducing ambiguity relative to direct prompting. We evaluate SCOPE on 1,500 hybrid reasoning questions over oncology clinical-trial tables against zero-shot, few-shot, chain-of-thought, TableGPT2, Blend-SQL, and EHRAgent. Results show that explicit multi-LLM planning improves accuracy for reasoning-based questions while offering a stronger accuracy-efficiency tradeoff than heavier agentic baselines. Our findings position clinical trial reasoning as a distinct table understanding problem and highlight hybrid planner-based decomposition as an effective solution