Quantitative Lesion-Level Modeling Reveals Organ-Dependent Therapeutic Response

Area of Science:

• Oncology
• Pharmacometrics
• Translational Medicine

Background:

• Current RECIST criteria limit understanding of organ-specific drug effects on metastatic lesions.
• This limitation hinders accurate efficacy signal interpretation for drug development and clinical decisions.

Purpose of the Study:

• To develop a lesion-level modeling framework for quantifying compartment-dependent therapeutic effects.
• To assess the independent contribution of metastatic site to response and progression hazards across cancer types.

Main Methods:

• Utilized nonlinear mixed-effects modeling to analyze lesion trajectories and estimate key kinetic parameters (kkill, kge, Fx).
• Applied pan-cancer multivariable Cox models, adjusting for clinical covariates, to evaluate metastatic site effects.
• Correlated organ-specific Vascular Perfusion and Leakiness Index (VaPLI) and immune surveillance with treatment outcomes.

Main Results:

• Metastatic site is a consistent determinant of response durability across cancer lineages.
• Liver metastases showed rapid shrinkage but higher progression risk; bone metastases demonstrated slower regression but durable control.
• Vascular Perfusion and Leakiness Index (VaPLI) correlated with response probability, and immune-tolerant sites had higher progression hazards.

Conclusions:

• A lesion-level modeling approach can differentiate true treatment effects from site-driven biases in efficacy evaluation.
• Organ site significantly influences metastatic lesion response dynamics and progression, impacting drug development and clinical decision-making.
• This framework supports lesion site-stratified efficacy evaluation for more balanced interpretation of treatment effects and dose-response relationships.