Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma

Abstract

Purpose: Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data. Methods: Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data. Results: The analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates. Conclusions: Overall these results show how analysis of the dynamics of individual lesions can shed light on the within and between patient differences in tumour shrinkage and resistance rates, which could be used to gain a macroscopic understanding of tumour heterogeneity.