Resistance models to EGFR inhibition and chemotherapy in non-small cell lung cancer via analysis of tumour size dynamics

Abstract

Purpose: Imaging time-series data routinely collected in clinical trials are predominantly explored for covariates as covariates for survival analysis to support decision-making in oncology drug development. The key objective of this study was to assess if insights regarding two relapse resistance modes, de-novo (treatment selects out a pre-existing resistant clone) or acquired (resistant clone develops during treatment), could be inferred from such data. Methods: Individual lesion size time-series data were collected from ten Phase III study arms where patients were treated with either first-generation EGFR inhibitors (erlotinib or gefitinib) or chemotherapy (paclitaxel/carboplatin combination or docetaxel). The data for each arm of each study were analysed via a competing models framework to determine which of the two mathematical models of resistance, de-novo or acquired, best-described the data. Results: Within the first-line setting (treatment naive patients), we found that the de-novo model best-described the gefitinib data, whereas, for paclitaxel/carboplatin, the acquired model was preferred. In patients pre-treated with paclitaxel/carboplatin, the acquired model was again preferred for docetaxel (chemotherapy), but for patients receiving gefitinib or erlotinib, both the acquired and de-novo models described the tumour size dynamics equally well. Furthermore, in all studies where a single model was preferred, we found a degree of correlation in the dynamics of lesions within a patient, suggesting that there is a degree of homogeneity in pharmacological response. Conclusions: This analysis highlights that tumour size dynamics differ between different treatments and across lines of treatment. The analysis further suggests that these differences could be a manifestation of differing resistance mechanisms.