Abstract LB-C14: Using Drug Exposure as a Metric for Predicting Clinical Response to Targeted Cancer Therapeutics from Preclinical Efficacy: A Retrospective Preclinical to Clinical Correlation
Authors: Linakis Matthew , Yates James , Masson Eric , Mugundu Ganesh 
Published: May 2016

Objective

The objective of this retrospective analysis was to evaluate the correlation between preclinical and clinical markers of efficacy, using available monotherapy data for AstraZeneca targeted oncology drugs.

Methods

For each drug, preclinical/clinical parameters were identified, including; dose/dosing schedule, tumor model,pharmacokinetic parameters (AUC, t1/2), clinically relevant dose (CRD), tumor growth inhibition (TGI), objective response rate (ORR), disease control rate (DCR), mean tumor shrinkage (MTS), and protein binding. Drugs were first examined to compare the concentrations (Cav) seen at CRDs to preclinical thresholds defined by the concentration required for 50% target inhibition (IC50). Each drug had a number of associated IC50 values, and in vivo values were preferentially used as the concentration target when available. Free Cav values were calculated from AUCs, and a ratio of Cav/IC50 &gt; 1 was used to determine whether the clinical drug exposure exceeded the preclinical efficacy target concentration.

The second objective was to determine the correlation between preclinical and clinical efficacy. This was accomplished by estimating murine TGI for each drug at either the allometrically-scaled, mouse-equivalent CRD or at the free exposure (CRE) seen in humans using a variety of dose-response models. Linear regression, weighted by the number of patients from whom clinical data was available, was performed on each comparison, and ANOVA was used to test the significance of each relationship using R v.3.2.2.

Results

Seventeen targeted drugs with clinical efficacy data were identified. A total of 9/15 (60%) drugs with available data exceeded a free Cav /IC50 ratio of 1 (ratio range of target attaining drugs: 3.6-63.3), indicating that target concentration had been achieved in those drugs.

Tumor growth inhibition predicted by the mouse-equivalent CRD ranged from 0.5-155.7% across 13 drugs, while it ranged from 53.4-179.9% across 9 drugs for which TGI could be predicted from the CRE. The weighted correlation between CRD-TGI and clinical ORR was significant (r = 0.71, p &lt; 0.01), while the correlation between CRE-derived TGI and ORR was not (r = 0.46, p = 0.12). While MTS data was only available for the late-stage and approved drugs (6/17 drugs), the linear relationship between CRD-TGI and clinical MTS was significant as well (r = 0.90, p &lt; 0.01). Based on the CRD-TGI regressions, a TGI of 46% translated into a ORR of 10%. Similarly, a TGI of 63% resulted in a clinical MTS of 10%.

Conclusions

Comparison of preclinical concentration targets and clinical exposures suggests that the CRD is only achieving the preclinical target in just over half of the drugs, highlighting the importance of choosing a relevant in vivo preclinical concentration to target clinically.

Conversely, a high correlation between CRD-based TGI and clinical ORR was observed suggesting that this marker may be more appropriate for prediction of clinical efficacy from preclinical data.

Overall, this study demonstrated a correlation between dose-predicted TGI and clinical efficacy. Although this is a small data set, this study confirmed the importance of setting an efficacy threshold preclinically before moving into the clinic with oncology targeted drugs.

Citation Format: Matthew Linakis, James Yates, Eric Masson, Ganesh Mugundu. Using Drug Exposure as a Metric for Predicting Clinical Response to Targeted Cancer Therapeutics from Preclinical Efficacy: A Retrospective Preclinical to Clinical Correlation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C14.