Modeling Tumor Growth and Treatment Resistance Dynamics Characterizes Different Response to Gefitinib or Chemotherapy in Non-Small Cell Lung Cancer

Mario Nagase, Sergey Aksenov, Hong Yan, James Dunyak, Nidal Al-Huniti, Mario Nagase, Sergey Aksenov, Hong Yan, James Dunyak, Nidal Al-Huniti

Abstract

Differences in the effect of gefitinib and chemotherapy on tumor burden in non-small cell lung cancer remain to be fully understood. Using a Bayesian hierarchical model of tumor size dynamics, we estimated the rates of tumor growth and treatment resistance for patients in the Iressa Pan-Asia Study study (NCT00322452). The following relationships characterize greater efficacy of gefitinib in epidermal growth factor receptor (EGFR) positive tumors: Maximum drug effect is, in decreasing order, gefitinib in EGFR-positive, chemotherapy in EGFR-positive, chemotherapy in EGFR-negative, and gefitinib in EGFR-negative tumors; the rate of resistance emergence is, in increasing order: gefitinib in EGFR positive, chemotherapy in EGFR positive, while each is plausibly similar to the rate in EGFR negative tumors, which are estimated with less certainty. The rate of growth is smaller in EGFR-positive than in EGFR-negative fully resistant tumors, regardless of treatment. The model can be used to compare treatment effects and resistance dynamics among different drugs.

Conflict of interest statement

M.N., A.S., Y.H., J.D., and N.A‐H. are employees of AstraZeneca Pharmaceuticals LP.

© 2020 Astra Zeneca. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Schematic of the tumor dynamic model. y is tumor volume at time t.
Figure 2
Figure 2
Observed and simulated tumor size profiles. CHEMO, chemotherapy; EGFR−, epidermal growth factor receptor negative; EGFR+, epidermal growth factor receptor positive; GEFI, gefitinib.
Figure 3
Figure 3
The percentage of patients achieving 30% shrinkage in sum of longest diameters. CHEMO, chemotherapy; EGFR−, epidermal growth factor receptor negative; EGFR+, epidermal growth factor receptor positive; GEFI, gefitinib.
Figure 4
Figure 4
Observed and estimated percent initial change from baseline in sum of longest diameters per week. CHEMO, chemotherapy; EGFR−, epidermal growth factor receptor negative; EGFR+, epidermal growth factor receptor positive; GEFI, gefitinib.
Figure 5
Figure 5
Posterior densities of model parameters. CHEMO, chemotherapy; EGFR−, epidermal growth factor receptor negative; EGFR+, epidermal growth factor receptor positive; GEFI, gefitinib; Y0, the initial tumor volume; kgrsl, the net tumor growth rate (scaled, log‐transformed); Δλs, the maximum intensity of the drug effect (scaled); αsl, the rate of resistance emergence (scaled, log‐transformed).
Figure 6
Figure 6
Typical sum of longest diameter profiles. CHEMO, chemotherapy; EGFR−, epidermal growth factor receptor negative; EGFR+, epidermal growth factor receptor positive; GEFI, gefitinib.

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Source: PubMed

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