Linking Tumor Growth Dynamics to Survival in Ipilimumab-Treated Patients With Advanced Melanoma Using Mixture Tumor Growth Dynamic Modeling

Yan Feng, Xiaoning Wang, Satyendra Suryawanshi, Akintunde Bello, Amit Roy, Yan Feng, Xiaoning Wang, Satyendra Suryawanshi, Akintunde Bello, Amit Roy

Abstract

Early tumor assessments have been widely used to predict overall survival (OS), with potential application to dose selection and early go/no-go decisions. Most published tumor dynamic models assume a uniform pattern of tumor growth dynamics (TGDs). We developed a mixture TGD model to characterize different patterns of longitudinal tumor sizes. Data from 688 patients with advanced melanoma who received ipilimumab 3 or 10 mg/kg every 3 weeks in a phase III study (NCT01515189) were used in a TGD-OS analysis. The mixture model described TGD profiles using three subpopulations (no-growth, intermediate, and fast). The TGD model showed a positive exposure/dose-response (i.e., a higher proportion of patients in no/intermediate growth subpopulations and a lower tumor growth rate with ipilimumab 10 mg/kg relative to the 3 mg/kg dose). Finally, the mixture TGD model-based measures of tumor response provided better predictions of OS compared with the nonmixture model.

Conflict of interest statement

Y.F., S.S., A.B., and A.R. are employees of Bristol‐Myers Squibb. Y.F., A.B., A.R., and X.W. hold stock in Bristol‐Myers Squibb.

© 2019 Bristol-Myers Squibb CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
The distribution of tumor growth dynamics (TGDs) mixture model parameters by subpopulation: no‐growth, intermediate tumor growth (TG) and tumor shrinkage (TS), and fast TG. The box plot shows the median and interquartile range of TGD parameter estimates in each group. SLD, sum of the longest diameter.
Figure 2
Figure 2
Individual time course of (a) observed and (b) predicted change in tumor size from baseline stratified by dose and subpopulation. SLD, sum of the longest diameter; TG, tumor growth; TS, tumor shrinkage.
Figure 3
Figure 3
Effect of covariates on the hazard ratio of overall survival (OS‐model 1). Missing postbaseline tumor burden (TB), patients only had baseline TB assessment and without post treatment TB assessment. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PRW8.MIXC, progressive rate at week 8 from covariate mixture model; ULN, upper limit of normal.
Figure 4
Figure 4
Model evaluation of overall survival (OS)‐model 1 analysis stratified (a) by treatment and (b) by treatment and subpopulation. PI, prediction interval; TG, tumor growth; TS, tumor shrinkage.

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