Modeling and simulation of maintenance treatment in first-line non-small cell lung cancer with external validation

BMC Cancer

Research Article

Jin Jin¹  Alan Sandler²  Laurent Claret³  Rene Bruno³  Kelong Han⁴  Asha Das⁵ 

[1] Genentech Inc, Clinical Pharmacology, South San Francisco, CA, USA;Genentech Inc, Product Development Oncology, South San Francisco, CA, USA;Genentech/Roche, 84 Chemin des Grives, 13013, Marseille, France;GlaxoSmithKline, Clinical Pharmacology Modeling & Simulations, 709 Swedeland Rd, 19406, King of Prussia, PA, USA;Tocagen Inc, Clinical Development and Medical Affairs, San Diego, CA, USA;

关键词: Non-small cell lung cancer;    Maintenance treatment;    Tumor growth inhibition;    Trial simulation;    Overall survival;    External validation;   

DOI  :  10.1186/s12885-016-2455-2

 received in 2015-09-22, accepted in 2016-06-20,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundMaintenance treatment (MTx) in responders following first-line treatment has been investigated and practiced for many cancers. Modeling and simulation may support interpretation of interim data and development decisions. We aimed to develop a modeling framework to simulate overall survival (OS) for MTx in NSCLC using tumor growth inhibition (TGI) data.MethodsTGI metrics were estimated using longitudinal tumor size data from two Phase III first-line NSCLC studies evaluating bevacizumab and erlotinib as MTx in 1632 patients. Baseline prognostic factors and TGI metric estimates were assessed in multivariate parametric models to predict OS. The OS model was externally validated by simulating a third independent NSCLC study (n = 253) based on interim TGI data (up to progression-free survival database lock). The third study evaluated pemetrexed + bevacizumab vs. bevacizumab alone as MTx.ResultsTime-to-tumor-growth (TTG) was the best TGI metric to predict OS. TTG, baseline tumor size, ECOG score, Asian ethnicity, age, and gender were significant covariates in the final OS model. The OS model was qualified by simulating OS distributions and hazard ratios (HR) in the two studies used for model-building. Simulations of the third independent study based on interim TGI data showed that pemetrexed + bevacizumab MTx was unlikely to significantly prolong OS vs. bevacizumab alone given the current sample size (predicted HR: 0.81; 95 % prediction interval: 0.59–1.09). Predicted median OS was 17.3 months and 14.7 months in both arms, respectively. These simulations are consistent with the results of the final OS analysis published 2 years later (observed HR: 0.87; 95 % confidence interval: 0.63–1.21). Final observed median OS was 17.1 months and 13.2 months in both arms, respectively, consistent with our predictions.ConclusionsA robust TGI-OS model was developed for MTx in NSCLC. TTG captures treatment effect. The model successfully predicted the OS outcomes of an independent study based on interim TGI data and thus may facilitate trial simulation and interpretation of interim data. The model was built based on erlotinib data and externally validated using pemetrexed data, suggesting that TGI-OS models may be treatment-independent. The results supported the use of longitudinal tumor size and TTG as endpoints in early clinical oncology studies.

【 授权许可】

CC BY   
© The Author(s). 2016