title: Modeling and simulation of maintenance treatment in first-line non-small cell lung cancer with external validation.
abstract: Maintenance 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.
  
  
  
  TGI 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.
  
  
  
  Time-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.
  
  
  
  A 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.
authors.affiliation: GlaxoSmithKline, Clinical Pharmacology Modeling & Simulations, 709 Swedeland Rd, King of Prussia, PA, 19406, USA. kelong.x.han@gsk.com.
authors.forename: Kelong
authors.initials: K
authors.lastname: Han
authors.affiliation: Genentech/Roche, 84 Chemin des Grives, 13013, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Claret
authors.affiliation: Genentech Inc, Product Development Oncology, South San Francisco, CA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Sandler
authors.affiliation: Tocagen Inc, Clinical Development and Medical Affairs, San Diego, CA, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Das
authors.affiliation: Genentech Inc, Clinical Pharmacology, South San Francisco, CA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Genentech/Roche, 84 Chemin des Grives, 13013, Marseille, France. rene.bruno@roche.com.
authors.forename: Rene
authors.initials: R
authors.lastname: Bruno
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality*; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D060046:Maintenance Chemotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000068437:Pemetrexed / Q000627:therapeutic use; D016016:Proportional Hazards Models; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000068437:Pemetrexed; D000069347:Erlotinib Hydrochloride
keywords: External validation; Maintenance treatment; Non-small cell lung cancer; Overall survival; Trial simulation; Tumor growth inhibition