Abstract
BACKGROUND: A modeling framework was previously developed to simulate overall survival (OS) using tumor growth inhibition (TGI) data from six randomized phase 2/3 atezolizumab monotherapy or combination studies in non-small-cell lung cancer (NSCLC). We aimed to externally validate this framework to simulate OS in patients with treatment-naive advanced anaplastic lymphoma kinase (ALK)-positive NSCLC in the alectinib ALEX study. METHODS: TGI metrics were estimated from a biexponential model using longitudinal tumor size data from a Phase 3 study evaluating alectinib compared with crizotinib in patients with treatment-naive ALK-positive advanced NSCLC. Baseline prognostic factors and TGI metric estimates were used to predict OS. RESULTS: 286 patients were evaluable (at least baseline and one post-baseline tumor size measurements) out of 303 (94%) followed for up to 5 years (cut-off: 29 November 2019). The tumor growth rate estimate and baseline prognostic factors (inflammatory status, tumor burden, Eastern Cooperative Oncology Group performance status, race, line of therapy, and sex) were used to simulate OS in ALEX study. Observed survival distributions for alectinib and crizotinib were within model 95% prediction intervals (PI) for approximately 2 years. Predicted hazard ratio (HR) between alectinib and crizotinib was in agreement with the observed HR (predicted HR 0.612, 95% PI 0.480-0.770 vs. 0.625 observed HR). CONCLUSION: The TGI-OS model based on unselected or PD-L1 selected NSCLC patients included in atezolizumab trials is externally validated to predict treatment effect (HR) in a biomarker-selected (ALK-positive) population included in alectinib ALEX trial suggesting that TGI-OS models may be treatment independent.