Multistate pharmacometric model to define the impact of second-line immuno-therapies on the survival outcome of IMpower131 study.

Overall survival (OS) is defined as the time since randomization into the clinical trial to event of death or censor (end of trial or follow-up), and is considered as the most reliable cancer endpoint. However, the introduction of second-line treatment after disease progression, could influence the survival, and be considered as a confounding factor. The aim of the current study was to set up a multistate model framework, using data from IMpower131 study, to investigate the influence of second-line immuno-therapies on overall survival analysis. The model adequately described the transitions between different states in advanced squamous NSCLC patients treated with or without atezolizumab (A) plus nab-paclitaxel and carboplatin (CnP), and characterized the survival data. High PD-L1 expression at baseline was associated with a decreased hazard of progression, while the presence of liver metastasis at baseline was indicative of high risk of disease progression after initial response. The hazard of death after progression was lower for subjects who had longer treatment response, i.e. longer time-to-progression. The simulations based on the final multistate model showed that the addition of atezolizumab to the CnP regimen had significant improvement in the patients' survival (HR=0.75, 95% PI: 0.61-0.90 favoring the A+CnP arm). The developed modeling approach can be applied to other cancer types and therapies to provide a better understanding of efficacy of drug and characterizing different states, and investigate the benefit of primary therapy in the survival while accounting for the switch to alternative treatment in case of disease progression.