Challenges with Estimating Long-Term Overall Survival in Extensive Stage Small-Cell Lung Cancer: A Validation-Based Case Study.

Objective: The study aimed to explore methods and highlight the challenges of extrapolating the overall survival (OS) of immunotherapy-based treatment in first-line extensive stage small-cell lung cancer (ES-SCLC). Methods: Standard parametric survival models, spline models, landmark models, mixture and non-mixture cure models, and Markov models were fitted to 2-year data of the CASPIAN Phase 3 randomised trial of PD-L1 inhibitor durvalumab added to platinum-based chemotherapy (NCT03043872). Extrapolations were compared with updated 3-year data from the same trial and the plausibility of long-term estimates assessed. Results: All models used provided a reasonable fit to the observed Kaplan-Meier (K-M) survival data. The model which provided the best fit to the updated CASPIAN data was the mixture cure model. In contrast, the landmark analysis provided the least accurate fit to model survival. Estimated mean OS differed substantially across models and ranged from (in years) 1.41 (landmark model) to 4.81 (mixture cure model) for durvalumab plus etoposide and platinum and from 1.01 (landmark model) to 2.00 (mixture cure model) for etoposide and platinum. Conclusion: While most models may provide a good fit to K-M data, it is crucial to assess beyond the statistical goodness-of-fit and consider the clinical plausibility of the long-term predictions. The more complex cure models demonstrated the best predictive ability at 3 years, potentially providing a better representation of the underlying method of action of immunotherapy; however, consideration of the models' clinical plausibility and cure assumptions need further research and validation. Our findings underscore the significance of adopting a clinical perspective when selecting the most appropriate approach to model long-term survival, particularly when considering the use of more complex models.