OBJECTIVES : Clinical trials have demonstrated that PD-1/PDL-1 inhibitors are associated with delayed treatment effects and long-term survivors. This results in a survival curve, which is challenging to model due to the complex hazard function and non-proportional treatment effect. We reviewed the recent National Institute for Health and Care Excellence (NICE) submissions for PD-1/PD-L1 inhibitors in oncology to assess the extent of PH assumption testing and the statistical approaches used in the absence of PH assumption.

METHODS : We searched the NICE website for the available appraisals of PD-1/PDL-1 agents for different oncology indications in the last five years. The methods for PH assessment and statistical approaches applied post-non-PH identification were extracted. We also reviewed published committee reports to determine the approach used by the agency in its assessment process.

RESULTS : We identified 27 NICE appraisals for avelumab, atezolizumab, cemiplimab, durvalumab, nivolumab, and pembrolizumab across eight oncology indications. All except one submission received a positive recommendation from NICE. PH assumption was reported/assessed in 23 of the 27 appraisals, though the method of assessment varied across these submissions. A total of 10 appraisals utilized cumulative hazard plots/the log cumulative hazard plots, and five submissions reported testing using the Schoenfeld residual plots. In-line with the NICE DSU guidelines, the survival curve fitting using standard parametric models (i.e., exponential, Weibull, Gompertz, log-logistic, and log-normal) was carried out in almost all submissions with PH violation. The most common methods used for network meta-analyses (NMA) were parametric NMA using Gompertz, Weibull, and a set of 2nd order fractional polynomials.

CONCLUSIONS : The current practice indicates that the PH assumption was tested consistently across PD1/PD-L1 NICE submissions. The parametric and spline-based models were the most common methods for curve fitting, and Gompertz, Weibull, and 2nd order FPs were the most common methods for conducting NMA in case of PH violation.