Slipping Away: Slippage in Hazard Ratios Over Datacuts and Its Impact on Immuno-oncology Combination Economic Evaluations

Objectives This study examines the impact of slippage in hazard ratios (tending toward the null over subsequent datacuts) for overall survival for combination treatment with a PD-(L)-1 inhibitor and a tyrosine kinase inhibitor in advanced renal cell carcinoma. Methods Four trials’ Kaplan-Meier curves were digitized over several datacuts and fitted with standard parametric curves. Accuracy and consistency of early data projections were calculated versus observed restricted mean survival time and fitted lifetime survival from the longest follow-up datacut. The change in economically justifiable price (eJP) was calculated fitting the same curve to both arms, using an assumed average utility of 0.7 and willingness-to-pay threshold of £30 000 per quality-adjusted life-year. The eJP represents the lifetime justifiable price increment for the new treatment, including differences in drug-, administration-, and disease-related costs. Results Slippage in hazard ratios was observed in trials with longer follow-up, potentially influenced by subsequent PD-(L)-1 use after tyrosine kinase inhibitor monotherapy, early stoppage of PD-(L)-1, and development of resistance. Lognormal and log-logistic curves were more likely to overpredict the observed result; Gompertz and gamma underpredicted. Statistical measures of goodness of fit did not select the curves that resulted in the RMST closest to what was observed in the final data cut. Large differences in incremental mean life-years were observed between even the penultimate and final datacuts for most of the fitted curves, meaningfully affecting the eJP. Conclusions This work demonstrates the challenge in predicting treatment benefits with novel therapies using immature data. Incorporating information on the impact of subsequent treatment is likely to play a key role in improving predictions.