OBJECTIVES: The phase 3 ClarIDHy study assessed overall survival (OS) with ivosidenib versus placebo in previously treated, locally advanced or metastatic mutant isocitrate dehydrogenase 1 cholangiocarcinoma. In the original published analysis, when the rank-preserving structural failure time model (RPSFTM) with re-censoring was used for crossover adjustment a significant OS benefit with ivosidenib was reported (hazard ratio (HR)=0.49 [95% confidence interval (CI): 0.34; 0.70]). This method of crossover adjustment has been questioned for later-line therapies without previously proven OS benefit. Therefore, an external analysis was conducted using other statistical methods to test the robustness of the ClarIDHy RPSFTM-adjusted results.

METHODS: To adjust for the high crossover rate (>70%) in ClarIDHy, an external analysis applied four recommended methods to the published OS results: the RPSFTM (‘treatment group’ without re-censoring and ‘on-treatment’ approaches), inverse probability of censoring weights (IPCW), and two-stage estimation (results not shown as this was deemed unviable for crossover adjustment in this highly imbalanced population). The RPSTFM is randomization-based, while IPCW is an observational-based method. The external analyses used individual patient data from the intent-to-treat population. Estimated HRs and 95% CIs of ivosidenib versus placebo were calculated.

RESULTS: The previously published RPSFTM-adjusted results showed that ivosidenib was associated with mortality risk reduction (MRR) versus placebo (HR=0.49 [95% CI: 0.34; 0.70]). The external analysis reported here, showed that ivosidenib was associated with MRR, using the RPSFTM ‘treatment group’ (not re-censored HR=0.52 [95% CI: 0.37; 0.75]), and ‘on-treatment’ approaches (re-censored HR=0.49 [95% CI: 0.28; 0.87]; not re-censored HR=0.52 [95% CI: 0.36; 0.74]). The IPCW-adjusted Cox proportional hazards regression analysis also showed that ivosidenib was associated with MRR (HR=0.74 [95% CI: 0.35; 1.56]).

CONCLUSIONS: All three crossover adjustment methods applied in this external re-analysis of ClarIDHy data showed that ivosidenib was associated with MRR, consistent with previously published RPSFTM-adjusted results.