Favourable benefit-risk profile for ivosidenib compared to placebo in patients with IDH1-mutated intrahepatic cholangiocarcinoma

The ClarIDHy trial was the first phase III study to demonstrate a clinical benefit with targeted therapy in IDH1-mutated cholangiocarcinoma. In this study, ivosidenib delivered significant improvements in progression-free survival, with a tolerable safety profile. At ESMO WCGIC 2023, results of a quantitative benefit-risk assessment were presented, clearly demonstrating a favourable benefit-risk profile for ivosidenib compared to placebo for this aggressive and life-threatening disease.

To date, the isocitrate dehydrogenase 1 mutation (IDH1m) is detected in approximately 13% of patients with cholangiocarcinoma. Therefore, the phase III ClarIDHy study evaluated ivosidenib, an oral inhibitor of the IDH1m protein, in patients with previously treated, non-resectable or metastatic IDH1 cholangiocarcinoma. In this trial, treatment with ivosidenib resulted in a significantly improved progression-free survival (PFS) as compared to placebo, with a median PFS of 2.7 vs. 1.4 months, respectively (HR[95%CI]: 0.37[0.25-0.54], p< 0.0001). As a quantitative benefit-risk assessment is a useful approach to assess the magnitude of benefit and risk of new cancer therapies, the aim of the study at hand was to quantitatively evaluate the benefit-risk of ivosidenib compared to placebo in the ClarIDHy study.

Study design

For this study, a panel of 7 experts was asked to determine the relevant key benefit and risk criteria for ivosidenib and placebo in order to create a ‘value tree’. In addition, elicited weights for each key criteria were also determined by the panel via an elicitation meeting. The benefit criteria were determined based on several efficacy endpoints and quality of life (QoL) subscales utilised in the ClarIDHy study. These criteria included the 3- and 6-month PFS rate; the 6-month overall survival (OS) rate and 6-month OS rate from the rank preserving structural failure time model (to adjust for crossover from placebo to ivosidenib); the objective response rate and the QoL subscales (EORTC-QLQ-C30 Physical Functioning, Pain and Appetite Loss subscales; EORTC-QLQ-BIL21 Pain and Eating subscales). The risk criteria determined by the expert panel included common adverse events (AEs) associated with ivosidenib: ECG QT prolongation; gastrointestinal events (diarrhoea; retching and vomiting; nausea); fatigue; AEs leading to treatment discontinuation or dose reduction. Furthermore, a ‘Scale Loss Score’ (SLoS) model (primary analysis) was applied to the data from ClarIDHy to estimate the probability that the benefit-risk profile of ivosidenib was better than that of placebo. Sensitivity analyses were also applied to the data (product model; linear model and random weights analysis) to confirm or refute the results of the SLoS model.

Results

The primary analysis by the SLoS model demonstrated a 95.24% probability that the benefit-risk profile of ivosidenib was superior to placebo. In addition, the sensitivity analyses applying the SLoS model to alternative sets of benefit and risk criteria in the value tree showed a consistently high probability of more than 94% for the benefit-risk profile in favour of ivosidenib vs. placebo for all endpoints that were evaluated. Sensitivity analyses using the linear model and the product model also showed a strong consistency of a high probability in favour of ivosidenib compared to placebo for all endpoints evaluated (linear model: >99%; product model: >94%). Finally, the robustness of the results could be demonstrated by the random weights analysis that showed a similar trend in favour of ivosidenib with all weights and the results converging quickly towards the main analysis results.

Conclusions

All analyses demonstrated highly positive results, supporting a favourable benefit-risk profile for ivosidenib compared to placebo in patients with IDH1-mutated intrahepatic cholangiocarcinoma. Furthermore, these results are in line with the previously reported PFS, OS and safety data of the ClarIDHy trial. As such, ivosidenib proved to be an effective treatment option, with a tolerable safety profile for this aggressive and life-threatening disease.

Reference

Lowery M, et al. Quantitative Risk-benefit Assessment of Ivosidenib Compared to Placebo in Patients with IDH1-mutated Intrahepatic Cholangiocarcinoma: Phase 3 ClarIDHy trial. Presented at ESMO WCGIC 2023; Abstract SO-2.