Ivosidenib vs. Placebo in IDH1-Mutated Cholangiocarcinoma

The IDH1 mutation (IDH1m) is found in about 13% of cholangiocarcinoma (CCA) patients (pts). The global phase 3 ClarIDHy study, which assessed ivosidenib (IVO) – an oral IDH1m protein inhibitor – versus placebo (PBO) in previously treated, inoperable or metastatic IDH1m CCA patients, highlighted that IVO considerably improved progression-free survival (PFS) over PBO (HR=0.37, p < 0.0001) and had a favorable safety profile. The researchers conducted a quantitative benefit-risk assessment comparing IVO to PBO using data from the ClarIDHy study.

A team of seven experts crafted a ‘value tree’ by establishing key benefit and risk metrics for both IVO and PBO. They aimed to evaluate data from the ClarIDHy study while minimizing bias appropriately. They based the benefit metrics on efficacy markers and quality of life indicators from the ClarIDHy study, including rates for 3-month and 6-month PFS, 6-month OS, and a special 6-month OS rate adjusting for any crossover from PBO to IVO. This also incorporated objective response rates and specific quality of life measures (like EORTC-QLQ-C30 Physical Functioning, Pain, and Appetite Loss metrics). 

The team identified risks by focusing on frequent adverse events linked to IVO, such as ECG QT prolongation, gastrointestinal symptoms, fatigue, and any adverse events prompting treatment cessation or dosage modification. They employed the ‘Scale Loss Score’ (SLoS) method for their primary analysis to predict IVO’s benefit-risk profile compared to PBO. Additionally, they performed sensitivity analyses using various models to either validate or challenge the SLoS model’s outcomes.

The primary analysis showed a 95.24% chance that IVO’s benefit-risk profile was superior to PBO’s. Sensitivity analyses consistently favored IVO, with over a 95% probability. The linear and product model analyses were consistent, supporting IVO over PBO for all evaluated endpoints.

IVO consistently demonstrated a superior benefit-risk profile over PBO. The results further established IVO as an effective and safe treatment for this aggressive, life-threatening disease, reinforcing previously reported data on PFS, OS, and safety.

Source: https://www.annalsofoncology.org/article/S0923-7534(23)00616-6/fulltext

Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT02989857

Valle, J., Abou-Alfa, G., Kelley, R., Lowery, M., Shroff, R., Bian, Y., Saint-Hilary, G., Liu, H., Teng, Z., Hua, Z., Gliser, C., Vogel, A., Javle, M. SO-2 Quantitative risk-benefit assessment of ivosidenib compared to placebo in patients with IDH1-mutated intrahepatic cholangiocarcinoma: Phase 3 ClarIDHy trial. https://doi.org/10.1016/j.annonc.2023.04.474