Quantitative risk-benefit assessment of ivosidenib compared to placebo in patients with IDH1-mutated intrahepatic cholangiocarcinoma: Phase 3 ClarIDHy trial

Isocitrate dehydrogenase 1 mutation ( IDH1m ) is detected in approximately 13% of patients with cholangiocarcinoma (CCA). In the global, phase 3 ClarIDHy study evaluating ivosidenib (IVO), an oral inhibitor of the IDH1m protein, and placebo (PBO) in patients with previously treated, non-resectable or metastatic IDH1m CCA, IVO significantly improved progression-free survival (PFS) compared to PBO (HR=0.37, p < 0.0001), and demonstrated a favourable safety profile. A quantitative benefit-risk assessment is a useful method to summarize the evidence and explicitly trade off the benefits and risks in comparing IVO with PBO. We present the results of a quantitative benefit-risk assessment of IVO compared to PBO from the ClarIDHy study.

A panel of seven experts determined relevant key benefit and risk criteria for IVO and PBO in order to create a ‘value tree,’ and agree appropriate models to assess data from the ClarIDHy study via elicitation to minimize potential bias. The benefit criteria were determined based on efficacy endpoints and quality of life (QoL) subscales utilised in the ClarIDHy study: 3-month and 6-month PFS rate; 6-month OS rate and 6-month OS rate from the rank preserving structural failure time model (to adjust for crossover from PBO to IVO); objective response rate and 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 IVO: ECG QT prolongation; gastrointestinal events (diarrhoea; retching and vomiting; nausea); fatigue; AEs leading to treatment discontinuation or dose reduction. 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 IVO was better than that of PBO. 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.

The primary analysis showed a 95.24% probability that the benefit-risk profile of IVO was better than the benefit-risk profile of PBO. Sensitivity analyses applying the SLoS model to alternative sets of benefit and risk criteria in the value tree showed consistently high probability (of >95%) for the benefit-risk profile in favour of IVO versus PBO for all endpoints evaluated. Sensitivity analyses using the linear model and the product model also showed a strong consistency of a high probability in favour of IVO compared to PBO for all endpoints evaluated (linear model: >99%; product model: >94%). Robustness of the results was demonstrated by the random weights analysis showing a similar trend in favour of IVO with all weights and the results converging quickly towards the main analysis results.

A consistent positive result in support of a favourable benefit-risk profile for IVO compared to PBO was demonstrated. These results support and provide comprehensive evidence that IVO is an effective treatment with a tolerable safety profile for this aggressive, life-threatening disease, in line with the previously reported PFS, OS and safety data.

NCT02989857.

Editorial assistance was provided by Liz Meredith of Empowering Strategic Performance and supported by Servier Pharmaceuticals LLC.

The authors.

This study was supported by Agios Pharmaceuticals, Inc. Servier Pharmaceuticals LLC has completed the acquisition of Agios’ oncology business.

G. Abou-Alfa: Advisory / Consultancy: Astellas, Astra Zeneca, Autem, Berry Genomics, BioNtech, Boehringer Ingelheim, BMS, Eisai, Exelixis, Fibriogen, Genentech/Roche, Helio, Incyte, Ipsen, Merck, Merus, Neogene, Newbridge, Novartis, QED, Servier, Tempus, Thetis, Vector, Yiviva; Research grant / Funding (self): Agenus, Arcus, Astra Zeneca, BioNtech, BMS, Elicio, Genentech/Roche, Helsinn, Parker Institute, Pertzye, Puma, QED, Yiviva. R. Kelley: Advisory / Consultancy: Astra Zeneca; Research grant / Funding (institution): Astra Zeneca; Travel / Accommodation / Expenses: Astra Zeneca. M. Lowery: Advisory / Consultancy: Astra zenica, Servier, Roche. R. Shroff: Advisory / Consultancy: AstraZeneca, Clovis, Genentech, Incyte, Merck, QED Therapeutics, Servier , Boehringer Ingelheim, Taiho, Zymeworks Biopharm, CAMI, Servier, SYROS; Research grant / Funding (institution): Bayer, BMS, Bristol-Myers Squibb, Exelixis Pharm., IMV Inc., LOXO, Novocure, NUCANA, Pieris, Rafael Pharm., Seagen, Taiho, QED. G. Saint-Hilary: Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Servier. H. Liu: Full / Part-time employment: Servier, Servier, Servier. Z. Teng: Full / Part-time employment: Servier. Z. Hua: Full / Part-time employment: Servier Pharmaceuticals. A. Vogel: Honoraria (self): AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, GSK, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Jiangsu Hengrui Medicines MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo; Advisory / Consultancy: AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, Terumo. M. Javle: Honoraria (self): QED Therapeutics, Inc., AstraZeneca/MedImmune, EMD Serono/Merck, TransThera Biosciences, Incyte, Merck; Advisory / Consultancy: QED Therapeutics, Inc., Oncosil, Incyte, Mundipharma EDO GmbH, AstraZeneca, Merck, EMD Serono, Basilea Pharmaceutical. All other authors have declared no conflicts of interest.