Background
ClarIDHy. Phase III RCT enrolled 187 patients with unresectable or metastatic IDH1-mutant cholangiocarcinoma who had progressed after 1–2 prior lines (gemcitabine- or fluorouracil-based) and were IDH-inhibitor-naïve, randomized 2:1.
Interventions and follow up
Arm A: Ivosidenib 500 mg orally once daily until progression, unacceptable toxicity, or withdrawal
Arm B: Placebo (crossover to ivosidenib permitted at progression)
Primary endpoint: PFS (by blinded independent review); secondary: OS
mFollow up: 6.9 mo
Arm B: Placebo (crossover to ivosidenib permitted at progression)
Primary endpoint: PFS (by blinded independent review); secondary: OS
mFollow up: 6.9 mo
Results
mPFS: 2.7 mo vs 1.4 mo; HR 0.37, 95%CI 0.25–0.54; P<.0001
mOS (ITT): 10.3 mo vs 7.5 mo (arm A vs B); HR 0.79, 95%CI 0.56–1.12; P=.09
mOS crossover-adjusted (placebo): 5.1 mo; HR 0.49, 95%CI 0.34–0.70; P<.001 (43 of 61 placebo patients crossed over)
ORR: 2% vs 0%
Stable disease: 51% vs 21%
mOS (ITT): 10.3 mo vs 7.5 mo (arm A vs B); HR 0.79, 95%CI 0.56–1.12; P=.09
mOS crossover-adjusted (placebo): 5.1 mo; HR 0.49, 95%CI 0.34–0.70; P<.001 (43 of 61 placebo patients crossed over)
ORR: 2% vs 0%
Stable disease: 51% vs 21%
Adverse events
Overall: Grade≥3 events 50% vs 37% (arm A vs B); treatment discontinuation for AEs 7% vs 8%
Cardiac/specific: QT prolongation 10% vs 3%; most common any-grade events nausea, diarrhea, and fatigue
Cardiac/specific: QT prolongation 10% vs 3%; most common any-grade events nausea, diarrhea, and fatigue
Conclusions
Ivosidenib significantly improved PFS and, after crossover adjustment, OS in previously treated IDH1-mutant cholangiocarcinoma, with a tolerable safety profile.
Key Limitations
Modest absolute PFS gain; ITT OS not statistically significant due to high (70%) placebo crossover; low objective response rate; benefit limited to the IDH1-mutant subset (~13% of intrahepatic cholangiocarcinoma).
Clinical Context
Led to FDA approval (2021) of ivosidenib for previously treated IDH1-mutant cholangiocarcinoma; EMA approval followed (2023). Endorsed in ESMO/ASCO biliary tract guidance for IDH1-mutant disease after gemcitabine-based therapy; reinforces molecular profiling at diagnosis.
References
Abou-Alfa GK et al, Lancet; PMID: 3241607
Final OS update: Zhu AX et al, JAMA Oncol, 2021; PMID:34554208
Final OS update: Zhu AX et al, JAMA Oncol, 2021; PMID:34554208