CLARIDHY
Regimen
- Experimental
- Ivosidenib 500 mg PO QD (continuous 28-day cycle) — selective IDH1 mutant inhibitor
- Control
- Placebo (2:1 randomization); crossover permitted at progression (confounds OS analysis)
Population
Previously treated (≥1 prior therapy) unresectable or metastatic CCA with IDH1 mutation (R132 hotspot) by central testing; ICC-enriched (~90% ICC, ~10% ECC/GBC) given IDH1 mutation biology. Randomized 2:1 ivosidenib:placebo. Primary pub: Abou-Alfa GK, Lancet Oncol 2020 (PMID 32416072). OS update: Zhu AX, JAMA Oncol 2021 (PMID 34554208).
Key finding
First positive phase 3 RCT for any targeted therapy in CCA, and the only phase 3 biomarker-selected CCA trial with a placebo comparator. Ivosidenib received FDA approval in August 2021 for previously treated IDH1-mutant CCA. PFS benefit was clear (HR 0.37), but the OS analysis was confounded by ~70% crossover from placebo arm; after adjusting for crossover, OS HR favored ivosidenib. The modest ORR (2.4%) highlights that IDH1 inhibition primarily stabilizes disease rather than inducing tumor shrinkage, consistent with mutant IDH1's role in epigenetic reprogramming rather than direct oncogenic signaling.
Source: PMID 32416072
Timeline
Guideline citations
- NCCN BTC (p.34)