ivosidenib

Overview

Ivosidenib is a selective inhibitor of mutant IDH1, targeting hotspot mutations that occur in 13–29% of intrahepatic cholangiocarcinoma (iCCA) and are rare in extrahepatic CCA. It received FDA approval for IDH1-mutant CCA based on the ClarIDHy phase III trial.

Evidence in the corpus

  • IDH1-mutant iCCA: ClarIDHy phase III ORR 2%, mPFS 6.9 vs. 2.7 months (placebo), mOS 10.3 vs. 7.5 months (adjusted-crossover OS benefit 5.1 months); IDH1 mutations occur in 13–29% of iCCA and are rare in eCCA; retrospective data show 14.5% prevalence in advanced iCCA with longer PFS for IDH1-mutant tumors under standard chemotherapy PMID:25526346
  • Endorsed as a precision option for IDH1-mutant iCCA based on the ClarIDHy phase III trial (PFS benefit); highlighted as the first targeted therapy approved for IDH1-mutant cholangiocarcinoma, with IDH1 mutations also epigenetically suppressing bile acid synthesis genes via 2-hydroxyglutarate accumulation PMID:25608663
  • IDH1/IDH2 mutations enriched in Fluke-Negative CCA Cluster 4 (31.6% vs 1.0%); ivosidenib (NCT02073994) nominated as therapeutic candidate for this subtype PMID:28667006

Resistance mechanisms

  • IDH inhibitor resistance in CCA is poorly characterized; secondary IDH mutations and isoform switching (IDH1 to IDH2) have been reported as resistance mechanisms extrapolated from AML data PMID:25526346

Cancer types (linked)

Sources

  • PMID:25526346
  • PMID:25608663
  • PMID:28667006 — Jusakul et al. 2017, ICGC 489-sample CCA multi-omic study; IDH1/IDH2 mutations in 31.6% of Cluster 4 CCAs; ivosidenib (NCT02073994) nominated as therapeutic candidate.

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