Molecular and Morphological Changes Induced by Ivosidenib Correlate with Efficacy in Mutant- IDH1 Cholangiocarcinoma

Abstract

Background: IDH1 mutations occur in approximately 13% of intrahepatic cholangiocarcinomas (IHCCs). The oral, targeted, mutant IDH1 (mIDH1) inhibitor ivosidenib (AG-120) suppresses production of the oncometabolite D-2-hydroxyglutarate, promoting disease stabilization and improved progression-free survival (PFS) in m IDH1 IHCC. Materials & methods: Harnessing matched baseline and on-treatment biopsies, we investigate the potential mechanisms underlying ivosidenib's efficacy. Results: mIDH1 inhibition leads to decreased cytoplasm and expression of hepatocyte lineage markers in patients with prolonged PFS. These findings are accompanied by downregulation of biliary fate, cell cycle progression and AKT pathway activity. Conclusion: Ivosidenib stimulates a hepatocyte differentiation program in m IDH1 IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors. Clinical trial registration: NCT02073994 ( ClinicalTrials.gov )

Challenges and Opportunities for Immunoprofiling Using a Spatial High-Plex Technology: The NanoString GeoMx® Digital Spatial Profiler

“…AKT phosphorylation levels were decreased upon treatment with ivosidenib across the samples, and PD-L1, PD1, and VISTA/B7-H5 were increased in post-treated tumor-infiltrated immune cells. These findings support the rationale of combining mIDH1 inhibition with checkpoint inhibition in patients with mIDH1 cholangiocarcinoma ( 56 ).…”

IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy

“…These signs of differentiation were associated with a better clinical response to ivosidenib and longer progression-free survival. 64 Translational data from IDH1/2mt glioma treated with mtIDH1/2 inhibitors are not available, probably due to the inherent difficulties of obtaining multiple tumor samples over time in glioma patients.…”

“…30,62,75 These findings can be partially extended to IDH1/2mt cholangiocarcinoma, in which gene signatures associated with activated RTK and PI3K/AKT-activity are associated with early progression upon treatment with ivosidenib. 64 In glioma, the presence of genetic alterations in cell cycle pathway genes was associated with a shorter progression-free survival. 34 In addition to these genetic hallmarks of mtIDH1/2-inhibitor primary resistance, leukemia stemness is associated with poor responses to mtIDH1/2 inhibitors in IDH1/2mt AML.…”

Biology of IDH mutant cholangiocarcinoma

“…[ 13 ] Secondly, comparison of pretreatment biopsy samples versus on‐treatment biopsies (cycle 3, day 1) revealed that ivosidenib up‐regulated a program of hepatocyte lineage genes, including targets of the master transcriptional regulator of hepatocyte identity, HNF4a, suggesting induction of tumor cell differentiation. [ 86 ] Notably, the degree of enrichment in this signature correlated with increased PFS. These findings are reminiscent of the observed induction of myeloid differentiation of leukemic blasts as the mechanism of action of mIDH inhibition in AML.…”

“…Preliminary studies suggest that ivosidenib also promotes immune checkpoint activation in human mIDH1 cholangiocarcinoma. [ 86 ] In particular, several checkpoint proteins (PD‐L1, PD‐1, and V‐domain Ig suppressor of T cell activation/B7‐H5) showed increased expression in on‐treatment biopsy specimens compared with baseline specimens, although the sample size was very limited (five matched pairs). It is worth noting that the time point of the on‐treatment biopsies (cycle 3, day 1, i.e., ~60 days from the start of treatment) may not have been ideal for monitoring immune parameters because data in the mouse model suggest that the most prominent immunological effects occur very early on IDH1 inhibition.…”