Details

Autor(en) / Beteiligte

• Zarei, Mehrdad
• Hue, Jonathan J.
• Hajihassani, Omid
• Graor, Hallie J.
• Katayama, Erryk S.
• Loftus, Alexander W.
• Bajor, David
• Rothermel, Luke D.
• Vaziri-Gohar, Ali
• Winter, Jordan M.

Titel

Clinical development of IDH1 inhibitors for cancer therapy

Ist Teil von

• Cancer treatment reviews, 2022-02, Vol.103, p.102334-102334, Article 102334

Ort / Verlag

Netherlands: Elsevier Ltd

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• •Approximately 1% of all cancers are mutant (mt) IDH1.•mtIDH1 inhibitors are biologically potent and well tolerated.•Ivosidenib (AG-120) is FDA-approved and the best characterized mtIDH1 inhibitor. Isocitrate dehydrogenase 1 (IDH1) has been investigated as a promising therapeutic target in select cancers with a mutated version of the enzyme (mtIDH1). With only one phase III trial published to date and two indications approved for routine clinical use by the FDA, we reviewed the entire clinical trial portfolio to broadly understand mtIDH1 inhibitor activity in patients. We queried PubMed.gov and ClinicalTrials.gov to identify published and ongoing clinical trials related to IDH1 and cancer. Progression-free survival (PFS), overall survival (OS), 2-hydroxyglutarate levels, and adverse events were summarized. To date, ten clinical trials investigating mtIDH1 inhibitors among patients with diverse malignancies (cholangiocarcinoma, acute myeloid leukemia, chondrosarcoma, glioma) have been published. Almost every trial (80%) has investigated ivosidenib. In multiple phase I trials, ivosidenib treatment resulted in promising radiographic and biochemical responses with improved survival outcomes (relative to historic data) among patients with both solid and hematologic mtIDH1 malignancies. Among patients enrolled in a phase III trial with advanced cholangiocarcinoma, ivosidenib resulted in a PFS rate of 32% at 6 months, as compared to 0% with placebo. There was a 5.2 month increase in OS with ivosidenib relative to placebo, after considering crossover. The treatment-specific grade ≥3 adverse event rate of ivosidenib was 2%-26% among all patients, and was just 3.6% among 284 patients who had a solid tumor across four trials. Although <1% of malignancies harbor IDH1 mutations, small molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well tolerated in patients with solid and hematologic mtIDH1 malignancies.