Tibsovo (ivosidenib)

P1, N=30, Recruiting, Servier Bio-Innovation LLC

P2, N=50, Not yet recruiting, PETHEMA Foundation

Current first-line therapy for advanced IDH1-mutant disease includes gemcitabine plus cisplatin combined with either durvalumab or pembrolizumab. Ivosidenib is commonly used as a second-line targeted therapy...More prospective clinical trials are needed to validate ctDNA-guided risk stratification, support treatment decisions on adjuvant therapy escalation or de-escalation, and enable treatment adaptation in IDH-mutant CCA, ultimately advancing precision oncology beyond the capabilities of imaging alone. This review aims to evaluate the potential of ctDNA-based MRD detection to refine precision treatment strategies in IDH-mutant CCA.

P1, N=18, Recruiting, Memorial Sloan Kettering Cancer Center | N=36 --> 18

Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them.

Standard-of-care surgery, radiation, and temozolomide yield a median survival of 14-16 months in patients with glioblastoma (GBM)...NGS yielded actionable alterations targeted after conventional surgery/chemoradiation therapy: imatinib (for KIT and PDGRA amplification) and bevacizumab (for KDR [VEGFR2] amplification); everolimus (mTOR inhibitor for TSC2 and PTEN loss-of-function alterations); and ivosidenib (IDH1 inhibitor for IDH1 mutations in two cases, including the oligosarcoma). Three patients remain in radiographic and clinical remission at 39+, 48, and 52+ months; the patient with oligosarcoma showed clinical and imaging response lasting 8 months. Our exceptional responders with high-grade gliomas suggest that biomarker-matched targeted therapy can benefit select patients with high-grade glioma and warrants prospective clinical trials.

Furthermore, fourteen candidate drugs targeting this network were predicted, and structural analogs of Lumacaftor and Ivosidenib showed promising docking affinities to CD1C and CXCR3, respectively. These findings provide preliminary insights into TIM-associated prognostic pathways and suggest candidate compounds for further investigation in BRCA.

P1, N=25, Recruiting, Servier Bio-Innovation LLC

Gemcitabine-based chemotherapy is the standard treatment regime for advanced intrahepatic cholangiocarcinoma (iCCA), but the frequent presence of chemoresistance limits its efficacy. The low level of Mg2+, an ion that competitively hinders binding of ivosidenib on wtIDH1, in iCCA tumor microenvironment contributed to the expanded therapeutic window of ivosidenib in patients with iCCA. Our work revealed the potency of combining targeting IDH1 and chemotherapy against wtIDH1 iCCA and other tumors.

P2, N=60, Not yet recruiting, French Innovative Leukemia Organisation

However, with the exception of IDH1 inhibitor ivosidenib, targeted therapies in higher-risk MDS remain the exception to the rule...Examining the history and evolution of investigational pharmacotherapy in higher-risk MDS may help identify where efforts to translate early phase successes into successful phase III trials have faltered. The expanding biological knowledge base and the design of better therapies will hopefully pave the way for future therapeutic breakthroughs.

Notably, ICC with concurrent IDH1 mutations and MYC amplification exhibited sensitivity to the MYC inhibitor (+)-JQ1, but remained resistant to the IDH1 mutation inhibitor AG120. MYC overexpression conferred resistance to IDH1 mutation inhibitor, while creating a therapeutic vulnerability to MYC-targeted agents. The selective efficacy of (+)-JQ1 against IDH1-mutant ICC identified MYC inhibition as a promising precision medicine strategy for this molecular subset.