The FGFR and IDH-1 pathways are the primary targets for therapy, with FGFR-2 and IDH-1 inhibitors, such as Pemigatinib and Ivosidenib respectively, already available on the market. This prospective study validates the prevalence of mutations documented in the literature and underscores the significance of NGS in presenting supplementary therapeutic avenues. Moreover, we demonstrated the role of other potential targets co-expressed with FGFR2 or IDH1 which could represent a crucial opportunity for novel combinations or sequences therapies.

These mutations are targetable using agents such as ivosidenib and vorasedinib in AML... The Biocartis Idylla IDH1-2 mutation assay shows good concordance with ddPCR and an LOD of 2.5% VAF. Though the analytical sensitivity of this assay is lower than ddPCR, this may not be a limitation in acute, newly diagnosed patients presenting with increased blast counts. This assay offers the advantage of direct specimen testing for PB and BM without DNA extraction with faster turnaround time than other methods.

P2, N=60, Not yet recruiting, Rigel Pharmaceuticals | Initiation date: Jun 2024 --> Nov 2024

P1, N=8, Not yet recruiting, Hutchmed

P1/2, N=31, Not yet recruiting, M.D. Anderson Cancer Center

The most common (≥20%) adverse reactions were nausea, fatigue, arthralgia, leukocytosis, dyspnea, pyrexia, rash, mucositis, diarrhea, and transaminitis. An assessment of long-term safety of olutasidenib is a condition of this approval.

P2, N=20, Recruiting, Washington University School of Medicine | N=15 --> 20 | Trial completion date: Jun 2026 --> Jan 2030 | Trial primary completion date: Jun 2026 --> Jan 2030

P=N/A, N=250, Recruiting, French Innovative Leukemia Organisation | Not yet recruiting --> Recruiting

P1, N=48, Not yet recruiting, Katy Peters, MD, PhD | Trial completion date: Aug 2027 --> Aug 2029 | Trial primary completion date: Aug 2025 --> Aug 2027

P1, N=90, Active, not recruiting, Hutchmed | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

"Thermo Fisher Scientific...has received approval from the U.S. Food and Drug Administration (FDA) for its Ion Torrent Oncomine Dx Target Test as a companion diagnostic (CDx) to identify patients eligible for treatment with Servier Pharmaceuticals, LLC’s VORANIGO (vorasidenib) tablets. VORANIGO is an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery including biopsy, sub-total resection or gross total resection...Today’s approval expands clinical indications for the Oncomine Dx Target Test, which is currently approved and reimbursed by government and commercial insurers in 19 countries, including the U.S., Japan, South Korea and countries across Europe and the Middle East, covering more than 550 million lives globally."

P1, N=9, Terminated, AnHeart Therapeutics Inc. | N=63 --> 9 | Trial completion date: May 2026 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2025 --> Aug 2024; Sponsor adjusted the study strategy

P=N/A, N=40, Not yet recruiting, Duke University

P1, N=18, Recruiting, University of Chicago | Not yet recruiting --> Recruiting

No abstract available

In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.

P2, N=6, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=17 --> 6

In the EU and other countries worldwide, regulatory review of vorasidenib in IDH-mutant glioma is currently underway. This article summarizes the milestones in the development of vorasidenib leading to this first approval for glioma.

P1/2, N=29, Not yet recruiting, Institute of Hematology & Blood Diseases Hospital, China

Our findings indicate an increasing need to personalize an approach for these patients with specific molecular alterations. With the advent of the IDH1 inhibitor ivosidenib and other inhibitors in this space, IDH1/2 mutation has both prognostic and predictive value. Our series builds upon the patterns and findings seen in these patients.

P=N/A, N=100, Not yet recruiting, iOMEDICO AG

P3, N=968, Active, not recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Recruiting --> Active, not recruiting | Trial completion date: May 2034 --> Sep 2034 | Trial primary completion date: Oct 2024 --> Apr 2027

P1/2, N=84, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P2, N=45, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=36, Not yet recruiting, Fudan University

In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH.

P1/2, N=78, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Nov 2024 --> Aug 2024

Notably, the patient experienced diffuse hair regrowth on the scalp, including in areas affected by severe androgenetic alopecia. This report holds significance as it highlights a previously unreported side effect, thereby enhancing our understanding of emerging therapies for brain tumors and their associated adverse reactions.

Finally, application of a two-tissue compartment model (2TCM) to the PET data indicated that preferential tracer uptake into U87-WT tumors results from higher specific binding rather than from differences in tracer perfusion. In conclusion, these results corroborate recent findings that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and indicate that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes.

P1/2, N=92, Active, not recruiting, Servier Bio-Innovation LLC | Recruiting --> Active, not recruiting

P2, N=15, Not yet recruiting, M.D. Anderson Cancer Center

P3, N=968, Recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Trial completion date: Mar 2033 --> May 2034 | Trial primary completion date: Mar 2023 --> Oct 2024

P1, N=18, Not yet recruiting, University of Chicago | Initiation date: May 2024 --> Nov 2024

This research will enable objective measurement of biological activity of safusidenib in patients with IDH1 mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention.Clinical Trial Registration: NCT05577416 (ClinicalTrials.gov).

P2, N=12, Active, not recruiting, Servier | N=21 --> 12

IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

P1, N=15, Recruiting, City of Hope Medical Center

This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.

A complete understanding of the mechanisms by which IDH mutations influence the development of leukemia, as well as the processes that enable resistance to mIDH inhibitors, may significantly improve the efficacy of this therapy through the use of an appropriate synergistic approach. The aim of this literature review is to present the role of IDH1/IDH2 mutations in the pathogenesis of AML and the results of clinical trials using mIDH1/IDH2 inhibitors in AML and to discuss the challenges related to the use of mIDH1/IDH2 inhibitors in practice and future prospects related to the potential methods of overcoming resistance to these agents.

P3, N=136, Recruiting, Servier Bio-Innovation LLC | Not yet recruiting --> Recruiting | Trial completion date: Apr 2031 --> Nov 2030 | Trial primary completion date: Dec 2026 --> Feb 2028

P1, N=95, Completed, Institut de Recherches Internationales Servier | Active, not recruiting --> Completed | Trial completion date: Mar 2024 --> Jun 2024

P1, N=16, Recruiting, Case Comprehensive Cancer Center | Trial completion date: Oct 2024 --> Dec 2026 | Trial primary completion date: Oct 2024 --> Jul 2026