IDH1 R132C

Significant differences in GA and immune biomarkers are noted between IDH1/2+ and IDHwt iCCA. IDH1-/2-mutated tumors appear immunologically cold without gLOH. These immunogenomic data provide insight for precision targeting of iCCA with IDH alterations.

The U.S. Food and Drug Administration (FDA) approved Ivosidenib, a molecular entity that targets IDH1 with R132 mutations, as a promising therapeutic option for AML with mIDH1 in 2018...RMSD showed that the four dynamics simulation systems remained stable, and RMSF and Rg showed that the screened molecules have similar local flexibility and tightness to the positive drug. Finally, the lowest energy conformation, hydrogen bond analysis, and free energy decomposition results indicate that in the entire system the key residues LEU120, TRP124, TRP267, and VAL281 mainly contribute van der Waals forces to the interaction, while the key residues VAL276 and CYS379 mainly contribute electrostatic forces.

With advancements in molecular diagnostics and precision therapy, IDH inhibitors such as ivosidenib, vorasidenib and enasidenib are now mainstay in management of patients with a susceptible mutation. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit (RUO) is a fully automated qPCR assay for the qualitative detection of 15 common mutations in IDH1 (R132C/H/G/S/L) and IDH2 (R140Q/L/G/W, R172K/M/G/W/S) at codon level. The Idyllaâ„¢ IDH1-2 Mutation Assay Kit demonstrates a high concordance with established reference methods across a range of different specimen types.

P1, N=75, Recruiting, Hutchmed | Trial completion date: Sep 2023 --> Jun 2025 | Trial primary completion date: Sep 2023 --> Sep 2024

P2, N=145, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

This is the first known report of skull base periosteal chondroma. Genetic testing was useful for confirming the diagnosis, and EES was effective for treatment. Should such a tumor show adhesion to an important structure, an intracapsular excision can be beneficial for avoiding complications.

No IDH2 mutations were found. The use of independent diagnostic methods may improve the detection of IDH-mutant specimens in chondroid tumors.

P1/2, N=92, Recruiting, Servier Bio-Innovation LLC

MB isolation had a higher yield than CB isolation (P<0.0001), and post-isolation vacuum increased the final concentration in both methods, with little effect on cfDNA integrity. Our study provides a protocol to maximize CSF-ctDNA concentrations in IVD testing and future studies.

P3, N=220, Recruiting, Servier Affaires Médicales | Phase classification: P3b --> P3

P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

Baseline bone blast count was strongly predictive of response to treatment. Further evaluation of these observations is needed.

P2, N=16, Completed, Jason J. Luke, MD | Recruiting --> Completed | N=35 --> 16 | Trial completion date: May 2026 --> Nov 2023 | Trial primary completion date: Mar 2024 --> Nov 2023

IDH1-mutated CrD-SBAs, which represent approximately one-fifth of total cases, are characterised by distinctive immunophenotypical features and methylation profiles, with potential therapeutic implications. Moreover, IDH1-mutated non-conventional, serrated dysplasia is likely to represent a precursor lesion to such CrD-SBAs.

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

CONCLUSION While IDH1 mutations are possible therapeutic targets with exciting preliminary responses, treatment response is likely complex and dependent on multiple mutations. Further analyses and validation studies are underway.

This case report aims to warn of the possibility that other driver mutations may be associated with the diagnosis of TCCRP, such as IDH1 R132 and not just IDH2 R172, and that a comprehensive testing approach of the IDH1/2 genes might be more accurate in these cases.

Interestingly, a rare IDH1 R132C was identified in CSF ctDNA, but not in the corresponding tumor sample. This study demonstrates a high concordance between integrated ctDNA diagnosis and the final diagnosis of gliomas, highlighting the practicability of NGS based detection of mutations of CSF in assisting integrated diagnosis of gliomas, especially glioblastoma.

P2, N=94, Recruiting, National Cancer Institute (NCI) | Active, not recruiting --> Recruiting

Additionally, several IDH1/IDH2 inhibitors such as ivosidenib and enasidenib have been approved by the FDA for treatment of AML patients with IDH1 and IDH2 mutations respectively. We have prototyped 18-plex assay designed to detect 7 IDH1 and 10 IDH2 mutations and call out its corresponding codon in EDTA whole blood samples using a single cartridge at an estimated LoD of 1%.

The Idylla Rapid IDH1/2 Mutation Assay had 92% concordance with NGS for FFPE sections. Compared with Idylla EGFR and KRAS assays (previously published) both control and target Cqs were considerably higher using the same number of sections or amount of DNA. A large DNA input requires stewardship for effective tissue utilization for molecular testing, especially in glioma biopsy samples, which may be limited.

P2, N=94, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting

No abstract available

P2, N=145, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

Conclusions Neoadjuvant D+GemCis resulted in a higher surgical resection rate in pts with localized BTC, and surgical resection was associated with better survival. ctDNA analysis was shown to be a feasible method for assessing actionable target gene alterations in early BTC.

P1/2, N=92, Not yet recruiting, Servier Bio-Innovation LLC | Trial primary completion date: Nov 2023 --> Mar 2026

SMU-DDCS cells exhibited low chemosensitivity to doxorubicin, methotrexate, and cisplatin. This SMU-DDCS cell line harboring an IDH1 mutation will be a useful tool for investigating DDCS development and for evaluating novel therapeutic agents against it.

P1/2, N=92, Not yet recruiting, Servier Bio-Innovation LLC

Practical implementation of routine molecular work-up of CNS tumors is compromised by impractically long turnaround times and economic restraints. Based on our results, we advocate a stepwise approach, providing fast-track results obtained by MLPA for first-line therapy decisions within a week after surgery.

Surgical operation is the main treatment. We suggest that patients with ovarian juvenile granulosa cell tumors and Ollier's disease should undergo regular investigation.

P1, N=8, Active, not recruiting, Academic and Community Cancer Research United | N=40 --> 8

P3b, N=220, Recruiting, Servier

P2, N=95, Recruiting, AnHeart Therapeutics Inc. | Not yet recruiting --> Recruiting | Trial completion date: Feb 2027 --> Jul 2027 | Trial primary completion date: Jan 2026 --> Mar 2027

P1, N=40, Active, not recruiting, Academic and Community Cancer Research United | Recruiting --> Active, not recruiting

A subset of patients with IDH1m R/R AML have prolonged CR on single agent IVO without HSCT (22.8% of CR/CRh responders), and no patients in CR for >2 years (14% of CR/CRh responders) relapsed. A low mutational burden, lack of RTK pathway mutations and canonical AML drivers, and co-occurrence of mutations associated with clonal hematopoiesis appear to be associated with exceptional response. relapsed/refractory, Ivosidenib, Acute myeloid leukemia

Combing with safety, tolerability, PK/PD and preliminary efficacy, the RP2D was set as 250 mg QD at Cycle 1, and then with 150 mg QD from Cycle 2. Dose expansion is ongoing. Clinical trialinformation: NCT04272957.

P1, N=75, Recruiting, Hutchmed | Trial completion date: Jan 2023 --> Sep 2023 | Trial primary completion date: Jan 2023 --> Sep 2023

The use of throughput molecular profiling analysis and advanced medical imaging will certainly increase the frequency with which tumor entities with rare molecular alterations will be identified. Whether these findings have any specific therapeutic implications or prognostic relevance requires further investigations.