IDH2 R172K

Target-capture NGS provides the opportunity to evaluate many genes in a single assay. Suitability for MRD requires highly uniform and sensitive target enrichment. Our study demonstrated reliable and accurate detection of variants down to 0.05% VAF, providing researchers with the capability to use capture-based NGS for myeloid MRD monitoring.

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.

The Idylla IDH1-2 Mutation Assay Kit performed on the Biocartis Idylla system demonstrated a rapid and cost-effective alternative to the standard approaches. This assay can be used to evaluate clinically relevant IDH variants in a much shorter turnaround time and from limited biological samples, which makes this a preferred technique to develop clinical tests for diagnosis, prognosis, and evaluation of treatment in AML.

P2, N=14, Active, not recruiting, National Cancer Institute (NCI) | N=94 --> 14 | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Jan 2024

P2, N=145, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jul 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

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

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

P3, N=331, Active, not recruiting, Institut de Recherches Internationales Servier

In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.

Introduction: Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain...The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ...Clinically, the patient has no symptoms from tumor. Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.

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%.

Almost all pts had AML, except one with MDS who progressed on treatment with azacitidine. The combination of ENA and VEN is safe and well tolerated in pts with R/R mIDH2 myeloid malignancies. The ENA-VEN combination compares favorably to ENA single-agent in this patient population. Further studies of targeted combination therapies using IDH2 and BCL2 inhibitors are warranted.

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

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

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.

This is the first comprehensive study to compare the sex ratio of driver genes at the variant level in a large cohort of hematological malignancies. Our findings extend the set of known sex-biased variant and support the hypothesis that male and female may have different mechanisms of oncogenesis, associated with potentiallydifferent outcomes, which needs to be further explored for precision medicine. Somatic mutation, Mutation analysis, MDS/AML

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

Oral administration of HMPL-306 remarkably decreased 2-HG level in plasma and tumor tissues in xenograft models carrying mIDH1 or mIDH2 and the inhibition is more potent and durable than either ivosidenib or enasidenib at the same dose...Combination treatment of HMPL-306 and azacitidine synergized in releasing the differentiation block in mIDH AML cells. HMPL-306 is a potent, dual inhibitor of IDH1/2 mutation. The strong activity and favorable PK profiles support further clinical evaluation.

Furthermore, NMR and mass spectrometry studies confirmed IDH1/2 variant-catalyzed production of alcohols in the cases of the 3-methyl-, 3-butyl-, and 3-benzyl-substituted 2OG derivatives; a crystal structure of 3-butyl-2OG with an IDH1 variant (R132C/S280F IDH1) reveals active site binding. The combined results highlight the potential for (i) IDH1/2 variant-catalyzed reduction of 2-oxoacids other than 2OG in cells, (ii) modulation of IDH1/2 variant activity by 2-oxoacid natural products, including some present in common foods, (iii) inhibition of IDH1/2 variants via active site binding rather than the established allosteric mode of inhibition, and (iv) possible use of IDH1/2 variants as biocatalysts.

He received a reduced dose of idarubicin and cytarabine therapy. Even 9 months after starting VEN+AZA, the patient is still alive and healthy without AML recurrence. Thus, VEN+AZA therapy may be highly effective for treating IDH2- and DNMT3A-mutated AML in elderly patients.

P2, N=94, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

Using overlapping PCR, transfection, immunoblotting, immunoprecipitation, measurements of enzyme activity, glucose, lactic acid, ATP, and reactive oxygen species (ROS), cell viability, protein degradation assays post-inhibition of the 26S proteasome (bortezomib) or HSP90 (17-AAG), and a homology model, we demonstrated that the properties of ten cancer-associated IDH2 variants (R140G/Q/W and R172S/K/M/W/G/C/P) arising from point mutations are closely related to their structure and stability...The homology model further revealed that changes in conformation and IDH2 protein stability appeared to be associated with these point mutations. Taken together, our findings provide information important for understanding the molecular mechanisms of IDH2 mutations in tumors.

Enasidenib (ENA), the first selective IDH2 inhibitor, was associated with impressive response rates in relapsed/refractory (R/R) AML and was approved by FDA in 2017. TQB3455 is well-tolerated for myeloid malignancy at the R2PD of 100 mg qd. It also yield high rates of clinical response in pts with mIDH2 AML. Patients with IDH2-R172K mutation fared much better than IDH2-R140Q/W with regard to response, this is in line with outcome of TQB3455 in vitro but different from previous reports of ENA.

Mutational burden and co-mutational profiles differed between patients with mIDH2-R140 and mIDH2-R172 relapsed/refractory AML. In the R172 subgroup, median OS and 1-year survival rate with enasidenib were approximately double those with CCR.

Patients were randomized 1:1 to enasidenib 100-mg/day or CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care). Mutational burden and co-mutational profi les differed between patients with mIDH2-R140 and mIDH2-R172 relapsed/refractory AML. In the R172 subgroup, median OS and 1-year survival rate with enasidenib were approximately double those with CCR.

In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

P2, N=145, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Jul 2022 --> Jul 2023

Conclusion The results confirm the utility of Raman spectroscopy/microscopy to identify the changes between mutated and wild type forms of IDH1/2 suggesting the potential of optical methods for studying point-mutations in cancer cells and subsequently screening of leukaemia. Further studies to improve and optimise the method and collect more data for machine learning are warranted.