IDH2 R140

In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.

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.

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.

P1/2, N=60, Completed, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Suspended --> Completed

P1/2, N=27, Terminated, University Health Network, Toronto | Trial completion date: Jul 2023 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2023 --> Oct 2023; Insufficient Funding

P1, N=15, Recruiting, City of Hope Medical Center | Phase classification: P1b --> P1 | Trial completion date: Mar 2024 --> May 2025 | Trial primary completion date: Mar 2024 --> May 2025

P1/2, N=60, Suspended, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Oct 2023 --> Dec 2023 | Trial primary completion date: Oct 2023 --> Dec 2023

In conclusion, post-HCT maintenance therapy with enasidenib is safe and feasible with highly favorable survival outcomes in mIDH2 AML. Treatment delays and dose reductions were commonly seen; however, most patients completed their 2-years maintenance.

Conclusion Allogeneic HCT in CR1 could bring some survival benefit on RFS in AML pts with IDH1/2 mutation, but not confirmed in MVA. Further study is warranted to reach a clearer conclusion with larger number of

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.

P1, N=23, Completed, Massachusetts General Hospital | Active, not recruiting --> Completed

P2, N=63, Recruiting, M.D. Anderson Cancer Center | N=105 --> 63

P1/2, N=60, Suspended, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Active, not recruiting --> Suspended

P=N/A, N=334, Completed, Chang Gung Memorial Hospital | Enrolling by invitation --> Completed | Trial completion date: Nov 2023 --> Jul 2023

P1/2, N=27, Active, not recruiting, University Health Network, Toronto | Trial primary completion date: Apr 2023 --> Jul 2023

"The IDH1/IDH2 cartridge-based assay for the Idylla system allows ultra-rapid, sensitive, and robust screening for recurrent mutations at residues R132 in IDH1 and R140 or R172 in IDH2. The system provides reliable analysis of both extracted and pre- extraction tumor tissue from numerous sources beyond FFPE, including direct blood and bone marrow samples. It markedly simplifies the workflows in the lab and enables rapid treatment decisions."

This meta-analysis demonstrates that IDH2R140 mutation improves OS in younger AML patients and that the prognostic value of IDH2R172 mutation is significantly heterogeneous. Differences in region and data type have a significant impact on the prognosis of AML patients with IDH2R140 and/or IDH2R172 mutations. Additionally, AML patients with IDH2R140 mutation have a better prognosis than those with IDH2R172 mutations, albeit with some degree of heterogeneity.

P1/2, N=60, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jul 2023 --> Oct 2023 | Trial primary completion date: Apr 2023 --> Oct 2023

P1, N=260, Active, not recruiting, Eli Lilly and Company | Trial primary completion date: May 2024 --> Aug 2023

P1, N=200, Active, not recruiting, Eli Lilly and Company | Trial completion date: May 2023 --> May 2024 | Trial primary completion date: May 2023 --> Aug 2023

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

P1, N=260, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

P1, N=200, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

We show that MNs with mR172 represent a morphologically and phenotypically distinct subtype, which in our cohort exhibited relatively favorable survival that is not captured in current AML risk assignment.

P2, N=105, Recruiting, M.D. Anderson Cancer Center | Active, not recruiting --> Recruiting | Trial completion date: Feb 2023 --> Feb 2025 | Trial primary completion date: Feb 2023 --> Feb 2025

P1/2, N=27, Active, not recruiting, University Health Network, Toronto | Recruiting --> Active, not recruiting | N=48 --> 27 | Trial primary completion date: Dec 2022 --> Apr 2023

P1b, N=15, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

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.

P1/2 | "At three-year follow-up, ENAm continues to be a safe and well-tolerated therapy in ND patients ≥ 60 years old with IDH2m AML both alone and with the risk-adapted addition of AZA. CR/CRi rates are high (48%, adjusted 95% CI 30.3-60.5) and remissions are durable (11.1 months, 95% CI 5.6-41.4). The composite CR (cCR) rate of ENAm appears comparable to the cCR rate achieved with ENA + AZA in AG221-AML-005, a phase 2 study comparing ENA + AZA to AZA alone in ND AML."

GVHD prophylaxis consisted of post-transplant cyclophosphamide-based (60%; n=9) or tacrolimus-based (40%; n=6) regimens (Tac/Siro= 4 and Tac/MTX= 2). While treatment delays and dose reductions were common, the majority of the study patients remained on the protocol therapy. Droplet digital PCR testing on bone marrow was done to study clearance of IDH2 clones post-HCT and these results will be available by December 2022.

Outcomes in this mIDH2 ND-AML cohort demonstrate robust clinical validation of the synergistic effects of ENA and AZA seen in vitro. BL co-mutational patterns differed between the IDH2-R140 and R172 variants. Rapid reductions in 2-HG and IDH2 VAF were observed during combination Tx with ENA + AZA.

With prior knowledge of the mutation of interest, dPCR is the most economical method for MRD detection at hotspots. saNGS performs similarly while evaluating any variant within the single amplicon region. NGS panels are most useful for MRD detection without prior mutation knowledge, with dupNGS affording the greatest sensitivity for SNVs.

P1, N=200, Recruiting, Eli Lilly and Company | Trial completion date: Sep 2023 --> May 2023

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.

P2, N=105, Active, not recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Feb 2022 --> Feb 2023

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.