Isocitrate Dehydrogenase Mutation Research Articles

Anatomical heterogeneity in low-grade and high-grade gliomas: A multiscale perspective.

Anatomical heterogeneity in low-grade and high-grade gliomas: A multiscale perspective.

From Inhibitors to PET: SAR-Based Development of [18F]SK60 for mIDH1 Imaging.

Mutations in isocitrate dehydrogenase 1/2 (mIDH1/2) are clinically significant biomarkers for diagnosis, prognosis, and therapy in cancer. To advance the noninvasive molecular imaging of mIDH1, we aim to develop a positron emission tomography (PET) radiotracer targeting IDH1R132H, the most common type of mIDH1/2. Starting from compound GSK321, a systematic structure-activity relationships (SAR) optimization was performed leading to the dimethylated derivative SK60 (19) with low nanomolar potency and high selectivity for IDH1R132H. Consequently, [18F]SK60 was developed via copper-mediated radiofluorination. Various in vitro studies with [18F]SK60 showed a high fraction of nonspecific binding. The in vivo evaluation revealed high metabolic stability with no detectable brain-permeable radiometabolite. In addition, limited brain uptake was observed by PET suggesting that further structural modifications to reduce lipophilicity might be needed for this structure. The present study led thus to a novel series of dimethylated GSK321 derivatives for further investigation in IDH1R132H-related therapies and PET imaging.

Isocitrate Dehydrogenase-Wildtype Glioma Adapts Toward Mutant Phenotypes and Enhanced Therapy Sensitivity Under D-2-Hydroxyglutarate Exposure

Background/Objectives: Isocitrate dehydrogenase (IDH) mutations are hallmark features in subsets of gliomas, producing the oncometabolite D-2-hydroxyglutarate (2HG). Although IDH mutations are associated with better clinical outcomes, their relationship with tumor progression is complex. This study aimed to investigate, in vitro and in vivo, the phenotypic consequences of IDH mutation and 2HG exposure in glioblastoma (GBM) under normoxic and hypoxic conditions and under temozolomide (TMZ) and radiation exposure. Methods: Experiments were conducted using IDH-wildtype (IDH-wt) and IDH-mutant (IDH-mut) glioma cell lines under controlled oxygen conditions. Functional assays included cell viability, cell cycle analysis, apoptosis profiling, migration, and surface marker expression via flow cytometry. Orthotopic xenografts were established in immunocompromised mice to assess in vivo tumor growth and morphology, followed by MRI and histological analysis. Treatments included TMZ, radiation, and 2HG at varying concentrations. Statistical analyses were performed using SPSS and RStudio. Results:IDH-wt cells exhibited faster proliferation and greater adaptability under hypoxia, while IDH-mut cells showed cell cycle arrest and limited growth. 2HG recapitulated IDH-mut features in IDH-wt cells, including increased apoptosis under TMZ, reduced proliferation, and altered CD24/CD44 expression. In vivo, IDH-wt tumors were larger and more infiltrative, while 2HG administration reduced tumor volume and promoted compact morphology. Notably, migration was initially similar across genotypes but increased in IDH-mut and 2HG-treated IDH-wt cells over time, though suppressed under therapeutic stress. Conclusions: IDH mutation and 2HG modulate glioma cell biology, including cell cycle dynamics, proliferation rates, migration, and apoptosis. While the IDH mutation and its metabolic product confer initial growth advantages, they enhance treatment sensitivity and reduce invasiveness, highlighting potential vulnerabilities for targeted therapy.

Predicting IDH Mutation in Glioma Patients Using Deep Learning Algorithms with Conformal Prediction.

The World Health Organization glioma classification highlights genetic profiles, such as isocitrate dehydrogenase (IDH) mutation. This study developed an uncertainty-aware deep learning model to predict IDH mutations in glioma patients, employing conformal prediction (CP) for uncertainty quantification (UQ). The UCSF dataset split into training (70%) and validation (30%) sets, and the UPENN dataset divided into calibration (30%) and external test (70%) sets. We developed various 3D convolutional neural network models and selected the best based on the validation set area under the precision-recall curve (AUPRC). Also, we trained a logistic regression (LR) ensemble classifier on the training set and selected the best ensemble model based on the validation set AUPRC. Finally, we employed CP, with nonconformity thresholds set at the error rate of 0.01. The conformal model was calibrated on the calibration set and was evaluated on the external test set using the AUPRC and the area under the receiver operating characteristic (AUROC). 3D convolutional models achieved a mean AUROC and AUPRC of 0.9004 and 0.8102 on the validation set, and a mean AUROC and AUPRC of 0.7340 and 0.2139 on the external test set, respectively. Using the LR ensemble model, the model achieved an AUROC and AUPRC of 0.79820 and 0.2583 on the external test set, respectively. CP with a 0.01 nonconformity threshold with 0.9917 coverage reached an AUROC and AUPRC of 0.8592 and 0.5217, respectively. Integrating CP for UQ improves the performance of deep learning models for predicting IDH mutation in glioma patients.

Assessing the predictability of isocitrate dehydrogenase mutational status in glioma patients using imaging features

Background: Radiogenomics, the intersection of imaging and genetics, is important in improving glioma diagnosis and treatment. This study aims to correlate imaging features with isocitrate dehydrogenase (IDH) mutation status, providing a non-invasive diagnostic tool to identify the genetic background of gliomas. Methods: In a retrospective sample of 59 patients with either IDH wild-type (WT) or IDH mutant gliomas, the study employed volumetric and morphologic magnetic resonance imaging (MRI) analyses to discern molecular alterations based on radiographic signatures. Key imaging biomarkers, such as the T2/fluid-attenuated inversion recovery mismatch, contrast enhancement patterns, and diffusion/perfusion metrics, were evaluated for their ability to differentiate between IDH-WT and mutant gliomas. Receiver operating characteristic curves were employed to evaluate diagnostic performance, and a logistic regression model was developed for patient classification based on imaging. Results: The results revealed that IDH mutant gliomas frequently exhibited distinct imaging characteristics, such as homogenous hyperintense T2 signals and absence of contrast enhancement. In addition, perfusion and diffusion metrics varied significantly between the IDH-WT and mutant groups, offering potential radiogenomic markers. A logistic regression model was developed to predict IDH status with high accuracy, identifying factors such as tumor enhancement size, presence of central necrosis, peritumoral edema, and patient age. Conclusion: The study’s results affirm the significance of radiogenomic correlations in predicting IDH status, resonating findings from prior research. We highlight the necessity of a multimodal approach in MRI analysis to enhance the non-invasive diagnostic accuracy for glioma patients.

Effect of the IDH1 inhibitor combined with hypomethylating agents on acute myeloid leukemia.

Mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) occur in approximately 6-10% of acute myeloid leukemia (AML) patients. Ivosidenib (IVO) is a small-molecule inhibitor of mutant IDH1. This study delves into the mechanism of IVO with hypomethylating agents (HMAs) (azacitidine or decitabine) for treating IDH1-mutated AML through the PI3K/AKT pathway. IDH1R132H-mutated MOLM-13 (IDH1R132H-MOLM-13) cells were constructed. The effects of the drugs, both individually and in combination, on IDH1R132H-MOLM-13 cell proliferation and apoptosis were assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry, with combination index (CI) values calculated using CompuSyn software. IDH1, DNMT1, PI3K and AKT gene mRNA levels, and the PI3K/AKT pathway- and histone lysine methylation-related protein levels in IDH1R132H-MOLM-13 cells were determined by RT-qPCR and Western blot. IDH1R132H-mutated MOLM-13 cells (IDH1R132H-MOLM-13) were successfully constructed. The IDH1 inhibitor, either as a monotherapy or combined with HMAs, effectively inhibited IDH1R132H-MOLM-13 cell proliferation, and the combination therapy exhibited synergistic effects (CI < 1). The combination therapy increased cell proportion in the G2/M phase and apoptotic rate. Both treatment modalities reduced IDH1, DNMT1, PI3K and AKT mRNA levels and histone lysine methylation levels (H3K4me3, H3K9me3, H3K27me3); besides, PI3K and AKT phosphorylation levels were reduced, with the reductions being more significant in cells undergoing combination therapy. The indexes did not differ significantly between cells undergoing the two modalities of combined treatments. The IDH1 inhibitor with HMAs suppressed IDH1R132H-MOLM-13 cell proliferation and viability and decreased the methylation level by repressing the phosphorylation of the PI3K/AKT pathway, showing a synergistic inhibitory effect.

Integration of MRI radiomics and germline genetics to predict the IDH mutation status of gliomas

The molecular profiling of gliomas for isocitrate dehydrogenase (IDH) mutations currently relies on resected tumor samples, highlighting the need for non-invasive, preoperative biomarkers. We investigated the integration of glioma polygenic risk scores (PRS) and radiographic features for prediction of IDH mutation status. We used 256 radiomic features, a glioma PRS and demographic information in 158 glioma cases within elastic net and neural network models. The integration of glioma PRS with radiomics increased the area under the receiver operating characteristic curve (AUC) for distinguishing IDH-wildtype vs. IDH-mutant glioma from 0.83 to 0.88 (PΔAUC = 6.9 × 10−5) in the elastic net model and from 0.91 to 0.92 (PΔAUC = 0.32) in the neural network model. Incorporating age at diagnosis and sex further improved the classifiers (elastic net: AUC = 0.93, neural network: AUC = 0.93). Patients predicted to have IDH-mutant vs. IDH-wildtype tumors had significantly lower mortality risk (hazard ratio (HR) = 0.18, 95% CI: 0.08–0.40, P = 2.1 × 10−5), comparable to prognostic trajectories for biopsy-confirmed IDH status. The augmentation of imaging-based classifiers with genetic risk profiles may help delineate molecular subtypes and improve the timely, non-invasive clinical assessment of glioma patients.

Characteristics and Outcomes of Patients With IDH-Mutant Grade 2 and 3 Gliomas After Deferred or Adjuvant Radiotherapy

Background and ObjectivesCurrent treatment guidelines for patients with isocitrate dehydrogenase (IDH)–mutant (IDHm) glioma recommend radiation (XRT) and chemotherapy after surgery in most cases based on studies in which XRT was compared with XRT plus chemotherapy. Although XRT has been shown to improve time to tumor progression, there has never been a controlled study in this population in which adjuvant XRT (aXRT) demonstrated superior overall survival (OS) over initial observation. The aim of this study was to evaluate the effect of timing of XRT on survival in IDHm-glioma.MethodsWe performed a retrospective observational cohort study, comprising a cohort of adult patients with grade 2 or 3 IDHm-gliomas seen at 2 academic centers (University of Washington and Stanford University) between 2007 and 2022 (identified through research data registries). The main comparison of interest was patients who received XRT within 3 months of diagnosis and before progression, that is, as adjuvant treatment (aXRT), versus those who did not have aXRT (deferred XRT, dXRT). The primary outcome measures were median progression-free survival and OS. Survival analysis was performed through multivariable Cox proportional hazard modeling, propensity matching, and subset analysis.ResultsA total of 450 eligible patients were identified (mean age 39.7 years; 41% female). The median survival of the combined cohort was 19.1 years (25th–75th percentiles 9.75–27.8 years). 47.1% of patients received aXRT. Patients with aXRT demonstrated similar time to next intervention (hazard ratio [HR] 0.83, 95% CI 0.65–1.07) but showed a markedly diminished OS compared with the dXRT cohort (HR of death 2.90, 95% CI 1.9–4.42, p < 0.001). This shorter OS with aXRT was appreciated in all assessed subgroups, including patients considered high risk by grade, age, and extent of resection. This shorter OS was also consistent in multivariable analysis and in propensity-matched cohorts.DiscussionAlthough retrospective, the marked OS difference between aXRT and dXRT groups suggests that aXRT may be not be as beneficial as what was once thought, especially regarding long-term survival. These results also offer justification for the use of a dXRT group in studies assessing adjuvant treatments, as well as a reconsideration of the current treatment paradigm for these patients, especially given the recent introduction of IDH inhibitors.

Effectiveness of olutasidenib versus ivosidenib in patients with mutated isocitrate dehydrogenase 1 acute myeloid leukemia who are relapsed or refractory to venetoclax: the 2102-HEM-101 trial versus a US electronic health record-based external control arm

First-line venetoclax (VEN) treatment for acute myeloid leukemia (AML) has high relapse rates, with limited evidence guiding subsequent therapy sequencing. This study evaluated the effectiveness of olutasidenib (OLU) versus ivosidenib (IVO) for patients withIDH1 relapsed/refractory (R/R) AML previously treated with VEN based therapy. Outcomes were compared between a subcohort of OLU-treated patients from the 2102-HEM-101 trial and an external control arm of IVO-treated patients from the Loopback Analytics electronic health record database. Entropy balancing was applied to align key prognostic variables. Risk differences (RD) for response/TI were estimated via logistic regression, and hazard ratios (HR) for OS via Cox regression. Following weighting, treatment with OLU versus IVO was associated with significantly higher rates of complete response (RD: 0.25; 95%CI: 0.01, 0.49), transfusion independence (RD: 0.27; 95%CI: 0.01, 0.53), and OS (HR: 0.33; 95%CI: 0.11, 0.94). Results suggest favorable effectiveness of OLU versus IVO in this population.

New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in Drosophila melanogaster.

D-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context. Specifically, neomorphic mutations in the mammalian genes Isocitrate dehydrogenase 1 (IDH1) and IDH2 result in the production of enzymes that inappropriately generate D-2HG from α-ketoglutarate (αKG). Within this genetic background, D-2HG acts as an oncometabolite and is associated with multiple cancers, including several diffuse gliomas. In contrast, loss-of-function mutations in the gene D-2-hydroxyglutarate dehydrogenase (D2hgdh) render cells unable to degrade D-2HG, resulting in excessive buildup of this molecule. D2hgdh mutations, however, are not generally associated with elevated cancer risk. This discrepancy raises the question as to why ectopic D-2HG accumulation in humans induces context-dependent disease outcomes. To enable such genetic studies in vivo, we generated two novel loss-of-function mutations in the Drosophila melanogaster gene D2hgdh and validated that these alleles result in ectopic D-2HG. Moreover, we observed that D2hgdh mutations induce developmental and metabolomic phenotypes indicative of elevated D-2HG accumulation. Overall, our efforts provide the Drosophila community with new mutant strains that can be used to study D-2HG function in human disease models as well as in the context of normal growth, metabolism, and physiology.

R-2-hydroxyglutarate-mediated inhibition of KDM4A compromises telomere integrity

Mutation, deletion, or silencing of genes encoding cellular metabolism factors occurs frequently in human malignancies. Neomorphic mutations in isocitrate dehydrogenases 1 and 2 (IDH1/2) promoting the production of R-2-hydroxyglutarate (R-2HG) instead of α-ketoglutarate (αKG) are recurrent in human brain cancers and constitute an early event in low-grade gliomagenesis. Due to its structural similarity with αKG, R-2HG acts as an inhibitor of αKG-dependent enzymes. These include the JUMONJI family of lysine demethylases, among which KDM4A is particularly sensitive to R-2HG-mediated inhibition. However, the precise molecular mechanism through which inhibition of αKG-dependent enzymes by R-2HG promotes gliomagenesis remains poorly understood. Here, we show that treatment with R-2HG induces cellular senescence in a p53-dependent manner. Furthermore, expression of mutated IDH1R132H or exposure to R-2HG, which leads to KDM4A inhibition, causes telomeric dysfunction. We demonstrate that KDM4A localizes to telomeric repeats and regulates abundance of H3K9(me3) at telomeres. We show that R-2HG caused reduced replication fork progression, and that depletion of SMARCAL1, a helicase involved in replication fork reversal, rescues telomeric defects caused by R-2HG or KDM4A depletion. These results establish a model whereby IDH1/2 mutations cause R-2HG-mediated inhibition of KDM4A, leading to telomeric DNA replication defects, telomere dysfunction, and associated genomic instability.

MRI-based radiomics for prediction of isocitrate dehydrogenase subtype in glioblastoma multiforme through artificial intelligence models: A systematic review and meta analysis.

2074 Background: Gliomas are aggressive tumours with poor prognosis. Isocitrate Dehydrogenase (IDH) mutations are present in approximately 12% of all Glioma tumours and are considered biomarkers for prognosis and response to chemotherapeutic agents. IDH mutant gliomas have better prognosis in comparison to IDH wild type Gliomas. IDH mutant Gliomas exhibit features like T2-Flair mismatch sign, reduced blood flow seen on perfusion-weighted images and reduced enhancement on MRI, which aid in identification of IDH mutation. Radiomic imaging techniques extract quantitative features from medical images like MRI and CT scans with the help of advanced algorithms and the extracted data can be utilized in the development of specific artificial intelligence (AI) models like Neural Networks for the prediction of IDH mutation. Thus, MRI based Radiomics is an emerging non invasive technique in comparison to conventional biopsy, for the determination of IDH mutation. The meta-analysis conducted aims to analyse the diagnostic potential of Radiomic imaging in predicting IDH mutations in Gliomas. Methods: A systematic search was conducted in PubMed, Google Scholar and Scopus. PRISMA guidelines were followed. A boolean expression was constructed to retrieve and select articles from major medical databases. The R Studio package was used to evaluate the potential of the diagnostic test. The Meta, Metadata and Mada packages were utilised to evaluate Pooled accuracy, sensitivity and specificity. Results: A total of 35 studies and 7522 radiomic features were assessed through this meta analysis. The Pooled Sensitivity and Specificity were estimated to be 86.70% ([74.85; 87.51], 95% CI, p&lt; 0.0001, I^2 = 92.7% [90.9%; 94.1%]) and 82.75% ([0.7912; 0.8587], 95% CI, p&lt;0.0001, I^2 = 82.8% [77.4%; 86.9%]) utilising the random effects model. The pooled Accuracy was found to be 81.28% ([0.6037; 0.9253], 95% CI, p&gt;0.01, I^2 = 0.0% [0.0%; 45.4%]). Conclusions: Through the compilation of previously conducted studies, MRI based Radiomics show High Pooled Sensitivity of 86.70% and High Pooled Specificity of 82.75% in the detection of Isocitrate Dehydrogenase mutations in Gliomas. Pooled Accuracy rate of 81.8% indicates steady reliability of Radiomics in the prediction of IDH mutations. MRI based Radiomics is a dependable and consistent non invasive technique in the detection of IDH mutations in GBM and can be utilized for the generation of predictive models, enhancing clinical diagnosis and tailored management based on IDH mutation.

Matching-adjusted indirect comparison (MAIC) of olutasidenib (OLU) and ivosidenib (IVO) in isocitrate dehydrogenase 1 (IDH1)-mutated relapsed/refractory (R/R) acute myeloid leukemia (AML).

6546 Background: OLU and IVO are allosteric type II IDH1 inhibitors approved by the FDA and recommended by NCCN for IDH1 mut R/R AML patients based on single-arm trials. In the absence of a head-to-head trial, a MAIC was performed to estimate relative treatment effects of OLU vs. IVO in IDH1 mut R/R AML. Methods: Analyses used registrational data for OLU (Study 2102-HEM-101; N=147; individual-level data) and IVO (AG120-C-001; N=174; study-level data). A logistic propensity score model was used to estimate weights based on the first moment for Study 2102-HEM-101 patients to match AG120-C-001, including the following characteristics identified from a literature review, validated by clinical experts: number of prior systemic therapies, age, prior stem cell transplant, AML type, relapse type, cytogenetic risk, ECOG PS, and IDH1 mutation. Complete remission (CR) and CR + CR with partial hematological recovery (CRh) were summarized as odds ratios (ORs) and 95% confidence intervals (CIs). Duration of CR (DoCR), duration of CR+CRh, and OS were summarized in terms of difference in medians and 95% CIs. OS was also summarized in terms of hazard ratios (HRs) and restricted mean survival time (RMST). A simulated treatment comparison (STC) was performed as a sensitivity analysis. Results: Table 1 summarizes MAIC-adjusted estimates. Naïve and adjusted rates of CR and CR+CRh for OLU vs. IVO were comparable, but point estimates favored OLU for CR. Differences in median DoCR were not statistically significant but favored OLU over IVO. OLU had a significantly longer duration of CR+CRh than IVO. For OS, the naïve comparison suggested OLU was better than IVO (HR=0.72; 95% CI 0.55, 0.92), whereas the MAIC was uncertain but favored OLU. STC results were consistent with the MAIC. Conclusions: Naïve and adjusted rates of response for OLU vs. IVO were comparable (adjusted point estimate favored OLU for CR and IVO for CR+CRh), while a longer duration of CR+CRh was observed with OLU. Adjusted OS was similar between the two groups, although the HR favored OLU, and could not be estimated by response category given lack of patient characteristics and reduction in effective sample size (ESS). Results rely on the assumption of no unmeasured confounders which reflects a limitation of the methodology. MAIC results. Outcome OLU – adjusted (95% CI) IVO – observed (95% CI) MAIC OLU vs. IVO (95% CI) N ESS CR 27% 25% OR=1.12 (0.61, 2.08) 147 73.03 CR + CRh 29% 33% OR=0.83 (0.46, 1.50) 147 73.03 DoCR, median mos 21.3 (12.0, NE) 10.1 (6.5, 22.2) Diff=11.18 (-4.30, 22.72) 47 17.76 Duration of CR+CRh, median mos 17.5 (12.0, 29.1) 8.2 (5.6, 12.0) Diff=9.84 (3.24, 22.28) 51 21.06 OS, median mos 9.7 (5.6, 16.4) 9.0 (7.4, 10.2) HR=0.75 (0.53, 1.07) 147 73.03 OS, RMST mos 15.6 (12.1, 19.2) 12.2 (10.6, 13.9) Diff=3.39 (-0.51, 7.29) 147 73.03 N, sample size; NE, not estimable.

Real-world survival outcomes with ivosidenib in Chinese patients with IDH1-mutated intrahepatic cholangiocarcinoma.

e16227 Background: The phase III ClarIDHy trial led to FDA approval of ivosidenib as a therapeutic option for locally advanced or metastatic cholangiocarcinoma (CCA) patients with isocitrate dehydrogenase 1 (IDH1) mutations. However, data regarding its efficacy and safety in Chinese population remains limited. Methods: We retrospectively analyzed survival outcomes of patients with locally advanced or metastatic IDH1-mutated intrahepatic cholangiocarcinoma (iCCA) treated with ivosidenib in clinical practice at our center from January 2019 to January 2025. Ivosidenib was administered at a standard dose of 500mg once daily in 28-days cycles. Molecular profiling was performed using next-generation sequencing. Results: As of January 20, 2025, five patients were included in the study. The cohort comprised predominantly men (60%) with a median age of 69 years (range: 54-78). At baseline, the overall Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of patients is 1-2, with 80% of patients having a score of 2. All patients were diagnosed with metastatic iCCA, with liver and lymph node metastases being most common (60% each). The IDH1 mutation type identified in all 5 patients was R132C missense mutation, and 3 patients reported traceable molecular analysis, highlighting TP53, ALK and ARID1A as the most common co-altered genes in these patients. Ivosidenib was administered as first-line therapy in 1 patient (20%), second-line therapy in 3 patients (60%) and third-line therapy in 1 patient (20%). At the data cutoff, two patients (40%) were long-term survivors (alive≥1 year) and their survival follow-up is ongoing. The median progression-free survival (PFS) from initiation of treatment with ivosidenib was 5.1 months (range: 2.0-28.5), and the median overall survival (OS) was 9.5 months (range: 3.2-30.5), regardless of the treatment line. One patient (20%) achieved a partial response (PR), while four patients (80%) maintained stable disease (SD) as their best response. Treatment-emergent adverse events (AEs) were reported in one patient, all of which were grade 1, including diarrhea, rash, and oral mucositis. Conclusions: This preliminary data suggested the clinical benefit of ivosidenib for metastatic IDH1-mutated iCCA in the Chinese population. Further multi-center studies with larger cohorts are warranted to validate these findings and explore the broader applicability of ivosidenib in this patient population. Start of ivosidenib regardless of treatment line. Patient ID Extent of disease Setting Best response Survival PFS (months) OS (months) IDH1 mutation Concomitant genetic alterations 1 IV II L PR Yes 4.6 15.3 R132C TP53 2 IV III L SD Yes 28.5 30.5 R132C ALK, ARID1A 3 IV I L SD No 2 3.2 R132C NA 4 IV II L SD No 5.1 9.5 R132C TP53 5 IV II L SD No 4.1 4.1 R132C NA

A phase 1b/2, safety lead-in and dose-expansion trial of ivosidenib plus durvalumab and gemcitabine/cisplatin as first-line therapy in patients with locally advanced, unresectable or metastatic cholangiocarcinoma with an IDH1 mutation.

TPS4219 Background: Cholangiocarcinomas (CCAs) are often advanced and incurable at the time of diagnosis. The phase 3 TOPAZ-1 trial showed improved OS and ORR with gemcitabine/cisplatin (GEM/CIS) and durvalumab (DURVA) vs GEM/CIS in unresectable advanced or metastatic biliary tract cancers. The phase 3 ClarIDHY trial demonstrated that the mIDH1 inhibitor ivosidenib (IVO) improved progression-free survival in CCA patients who have progressed from first or second-line chemotherapy and who have activating mutations in isocitrate dehydrogenase-1 (mIDH1). Additionally, mIDH1 suppresses key immune-related genes, with reversal of this effect when mIDH1 inhibitors are administered in preclinical CCA models. Finally, encouraging activity has been observed in treatment-naive mIDH1 patients administered with the mIDH1 inhibitor LY3410738 in combination with GEM/CIS. Given the ability of ivosidenib to stabilize advanced CCA, ability of IDH1 inhibition to restore immune activity, promising clinical activity of an mIDH1 inhibitor in combination with GEM/CIS, and the limited overlapping toxicities of these treatments, this study seeks to explore safety and preliminary activity of the quadruplet combination. Methods: This is a phase 1b/2, multicenter, safety lead-in and dose expansion, open-label study of IVO in combination with DURVA/GEM/CIS in first-line therapy of locally advanced, unresectable, or metastatic CCA with mIDH1. Treatment with up to one cycle of DURVA/GEM/CIS is permitted before initiation of study treatment. Key eligibility criteria include: a histopathological diagnosis; tumor mIDH1 based on local or centralized tissue testing (local testing by plasma ctDNA may be used); at least 1 measurable lesion as defined by RECIST v1.1; and adequate bone marrow, hepatic, and renal function. The study has a safety lead-in phase where IVO will be administered orally to the first 6 patients at a starting dose of 500 mg QD on every day of the 21-day cycle, plus DURVA 1500 mg IV infusion every 3 weeks for up to 8 cycles, plus GEM 1000 mg/m2 IV and CIS 25 mg/m2 IV on days 1 and 8 of each 21-day cycle, followed by IVO 500 mg QD and DURVA 1500 mg every 4 weeks of a 28-day cycle. Dose-limiting toxicities (DLTs) will be evaluated during the first cycle of quadruplet treatment. 6 additional patients may be enrolled to evaluate an alternative reduced dose of IVO 250 mg QD. The primary objective is to evaluate the safety and tolerability of the quadruplet combination, and to determine the recommended combination dose (RCD). The expansion phase will enroll approximately 40 patients who will be treated with the RCD, with the primary objective being to assess the clinical activity of the combination, as determined by a primary endpoint of confirmed complete or partial response using RECIST v1.1 criteria. Clinical trial information: NCT06501625 .

A phase 2 study of the olaparib and AZD6738, an ATM/ATR inhibitor, in isocitrate dehydrogenase (IDH) mutant solid tumors.

3089 Background: Pre-clinical data has shown that mutations in isocitrate dehydrogenase (IDH) 1 and 2 can lead to impaired homologous recombination repair. IDH1/2 mutations are frequently present in gliomas and cholangiocarcinomas but also in other solid tumors, such as chondrosarcomas. AZD6738 is an ATR inhibitor, and Olaparib is a PARP inhibitor. Preclinical evidence showed a synergistic effect of this combination in models with DNA damage repair effects. This study aims to evaluate the efficacy of Olaparib and AZD6738 in treating advanced IDH1/2 mutated solid. Methods: NCI 10222 is an open-label Phase II clinical trial performed in the NCI National Clinical Trials Network evaluating olaparib 300 mg twice daily with AZD6738 160 mg daily for IDH mutated solid tumors refractory to standard treatment. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: From January 2020 until March 2023, a total of 24 patients with IDH1/IDH2 mutant tumors were enrolled in the study across 8 sites. Of these, 14 (58%) had cholangiocarcinoma, 4 (17%) had chondrosarcomas, and 6 (25%) had other tumors. Most tumors had IDH1 mutations (n = 16, 70%). The median age was 59 years (range 29-83), and 15 (63%) participants were male. Patients had received a median of 3 prior lines of therapy (0-6). After a mean follow-up time of 3 months (0.2-ongoing), no objective responses were seen, leading to the closure of enrollment. The median PFS was 2 months (95% CI 2-4), and the median OS was 7 months (95% CI 3-NE). Only three patients had a clinical benefit, defined as PFS &gt; 6 months, with one patient diagnosed with G1 chondrosarcoma still on treatment with stable disease. Combination of Olaparib with AZD6738 resulted in G3 AE in 9 (38%) patients, leading to 4 (17%) discontinuations. Conclusions: Olaparib with AZD6738 did not demonstrate activity in IDH mutant solid tumors. However, the stability seen in the patient with low-grade tumors could suggest that the effect is restricted to lower-grade tumors, still dependent on IDH mutations. Further evaluation of the correlative data is required to elucidate why pre-clinical evidence suggesting potential efficacy did not translate into clinical benefit in IDH mutant solid tumors. Clinical trial information: NCT03878095 .

A phase 2 study of olaparib in IDH1 and IDH2 mutant advanced chondrosarcomas and other solid tumors.

3087 Background: Pre-clinical data have shown that mutations in isocitrate dehydrogenase (IDH) 1 and 2 can lead to a “BRCAness” phenotype by impairing homologous recombination (HR) repair. Olaparib, a PARP inhibitor effective in BRCA-mutated cancers such as ovarian, prostate, pancreas and breast cancer, may also be effective in IDH1/2 mutant solid tumors. IDH1/2 mutations are frequently present in gliomas and cholangiocarcinomas but also in other solid tumors, such as chondrosarcomas, and melanomas. This study evaluated the efficacy of olaparib in treating advanced IDH1/2 mutated solid tumors other than cholangiocarcinoma and gliomas. Methods: NCI 10129 was a 3-arm, open-label Phase II clinical trial performed in the NCIExperimental Therapeutics Clinical Trials Network (ETCTN) evaluating olaparib 300 mg twice daily for IDH mutated solid tumors refractory to standard treatment. Patients with solid tumors, excluding cholangiocarcinoma and glioblastoma, were enrolled in cohort 3 of the Phase II trial. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: From March 2019 until January 2024, a total of 26 patients with IDH1/IDH2-mutant tumors were enrolled in the study across 10 sites. Of these, 14 (53%) had chondrosarcomas, with 5 (35%) being dedifferentiated. Following, the most prevalent histologies were gastrointestinal adenocarcinomas (4, 15%), other sarcomas (3, 12%) and other tumors (5, 19%). Most tumors had IDH1 mutations (n = 20, 77%), with R132C (n = 12, 60%) being the most common substitution. The median age was 62 years (range 43-78), and 18 (69%) participants were male. Patients had received a median of 1.5 prior line of therapy (0-9). After a mean follow-up time of 8.6 months (0.8-62.6), no objective responses were seen, leading to the closure of enrollment. The median PFS was 2 months (95% CI 1.8-2.2), and the median OS was 7.5 months (95% CI 1.3-13). Only two patients had a clinical benefit, defined as PFS &gt; 6 months. Olaparib was tolerable, with most adverse events scored as grades 1-2. Conclusions: Olaparib did not demonstrate activity in IDH-mutant chondrosarcomas and other solid tumors. This study underscores the remarkably poor outcome associated with IDH mutant tumors, emphasizing the urgent need for additional therapeutic options. Further evaluation of the correlative data, including assessment of HR proficiency, is required to elucidate why pre-clinical evidence suggesting potential efficacy did not translate into clinical benefit in IDH mutant solid tumors. Clinical trial information: NCT03212274 .

In-depth characterization of vaccine-induced neoantigen-specific T cells in patients with IDH1-mutant glioma undergoing personalized peptide vaccination.

Isocitrate dehydrogenase (IDH) mutant glioma is a malignant primary brain tumor diagnosed in adults. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors. The first targeted IDH-inhibitor was approved by the US Food and Drug Administration in August 2024 for grade 2 gliomas, in light of results of a phase III trial which showed significant advantages in progression-free survival. However, biologic therapy is not curative, and subsequent treatment options offer only limited clinical benefit and often result in long-term toxicities. In addition, targeted treatment options for grade 3 and grade 4 IDH-mutant gliomas are still missing. In this study, we present n=52 patients with glioma (grade 2, 3 and 4) with confirmed IDH1 mutation (mutIDH1) in the newly diagnosed and recurrent setting who, in addition to standard-of-care, received a personalized neoantigen-targeting peptide vaccine. Each tumor was initially analyzed for somatic mutations by whole exome sequencing, and a peptide vaccine containing potential neoepitopes was designed, manufactured and vaccinated. Each vaccine consisted of peptides derived from numerous somatic mutations, including at least one peptide targeting the mutIDH1.Vaccine immunogenicity was determined by intracellular cytokine staining and simultaneous measurement of four T-cell activation markers (Interferon-γ, Tumor Necrosis Factor, Interleukin-2, CD154) after 12-day in vitro expansion of pre and post vaccination peripheral blood mononuclear cells. Extracellular CD154 staining was used to sort mutIDH1-specific CD4+T cells.Immunomonitoring revealed that the vaccines were immunogenic and induced mainly CD4 but also CD8 T cell responses. Vaccine-induced immune responses were robust and polyfunctional. Immunogenicity against mutIDH1 was high (89%). We implemented an assay which allowed us to isolate functional antigen-specific CD4+T cells in an HLA-independent manner. Subsequent T cell receptor (TCR) repertoire sequencing revealed that CD4+T cells reacting on mutIDH1 stimulation were polyclonal. Strikingly, we detected two mutIDH1-specific TCRβ candidate sequences in three different patients. These three patients had the same human leukocyte antigen (HLA) DQA-DQB alleles. The obtained TCRβ sequences could be tracked in autologous ex-vivo single-cell transcriptomic data. Our results provide a rationale for pursuing vaccination and T cell transfer strategies targeting IDH1. Furthermore, our findings indicate that personalized neoantigen-targeting vaccines might be considered for the treatment of IDH1-mutant gliomas.

Assessment of age in the clinical risk stratification of patients with IDH-mutant gliomas.

2058 Background: Prognosis for mutant isocitrate dehydrogenase (mIDH) gliomas is influenced by tumor type, size, neurologic deficits, and age. Traditionally, patients over 45 are considered high-risk, prompting consideration of early chemoradiation. Recent promising results with the mIDH inhibitor vorasidenib challenge traditional age-based risk stratification, sparking debate over its role in treatment decisions. We evaluated survival relative to age and molecular data obtained from next-generation sequencing (NGS). Methods: Tumor specimens from 598 mIDH gliomas were analyzed using NGS and WTS at Caris Life Sciences (Phoenix, AZ). Samples were stratified by age at diagnosis into four groups: 12-26y, 27-40y, 41-60y, and &gt; 60y. Real-world overall survival (calculated from initial diagnosis to last contact) was obtained from insurance claims data and analyzed using Kaplan-Meier and Cox proportional hazards models. Covariates in the multivariate regression analysis included radiation treatment, temozolomide treatment, and mutation status of different biomarkers. Results: In mIDH astrocytoma group, age distribution was 12-26y, n = 74 (12.4%); 27-40y, n = 271 (45.3%); 41-60y, n = 205 (34.3%); and &gt; 60y, n = 48 (8.0%). In mIDH oligodendroglioma group, age distribution was 12-26y, n = 18 (5.5%); 27-40y, n = 76 (23.2%); 41-60y, n = 137 (41.8%); and &gt; 60y, n = 57 (17.4%). For each subtype, comparisons in survival were made between patients 27-40y vs. 41-60y given larger sample size, and patients with temozolomide treatment before biopsy were excluded (about 10%). Univariate analysis showed that 27-40y patients had shorter survival in astrocytoma (HR = 1.63, 95% CI: 1.07 – 2.50, p = 0.022). However, after adjusting for confounding factors in multivariate analysis, age was not associated with survival. In contrast, TP53 (HR = 4.0, 95% CI: 1.43-11.24, p = 0.008 – mutation rate = 95.4%) and TERT-promoter (HR = 10.36, 95% CI: 4.05-26.45, p &lt; 0.0001 – mutation rate = 9.0%) mutations were independently associated with poorer survival in astrocytoma patients. Univariate analysis showed that age was not associated with survival in oligodendroglioma (HR = 1.07, 95% CI: 0.79-3.65, p = 0.168). KRAS mutations were independently associated with poorer survival in oligodendroglioma patients (HR = 4.36, 95% CI: 1.12-16.92, p = 0.033 - mutation rate = 3%). Conclusions: In this enriched dataset of mIDH low grade glioma patients, which included NGS, age did not contribute to survival differences when comparing patients between 27-40 years with those aged 41-60 years. Rather, selected genetic alterations such as KRAS for oligodendroglioma and TP53 and TERT mutations for astrocytoma were associated with poorer survival. The results suggest that NGS, rather than age, may drive prognosis for mIDH glioma patients.

Advances in IDH-mutant glioma management: IDH inhibitors, clinical implications of INDIGO trial, and future perspectives.

The discovery of isocitrate dehydrogenase (IDH) mutation in gliomas marked the new era of molecular classification of CNS tumors. Understanding the complex role of IDH mutation in oncogenesis led to the evaluation of novel small molecules targeting this enzyme as a potential therapeutic intervention. Vorasidenib, a brain-penetrant inhibitor of both IDH1 and IDH2-mutant enzymes, was one such agent. The phase 3 INDIGO trial evaluated vorasidenib and demonstrated its efficacy in IDH-mutant low-grade gliomas (LGG). This study established vorasidenib as an effective inhibitor of both IDH1 and IDH2-mutant enzymes, highlighting its great potential in advancing the therapeutic armamentarium for patients with LGG. While vorasidenib has been recently included in several treatment guidelines for CNS tumors, further research on the use of this novel agent, as monotherapy or in combination with other drugs, becomes imperative to exploit fully its potential in the management of IDH-mutant gliomas.