Explore the vast range of titles available.

Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)—a small-molecule targeted inhibitor of mutated IDH1—in patients with previously treated IDH1-mutant cholangiocarcinoma. This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857. Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8–10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6–4·2] vs 1·4 months [1·4–1·6]; hazard ratio 0·37; 95% CI 0·25–0·54; one-sided p<0·0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. Agios Pharmaceuticals.

A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.

SummaryBackground Mutant isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) enzymes produce the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (AG-120) is a targeted mutant IDH1 inhibitor under evaluation in a phase 1 dose escalation and expansion study of IDH1-mutant advanced solid tumors including cholangiocarcinoma, chondrosarcoma, and glioma. We explored the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ivosidenib in these populations. Methods Ivosidenib was administered orally once (QD) or twice (BID) daily in continuous 28-day cycles; 168 patients received ≥1 dose within the range 100 mg BID to 1200 mg QD. PK and PD were assessed using validated liquid chromatography-tandem mass spectrometry assays. Results Ivosidenib demonstrated good oral exposure after single and multiple doses, was rapidly absorbed, and had a long terminal half-life (mean 40–102 h after single dose). Exposure increased less than dose proportionally. Steady state was reached by day 15, with moderate accumulation across all tumors (1.5- to 1.7-fold for area-under-the-curve at 500 mg QD). None of the intrinsic and extrinsic factors assessed affected ivosidenib exposure, including patient/disease characteristics and concomitant administration of weak CYP3A4 inhibitors/inducers. After multiple doses in patients with cholangiocarcinoma or chondrosarcoma, plasma 2-HG was reduced by up to 98%, to levels seen in healthy subjects. Exposure-response relationships for safety and efficacy outcomes were flat across the doses tested. Conclusions Ivosidenib demonstrated good oral exposure and a long half-life. Robust, persistent plasma 2-HG inhibition was observed in IDH1-mutant cholangiocarcinoma and chondrosarcoma. Ivosidenib 500 mg QD is an appropriate dose irrespective of various intrinsic and extrinsic factors. Trial RegistrationClinicalTrials.gov (NCT02073994).

Significance Current genomic and biochemical analysis revealed mutations in isocitrate dehydrogenase ( IDH ) genes associated with several neoplasms and a novel enzymatic activity of IDH mutations to catalyze α-ketoglutarate to d -2-hydroxyglutarate, contributing to tumorigenesis. We identified a broad range of IDH1 mutations, including a previously unidentified IDH1 -R132Q mutation, in cartilage tumors. Cartilage-specific Col2a1-Cre/ERT2;Idh1-R132 mutant knock-in mice developed multiple enchondroma-like lesions. These data show that mutant Idh in growth-plate cells causes persistence of chondrocytes, giving rise to enchondromas adjacent to the growth cartilage in bone. Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes ( IDH1 and IDH2 ) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1 -R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d -2-hydroxyglutarate ( d -2HG). Mice expressing Idh1 -R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1 -R132Q or 2HG treatment. Col2a1-Cre; Idh1 -R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d -2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.

Background Ivosidenib (IVO), a first-in-class, oral, targeted, small-molecule inhibitor of mIDH1 is approved for the treatment of patients with previously treated locally advanced or metastatic mIDH1 cholangiocarcinoma (CCA). Pre-clinical and clinical data suggest combining mIDH1 inhibitor with immune checkpoint inhibitors (ICI) has synergistic anti-tumor activity in mIDH1 CCA. This study was the first to test IVO plus ipilimumab (IPI) and nivolumab (NIVO) in these patients. Methods This phase 1/2, multicenter, open-label study evaluated IVO plus IPI and NIVO in unresectable/metastatic mIDH1 CCA. It consisted of safety lead-in and expansion phases (NCT05921760). Eligible patients had progressed on or were intolerant to 1-2 prior therapies, ECOG PS 0–1, and RECIST v1.1 measurable disease. DLTs were evaluated during the first 2 cycles of study treatment. Results The safety lead-in phase enrolled 7 patients: 4 patients to the starting dose of IVO 500 mg QD PO + IPI 1 mg/kg (IV) and NIVO 3 mg/kg (IV). All developed immune-mediated adverse events (IMAEs), including intolerable rashes arising within a median of 12 days (10–41 days) of study treatment initiation. This led to dose de-escalation in IVO to 250 mg QD. All 3 patients enrolled in the IVO 250 mg cohort also developed IMAEs, including rashes. All events of immune-mediated rash required dose modifications, including 3 nonserious and 3 serious grade 3 events, with 1 DLT in the IVO 250 mg cohort. Based on IMAE frequency, onset, and outcome (Table 1), and in the absence of documented radiographic responses, further recruitment was stopped Conclusions While no new safety signals were specifically identified for IVO during this prematurely terminated study, IMAEs, including immune-mediated rashes, were observed in 100% of patients. The decision was made to stop the study. Further studies to optimize mIDH1 inhibition in CCA are ongoing including IVO plus durvalumab + gemcitabine/cisplatin in front-line CCA [NCT06501625]. 35 Table Immune-mediated adverse events related to any study drug. Immune mediated AE Ivosidenib 500 mg QD PO + nivolumab (3 mg/kg) + ipilimumab (1 mg/kg) (N = 4) Ivosidenib 250 mg QD PO + nivolumab (3 mg/kg) + ipilimumab (1 mg/kg) (N = 3) Overall (N = 7) Grade 1-2 n (%) Grade 3-4 n (%) Grade 1-2 n (%) Grade 3-4 n (%) Grade 1-2 n (%) Grade 3-4 n (%) Dermatitis 1 (25.0) 3 (75.0) 0 (0) 3 (100.0) 1 (14.3) 6 (85.7) Fatigue 1 (25.0) 0 (0) 1 (33.3) 0 (0) 2 (28.6) 0 (0) Diarrhea 2 (50.0) 0 (0) 0 (0) 1 (33.3) 2 (28.6) 1 (14.3) Pruritus 2 (50.0) 1 (25.0) 0 (0) 0 (0) 2 (28.6) 1 (14.3) Pyrexia 2 (50.0) 0 (0) 1 (33.3) 0 (0) 3 (42.9) 0 (0) Hepatitis 0 (0) 1 (25.0) 0 (0) 0 (0) 0 (0) 1 (14.3) Lung disease 0 (0) 0 (0) 1 (33.3) 0 (0) 1 (14.3) 0 (0)

Gain-of-function mutations in isocitrate dehydrogenase ( IDH ) are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly cancer of the liver bile ducts; now mutant IDH is shown to block liver cell differentiation through the suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence, leading to expansion of liver progenitor cells primed for progression to IHCC. Mechanism of induction of a liver cancer Cancer-associated gain-of-function isocitrate dehydrogenase (IDH) mutations produce the 'oncometabolite' 2-hydroxyglutarate (2HG) that can inhibit a-ketoglutarate-dependent dioxygenase enzymes. Nabeel Bardeesy and colleagues show here that 2HG plays an active role in carcinogenesis: mutant IDH blocks liver progenitor cells from undergoing hepatocyte lineage progression through the production of 2HG and suppression of HNF4a, a master regulator of hepatocyte differentiation. Moreover, where mutant IDH coexists with activated Kras , it drives the expansion of liver progenitor cells, development of premalignant biliary lesions and progression to metastatic intrahepatic cholangiocarcinoma. The transgenic mouse model used here should facilitate further study of IDH function, particularly important in relation to cholangiocarcinoma, which is resistant to current treatments. Mutations in isocitrate dehydrogenase 1 ( IDH1 ) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer 1 , 2 , 3 , 4 , 5 . Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation 6 , 7 , 8 , 9 , 10 . However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs 4 , 5 , cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.

PurposeReport pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.MethodsPatients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 − 2, pre-dose and 2 h post-dose on D15 of C1 − 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.ResultsPK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).ConclusionOnce-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma.Clinical trial registrationNCT02989857 Registered February 20, 2017.

BackgroundSomatic isocitrate dehydrogenase 1 mutations (IDH1m) convert α-ketoglutarate to the oncogenic metabolite R-2-hydroxyglutarate (2-HG). IDH1m are detected in approximately 13% of intrahepatic cholangiocarcinomas (CCAs).1 Ivosidenib, an oral inhibitor of the IDH1m protein inhibits 2-HG and restores immune response in CCA.2 We analyzed pre-treatment samples, using machine learning models to quantify histologic features of the CCA tumor microenvironment, enabling identification of correlates of IDH1m status, early disease progression (patients experienced progression or death within 1.54 months), and plasma 2-HG levels (median, 630 ng/ml).MethodsA set of H&E images, including from ClarIDHy3, a phase 3 placebo controlled clinical trial of ivosidenib in IDH1m CCA, were split into training/validation (n=200) and test sets for model development. Whole slide images were annotated by GI pathologists to identify and quantify more than 500 different human interpretable features (HIFs), including cell (cancer cell, lymphocyte, macrophage, plasma cell, fibroblast) and tissue (cancer epithelium, stroma, necrosis) features. Utilizing IDH1m and wild type (WT) screening samples, multivariate logistic regression models were trained to predict IDH1m status. P-values were calculated by univariate logistic regression and corrected for multiple comparisons via adjustment for FDR.ResultsA HIF-based multivariate model discriminated between IDH1m and WT CCA (AUC, 0.83; 95% CI, 0.74-0.92). IDH1m was associated with a lower proportion of lymphocytes throughout the tumor (OR, 0.64; P<0.01; FDR P=0.022), and higher proportion of fibroblasts (OR, 1.8; P<0.01; FDR P=0.023) and lower proportion of plasma cells in the stroma (OR, 0.68; P<0.01; FDR P=0.032 ) (figure 1A). In a subset of samples, CD3 and CD8 staining showed reduced T-lymphocyte infiltration patterns in IDH1m (n=5) samples relative to IDH1 WT (n=19) (figure 1B). Early disease progression of enrolled ClarIDHy patients (ivosidenib n=61, placebo n=38) was associated with a higher proportion of macrophages (OR, 1.70; P<0.01; FDR P=0.08) and a lower proportion of tumor infiltrating lymphocytes (OR, 0.63; P<0.01; FDR P=0.08), (figure 2A). When correcting for treatment effect, the proportion of lymphocytes in the tumor were still associated with improved PFS (P=0.011). Consistent with previously published data2, high 2-HG levels were associated with lower numbers of tumor infiltrating lymphocytes (OR, 0.63; P=0.011; FDR P=0.08) (figure 2B).ConclusionsQuantitative histologic evaluation suggests that pre-treatment IDH1m CCA samples have a colder tumor microenvironment relative to IDH1 WT CCA, with an immunosuppressive tumor microenvironment being associated with early progression. Results from this analysis support exploration of combination with immune checkpoint inhibitors.Trial RegistrationNCT02989857ReferencesBoscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol. 2019;10(4):751–765. doi: 10.21037/jgo.2019.03.10.Wu MJ, Shi L, Dubrot J, et al. Mutant IDH Inhibits IFN?-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma. Cancer Discov. 2022;12(3):812–835. doi: 10.1158/2159-8290.CD-21-1077.Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(6):796–807. doi: 10.1016/S1470-2045(20)30157-1. Epub 2020 May 13. Erratum in: Lancet Oncol. 2020 Oct;21(10):e462.Ethics ApprovalThis study was done according to the International Conference on Harmonisation of Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Approval from the institutional review board and international ethics committee was obtained at each study site. Patients provided written, informed consent before participating in the study.Abstract 552 Figure 1Tumor microenvironment of IDH1m vs IDH1 WTTumor microenvironment of IDH1m CCA compared to IDH1 WT at screening. (A) 163 screening samples, including IDH1m (n=138) and IDH1 WT (n=25) subjects were analyzed by machine learning of histological features. Samples deemed by a panel of GI pathologist to be extrahepatic as a best response were excluded from the analysis. IDH1m status in CCA was associated with lower proportions of lymphocytes in the tumor (Upper Row), higher proportions of fibroblasts in the stroma (Middle Row), and lower proportions of plasma cells in the stroma (Bottom Row). Tumor includes cancer epithelium and stroma tissues in the whole sections. Uncorrected P values are displayed on the Figures (B) Further analysis of a subset of screening samples (n=5 IDH1m, n=19 IDH1 WT) by CD3 and CD8 staining was performed. Representative whole slide biopsy H&E images indicating lower proportions of lymphocytes in the IDH1m CCA tumor via machine learning-derived predictions (Upper Row; Lymphocytes are indicated with dark green marker overlay. MLO=Machine Learning Overlay, representative image for CD3 immunohistochemistry (Middle Row), and representative image for CD8 immunohistochemistry (Bottom Row).[Figure omitted. See PDF]Abstract 552 Figure 2Differences in CCA tumor microenvironment.Differences in CCA tumor microenvironment based on early disease progression and pre-treatment plasma 2-HG levels. (A) Pre-treatment screening samples from 99 (ivosidenib cohort n=61, placebo cohort n=38) patients treated on the ClarIDHy study were analyzed for association with early disease progression, defined as experiencing progression or death within 1.54 months (47 days) (PFS<1.54 months) Early disease progression was associated with lower proportions lymphocytes over immune cells in cancer epithelium (Upper Row) and higher proportions of macrophages (Bottom Row) over immune cells in cancer epithelium (B) Plasma 2-HG levels were available for 100 IDH1m patients, with sample groups separated based on the median plasma 2-HG level (630 ng/ml). Higher plasma 2-HG levels were associated with lower proportions of lymphocytes in CCA tumor. Uncorrected P values are displayed on the Figures (A and B)[Figure omitted. See PDF]

Nature 513, 110–114 (2014); doi:10.1038/nature13441 corrigendum Nature 519, 118 (2015); doi:10.1038/nature14149 In Extended Data Fig. 1b of this Letter, the photomicrographic images of the hepatoblast cells grown under normal conditions were mismatched. The figure shows control images indicating that cells expressing mutant IDH1 (R132C and R132H) or mutant IDH2 (R140Q and R172K) have similar morphology to those expressing wild-type (WT) IDH1 or IDH2 or empty vector (EV).