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266 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (m IDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

4576 Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) are detected in ~13% of IHCs. Ivosidenib (IVO) is a first-in-class, oral inhibitor of the mutant IDH1 (mIDH1) protein. In ClarIDHy, a global, phase 3, double-blind study in previously treated patients with advanced m IDH1 IHC (N = 186), IVO demonstrated an improvement in progression-free survival (PFS) vs placebo (hazard ratio 0.37, p < 0.001) (Abou-Alfa et al., Ann Oncol 2019; NCT02989857). Feasibility of m IDH1 detection in plasma ctDNA from patients with IHC was demonstrated and was highly concordant with mutation status in tumor tissue (Aguado-Fraile et al., Cancer Res 2019). This analysis was extended to the larger patient cohort from ClarIDHy, and longitudinal m IDH1 detection from ctDNA was assessed and correlated with clinical response. Methods: Baseline plasma and tumor tissue samples were obtained before randomization; longitudinal plasma samples were collected on day 1 of each treatment cycle. m IDH1 status in tissue was prospectively and centrally confirmed using Oncomine Focus Assay. A BEAMing digital PCR test was used for quantification of m IDH1 in plasma. IDH1 mutation clearance ( IDH1-MC) was achieved when plasma m IDH1 variant allele frequency was below the assay’s sensitivity (0.02% for R132C/L/S/G; 0.04% for R132H). Results: m IDH1 detection in plasma ctDNA and tissue was concordant in 92% (193/210) of samples screened. As of 31 Jan 2019, median PFS was 2.7 months for IVO vs 1.4 months for placebo. Longitudinal analysis with biomarker data available as of Jan 2020 demonstrated IDH1-MC in plasma from 10 IVO-treated patients with PFS ≥2.7 months (n = 36) vs 0 patients with PFS < 2.7 months (n = 40). No IDH1-MC was observed in patients treated with placebo, irrespective of response (n = 49). Conclusions: These results reinforce the feasibility of IDH1-R132 detection in plasma from patients with IHC, with a 92% concordance with detection in tumor tissue, supporting m IDH1 detection in liquid biopsy as a viable patient selection strategy where tissue exhaustion can limit conventional methods. Plasma IDH1-MC was also observed in a subset of IVO-treated patients who achieved disease control. Clinical trial information: NCT02989857 .

TPS7074Background: Acute myeloid leukemia (AML) is a hematologic malignancy with limited treatment options for patients who are ineligible for intensive chemotherapy, corresponding to a median over...

TPS545 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease with limited effective chemotherapy options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in 13–15% of CC cases, and up to 25% of intrahepatic CC cases, leading to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib), a first-in-class oral mIDH1 inhibitor, displayed a favorable safety profile and clinical activity in a phase 1 study enrolling 73 mIDH1 CC patients who had received ≥1 prior systemic regimen. As of 10 Mar 2017, 4/73 (5%) had a partial response and 41/73 (56%) stable disease. Progression free survival (PFS) rates at 6 months and 12 months were 38.5% and 20.7%, respectively. The 500 mg once daily dose level of AG-120 was selected for further development in mIDH1 CC. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind, randomized (2:1) study of AG-120 (500 mg once daily) vs. matched placebo in 186 mIDH1 CC patients (ClinicalTrials.gov NCT02989857). Key eligibility criteria: non-resectable or metastatic CC, documented mIDH1 by central laboratory testing, ECOG performance status 0–1, measurable disease (RECIST v1.1), documented disease progression after ≤2 prior systemic therapies in the advanced setting including at least 1 gemcitabine- or 5-fluorouracil-containing regimen, and no prior mIDH inhibitor therapy. Crossover from placebo to AG-120 will be allowed at time of radiographic disease progression. Primary endpoint: PFS assessed by independent radiologists. Secondary endpoints: safety, tolerability, overall response rate (RECIST 1.1), overall survival, pharmacokinetic/pharmacodynamic analyses, and quality of life (EORTC QLQ-C30 and QLQ-BIL21 scales). An independent data monitoring committee will monitor the data during study conduct. The ClarIDHy study is currently activated at participating sites in the US, UK, EU, and S. Korea. R eused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2017 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT02989857.

TPS4142 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease for which there are limited therapeutic options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in up to 25% of intrahepatic CC cases. mIDH1 lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite, D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class oral inhibitor of the mIDH1 enzyme, and is being tested in a phase 1 study that enrolled 73 patients (pts) with mIDH1 CC who had received a median of 2 prior therapies (range 1–5). AG-120 has demonstrated a favorable safety profile and clinical activity in this study. Among the 72 efficacy evaluable pts (≥1 post-baseline response assessment or discontinued prematurely), 6% (n = 4) had a confirmed partial response and 56% (n = 40) had stable disease. Progression-free survival (PFS) rate at 6 months was 40% as of Dec 16, 2016. The 500 mg once daily (QD) dose of AG-120 was selected for the ongoing phase 3 study in mIDH1 CC described here. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind study randomizing 186 pts with mIDH1 CC in a 2:1 ratio to AG-120 (500 mg QD) or matched placebo (NCT02989857). Key eligibility criteria: nonresectable or metastatic CC; documented mIDH1 based on central laboratory testing; ECOG 0–1; measurable disease (RECIST v1.1); documented disease progression following ≤2 prior systemic therapies in the advanced setting, including at least 1 gemcitabine- or 5-fluorouracil-containing regimen; and no prior mIDH inhibitor therapy. Crossover from the placebo arm to the AG-120 arm will be permitted. The primary endpoint is PFS as assessed by an independent review. Secondary endpoints include safety, tolerability, overall response rate, overall survival, pharmacokinetic and pharmacodynamic analyses on plasma, and quality of life as assessed by the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L instruments. An independent data monitoring committee will monitor the data throughout the study. The ClarIDHy study is currently activated at participating sites in the US and will be activated in centers throughout Europe and in South Korea. Clinical trial information: NCT02989857.

2073 Background: IDH1 mutated glioblastoma (GB) has a better prognosis than IDH1 wildtype GB. Clinical trials for recurrent GB currently do not stratify patients (pts) based upon IDH status. It is not known if pts with IDH1 mutated GB on clinical trials are more likely to have a higher 6-month progression free survival (PFS6) or radiographic response (RR) rate. Methods: A retrospective review of GB pts treated at MD Anderson Cancer Center between 2006-2012 identified 330 pts enrolled in recurrent GB trials. 93 pts (28%) either had PFS6 or a complete or partial RR per RANO criteria. 49/93(53%) pts with PFS6 or a complete or partial RR were found to have tumor tissue available for IDH1 testing. A matched cohort of pts on the same recurrent GB clinical trials with tissue for IDH1 testing but no PFS6 or RR was identified based on the specific clinical trial, age and KPS. 49 pts were identified for comparison resulting in a total of 98 patients. Results: IDH1 status was obtained in 92 (94%) pts of which 17 (18...

2037 Background: Patients with an anaplastic glioma (WHO III°) without IDH1 mutation have a comparable disease course to glioblastoma. Dynamic 18FET-PET has been shown to provide prognostic informa...

e17085 Background: Diagnostic of the IDH1 mutation (IDH1mut) is so far based on DNA sequencing and immunohistochemistry (IHC), methods limited in terms of sensitivity and ease of use. Recently, mea...

e22193 Background: Several studies have observed a change in MGMT silencing and IDH1 mutation in secondary glioblastomas (sGBMs). However, reports about the prognostic value of promoter methylation of the MGMT gene and IDH mutations in secondary glioblastomas (sGBMs) are few in number. Methods: The study involved primary and secondary tumor tissue samples from 89 GBMs pts (P/S: 42/47) diagnosed and treated within the First Hospital of Jilin University from Jan 2006 to Nov 2011. After surgical treatment, all GBM pts were subjected to radiotherapy with concomitant administration of TMZ. Pts with GBM were screened for promoter status of MGMT gene, by the methylation-specific polymerase chain reaction (MSP), and, for IDH mutations by direct sequencing. Results: A total of 42 of 89 pts (47.2%) had primary GBMs (pGBMs) (Group 1), while 47 pts (52.8%) had secondary GBMs (Group 2). In Group 2, 23 pts (21/47, 44.7%) developed a sGBM through progression from a low grade glioma (LGG) WHO grade II and a secondary anaplastic gliomas (sAG) (Group 2a), whereas 26 pts (26/47, 55.3%) showed a direct malignant transformation from a LGG to a sGBM (Group 2b). MGMT methylation was observed in 38 (42.7%) GBMs, with a higher frequency in sGBMs than pGBMs (24/14, 51.1 vs. 33.3%; p = 0.008). MGMT methylation status was associated with increased median survival time in pGBMs and sGBMs pts. IDH1 mutations are present in the majority of sGBMs but rare in pGBMs (31/5, 66.0 vs. 11.9%; p < 0.001). Group 2a had a higher frequency with IDH1 mutation than group 2b (18/12, 78.3 vs. 46.2%; p < 0.01). The median survival time after malignant progression of all sGBMs pts with an IDH mutation was longer than in pts with wild-type IDH (3.2 vs. 1.1ys; p < 0.01). IDH1 mutation had an improved outcome in group2a, which is compared with group 2b (3.9 ys vs. 2.1 ys; p < 0.05). Conclusions: In our population, pts with sGBM and IDH mutation had a significantly improved outcome. In addition, MGMT methylation is also a powerful prognostic marker in sGBM pts.

2026 Background: The genetic alterations of glioma have been studied extensively. IDH1 mutation is associated with younger age and better survival. However, differences in molecular ontogeny within glioma related to IDH1 mutation remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) between IDH1mut vs IDH1wt gliomas of grade 2-3 and 4. Methods: CNA were detected by molecular inversion probes (Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE samples including grade 2-3: IDH1wt (n = 17) and IDH1mut (n = 28), and grade IV: IDH1wt ( n = 25) and IDH1mut(n = 24). Chromothripsis was detected using a stringent criteria of at least ten switches of CNA in individual chromosomes. Results: We validated prior findings that IDH1wt GBM have higher frequency of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). Other CNA across all grades were: gain of 19q12 and loss of 14q11 in IDH1wt, and gain of 11q21, 10p11, 8q21 and loss of 11p15, 19q13 in IDH1mut. Within grade 2-3 samples, few CNA were associated with mutation status: 2-3wt demonstrated higher frequencies of gain of 7q and loss of 10q, 14q11, and 22q13, while 2-3mut demonstrated higher frequencies of 11q21 gain and 19q13 loss. Grade 4 tumors demonstrated more CNA that differed by mutation status, with 4wt tumors demonstrating gain of 7 and loss of 10 and 14q11, while 4mut demonstrated gains of 8q, 10p, 12p13, 1q23, and loss of 11p15, 3p, 19q13, among others. Comparison of grade 2-3mut vs grade 4mut tumors demonstrated larger number of CNA in the grade 4mut tumors including gain of 1p, 14q, 13q33, 9p, 8q and loss of 22q, 11p15, 10q, and 3p, among others. A significantly higher incidence of chromothripsis events was observed in grade 4mut compared to grade 4wt (p = 0.0374). Conclusions: CNA analysis showed significant differences in molecular ontogeny between IDH1wt and IDH1mut, some of which may further elucidate pathogenesis. Significant CNA increases and increased chromthripsis in grade 4mut support malignant transformation of low grade gliomas through accumulation of genomic instability and genomic catastrophe.

2082 Background: In gliomas, relationship between radiological characteristics and several biomarkers was the subject of numerous publications. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified recently to play a key role in these tumors occuring in up to 75% of low-grade diffuse (WHO grade II) and anaplastic (WHO grade III) astrocytic, oligodendroglial and mixed oligodendroglial neoplasms. However, the correlation with magnetic resonance imaging (MRI) features has been little studied. Methods: Patients treated for WHO grade II and III oligodendroglial tumors between 2005 and 2011 were retrospectively identified. Each case has been reviewed by the same neuropathologist. IDH1 and IDH2 mutations were available. Preoperative MRI, including T1 weighted, T2 weighted, T1 contrast enhanced, FLAIR, T2* weighted, diffusion weighted (ADC ratio), perfusion weighted (CBV ratio) and MR spectroscopy, were analyzed by two radiologists blinded from molecular data. Logistic regression analysis and Fisher’s test were used to develop predictive models of genetic profile from imaging. Results: Sixty eight patients, WHO grade II (n= 37) and grade III (n=31) patients were identified. Mean age at diagnosis was 46 years; ratio male/female was 40/28. IDH1 mutations were identified in 42 patients (62 %), IDH2 in 4 patients (6 %). Analysis of tumor location, size, borders, morphological aspect, and signal did not shown any significant difference between IDH1 mutated group and IDH1 non mutated group neither in grade II nor in grade III oligodendroglial tumors. In the same way, MR spectroscopy (Choline/NAA ratio and detection of lipid and lactate) was not relevant to discern the two groups. As well, ADC ratio (1,5 versus 1,4; p=0,35) and CBV ratio (3,4 versus 4,2; p= 0,46) did not reveal any difference between mutated group and non mutated group. Conclusions: In our study, IDH1 mutations were not correlated with MRI features available during routine MRI. Nevertheless, recent studies suggest the ability of MR spectroscopy to detect 2-hydroxyglutarate as an MRI marker of IDH1 mutated tumors, which encourage carrying on research in molecular imaging.

2053 Background: Glioblastoma multiforme (GBM) is a highly malignant, and the most common primary tumor of the central nervous system. Hypermethylation of MGMT promoter region can silence its expre...