Gliser, Camelia

Abstract Purpose: Mutant IDH1 (mIDH1) defines a therapeutically targetable subtype of intrahepatic cholangiocarcinoma (ICC), with the mIDH1 inhibitor ivosidenib approved for advanced disease. A subset of patients experiences prolonged disease stabilization; however, the molecular basis for eventual progression remains poorly defined. Experimental Design: We performed molecular profiling of matched baseline and postprogression circulating tumor DNA (ctDNA) samples from patients with mIDH1 ICC enrolled in the ClarIDHy phase III trial. Functional studies were conducted to characterize candidate resistance mechanisms. Results: Longitudinal ctDNA analysis of 18 patients treated with ivosidenib for >6 months revealed emergent genomic alterations in multiple cases. Acquired mutations in mitogen-activated protein kinase (MAPK) pathway genes (KRAS, NRAS, MAP2K1, NF1) were identified in five cases, with instances of concurrent alterations and/or high variant allele fractions (VAF). Additional candidate resistance events included a secondary IDH1 mutation and a hotspot IDH2 mutation, detected at low VAF in the same patient. Functional studies showed that these IDH mutations conferred sustained 2-hydroxyglutarate production and ivosidenib resistance, whereas MAPK activation blunted gene expression induced by ivosidenib plus IFNγ, a key therapeutic output of mIDH1 inhibition. In parallel, baseline ctDNA profiling of 81 patients revealed that ARID1A mutations and elevated mIDH1 VAF were associated with reduced clinical benefit. Conclusions: MAPK pathway alterations represent a recurrent mechanism of resistance to mIDH1 inhibition in ICC, whereas emergent IDH1/IDH2 mutations appear infrequent. Functional data suggest that MAPK-mediated resistance may involve impaired IFN signaling. These results support MAPK-directed combination strategies and highlight the utility of ctDNA profiling to identify predictive and resistance biomarkers in mIDH1-driven ICC.

Abstract Background: Ivosidenib (IVO) is a first-in-class oral inhibitor of the IDH1 mutant (mIDH) enzyme. In the ClarIDHy phase 3 study of previously treated patients with mIDH cholangiocarcinoma (CCA), IVO treatment led to improved progression-free survival (PFS) and overall survival (OS) vs placebo (median PFS: 2.7 vs. 1.4 months and OS 10.3 vs. 5.1 months, when adjusted for the 70% crossover rate; HR, 0.49 [95% CI, 0.34-0.70]; 1-sided P<0.001. Here, we studied the dynamics of mutations emerging after 6 months of IVO treatment using ctDNA analyses. Methods: Prior to enrollment, all subjects in ClarIDHy had IDH1 R132 mutations confirmed by a central NGS panel utilizing tumor biopsy tissue. Since post-progression tissue samples were unavailable, discovery of emerging mutations was limited to plasma ctDNA assessments. To explore molecular changes associated with acquired resistance, an analysis was performed on 18 subjects treated with IVO for ≥6 months (4 partial response; 12 stable disease, 2 NA) using matched baseline and end of treatment (EOT) samples (PGDx elioTM plasma complete, 521 gene panel). A subset of the oncogenic alterations identified were selected for confirmation by ddPCR analysis in ctDNA samples collected longitudinally. Longitudinal plasma 2HG levels were also evaluated. Results: This analysis identified several EOT mutations not present at baseline. The most common mutations were in the MAPK pathway, including activating KRAS, NRAS, and MAP2K1 mutations and loss-of-function NF1 mutations (6/18 patients, 33%). In 2/6 patients, multiple MAPK pathway mutations were detected. There was a range of variant allele frequencies (VAFs) of RAS alterations, including some that had comparable levels to the truncal mIDH, suggesting that MAPK activation may have made a major contribution to the burden of resistant disease. ddPCR analyses from longitudinal plasma samples from selected cases confirmed these findings. In addition, 2 patients had mutations affecting transcription/epigenetics (WT1 and KMT2C). Finally, only 1 patient had acquired mutations in IDH genes (IDH2-R172K and IDH1-G131V). The WT1, KMT2C, and IDH variants had a low VAF. Accordingly, EOT plasma 2HG levels were reduced vs pre-treatment levels in the patient with secondary mIDH, indicating a limited role in the overall emergence of resistance. Conclusion: Analyses of paired baseline/EOT samples suggest that multiple acquired mutations could contribute to IVO resistance, with oncogenic MAPK pathway alterations being the most common. Consistent with previous clinical studies conducted in AML, IDH1 second site mutations and isotype switching to IDH2, rarely emerge during IVO treatment. The lack of detectable mutations in the majority of patients could reflect the sensitivity of the NGS assay or a role for non-genetic mechanisms of resistance. Citation Format: Hatice Duygu Saatcioglu, Haley Ellis, Jinkai Wan, Sam Lubner, Milind Javle, Ghassan K. Abou-Alfa, James M. Cleary, Robin Kate Kelley, Mitesh J. Borad, Teresa Macarulla, Do Youn Oh, Camelia Gliser, Susan Pandya, Sung Chloe, Nabeel Bardeesy, Adriana Tron. Circulating tumor DNA analysis demonstrates newly emerging alterations in previously treated IDH1 mutated cholangiocarcinoma patients enrolled in the ClarIDHy study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4648.

4069 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 (mIDH1). 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.

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.

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.