11532
Background: Chondrosarcomas (CS) are rare primary bone malignancies for which there are no approved systemic therapies. 85% of CS are the conventional subtype. Mutations in the isocitrate ...dehydrogenase 1 ( IDH1) gene occur in ~50% of conventional CS. In a phase 1 study in patients (pts) with IDH1-mutated advanced solid tumors, ivosidenib (IVO), an oral potent inhibitor of mutant IDH1, demonstrated manageable toxicity (without dose-limiting toxicities), suppression of the oncometabolite 2-hydroxyglutarate at dose levels ≥300 mg/day, and disease control in pts with conventional CS. We report long-term safety, tolerability and efficacy of IVO in pts with conventional CS. Methods: In this phase I multicenter open-label dose-escalation and expansion study, IVO was administered orally (100 mg twice/day BID to 1200 mg once/day QD) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcomes included clinical activity (objective response rates ORR, defined as complete response (CR) + partial response (PR), stable disease SD and progression-free survival PFS). Adverse events (AEs) were assessed every visit and reported per the Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: 13 pts with advanced conventional CS were included in this analysis (data cut off 15 September 2022; women, n = 4; median age 54.0; AJCC tumor grade I n = 2, II n = 8, III n = 1, unknown n = 2; 6 had received prior systemic therapy; received 100 mg IVO BID n = 1, 400 mg QD n = 1, 500 mg QD n = 7, 800 mg QD n = 2, and 1200 mg QD n = 2). Median treatment duration was 11.3 months (range: 0.5-92.6 months). Four pts (30.8%) have continued therapy for > 6 years (two of which were treated for > 7 years). Median relative dose intensity was 100%. The most frequent treatment emergent AEs (in > 4 pts; mostly grade 1/2) were diarrhea (n = 5) and nausea (n = 5). Six pts experienced grade ≥3 AEs. Three pts experienced serious AEs (none considered related to treatment). There were no discontinuations, dose reductions or deaths due to AEs. The ORR was 23.1%. Median duration of response was 42.5 months (range: 25.8-51.8 months). One pt with a base of the skull lesion achieved a CR (1200 mg IVO QD); two achieved PR (one 500 mg and one 1200 mg IVO QD); seven had SD (five received ≥500 mg IVO QD) and two had PD (both received ≥500 mg IVO QD). All responses occurred after > 2 years on treatment. Median PFS was 7.4 months (95% CI: 2.0-61.3). Conclusions: In pts with IDH1 mutated advanced conventional CS, IVO demonstrates manageable toxicity and durable disease control including long-term responses, extending several years for a proportion of pts. Future studies are warranted to better understand the efficacy of IVO in pts with advanced conventional CS. Clinical trial information: NCT02073994 .
Abstract only
2008
Background: Somatic mutations in IDH1 and IDH2 occur in ̃80% and ̃4% of LGGs, respectively, promoting tumorigenesis via increased levels of the oncometabolite D-2-hydroxyglutarate ...(2-HG). Vorasidenib (VOR; AG-881) is an oral, brain-penetrant, dual inhibitor of mIDH1/2; ivosidenib (IVO; AG-120) is a first-in-class oral inhibitor of mIDH1. In this ongoing perioperative study, treatment with IVO/VOR reduced 2-HG levels in resected tumors vs untreated control tumors in patients (pts) with LGG (NCT03343197; Mellinghoff SNO 2019). We assessed the biological impact of 2-HG suppression on tumors and TIME. Methods: Pts (n = 49) with recurrent, non-enhancing, mIDH1-R132H LGG eligible for resection were randomized to IVO (500 mg QD/250 mg BID), VOR (10/50 mg QD), or no treatment, for 4 weeks preoperatively. Tumor tissue samples collected at surgery were assessed in genomic (n = 42), transcriptomic (n = 42), and immunohistochemistry (IHC; n = 43) analyses. Unpaired t-test was used for statistical comparisons. Results: Optimal 2-HG suppression (post-treatment 2-HG below the upper limit of 2-HG levels in a reference set of 15 wild-type wt IDH samples) was observed in 23 of 40 pts, including 9 (90%) pts receiving VOR 50 mg QD and 6 (50%) receiving IVO 500 mg QD. Of samples with valid biomarker data, those with optimal 2-HG suppression (n = 21) showed upregulation of neural differentiation-related gene expression, but downregulation of stemness-related gene expression, vs those with suboptimal 2-HG suppression (post-treatment 2-HG above upper limit of wt IDH 2-HG levels; n = 17; p < 0.01). IHC analysis of the proliferation marker Ki-67 showed a ̃2-fold decrease in Ki-67–positive cells in samples with optimal 2-HG suppression (mean 2.7%; n = 22) vs those with suboptimal suppression (5.8%; n = 16; p < 0.05). Epigenetic analysis revealed a ̃2-fold increase in mean 5-hydroxymethylcytosine (5hmC) levels in samples with optimal (0.36%; n = 17) vs suboptimal 2-HG suppression (0.2%; n = 15; p < 0.05), suggesting reversal of TET2 inhibition. IHC analysis of TIME revealed increases in mean CD3+ and CD8+ tumor-infiltrating lymphocyte levels in samples with optimal (1.05% CD3/0.22% CD8; n = 22) vs suboptimal 2-HG suppression (0.44% CD3/0.07% CD8; n = 16; p < 0.05). Optimal 2-HG suppression was associated with upregulation of gene expression related to type I interferon signaling and antigen presentation (p < 0.01). Conclusions: These data suggest that both tumor-intrinsic and -extrinsic mechanisms underlie 2-HG suppression by VOR and IVO. VOR, and IVO to a lesser extent, increased 5hmC, promoted cellular differentiation, and inhibited tumor cell proliferation; both also increased T-cell infiltration, activated interferon signaling, and increased antigen presentation capability. These data support development of VOR in combination with immunotherapy. Clinical trial information: NCT03343197.
e19024
Background: Ivosidenib (IVO) is a potent, targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is approved for acute myeloid leukemia (AML). IVO plus azacitidine (AZA) ...demonstrated clinical benefit compared with placebo (PBO) and AZA in the AGILE study (NCT03173248), and here we report the impact of IVO+AZA versus PBO+AZA on health-related quality of life (HRQoL). Methods: In the double-blind, PBO-controlled phase 3 AGILE study, patients (pts) were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m
2
SC or IV for 7 days in 28-day cycles, or PBO+AZA. HRQoL was a secondary endpoint assessed using two validated questionnaires: the European Organisation of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and the EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L). Questionnaires were administered pre-dose on cycle (C) 1 Day (D) 1, on C1D15, C2D1, C2D15, and on D1 of every odd cycle thereafter until the end of treatment. Score change from baseline across visits for all subscales of EORTC QLQ-C30 was analyzed with mixed models. A 10-point threshold in EORTC QLQ-C30 subscale score was used to evaluate clinically meaningful changes from baseline or differences between arms. Two-sided nominal p-values are reported. Results: At baseline, 69 and 68 pts out of 72 receiving IVO+AZA completed the EORTC QLQ-C30 and EQ-5D-5L, respectively, and 66 pts out of 74 receiving PBO+AZA completed both. Mean baseline HRQoL scores were similar between treatment arms. There was an initial decline in HRQoL (EORTC QLQ-C30 global health status GHS/QoL) in both arms for ̃4 months, consistent with time to response, and which was generally not clinically meaningful. IVO+AZA was associated with preserved or improved HRQoL compared to baseline for most subscales of the EORTC QLQ-C30 from C5 to C19 (after which no PBO+AZA HRQoL data were available), and at most timepoints for EQ-5D-5L VAS scores and index values. EORTC QLQ-C30 subscales with clinically meaningful improvements from baseline at most timepoints from C5 to C19 in the IVO+AZA arm included GHS/QoL, fatigue, pain and appetite loss. In contrast, there were few clinically meaningful improvements from baseline in PBO+AZA pts. GHS/QoL scores were significantly improved (p≤0.05) for IVO+AZA versus PBO+AZA at C2D1, C2D15, C7 and C9, and differences were clinically meaningful at C2D1 (10.2 point difference), C2D15 (10.1), C7 (12.6), C9 (22.6), C13 (14.9), C15 (15.4) and C19 (19.2). Likewise, improvements in EORTC QLQ-C30 fatigue, appetite loss, nausea and vomiting, diarrhea, cognitive functioning and social functioning favored IVO+AZA over PBO+AZA at multiple timepoints. Conclusions: Data from the AGILE study show that patients with mIDH1 AML receiving treatment with IVO+AZA tended to report maintenance or improved HRQoL from cycle 5 through to cycle 19 compared with PBO+AZA. Clinical trial information: NCT03173248.
LBA1
Background: Grade 2 gliomas are slowly progressive, malignant brain tumors with a poor long-term prognosis. Current treatments (surgery followed by observation or adjuvant radiation and ...chemotherapy) are not curative and can be associated with short- and long-term toxicities. Mutations in isocitrate dehydrogenase (IDH) 1 or 2 occur in approximately 80% and 4% of grade 2 gliomas, respectively, and are a disease defining characteristic in the World Health Organization (WHO) 2021 definition. Vorasidenib (VOR) – an oral, brain-penetrant, dual inhibitor of mutant (m)IDH1/2 enzymes has shown a tolerable safety profile and preliminary clinical activity in phase 1 studies. Methods: In this randomized, double-blind, placebo-controlled phase 3 study (NCT04164901) patients (pts) were randomized 1:1 to receive VOR 40 mg daily or placebo (PBO) daily in 28-day cycles. Patients were stratified by 1p19q status and baseline tumor size. Key eligibility criteria included: age ≥12; KPS >80; residual or recurrent grade 2 IDH1m or IDH2m oligodendroglioma or astrocytoma; measurable non-enhancing disease; no prior treatment for glioma with most recent surgery 1-5 years from randomization; and not in immediate need of chemotherapy/radiation. Primary endpoint: radiographic progression-free survival (PFS) by blinded independent radiology committee (BIRC). Key secondary endpoint: time to next intervention (TTNI). Results: As of 6Sep2022 (2
nd
planned interim analysis data cutoff), 331 pts were randomized across 10 countries: 168 to VOR and 163 to PBO. Of the 331 pts: median age: 40.4 years (range, 16 to 71); KPS =100: 53.5%; histological subtype: oligodendroglioma: 172 and astrocytoma: 159; median time from last surgery until randomization: 2.4 years. Two hundred twenty-six (68.3%) pts remained on treatment (131VOR; 95PBO). PFS by BIRC was statistically significant in favor of the VOR arm (HR, 0.39; 95% CI, (0.27, 0.56); P=0.000000067). Median PFS: VOR: 27.7 mos; PBO: 11.1 mos. TTNI was statistically significant in favor of the VOR arm (HR, 0.26; 95% CI, (0.15, 0.43); P=0.000000019). Median TTNI: PBO: 17.8 mos; VOR: not reached. All reported P values are one-sided. All-grade adverse events (AEs) occurring in >20% pts receiving VOR vs PBO were alanine aminotransferase increased (38.9% vs 14.7%), COVID-19 (32.9% vs 28.8%), fatigue (32.3% vs 31.9%), aspartate aminotransferase increase (28.7% vs 8.0%), headache (26.9% vs 27.0%), diarrhea (24.6% vs 16.6%), nausea (21.6% vs 22.7%). Common grade ≥3 AEs (>5%): ALT increased (9.6% vs 0%). Conclusions: This is the first prospective, randomized phase 3 study of a targeted therapy in grade 2 mIDH glioma. VOR significantly improved PFS by BIRC compared with PBO with a manageable safety profile. These data demonstrate the clinical benefit of VOR in this pt population for whom chemotherapy and radiotherapy are being delayed. Clinical trial information: NCT04164901 .
Background: Overall survival (OS) in adults with ALL remains around 40%, but treatment with asparaginase (ASP)-containing pediatric-inspired regimens demonstrated a 3- or 4-year OS of 67-76%, ...including in patients with T-cell ALL, with manageable toxicities (Geyer 2020, Stock 2019, DeAngelo 2015). Recent studies in adults with reduced pegaspargase (PEG-ASP) doses showed survival outcomes similar to those with standard doses, with reduced toxicities, including pancreatitis, hepatic and thromboembolic events (Derman 2020, Patel 2020).
Calaspargase pegol (ASPARLAS; Cal-PEG), similar to PEG-ASP, is an E. coli L-asparaginase covalently conjugated to monomethoxy polyethylene glycol, but with a more chemically stable succinimidyl carbonate linker, providing sustained asparagine depletion with less frequent dosing (every 21 days).
The efficacy and safety of Cal-PEG 2500 U/m 2, vs PEG-ASP 2500 U/m 2, was evaluated in 2 multicenter, randomized clinical trials (AALL07P4 n=166 and DFCI 11-001 n=239) in newly diagnosed patients with ALL ≤21 years. Complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and OS were similar in both arms, with a 94% 5-year OS for Cal-PEG. The safety profile was consistent with that of PEG-ASP, with similar rates of hypersensitivity, pancreatitis, thrombosis, and hyperbilirubinemia (Vrooman 2021). Plasma asparaginase activity (PAA) levels were ≥0.1 U/mL 25 days after the induction dose in 95% of patients (Angiolillo 2014).
The absence of a standardized treatment and the inadequate outcome of adult treatment regimens, as well as a lack of targeted immunotherapies for T-ALL, highlight a critical unmet need for improved therapeutic approaches. A treatment protocol with less frequent Cal-PEG administration due to a more sustained asparaginase activity as well as age- and weight-based dose adjustments may improve clinical outcomes without added toxicities, and possibly extend the upper age limit of ASP-containing regimen for older adults.
Trial Design: We present a clinical trial design of an ongoing, multicenter, phase 2/3 study (NCT04817761) assessing the safety and anti-leukemic activity of Cal-PEG in newly diagnosed patients with Philadelphia-negative B- or T-cell ALL. Patients aged ≥22 years are eligible with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis or severe hepatic impairment.
This trial comprises two parts: dose confirmation run-in (part 1) and the expansion phase (part 2). Part 1 is open for enrollment and is the focus of this abstract.
Starting doses of Cal-PEG are based on the patients' age and BMI, with older patient groups assigned to lower doses (Table 1). A minimum of 4 (initial cohort) and up to 8 patients will be admitted per patient group. A total of 6 Cal-PEG doses will be administered during the treatment period as part of a multiagent chemotherapy regimen based on CALGB 10403 trial (Figure 1; Table 2), with end of treatment visit 1 year after the induction dose, and an additional 2 years of survival follow-up.
The primary endpoints in part 1 are 1) the safety of Cal-PEG, including incidence of pre-defined unacceptable toxicities (UT) within 30 days after the induction dose and 2) PAA profiles, including achieving PAA ≥0.1 U/mL at pre-specified time points. Secondary endpoints include immunogenicity, CR, end of induction and consolidation MRD, and 1-, 2- and 3-year EFS, disease-free survival, and OS.
Bayesian optimal interval design (BOIN) will be used to evaluate UT with specified boundaries for dose confirmation, expansion, or reduction. For each patient group, the observed UT rate at a dose level will be compared with the safety boundary (23.6%) and toxicity boundary (35.8%) to guide safety confirmation. PAA data from previous pediatric studies and each run-in cohort will also be used to confirm the tested dose through population PK modeling-based predictions. The decision to confirm or adjust the dose will be based on the accumulated safety and induction PAA data at end-of-cohort meetings with the investigators, sponsor and in consult with DSMB recommendations.
Part 1 started in July 2021 and will enroll ≈16-32 patients at multiple sites in the US. Part 2 will commence once the safety and PAA data from part 1 are analyzed and the expansion doses are confirmed. Up to 122 patients are expected to be enrolled in both phases of the trial.
Clinical trial information: NCT04817761
Display omitted
Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Park: Kura Oncology: Consultancy; Autolus: Consultancy; Intellia: Consultancy; Affyimmune: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; BMS: Consultancy; PrecisionBio: Consultancy; Minerva: Consultancy; Innate Pharma: Consultancy; Curocel: Consultancy; Servier: Consultancy; Artiva: Consultancy. Emadi: Secura Bio.: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. Abdul-Hay: Jazz: Other: Advisory Board, Speakers Bureau; Servier: Other: Advisory Board, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Takeda: Speakers Bureau. Cassaday: Kite/Gilead: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Webster: AmGen: Consultancy; Pfizer: Consultancy. Pandya: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Mogul: Servier Pharmaceuticals: Current Employment. Shvenke: Servier Pharmaceuticals: Current Employment. Zhu: Servier Pharmaceuticals: Current Employment. Tessier: Servier: Current Employment. DeAngelo: Abbvie: Research Funding; Incyte Corporation: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Agios: Consultancy; Autolus: Consultancy; Forty-Seven: Consultancy; Blueprint Medicines Corporation: Consultancy; Jazz: Consultancy; GlycoMimetics: Research Funding.
Calaspargase pegol is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years, with recommended dosage of 2,500 units/m2 intravenously no more frequently than every 21 days
Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib - an oral, potent inhibitor of the mutant IDH1 (mIDH1) ...enzyme - is FDA-approved for adults with relapsed/refractory m IDH1 AML and adults with newly diagnosed m IDH1 AML who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy (IC). Data from a phase 1b study of 23 patients with newly diagnosed m IDH1 AML showed a favorable safety profile and encouraging clinical activity of ivosidenib + azacitidine (IVO+AZA; NCT02677922).
Methods: In this global, double-blind, randomized, placebo-controlled, phase 3 study, patients were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m 2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA), and stratified by region and de novo vs secondary AML. Key eligibility: untreated AML (WHO criteria), centrally confirmed m IDH1 status, not eligible for IC, ECOG 0-2. Primary endpoint: event-free survival (EFS; time from randomization until treatment failure, i.e. failure to achieve complete remission CR by week 24, relapse from remission, or death from any cause). Key secondary endpoints: CR rate, overall survival (OS), CR + CR with partial hematologic recovery (CRh) rate, and objective response rate (ORR).
Results: From 19-Mar-2018 to 18-Mar-2021, 146 patients were randomized: 72 to IVO+AZA (median interquartile range age, 76.0 70.5-79.5 years) and 74 to PBO+AZA (median interquartile range age, 75.5 70.0-80.0 years). Fifty-four (75.0%) patients had de novo AML vs 18 (25.0%) with secondary AML in the IVO+AZA arm. Sixteen (22.2%) patients receiving IVO+AZA had poor-risk genetics per ELN guidelines vs 20 (27.0%) patients receiving PBO+AZA. Thirty-nine (26.7%) patients remain on treatment (27/72 patients in the IVO+AZA arm vs 12/74 patients in the PBO+AZA arm). EFS was statistically significant (HR = 0.33 95% CI 0.16, 0.69; P = 0.0011) in favor of the IVO+AZA arm. Median OS with IVO+AZA was 24.0 months vs 7.9 months with PBO+AZA (HR = 0.44 95% CI 0.27, 0.73; P = 0.0005). CR rate with IVO+AZA was 47.2% (34/72 patients; 95% CI 35.3%, 59.3%) vs 14.9% (11/74 patients; 95% CI 7.7%, 25.0%) with PBO+AZA (P < 0.0001). Median time to CR was 4.3 months with IVO+AZA vs 3.8 months with PBO+AZA. CR+CRh rate with IVO+AZA was 52.8% (38/72 patients; 95% CI 40.7%, 64.7%) vs 17.6% (13/74 patients; 95% CI 9.7%, 28.2%) with PBO+AZA (P < 0.0001). The CR rate by 24 weeks for IVO+AZA vs PBO+AZA was 37.5% and 10.8%, respectively. ORR with IVO+AZA was 62.5% (45/72 patients; 95% CI 50.3%, 73.6%) vs 18.9% (14/74 patients; 95% CI 10.7%, 29.7%) with PBO+AZA (P < 0.0001). All reported P-values are 1-sided. Common all-grade adverse events (AEs) occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA were nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%). Sixty-six (93.0%) patients receiving IVO+AZA vs 69 (94.5%) patients receiving PBO+AZA experienced a grade ≥ 3 AE. Common grade ≥ 3 AEs occurring in > 20% of patients receiving IVO+AZA vs PBO+AZA included febrile neutropenia (28.2% vs 34.2%), anemia (25.4% vs 26.0%), thrombocytopenia (23.9% vs 20.5%), and pneumonia (22.5% vs 28.8%). Frequency of all-grade differentiation syndrome (DS) as assessed by investigators was 14.1% with IVO+AZA vs 8.2% with PBO+AZA, and that of grade ≥ 3 DS was 4.2% with IVO+AZA vs 4.1% with PBO+AZA. Based on the recommendation of the Independent Data Monitoring Committee, further enrollment into the study was prematurely discontinued due to evidence of benefit.
Conclusions: IVO+AZA significantly improved EFS, OS, and clinical response (CR, CR+CRh, ORR) compared with PBO+AZA in patients with IC-ineligible, newly diagnosed m IDH1 AML. The safety profile of IVO+AZA was favorable and consistent with previous studies. These data demonstrate the clinical benefit of IVO+AZA in this difficult-to-treat AML population.
Montesinos: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Forma Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Recher: Incyte: Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding. Heuser: Tolremo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding; BergenBio: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Calado: AA&MDS International Foundation: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis Brasil: Honoraria; Instituto Butantan: Consultancy; Alexion Brasil: Consultancy. Schuh: Kite/Gilead: Research Funding; GlycoMimetics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Daigle: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Hui: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Boehringer Ingelheim: Ended employment in the past 24 months. Zhang: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Pandya: Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Servier: Current Employment. Gianolio: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. de Botton: Pierre Fabre: Othe
Abstract only
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 .
Abstract only
539
Background: Mutations in isocitrate dehydrogenase 1 (m IDH1) occur in up to 20% of intrahepatic cholangiocarcinomas (CC), leading to accumulation of 2-hydroxyglutarate (2-HG) and ...epigenetic dysregulation, promoting oncogenesis. Ivosidenib (IVO; AG-120), a first in-class, oral, targeted inhibitor of the mIDH1 enzyme, showed improved progression-free survival and a positive trend in overall survival versus placebo (PBO) in ClarIDHy, a global, phase 3, multicenter, double-blind study (Abou-Alfa et al. ESMO 2019 LBA10_PR; NCT02989857). Methods: Patients (pts) with unresectable or metastatic m IDH1 CC were randomized 2:1 to IVO (500 mg once daily in continuous 28-day cycles) or matched PBO, stratified by number of prior systemic therapies (1 or 2). Crossover from PBO to IVO was permitted at radiographic progressive disease. Blood samples for PK/PD analyses, a secondary endpoint, were collected predose, 0.5, 2, and 4 h postdose on day (D) 1 of cycles (C) 1–2, predose and 2 h postdose on D15 of C1–2, and predose on D1 from C3 onwards. Plasma IVO and 2-HG were measured using validated or qualified LC-MS/MS methods. Results: As of 31Jan2019, 185 pts were randomized to IVO (n = 124) or PBO (n = 61); 35 pts crossed over to IVO. PK/PD analysis was available from 156 pts receiving IVO. IVO was absorbed rapidly following single and multiple oral doses; exposure, as measured by C
max
and AUC, was higher at C2D1 than after a single dose, with low accumulation. Plasma IVO reached steady state within C1 of daily dosing. In pts receiving IVO, baseline mean plasma 2-HG concentration was reduced from 1108 ng/mL to 97.7 ng/mL at C2D1, close to levels in healthy subjects (72.6±21.8 ng/mL). 2-HG inhibition was robust and persistent up to Cycle 19. An average 2-HG inhibition of 75.0% (up to 97.3%) was observed at steady-state after multiple IVO administrations. No plasma 2-HG decreases were seen with PBO. Analyses of plasma 2-HG levels and association with clinical outcomes will be presented. Conclusions: In pts with advanced m IDH1 CC, oral IVO 500 mg once-daily demonstrated good exposure, and maintained the inhibition of 2-HG to levels observed in healthy subjects, whereas 2-HG remained elevated with PBO. Clinical trial information: NCT02989857.
PDF