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High Rate of IDH1 Mutation Clearance And 2706 High rate of IDH1 mutation clearance and measurable residual disease (MRD) negativity in patients with IDH1-mutant newly diagnosed acute myeloid leukemia treated with ivosidenib (AG-120) and azacitidine Scott R Daigle1, Sung Choe1, Lynn Quek2, Courtney D DiNardo3, Anthony S Stein4, Eytan M Stein5, Amir T Fathi6, Olga Frankfurt7, Andre C Schuh8, Hartmut Döhner,9 Giovanni Martinelli,10 Prapti A Patel,11 Emmanuel Raffoux,12 Peter Tan,13 Amer Zeidan,14 Stéphane de Botton,15 Hagop M Kantarjian3, Richard M Stone16, Mark G Frattini17, Vickie Zhang1, Thomas Winkler1, Paresh Vyas2, Bin Wu1 1Agios Pharmaceuticals, Inc., Cambridge, MA, USA; 2University of Oxford, Oxford, UK; 3University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4City of Hope Medical Center, Duarte, CA, USA; 5Memorial Sloan Kettering Cancer Center, New York, NY, USA; 6Massachusetts General Hospital Cancer Center, Boston, MA, USA; 7Northwestern University, Chicago, IL, USA; 8Princess Margaret Cancer Centre, Toronto, ON, Canada; 9Ulm University Hospital, Ulm, Germany; 10Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 11University of Texas Southwestern Medical Center, Dallas, TX, USA; 12Hôpital Saint-Louis, Paris, France; 13Royal Perth Hospital, Perth, Australia; 14Yale Cancer Center, New Haven, CT, USA; 15Institut Gustave Roussy, Villejuif, France; 16Dana-Farber Cancer Institute, Boston, MA, USA; 17Celgene Corp., Summit, NJ, USA Table 1. Baseline demographic and disease characteristics Figure 2. Treatment duration, response, and mutation clearance (N=23) Figure 4. Multiple orthogonal measures of MRD in bone marrow samples Figure 6. Examples of relapse BACKGROUND All patients demonstrate high rate of molecular remissions N=23 • To date, of 18 patients achieving a clinical response (CR, CRh, or • Somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in Age, median (range), years 76 (61–88) Summary of mutation clearance and MRD assessments MLFS), four have relapsed (22%). 6–10% of patients with acute myeloid leukemia (AML).1-4 ≥75 years, n (%) 12 (52) a Mutation clearance − Emergence of an IDH2 mutation occurred in two of four • Mutant IDH1 (mIDH1) enzymes catalyze the reduction of alpha- a Male/female, n 11/12 mIDH1, BEAMing digital PCR ≥2 non-DTA genes, NGS Flow MRD patients, with concurrent increases in plasma 2-HG. ketoglutarate to the oncometabolite D-2-hydroxyglutarate (2-HG),5 (n=21) (n=17) (n=14) b and the resulting 2-HG accumulation leads to epigenetic mIDH1 VAF in BMMCs, median (range), %a,b 42 (17–48) Assay cutoff 0.02–0.04% 2% 1.25% − Outgrowth of non-IDH clones occurred in two of four patients, CR+CRh 11/16 (69) 9/13 (69) 10/12 (83) 6-8 b IDH1 mutation detected with both cases having TP53 mutations at baseline. dysregulation and impaired cellular differentiation. No IDH1 mutation detected ECOG PS, n (%) CR 10/14 (71) 8/11 (73) 8/10 (80) CR • Ivosidenib (AG-120) is a first-in-class, oral, targeted inhibitor of the 0 5 (22) CRi/CRp CRh 1/2 (50) 1/2 (50) 2/2 (100) MLFS/PR Non-CR+CRh responders 1/2 (50) 0/2 (0) 0/1 (0) IDH-mediated relapse Non-IDH–mediated relapse mIDH1 enzyme that is approved in the US for the treatment of AML 1 14 (61) SD Relapse Nonresponders 0/3 (0) 0/2 (0) 0/1 (0) with a susceptible IDH1 mutation as detected by an FDA-approved 2 4 (17) CR CR Relapse NA 50 50 MLFS Relapse Deathc test in adults with newly diagnosed AML who are ≥75 years of age or 40 IDH1 Disease history, n (%) Ongoing 40 IDH1 TP53 who have comorbidities that preclude the use of intensive induction HSCT Results of mutation clearance and MRD assessments by patient 30 TET2 30 De novo AML 15 (65) – + ATM C Rh criteria met MRD MRD No sample NGS IDH2 chemotherapy and in adults with relapsed or refractory AML. It is analysis 20 20 CEBPA VAF (%) Secondary AML 8 (35) VAF (%) Mutation clearance currently under review for approval in Europe. 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 10 10 Cytogenetic risk status, n (%) Treatment duration (months) IDH1, BEAMing ≥2 non-DTA 0 0 Best overall response digital PCR genes, NGS Flow MRD Intermediate 15 (65) 0 100 200 300 400 500 0 50 100 150 200 250 aPatient continued on commercially available ivosidenib Poor 5 (22) bPatient had mIDH1 clearance in PBMCs only (BMMCs not available); all other patients had mIDH1 clearance in both BMMCs and PBMCs Assay cutoff 0.02–0.04% 2% 1.25% Days Days cOnly deaths occurring within 60 days of last dose were included HSCT = hematopoietic stem cell transplantation CR EXPLORATORY OBJECTIVES Failure/missing 3 (13) CR CR Relapse MLFS Relapse 500 300 CR a17 of 23 patients had baseline BMMC samples available for retrospective analysis b 400 250 • To study the impact of ivosidenib + azacitidine on longitudinal mIDH1 VAF quantified by NGS (ACE Cancer Panel, Personalis) ECOG PS = Eastern Cooperative Oncology Group performance status CR 200 variant allele frequency (VAF) in both bone marrow mononuclear cells Figure 3. IDH1 mutation clearance is deep and durable with VAF reductions CR 2-HG 300 analysis 150 (BMMCs) and peripheral blood mononuclear cells (PBMCs). associating with CR/CRh (BEAMing digital PCR) CR 200 2-HG (ng/mL) 100 2-HG (ng/mL) CR 100 • To compare IDH1 mutation clearance as a molecular marker of RESULTS 50 Sample type Mutation clearance call CR 0 0 measurable residual disease (MRD) with clearance of co-mutations BMMC Mutation detected 0 100 200 300 400 500 CR 0 50 100 150 200 250 • As of February 19, 2019, 10 patients (43.5%) remained on study IDH1 mutation clearance is durable PBMC No mutation detected and MRD by flow cytometry (flow MRD). Days Days CR treatment and the median number of treatment cycles was 15 (range, CR CR Dotted line represents the lower limit of detection for each analysis • To utilize next-generation sequencing (NGS) to identify genetic 1–30). CR 100 SD CR CR CR CR CR CR CR CR CR CR 100 SD CR CR CR CR CR CR CR CR CR CR CR alterations associated with clinical response, primary resistance, MLFS CRh CR 10 10 • ORR was 78.3% (n=18), which included investigator-reported 1% VAF cutoff CR VAF and relapse. VAF 1% VAF cutoff responses of CR (60.9%; n=14), CRi/CRp (8.7%; n=2), and MLFS 1 1 IDH1 IDH1 0.1 0.1 CR m m CONCLUSIONS 0.02–0.04% VAF cutoff 0.02–0.04% VAF cutoff (8.7%; n=2). 0.01 0.01 CR 0.001 0.001 CRh • Ivosidenib + azacitidine treatment leads to a high rate of durable • The ivosidenib + azacitidine combination was well tolerated, with no 0 250 500 750 1000 0 250 500 750 1000 METHODS CRh molecular remissions in intensive chemotherapy–ineligible patients deaths occurring within 30 days of treatment initiation and one death Relative day Relative day MLFS with newly diagnosed AML. occurring within 60 days. • Samples for this analysis were obtained from patients with newly MLFS VAF reduction <1% attained in CR/CRh patients not achieving mutation clearance • With a limited dataset, a greater fraction of patients (3/5) with RTK diagnosed mIDH1 AML who were ineligible for intensive SD Table 2. Response rates CR CRh pathway mutations (KRAS, NRAS, PTPN11) achieved CR/CRh with chemotherapy and treated in a phase 1b/2, open-label, multicenter SD 100 SDCR CR CR CR CR CR CR CR CR CR 100 SD SD CRh CRp CRi CRi CRi CRh CRi CRi ivosidenib and azacitidine combination therapy compared with Response parameter All patients SD trial with ivosidenib + azacitidine (ClinicalTrials.gov NCT02677922). 10 10 10 VAF VAF ivosidenib monotherapy (0/7). N=23 1% VAF cutoff 1% VAF cutoff 1 1 a IDH1 • mIDH1 VAF in BMMCs and PBMCs was quantified by BEAMing IDH1 Mutation clearance of all baseline co-mutations identified by NGS, excluding genes involved in clonal hematopoiesis DNMT3A/TET2/ASXL1( – “DTA” genes) m m 0.1 0.1 bThe average sensitivity is 1.25%, with a range from 0.13% to 1.84% owing to variability in the surface markers and LAIPs detected CR, n (%) [95% CI] 14 (60.9) [38.5, 80.3] 0.02–0.04% VAF cutoff • A strong association between mutation clearance and other MRD digital PCR. 0.02–0.04% VAF cutoff DTA = DNMT3A/TET2/ASXL1 Time to CR, median (range), months 3.7 (0.8–15.7) 0.01 0.01 analyses warrants further investigation of mIDH1 VAF as a biomarker 0.001 0.001 − IDH1 mutation clearance was defined as mIDH1 VAF below the Duration of CR, median [95% CI], months NE [9.3, NE] 0 250 500 750 1000 0 250 500 750 1000 for monitoring response in patients with mIDH1 AML treated with –4 limit of detection of 0.02–0.04% (2–4 × 10 ) for at least one Relative day Relative day a ivosidenib + azacitidine. on-study time point (Sysmex OncoBEAM™). CR+CRh, n (%) [95% CI] 16 (69.6) [47.1, 86.8] Time to CR+CRh, median (range), months 2.8 (0.8–11.5) CR CR • On the basis of these phase 1b results, the ivosidenib + azacitidine Figure 5. Co-occurring baseline mutations identified by NGS (2% VAF 100 PRCR CR CR CR CR CR CR CR CR 100 SD CR • Bulk baseline and longitudinal co-occurring mutations were identified Duration of CR+CRh, median [95% CI], months NE [12.2, NE] CRp CRi CRh CRi CRi CRi CRi combination is currently being investigated in the actively enrolling 10 10 cutoff; N=23) VAF using a 1400-gene NGS panel capable of detecting sequence VAF 1% VAF cutoff 1% VAF cutoff phase 3 AGILE study (ClinicalTrials.gov NCT03173248).
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