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| Authors | Stéphane De Botton, Karen W. L. Yee, Christian Recher, Andrew Wei, Pau Montesinos, David Taussig, Arnaud Pigneux, Thorsten Braun, Antonio Curti, Jordi Esteve, Carolyn Grove, Brian Andrew Jonas, Asim Khwaja, Ollivier Legrand, Pierre Peterlin, Olga Polyanskaya, Jennifer Sweeney, Hesham Mohamed, Jorge E. Cortes, Pierre Fenaux | ||||||||||||
| Title | Effect of olutasidenib (FT-2102) on complete remissions in patients with relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML): Results from a planned interim analysis of a phase 2 clinical trial. | ||||||||||||
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| URL | https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.7006 | ||||||||||||
| Abstract Text | Background: Olutasidenib, a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1), has exhibited favorable tolerability and clinical activity in high-risk AML patients (pts) in a phase 1 trial (Watts, Blood 2019). Here, we present interim analysis results of a phase 2 trial (NCT02719574) in R/R mIDH1 AML pts receiving olutasidenib monotherapy 150 mg twice daily. Methods: The efficacy evaluable (EE) set comprised mIDH1R132X pts whose first dose was ≥180 days before the data cut-off (18-JUN-20). The primary endpoint was CR+CRh (complete remission [CR] or CR with partial hematologic recovery [CRh] according to modified IWG 2003 criteria) rate. CRh was defined as bone marrow blasts <5%, absolute neutrophil count >0.5×109/L, and platelet count >50×109/L. Overall response rate (ORR) comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial response (PR). Duration of treatment (DOT), duration of response (DOR), and overall survival (OS) were estimated using Kaplan-Meier methodology. Results: This clinical trial met its pre-specified early enrollment-stopping criteria for efficacy. A total of 153 pts with R/R AML received olutasidenib; median DOT, 5.5 mo (95% CI: 4.4, 8.7). 43 pts (28%) remain on treatment and 110 (72%) discontinued, most commonly due to: disease progression, 31%; AEs, 14%; death, 10%; and transplant, 8%. For the EE set (123 pts), the median age was 71 y (range: 32‒87) with a median number of prior therapies of 2 (1‒7). The CR+CRh rate was 33% including 30% of pts in CR (Table). Median duration of CR+CRh was not reached (NR) and 13.8 mo in a sensitivity analysis when HSCT or relapse was deemed end of response. ORR was 46% and median duration of ORR was 11.7 mo. Of responders who were transfusion-dependent at baseline, 56-day platelet transfusion independence (TI) and RBC TI were gained by 100% and 83%, respectively, of pts who achieved CR+CRh, and by 56% and 50% who did not. Median OS was 10.5 mo (EE set). In CR+CRh responders, median OS was NR and the estimated 18-mo OS was 87%. TEAEs in ≥25% of pts were nausea, 38%; constipation, 25%; leukocytosis, 25%. Grade 3/4 all-causality TEAEs in >10% of pts were febrile neutropenia, 20%; anemia, 19%; thrombocytopenia, 16%; neutropenia, 13%. Investigator-assessed IDH1 differentiation syndrome (any grade) was observed in 21 pts (14%); most cases resolved with treatment management; one case was fatal; 19 pts had concomitant leukocytosis. Conclusions: Olutasidenib was well tolerated and induced durable CR in a subset of high-risk R/R mIDH1 AML pts. TI was achieved in all response groups. Clinical benefit, per DOR and OS, extended beyond CR+CRh responders. Clinical trial information: NCT02719574. | ||||||||||||
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| IDH1 R132G | acute myeloid leukemia | sensitive | Olutasidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial (Study 2102-HEM-101) that supported FDA approval, Rezlidhia (olutasidenib) treatment resulted in an objective response rate of 46% (57/123, 37 complete remission (CR), 4 CR with partial hematologic recovery, 14 CR with incomplete recovery, 1 morphologic leukemia-free state, 1 partial response) in patients with relapsed/refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132G/C/H/L/S) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7006; NCT02719574). | detail... detail... detail... |
| IDH1 R132L | acute myeloid leukemia | sensitive | Olutasidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial (Study 2102-HEM-101) that supported FDA approval, Rezlidhia (olutasidenib) treatment resulted in an objective response rate of 46% (57/123, 37 complete remission (CR), 4 CR with partial hematologic recovery, 14 CR with incomplete recovery, 1 morphologic leukemia-free state, 1 partial response) in patients with relapsed/refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132L/C/G/H/S) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7006; NCT02719574). | detail... detail... detail... |
| IDH1 R132C | acute myeloid leukemia | sensitive | Olutasidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial (Study 2102-HEM-101) that supported FDA approval, Rezlidhia (olutasidenib) treatment resulted in an objective response rate of 46% (57/123, 37 complete remission (CR), 4 CR with partial hematologic recovery, 14 CR with incomplete recovery, 1 morphologic leukemia-free state, 1 partial response) in patients with relapsed/refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132C/G/H/L/S) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7006; NCT02719574). | detail... detail... detail... |
| IDH1 R132H | acute myeloid leukemia | sensitive | Olutasidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial (Study 2102-HEM-101) that supported FDA approval, Rezlidhia (olutasidenib) treatment resulted in an objective response rate of 46% (57/123, 37 complete remission (CR), 4 CR with partial hematologic recovery, 14 CR with incomplete recovery, 1 morphologic leukemia-free state, 1 partial response) in patients with relapsed/refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132H/C/G/L/S) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7006; NCT02719574). | detail... detail... detail... |
| IDH1 mutant | acute myeloid leukemia | sensitive | Olutasidenib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase II trial (Study 2102-HEM-101) that supported FDA approval, Rezlidhia (olutasidenib) treatment resulted in an objective response rate of 46% (57/123, 37 complete remission (CR), 4 CR with partial hematologic recovery, 14 CR with incomplete recovery, 1 morphologic leukemia-free state, 1 partial response) in patients with relapsed/refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132C/G/H/L/S) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7006; NCT02719574). | detail... detail... detail... |
| IDH1 R132S | acute myeloid leukemia | sensitive | Olutasidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial (Study 2102-HEM-101) that supported FDA approval, Rezlidhia (olutasidenib) treatment resulted in an objective response rate of 46% (57/123, 37 complete remission (CR), 4 CR with partial hematologic recovery, 14 CR with incomplete recovery, 1 morphologic leukemia-free state, 1 partial response) in patients with relapsed/refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132S/C/G/H/L) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7006; NCT02719574). | detail... detail... detail... |