Olutasidenib in post-venetoclax patients with mIDH1 AML.

person Jorge E. Cortes Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA info_outline Jorge E. Cortes, Gary J. Schiller, Robert Numerof, Daniel Floryk, Brian Andrew Jonas

Authors person Jorge E. Cortes Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA info_outline Jorge E. Cortes, Gary J. Schiller, Robert Numerof, Daniel Floryk, Brian Andrew Jonas Organizations Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA, Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, Rigel Pharmaceuticals, Inc., South San Francisco, CA, Rigel Pharmaceuticals Inc., South San Francisco, CA, UC Davis Comprehensive Cancer Center, Sacramento, CA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Rigel Pharmaceuticals, Inc., Forma Therapeutics Background: Olutasidenib is a potent, selective, oral inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Olutasidenib is FDA approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) based on the registrational cohort (n = 153) of the Phase 2 trial, which demonstrated a rate of complete remission (CR) or CR with partial hematologic recovery (CRh) of 35%, with a duration of response of 25.9 months. Venetoclax (VEN) in combination with a hypomethylating agent (HMA) is standard treatment for AML patients unfit for chemotherapy and has adequate efficacy in IDH1-mutated AML. The sequence of therapy following failure of a VEN-based regimen in IDH1-mutated AML has not been established. We evaluated the efficacy and safety of olutasidenib in a subset of 17 patients from the Phase 2 trial (NCT02719574) previously treated with VEN combination regimens. Methods: Adults with mIDH1 R/R AML received olutasidenib 150 mg twice daily alone (n = 15) or in combination with azacitadine (AZA) (n = 2). The primary endpoint was achievement of a CR/CRh. Secondary endpoints included time to and duration of CR+CRh and rate of transfusion independence (TI). Data cut-off for the analysis was 18 June 2021. Results: Of 17 patients with prior VEN treatment, 5 are ongoing and 12 discontinued due to progressive disease (6), adverse events (4), or withdrawal by subject (2). Median age was 73 (range 65-83). Median time since diagnosis was 19.5 months (1.2-41). Cytogenetic risk class was intermediate in 9, poor in 6, favorable in 1 and unknown in 1. Most patients had relapsed; 6 were refractory to prior treatment. The median number of prior regimens was 2 (range 1-6); 13 had prior HMA, 2 had prior olutasidenib. VEN was generally used for induction. Some patients received VEN in multiple regimens. VEN was used with azacytidine (AZA) in 8 patients, after AZA (1), and with decitabine (5), cytarabine +/- idarubicin (5), and dinaciclib (2). The best response to olutasidenib was CR/CRh in 5/17 (29.4%), of which 4 (23.5%) were CR. In the 8 patients who previously received the combination of VEN-AZA, 3 (37.5%) patients achieved a CR/CRh. Time to CR/CRh was median 2.1 months (actual: 1, 1.9, 2.1, 2.8 and 2.8). Duration of CR/CRh was median 18.5+ months (4.8, 9.0+, 18.5+, 22.6+, and 28.5+ months as of cut-off date). Other responses included CR with incomplete blood count recovery (CRi) in 2 patients, stable disease (SD) in 2, progressive disease (PD) in 3, not done (ND) in 2, not evaluable (NE) in 1 and not listed in 2. At baseline 14/17 were red blood cell (RBC) dependent, and 4 of the 14 (28%) had a 56-day period of RBC transfusion independence (TI). Ten were platelet dependent at baseline and 5 of the 10 (50%) had a 56-day period of platelet TI while receiving olutasidenib. Conclusions: Olutasidenib induced durable remissions in patients with mIDH1 R/R AML, including those failing prior treatment with a venetoclax-based regimen. Clinical trial information: NCT02719574.

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