AML-348 A Phase Ib/II Study of Ivosidenib With Venetoclax +/- Azacitidine in IDH1-Mutated Hematologic Malignancies
Lachowiez C., Borthakur G., Loghavi S., Zeng Z., Kadia T., Masarova L., Takahashi K., Tippett G., Garcia J., Bose P., Jabbour E., Ravandi F., Daver N., Manero GG., Vyas P., Kantarjian H., Konopleva M., DiNardo C.
Context: IDH1-mutated (IDH1+) myeloid malignancies depend on the anti-apoptotic protein BCL-2 for survival. Combining the IDH1 inhibitor ivosidenib (IVO) with the BCL-2 inhibitor venetoclax (VEN) may improve outcomes. We report the completed P1b portion of a P1b/II study investigating IVO (500 mg PO daily D15-continuous) with VEN (D1–14), with or without azacitidine (AZA; 75 mg/m2 D1–7) every 28 days. Objectives: Primary P1b objectives included safety, tolerability, and IWG-defined overall response (ORR: CR+CRi+CRh+PR+MLFS). Design: A dose-escalation/-de-escalation study evaluating cohorts of 6 patients enrolled within 4 dose levels: DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). Participants: Eligible patients were ≥ age 18 with IDH1+ MDS, newly diagnosed (ND) or relapsed/refractory (R/R) AML. Results: Thirty-one patients enrolled with a median follow-up of 26 months. The median age was 67 years (range: 44–84), 71% had AML (ND: N=14, R/R: N=8), and 29% had MDS. ELN risk was intermediate or adverse in 19% and 55%, respectively (N=17). The ORR was 94% (DL1: 67%, DL2–DL4: 100%); composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). Of the AML patients, 60% attained measurable residual disease–negative CRc by multiparameter flow cytometry. IDH1+ mutation clearance by digital droplet PCR (sensitivity: 0.1%–0.25%) occurred in 64% of patients following cycle 5. Grade 3–5 adverse events (AEs) in ≥ 10% of patients included febrile neutropenia (29%) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in 2 (dose-limiting toxicity in 1), and differentiation syndrome in 4 (G2: N=2, G3: N=2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months, respectively, and 24-month OS was 71% (95% CI: 55–91; ND-AML: 67%, R/R-AML: 50%, MDS: 100%). MRD-negative CRc improved OS (median NR vs. 8 months, P: 0.002) in ND- and R/R-AML. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. Conclusions: IVO+VEN±AZA is an effective treatment for IDH1+ myeloid malignancies with an expected toxicity profile and notable activity across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented.