In patients with acute myeloid leukemia (AML) across several study cohorts, ivosidenib (IVO) + venetoclax (VEN), with or without azacytidine (AZA), showed an anticipated and satisfactory safety profile with robust responses and prolonged survival. These findings were the result of a phase 1b/2 clinical trial (NCT03471260) presented at the 10th Annual Society of Hematologic Oncology Annual Meeting.

“In particular, high minimal residual disease (MRD)–negative clinical complete response (cCR) rates were observed with the triplet,” wrote Curtis Lachowiez, MD, and colleagues. The researchers conducted a dose escalation/de-escalation study assessing patients enrolled within four arms of treatment levels: DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), and DL4 (IVO+VEN 800 mg+AZA).

Safety, Tolerability & Overall Response Rate Were Primary End Points

Participants in the trial included adults (N=31; median age, 67) with newly diagnosed or relapsed/refractory AML (71%), advanced myelodysplastic syndrome (MDS, 29%), or myeloproliferative neoplasms (MPN), having at least 10% blasts, an ECOG performance score of 2 or less, an IDH1 R132 mutation, and adequate renal and hepatic function. The median follow-up was 26 months. In 19% and 55% of patients, respectively, European LeukemiaNet (ELN) risk was intermediate or adverse.

Safety, tolerability, and overall response rate were the primary endpoints, including CR, CR with partial hematologic recovery, CR with incomplete hematologic recovery, partial response (PR), and morphological leukemia-free state. Additionally, the study team aimed to determine the maximum tolerated dose and a recommended phase 2 dose. A pharmacokinetic analysis of the IVO+VEN combination was included in the secondary endpoints, as were the presence of cellular or molecular predictive biomarkers, overall survival (OS), duration of response, and event-free survival (EFS).

The composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%); the overall response rate (ORR) was 94% (DL1: 67%, DL2–DL4: 100%). Of patients with AML, 60% attained measurable residual disease-negative CRc by multiparameter flow cytometry. In 64% of patients following cycle 5, IDH1+ mutation clearance by digital droplet PCR (sensitivity: 0.1%–0.25%) was observed.

Adverse effects (AEs) observed by Dr. Lachowiez and colleagues included abdominal pain (10%), febrile neutropenia (29%), lung infection (19%), musculoskeletal pain (10%), and otitis media (6.5%). Differential syndrome and tumor lysis were noted as AEs of special interest.

100% of Patients Responded to Treatment

“In total, 100% of patients with de novo AML and MDS or MPN responded to the study treatment, with 100% in each achieving a cCR, as did 100% of patients with secondary AML or treated secondary AML, 80% of whom achieved cCR,” wrote Dr. Lachowiez and team. “Of the patients with relapsed/refractory AML, 75% responded, including 63% who achieved cCR.”

Dr. Lachowiez and colleagues concurred that “IVO+VEN±AZA is an effective treatment for IDH1 plus myeloid malignancies with an expected toxicity profile and notable activity across disease groups. Based on the findings from this trial, DL2 has been selected as the recommended phase 2 dose.”