A phase 1b/2 trial (NCT04435691) evaluated the safety and antileukemic activity of the addition of the anti-CD47 antibody magrolimab to the azacitidine (AZA)/venetoclax (VEN) backbone in patients with newly diagnosed older/unfit or high-risk acute myeloid leukemia (AML) and relapsed/refractory (R/R) AML.
The study enrolled patients ≥18 years with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and white blood count <15 × 109/L with adequate organ function. In the phase 1b portion, only patients with R/R AML were enrolled; the phase 2 portion of the study enrolled patients in 3 cohorts: newly diagnosed, VEN-naïve R/R AML, and VEN-exposed R/R AML. The newly diagnosed cohort enrolled patients aged ≥75 years, or patients with documented comorbidities conferring ineligibility for intensive therapy, or patients with adverse risk karyotype and/or TP53 mutation regardless of age/fitness. Eligible patients received AZA 75 mg/m2 on days 1 to 7 and VEN 400 mg on days 1 to 28, plus magrolimab (cycle 1: days 1, 4, 8, 11, 15, 22; cycle 2: weekly; cycle 3+: every 2 weeks). Primary end points were safety, maximum tolerated dose, and recommended phase 2 dose (RP2D) of the triplet; secondary end points were objective response rate (ORR), complete response (CR)/incomplete CR (CRi) rate, duration of response (DOR), overall survival (OS), complete cytogenetic response (CCyR), and minimal residual disease (MRD) negativity by multiparameter flow cytometry.
The phase 1b portion of the study enrolled 6 patients. There were no dose-limiting toxicities reported; the magrolimab RP2D dose was established as 1 mg/kg on cycle 1 of day 1 and cycle 1 of day 4, 15 mg/kg on cycle 1 of day 8, and 30 mg/kg on cycle 1 of day 11 and subsequent doses.
The phase 2 portion of the study enrolled 38 patients; of these, 25 patients were enrolled in the newly diagnosed cohort, 8 in the VEN-naïve R/R cohort, and 15 in the VEN-failure R/R cohort. In the newly diagnosed cohort, 14 patients had TP53 mutations and 11 were TP53 wild-type. The median age of the TP53-mutated cohort was 67 years; the majority had secondary AML (71%, n = 10) or high-risk features, including 11 (86%) patients with adverse risk disease per European LeukemiaNet and 7 (50%) with ECOG PS ≥2.
In the TP53-mutated frontline cohort (n = 14), a CR/CRi rate of 86% was achieved, with a CR rate of 64%. Among the 9 CR/CRi evaluable patients, CCyR was achieved in 4 (44%) patients and MRD negativity in 5 (55%) patients. At median follow-up of 3.9 months in the TP53-mutated frontline cohort, 6-month DOR was 83% and 6-month OS was 100%.
In the TP53 wild-type frontline cohort, a CR/CRi rate of 100% was achieved, with a CR rate of 64%; at median follow-up of 7.0 months, 6-month DOR was 80% and 6-month OS was 81%. The median time to absolute neutrophil count recovery (to >0.5 × 109/L) was 28 days; median time to platelet recovery (to >50 × 109/L) was 24 days.
In the VEN-naïve R/R cohort (n = 8), the ORR was 75%, CR/CRi rate was 63%, CCyR was 60%, and median OS was not reached. In the VEN-failure R/R cohort (n = 15), the ORR was 20%, CR/CRi rate was 20%, CCyR was 50%, and median OS was 3.1 months.
The most common any-grade nonhematologic treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients included febrile neutropenia, lung infection, hypokalemia, hyperbilirubinemia, hypotension, skin infection, elevated alanine transaminase, and sepsis. Grade 3/4 nonhematologic TEAEs (occurred in ≥10% of patients) included blood bilirubin increased and lung infection. Anemia occurred early in the treatment and was manageable with close monitoring after dose 1 and dose 2 of the 3-drug regimen. There were no serious adverse events, immune-related adverse events, treatment interruptions, or discontinuations due to anemia.
Based on these results, the authors concluded that the triplet combination of magrolimab plus AZA-VEN was safe and yielded high CR/CRi rates in newly diagnosed patients, with robust absolute neutrophil count and platelet recovery.
Source: Daver N, et al. ASH 2021; abstr 371.