Novel AML Therapy, Pivekimab Sunirine, Shows Promising Anticancer Activity

Monotherapy with pivekimab sunirine, a first-in-class antibody-drug conjugate of a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload, demonstrated activity in patients with relapsed or refractory CD123-positive acute myeloma leukemia (AML), and researchers identified a recommended phase II dose of 0.045 mg/kg once every three weeks.

Findings from the study, led by Naval Daver, MD, of MD Anderson Cancer Center in Houston, Texas, were published in The Lancet Oncology.

The phase I/II dose escalation and expansion trial enrolled 91 patients across nine hospitals in France, Italy, Spain, and the United States. Of these, 68 patients received a dosing schedule of day one of a three-week cycle and 23 patients received a fractionated dosing schedule of days one, four, and eight of a three-week cycle.

Pivekimab Sunirine Effective in AML Treatment

The primary endpoints were the maximum tolerated dose and a recommended phase II dose, and the secondary endpoint was antileukemia activity based on overall response and a composite of complete remission outcomes. The fractionated dosing schedule was discontinued after comparing safety and antileukemia activity outcomes with the single-day dosing schedule.

Participants received six doses escalating from 0.015 mg/kg to 0.450 mg/kg. No maximum tolerated dose was identified, though three dose-limited toxicities were reported: two cases of reversible veno-occlusive disease at 0.180 mg/kg and 0.450 mg/kg, and one case of neutropenia at 0.300 mg/kg.

In 29 patients treated with the recommended phase II dose of 0.045 mg/kg once every three weeks, the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (n=3), infusion-related reactions (n=2), and anemia (n=2). The overall response rate was 21% (n=6; 95% CI, 8-40) and the composite complete remission outcome rate was 17% (n=5; 95% CI, 6-36).

Treatment-related serious adverse events in 5% or more of the 29 patients included two cases of febrile neutropenia and two infusion-related reactions. In the 68 patients on schedule A, one death with an unknown cause was deemed related to pivekimab sunirine at a dose of 0.300 mg/kg.

In closing, Dr. Daver and colleagues noted that the results of this study motivated a phase Ib/II trial on pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive AML.

Reference

Daver NG, Montesinos P, DeAngelo DJ, et al. Pivekimab sunirine (IMGN632), a novel CD123-targeting antibody-drug conjugate, in relapsed or refractory acute myeloid leukaemia: a phase 1/2 study. Lancet Oncol. 2024;25(3):388-399. doi:10.1016/S1470-2045(23)00674-5