An unmet clinical need exists for novel active therapies that improve clinical outcomes for unfit or elderly patients with acute myeloid leukemia (AML). Based on encouraging preclinical evidence, this phase 1b/2 study evaluated the safety, tolerability, and antileukemic activity of the triplet combination consisting of the antibody–drug conjugate IMGN632 targeting CD123 (alpha subunit of the IL-3 receptor) plus azacitidine and venetoclax in patients with CD123-positive AML. Initial safety and antileukemic activity findings are summarized here.
The study included 5 dose-escalation cohorts that received the triplet combination. Of these, 4 cohorts dosed IMGN632 on day 7 of each cycle (day 7: C15A50V8, C15A50V14, C15A75V21, C45A50V8; C for IMGN632 [15 or 45 mcg/kg], A for azacitidine [50 or 75 mg/m2 × 1-7 days], V for venetoclax [400 mg once daily for 8, 14, or 21 days], and 1 cohort dosed on day 1 of each cycle (day 1: C15A50V14).
A total of 51 evaluable patients were included in this analysis. The median age of the study population was 67 years; 27% of patients had secondary AML, and 49% were classified as adverse risk per European LeukemiaNet. Patients had received a median of 2 prior therapies, 35% were primary refractory, 51% had prior venetoclax exposure, and 20% had FLT3 mutations.
The most common any-grade treatment-emergent adverse events (TEAEs) that occurred in >20% of patients were infusion-related reactions (IRRs; 33%), febrile neutropenia (31%), hypophosphatemia (26%), dyspnea (28%), diarrhea (22%), hypokalemia (22%), nausea (22%), vomiting (22%), pneumonia (20%), and fatigue (28%). The most common grade ≥3 TEAEs were febrile neutropenia (26%), pneumonia (16%), IRRs (2%), hypophosphatemia (2%), and dyspnea (8%). There were no reports of tumor lysis syndrome, veno-occlusive disease, capillary leak syndrome, or cytokine release syndrome. Treatment discontinuations due to adverse events were reported in 8% of patients. The 30-day and 60-day mortality rates were 0% and 10%, respectively.
In the overall efficacy evaluable population, including all doses and schedules (n = 46), the objective response rate (ORR) was 48%, the composite complete remission (CCR) rate was 30%, which included 4 complete responses (CRs), 8 CRs with partial hematologic recovery, 1 CR with incomplete platelet recovery, and 1 CR with incomplete hematologic recovery. Higher response rates were achieved in the higher intensity cohorts (IMGN632 dose 45 mcg/kg or 14-21 days of venetoclax) on the day 7 schedule (n = 29); ORR was 59% and the CCR rate was 38%. Among other subsets of interest, the venetoclax-naïve cohort (n = 15) achieved an ORR of 73% and a CCR rate of 53%, the FLT3 internal tandem duplication mutant cohort (n = 9) achieved an ORR of 89% and a CCR rate of 79%. Responses were also achieved in the cohort of patients who had failed the hypomethylating agent + VEN combination (ORR, 42%; CCR, 25%). Among the 17 responders in the higher intensity cohorts, 6 (35%) patients went on to receive a transplantation.
Based on these results, it was concluded that the novel triplet combination of IMGN632 plus azacitidine and venetoclax was associated with a manageable safety profile and promising antileukemic activity in patients with relapsed/refractory AML.
Source: Daver N, et al. ASH 2021; abstr 372.