IMGN632, a CD123-Targeting ADC Bearing a DNA-Alkylating IGN Payload, Combines Effectively as a Triplet Regimen with Azacitidine and Venetoclax In Vivo, Prolonging Survival in Preclinical Models of Human Acute Myeloid Leukemia (AML)

Context IMGN632, a novel CD123-targeting ADC, demonstrates a favorable safety profile and complete remissions as a monotherapy in patients with relapsed/refractory AML and BPDCN ( NCT03386513 ). In pre-clinical models, IMGN632 has been shown to be synergistic with venetoclax (BCL-2 inhibitor) (EHA, 2019, abstract #PF201). Objective Given the recent approval of the combination of azacitidine (AZA, a hypomethylating agent) and venetoclax (VEN) in AML patients unfit for intensive chemotherapy, we investigated the combination of IMGN632 with AZA and the triple combination of IMGN632, AZA, and VEN in preclinical models. Results IMGN632, AZA, and VEN were highly active and prolonged survival in a cell line-derived AML model and patient-derived AML xenograft (PDX) models. In EOL-1, treatment with the triple combination IMGN632+AZA+VEN was the most active and resulted in 100% reduction in tumor growth inhibition (T/C) when compared to Vehicle, IMGN632, and AZA+VEN treatments. In PDX 4023126, the triple combination group survived the longest and was highly active with 74-day tumor growth delay (T-C) and 128% increased life span (% ILS) demonstrating highest survival benefit over IMGN632 (33-day T-C; 57% ILS), and AZA+VEN (52-day T-C; 90% ILS). In PDX model, 4079574, the triple combination was highly active (62-day T-C; 105% ILS) compared to both IMGN632 alone (15-day T-C; 25.4% ILS) and VEN+AZA (1-day T-C; 1.7% ILS). In model 3912018, VEN+AZA (2-day T-C; 3% ILS) was not very active, and strikingly, the triple combination (231-day T-C; 335% ILS) was highly active and prolonged survival the most compared to IMGN632 alone (190-day T-C; 275% ILS) with all the mice surviving for >300 days. Conclusion The addition of IMGN632 to AZA+VEN in multiple AML xenograft and PDX models led to improved survival. These data support the addition of a CD123-targeted ADC with a novel DNA-damaging payload to standard of care, AZA+VEN in AML patients. The combination of IMGN632 and Venetoclax and/or Azacitidine is currently being tested in a Phase1b/2 clinical trial ( NCT04086264 ).