Data from a phase 1b/2 study on IMGN632 in combination with azacitidine and venetoclax for patients with R/R AML were presented at the 2021 ASH Annual Meeting.

Data from a phase 1b/2 study on IMGN632 in combination with azacitidine and venetoclax for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) were presented at the 2021 American Society of Hematology (ASH) Annual Meeting.

“Despite improvements in the treatment of ‘unfit or older’ AML patients with the combination of azacitidine and venetoclax, long-term survival for these patients remains poor. Additions to this new regimen may further improve patient outcomes. Overexpression of CD123, the alpha subunit of the IL-3 receptor, is see in AML blasts. IMGN632 is a CD123-targeting antibody drug conjugate comprised of a high-affinity anti-CD123 antibody coupled to a DNA-akylating payload of the novel IGN class. Preclinical data have demonstrated synergy between IMGN632 and azacitidine and/or venetoclax,” explained Naval Daver, MD, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, and co-investigators.

Thus, Dr Daver reported on the safety, tolerability, and anti-leukemia activity of this novel triplet.

The study enrolled 35 patients (median age 69) with relapsed or refractory (R/R) AML, with 23 percent having secondary AML, 86 percent who had prior intensive therapies, 37 percent were refractory to first line therapy, 51 percent received prior venetoclax, and 23 percent had FLT3 mutations. In all, 29 patients were efficacy evaluable.

To date, the triplet combination escalation consists of 5 cohorts of IMGN632 plus azacitidine and venetoclax, with 4 cohorts administering IMGN632 on day 7 of each cycle (C15A50V8, C15A50V14, C15A75V21, C45A50V8), and 1 cohort dosing IMGN632 on day 1 of each cycle (Day 1 C15A50V14).

Responses were determined using modified ELN criteria with a 14-day count recovery window.

Efficacy was seen in all cohorts, doses, and schedules. The objective response rate (ORR) was 55 percent with a composite complete remission (CCR) rate of 31 percent. Higher intensity cohorts (IMGN632 dose 45 mcg/kg or 14-21 days of venetoclax) on the day 7 schedule (n=20) were associated with higher response rates, an ORR of 75 percent, and a CCR rate of 40 percent. The venetoclax naïve subset (n=20) had ORR/CRR rates of 100 percent and 60 percent, respectively. There was also significant activity seen in the FLT3 mutant subset (n=7) with an ORR/CRR rate of 100 percent and 71 percent, respectively.

“The toxicity profile was manageable in this R/R AML population with multiple prior therapies,” said Dr Daver et al.

The most common treatment emergent adverse events (AEs) of all grades included infusion-related reactions (37%), febrile neutropenia (26%), hypophosphatemia (26%), dyspnea (26%), pneumonia (20%), and fatigue (20%). One patient in the Day 1 C15A50V14 cohort discontinued IMGN632 treatment due to a treatment-related AE. Cytopenias were similar with the azacitidine plus venetoclax regimen for this patient population.

“With a manageable safety profile in this R/R AML population, the novel IMGN632 triplet demonstrated compelling anti-leukemia activity. Ongoing escalation cohorts aim to optimize safety and efficacy of the triplet therapy. Expansion proof-of-concept cohorts are planned in both relapsed and frontline AML patients. Updated safety, efficacy, and PK data will be presented,” concluded Dr Daver et al.—Emily Bader

Daver N, Aribi A, Montesinos P, et al. Safety and Efficacy from a Phase 1b/2 Study of IMGN632 in Combination with Azacitidine and Venetoclax for Patients with CD123-Positive Acute Myeloid Leukemia. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 372.