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

BACKGROUND: Despite improvements in the treatment of "unfit or older" AML patients with the combination of azacitidine (AZA) and venetoclax (VEN), 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 seen in AML blasts. IMGN632 is a CD123-targeting antibody-drug conjugate (ADC) comprised of a high-affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. Preclinical data have demonstrated synergy between IMGN632 and AZA and/or VEN, including overcoming AZA/VEN resistance in murine AML models (Kuruvilla ASH 2020), supporting the clinical exploration of these combinations. Doublets of IMGN632 with both AZA and VEN were studied in AML patients and supported testing of the triplet of IMGN632, AZA, and VEN. Here we report the initial safety and anti-leukemia activity findings from this novel triplet.METHODS: This Phase 1b/2 study was designed to determine the safety, tolerability, and preliminary anti-leukemic activity of IMGN632 combined with AZA and VEN in patients with CD123-positive AML. To date, the triplet combination escalation consists of 5 cohorts of IMGN632 plus AZA and VEN, each agent designated by "C" for IMGN632 dose in mcg/kg, "A" for AZA dose in mg/m2 x7 days, or "V" for VEN # of days at 400mg QD. Four cohorts dosed IMGN632 on Day 7 of each cycle (C15A50V8, C15A50V14, C15A75V21, C45A50V8), and one cohort dosed IMGN632 on Day 1 of each cycle (Day 1 C15A50V14). Responses are determined using modified ELN criteria with a 14-day count recovery window.RESULTS: At the time of this analysis, preliminary safety data are available for 35 relapsed or refractory (R/R) AML patients. The median age was 69y, 23% had secondary AML, 86% received prior intensive therapies, 37% that were refractory to first line therapy, and 51% had received prior VEN. Twenty-three percent of patients had FLT3 mutations.The toxicity profile was manageable in this R/R AML population with multiple prior therapies. The most common treatment emergent adverse events (TEAE) all grades [grade 3+ events] seen in >20% of patients were infusion-related reactions (IRR, 37% [3%]), febrile neutropenia (26% [23%]), hypophosphatemia (26% [3%]), dyspnea (26% [6%]), pneumonia (20% [14%]), and fatigue (20% [0%]). One patient in the Day 1 C15A50V14 cohort discontinued IMGN632 due to a TEAE (DLT IRR, resolved). Cytopenias and infections were consistent with those observed with the AZA+VEN regimen in this R/R population. No TLS, VOD, capillary leak or cytokine release were observed. 30-day mortality was 0%.Efficacy was seen across all cohorts/doses and schedules (efficacy evaluable population, n=29). The objective response rate (ORR) was 55% with a composite complete remission (CCR) rate of 31% (1 CR, 4 CRh, 2 CRp, 2 CRi). Higher intensity cohorts (IMGN632 dose 45 mcg/kg or 14-21 days of VEN) on the Day 7 schedule (n=20) were associated with higher response rates: ORR 75%, CCR rate 40% (Figure 1). At these higher intensity cohorts, in the VEN naïve subset (n=10), ORR/CCR rates were 100%/60%, respectively. Significant activity was also seen in the FLT3 mutant subset (n=7), with ORR/CCR rates of 100%/71%.CONCLUSION: 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 (NCT04086264). Updated safety, efficacy, and PK data will be presented.Figure 1 Figure 1.

Duke Scholars

Author Harry Paul Erba Medicine, Hematologic Malignancies and Cellular Therapy