ADC Targeting CD123 Active in R/R AML and BPDCN

IMGN632, an investigational anti-CD123 antibody-drug conjugate, demonstrated preliminary activity in patients with relapsed/refractory acute myelogenous leukemia or blastic plasmacytoid dendritic cell neoplasm.

Naval G. Daver, MD

IMGN632, an investigational anti-CD123 antibody-drug conjugate (ADC), demonstrated preliminary activity in patients with relapsed/refractory acute myelogenous leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to results from a phase I/Ib trial presented at the 2019 ASH Annual Meeting.1

Overall, 13 of 71 patients with AML who received the ADC in the trial obtained a complete response with or without complete hematologic recovery (CR/CRi). Additionally, 2 of 9 patients with BPDCN obtained a CR/CRi and 1 had a partial response. Responses were observed across the range of patient subsets represented in the study population. In most cases, responses occurred after the first or second dose of the drug.

The most common treatment-related adverse events (TRAEs) were infusion-related reactions, said Naval G. Daver, MD, of MD Anderson Cancer Center, in a presentation at the meeting. Furthermore, toxicity, in general, was limited to higher doses of the ADC.

“This agent is generally well tolerated and can be given as an infusion on an outpatient basis,” Daver said. “We don’t see cytokine release syndrome (CRS) at this point in time, and the main issue is infusion-related reactions, which are manageable with dexamethasone prophylaxis.

“I would say the response rate is in the 20% to 30% range [with IMGN632] as a single agent,” he added. “As we all know, the AML field is very competitive now, and I believe we will probably need to move forward with combination approaches. In BPDCN, [we have seen] good responses, even in [patients] who have had prior SL-401.”

CD123 is the alpha subunit of interleukin-3 receptor; it is expressed in more than 90% of AML cases, and almost universally in BPDCN.2 IL-3R/CD123 is a validated target in BPDCN, and CD123 expression is increased in AML blasts and leukemic stem cells as compared with normal hematopoietic stem and progenitor cells.3

“CD123-directed therapy may be able to debulk and potentially eliminate the source of disease,” explained Daver. “CD123 is rapidly internalized, making it well suited for ADC-based therapeutic strategies.”

Preclinical studies of IMGN632 provided evidence of efficacy in AML, BPDCN, and B-cell acute lymphoblastic leukemia models. Laboratory studies also yielded evidence of increased antitumor activity with IMGN632 when used in combination with a variety of existing therapies for hematologic malignancies.4

The primary objectives of the phase I study of IMGN632 were to establish the maximum-tolerated dose and determine the phase II dose and optimal dosing schedule for single-agent treatment in patients with relapsed/refractory AML and BPDCN. Secondary objectives were to determine the safety and tolerability of IMGN632 and to describe preliminary antileukemic activity as well as the pharmacokinetic profile of the agent in AML and BPDCN.

To be eligible for enrollment, patients had to have CD123-positive relapsed/refractory AML or BPDCN and have received no more than 3 prior lines of therapy. Intravenous doses of 0.015-0.045 mg/kg were evaluated in 2 dosing schedules: day 1 of a 3-week cycle and a fractionated schedule with dosing on days 1, 4, and 8 of a 3-week cycle.

Investigators enrolled a total of 95 patients; all but 10 patients had AML. The median age of the participants was 66 years (range, 33-83), almost half had adverse cytogenetics, two-thirds had received prior intensive therapy, including 23% with prior stem-cell transplantation.

The most common TRAEs observed with the ADC were infusion related reactions (25%), nausea (11%), and febrile neutropenia (10%). Febrile neutropenia was the only grade ≥3 TRAE that occurred in as many as 10% of patients.

The trial had a 30-day any cause mortality of 6%. Five deaths were considered unrelated to treatment; progressive disease occurred in 2 patients and 1 case each of lung infection, respiratory failure, and sepsis were reported. One potential treatment-related death involved an unknown cause.

The 13 responses observed in 71 evaluable patients with AML included patients with relapsed/refractory disease, those with relapsed/refractory de novo disease, those with adverse cytogenetics as defined by European LeukemiaNet criteria, and those with prior stem-cell transplantation.

The 3 responding patients with BPDCN had received SL-401, 2 also had prior intense chemotherapy and/or transplant, and all 3 had skin, PET, and bone marrow disease. In all 3 of these patients, bone marrow disease cleared from baseline 28%, 37%, 84%, to 0% blasts with IMNG632.

The trial resulted in a recommended phase II dose of 0.045 mg/kg, said Daver. Accrual to the trial continues, and enrollment has expanded to include patients with acute lymphocytic leukemia.

Furthermore, an ongoing phase Ib/II trial is evaluating IMGN632 in combination with azacytidine plus venetoclax (Venclexta). The ADC is also being examined as a frontline monotherapy for patients with minimal residual disease—positive AML.

References

  1. Daver NG, Montesinos P, DeAngelo DJ, et al. Clinical profile of IMGN632, a novel CD123-targeting antibody-drug conjugate (ADC) in patients with relapsed refractory (R/R) acute myeloid leukemia (AML) or blastic plasmacytoid dendritic cell neoplasm (BPDCN). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 734. bit.ly/38qt4ct.
  2. Testa U, Pelosi E, Frankel A. CD 123 is a membrane biomarker and a therapeutic target in hematologic malignancies. Biomark Res. 2014;2(1):4. doi: 10.1186/2050-7771-2-4.
  3. Ehninger A, Kramer M, Rölig C, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J. 2014;4:e218. doi: 10.1038/bcj.2014.39.
  4. Kuruvilla VM, McCarthy R, Zhang Q, et al. IMGN632. A CD123-alkylating ADC bearing a DNA-alkylating IGN payload, combines effectively with azacitidine and venetoclax in vivo, prolonging survival in preclinical models of human acute myeloid leukemia (AML). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 1375. bit.ly/2LHyhTs.

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