The novel CD123-targeting antibody-drug conjugate IMGN632 demonstrated promising clinical activity in a cohort of heavily pretreated patients with relapsed/refractory blastic plasmacytoid dendritic cell neoplasm and had a favorable tolerability.
The novel CD123-targeting antibody-drug conjugate (ADC) IMGN632 demonstrated promising clinical activity in a cohort of heavily pretreated patients with relapsed/refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN) and had a favorable tolerability, according to findings from phase 1/2 clinical trial (NCT03386513).
Among patients with heavily pretreated disease, which included those who had progressed following tagraxofusp-erzs, intensive chemotherapy, and transplant, the objective response rate was 30% with IMGN632 with a complete response (CR) or composite CR (Crc) in 4 patients with notable durations of response. The safety profile was favorable, including limited grade 3 or higher treatment-emergent adverse events (TEAEs) or serious AEs (SAEs) and no deaths.
This study, which was presented during the 2020 American Society of Hematology (ASH) Annual Meeting, represents the largest-to-date prospective group of uniformly treated patients with this rare hematologic malignancy. Limited efficacy has been observed with the currently available therapy for patients with relapsed/refractory BPDCN has seen minimal efficacy with the currently, and this treatment also has significant safety and tolerability concerns, underscoring the high unmet need for new therapies in this patient population.
"This is a new CD123-targeting agent, which has actually recently received FDA Breakthrough Therapy designation for patients with relapsed/refractory BPDCN, and it was very encouraging data,” lead author Naveen Pemmaraju, MD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, told Targeted Oncology. “This reminds us is that no matter how rare or challenging of a disease or a blood cancer, it just gives hope that there are folks all around the world who are trying to focus on even the rarest of rare blood cancers. We're trying to find clinical breakthroughs there, so I think that’s very exciting."
The FDA granted its Breakthrough Therapy designation to IMGN632 in October 2020, for the treatment of patients with relapsed/refractory BPDCN, and the agent remains under evaluation in the phase 1/2 study in this rare disease, as well as other hematologic malignancies.
Overall, 23 patients with relapsed/refractory BPDCN were enrolled with a median age of 73 years (range, 19-82), and 74% were male. Investigators indicated that 52% had at least 2 prior therapies, 52% had received previous intensive therapies, and 22% had an allogeneic stem cell transplant, but most importantly, 43% had prior exposure to tagraxofusp. At study enrollment, 70% of patients had skin involvement, 61% bone marrow involvement, and 48% lymph node involvement.
Objective responses were observed in 7 of the 23 patients. The CRc rate was 22%, and the durations of response, including time to partial response (partial response), among the 4 patients with a CR/CRc, 9.2, 6.8+, 3.1, and 3+ months without transplant. Among the 10 patients with prior exposure to tagraxofusp, 30% achieved an objective response, including 1 CR, 1 incomplete CR (CRi), and 1 PR.
Investigators noted 2 remarkable responders who had 3 previous therapies, which included tagraxofusp followed by intense or other therapies and presented with diffuse disease involvement with skin, nodal, and bone marrow infiltration. These patients both cleared all 3 disease compartments after 1 and 2 doses of IMGN632, with 1 patient remaining in CR for 9.2 months.
Among the 12 patients with bone marrow involvement and a response assessment, 9 patients (75%) had a reduction in the bone marrow blasts and 50% achieved a bone marrow CR, including patients who had received prior tagraxofusp.
The most common TEAEs of all-grade included nausea (35%), peripheral edema (26%), and infusion-related reactions (22%). The most common grade 3 or higher TEAE was infusion-related reactions, and no grade 3 or higher nausea or peripheral edema were observed. No treatment-related toxicities of grade 3 or higher were seen in > 1 patient, and no capillary leak syndrome was reported.
Grade 3 or higher liver function test elevations, neutropenia, and thrombocytopenia were noted in 1 patient each, but no deaths were recorded within 30 days of the last study dose.
This multicenter, open-label study aims to determine the maximum tolerated dose of IMGN632 and assess the safety and tolerability of the therapy in patients with CD123-positive disease, including acute myeloid leukemia (AML), BPDCN, and acute lymphoblastic leukemia (ALL). The primary end point is the maximum tolerated dose, and secondary end points include TEAEs, objective response rate, pharmacokinetic parameters, and the immunogenicity of the ADC.
Patients with relapsed/refractory or untreated BPDCN who were inappropriate for available therapies were entered into cohort 1 of the study, while cohort 2 included patients with relapsed AML, cohort 3 relapsed/refractory ALL, cohort 4 other relapsed/refractory hematologic malignancies, and cohort 5 AML who were relapsed/refractory to non-intense therapies. Patients had to have a confirmation of CD123 positivity by flow cytometry or immunohistochemistry, and they were excluded if they had an active central nervous system or were appropriate for standard of care therapies.
Pemmaraju N, Martinelli G, Todisco E, et al. Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 167.