Patients with heavily pretreated relapsed or refractory (R/R) follicular lymphoma (FL) treated with AZD0486, a bispecific T-cell engager, had a high response rate, according to results from a first-in-human phase I trial that were presented at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego.1
“The most exciting aspect of our data is that nine out of 10 of the patients with FL responded to treatment with AZD0486, and at some doses, 100% of patients had a complete response (CR),” study author Jing-Zhou Hou, MD, PhD, of the Mario Lemieux Center for Blood Cancers at UPMC Hillman Cancer Center in Pittsburgh, told ASH Clinical News. “These responses were deep and durable in the majority of patients. Response to therapy was consistently high across challenging subgroups, such as CD20-negative disease, disease that was refractory to previous treatment, and disease progression within 24 months of front-line chemoimmunotherapy (POD24).”
AZD0486 is an intravenous IgG4 fully human CD19xCD3 bispecific T-cell engager with a half-life of 8 to 12 days.
Dr. Hou and his colleagues enrolled patients with R/R non-Hodgkin lymphoma (NHL), primarily FL or diffuse large B-cell lymphoma (DLBCL), who had received at least two prior therapies, onto the phase I clinical trial.2 Patients were required to have CD19+ disease and could have previously received CD20-targeted bispecific antibodies or CD19-targeted therapy including chimeric antigen receptor (CAR) T-cell therapy. The primary objectives of the phase I trial were to evaluate safety, tolerability, and pharmacokinetics and pharmacodynamics and to identify the recommended phase II dose. In the earlier part of the study, patients received either fixed-target dose (no step-up) or a single step-up dose for cycle 1, but all subsequent patients received a double step-up dose, which significantly mitigated the risk of cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). From cycle 2, patients were given the therapy every two weeks in 28-day cycles.
Among the 56 patients with R/R FL, the median age was 62 years, with 12 patients (21%) having bulky disease and 19 patients (34%) with POD24. Patients had received a median of three prior therapies, and 11 patients (20%) had disease refractory to their prior treatment.
Among the 41 patients who received target doses of 2.4 mg or greater, the overall response rate (ORR) was 95%, and the CR rate was 85%. Of the 14 POD24 patients who received a dose of 2.4 mg or greater, 100% had a CR, and of the nine patients with bulky disease, 78% had an OR, and 56% had a CR. Of the six patients with refractory disease, 83% had a CR. Of the four patients who previously received a CD20-targeted bispecific antibody, three (75%) had a CR.
After a median follow-up of 8.4 months, the median duration of response (DoR) had not been reached, and the nine-month DoR was 77%. Of the 41 patients who achieved CR, only two experienced disease relapse so far. Among the patients who received the target 2.4 mg dose, the estimated nine-month progression free survival rate was 79%.
Of the patients who received the target 2.4 mg dose, 89% (8 of 9 patients) had undetectable measurable residual disease (uMRD) within 12 weeks of treatment initiation. Among the 26 patients who received a dose higher than 2.4 mg, 92% (n=24) achieved uMRD within 12 weeks of starting treatment, and 96% (n=25) achieved uMRD anytime on study.
No patient discontinued treatment due to an adverse event (AE). The most common treatment-emergent AEs among all 65 patients across all dose cohorts on study were CRS, all of which were grade 1 or 2, anemia, decreased lymphocyte count, nausea, neutropenia, decreased white blood cell count, and headache.
Among the 38 patients who received step-up dosing, 19 patients (50%) experienced CRS, all of which was grade 1. Two CRS events occurred at the target dose. ICANS was seen in one (3%) of these 38 patients and was grade 1, and no patient experienced ICANS at the target 2.4 mg dose. “One patient experienced transient ICANS, which occurred after a cycle 1 step-up dose and fully resolved. Many of my patients did so well they returned to work and going to the gym,” Dr. Hou said.
This study also enrolled patients with DLBCL, and these data were also presented at the ASH annual meeting.3
“Several other studies have either started or are in the planning stages with AZD0486 in front-line FL, as well as mantle cell lymphoma, chronic lymphocytic leukemia, and B-cell acute lymphoblastic leukemia. Some studies will look at different combinations of treatments as well as subcutaneous administration of AZD0486,” Dr. Hou said.
Added Dr. Hou, “One of the most rewarding aspects as an investigator and clinician is working to develop better therapies for patients and seeing these incredible results. Despite advances in the field, a significant unmet need remains for patients with R/R B-cell NHL.”
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
- Hou JZ, Nair R, Jacobs R, et al. Escalating doses of AZD0486, a novel CD19xCD3 T-cell engager, result in high complete remissions with rapid clearance of minimal residual disease in patients with relapsed/refractory follicular lymphoma. Abstract 341. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 7, 2024; San Diego, California.
- Clinical Trials.gov. NCT04594642. A Study of AZD0486 in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma. November 27, 2024. Accessed December 8, 2024. https://www.clinicaltrials.gov/study/NCT04594642.
- Gaballa S, Hou JZ, Devata S, et al. Evaluation of AZD0486, a novel CD19xCD3 T-cell engager, in relapsed/refractory diffuse large B-cell lymphoma in an ongoing first-in-human phase 1 study: high complete responses seen in CAR-T–naive and CAR-T–exposed patients. Abstract 868. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
