EX103, a Newly Re-Designed CD20×CD3 Molecule, Induces High Response in Heavily Pretreated Relapsed/Refractory (R/R) Patients with B-Cell Non-Hodgkin Lymphoma (B-NHL)

Introduction:

T-cell engager (TCE) therapies are introduced to treat blood malignancies, including R/R B-NHL. However, managing toxicities such as severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain a significant challenge. EX103 is a re-designed CD20×CD3 TCE with a much lower affinity to CD3, providing a promising therapy for B-NHL. We present here updated safety and efficacy data from an ongoing first-in-human phase I/II study of EX103 monotherapy in heavily pretreated patients with R/R B-NHL (NCT06021678).

Methods:

R/R B-NHL patients who had previously received at least two lines of therapy were included in this study. Eight dose levels are included in phase I dose-escalation stage (ranging from 1.2 to 36 mg). Accelerated titration combined standard 3+3 design are used to establish preliminary safety profile and determine the recommended expansion dosage. Eligible patients will receive EX103 treatment with 3 step-up doses followed by target doses in 28-day cycles (iv, QW: Cycle 1-2; Q2W thereafter) until disease progression or unacceptable toxicity. CRS and ICANS were assessed by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019), other adverse events (AEs) were assessed by CTCAE v5.0.

Results:

As of July 8, 2024, seven dose levels of EX103, ranging up to 30 mg, have been completed, with dose-expansion ongoing at 24 mg and 30 mg dose levels. A total of 69 patients (median age 53 years [range: 26-72]; 59.4% male) were enrolled and received at least one dose of EX103, including patients with diffuse large B-cell lymphoma (DLBCL) (n=53), follicular lymphoma (FL) 1-3a (n=7), chronic lymphocytic leukemia (n=3), FL grade 3B (n=2), marginal zone lymphoma (n=2), and mantle cell lymphoma (n=2).The median number of prior therapies was 3 (range: 2-13). The median time since last therapy was approximately 1.9 months (range: 0.3-34.2). Among the patients who failed prior CD19-targeting therapies, 9 patients received CD19 CAR-T therapy and 2 patients received CD19×CD3 TCE therapies. 8 patients had received autologous stem cell transplantation (ASCT).

In 48 efficacy evaluable patients, 31 (64.6%) continue receiving EX103 treatment in study, with the longest duration of response lasting for 20.5 months. The median time to initial response was 45 days (range: 39-281) in the 24 mg cohort and 43 days (range: 31-62) in the 30 mg cohort. Among the DLBCL patients in the 24 mg cohort (n=13), the overall response rate (ORR) and complete response (CR) rate were 69.2% and 38.5%, respectively. In the DLBCL patients treated with a dose of 30 mg (n=17), the ORR was 76.5%, and 94.1% of patients continuing treatment. In 10 patients who failed prior CD19-targeting therapies (CD19 CAR-T therapy, n=8; CD19×CD3 TCE therapies, n=2), the ORR and CR rate were 90.0% and 40.0%, respectively. Patients who failed ASCT therapies reached a CR (n = 2) or partial response (PR; n = 4), the ORR was 85.7%.

No dose-limiting toxicity (DLT) or treatment-related death was observed. CRS events were the most common treatment related adverse events and occurred in 66.7% of the patients, with 50.7% grade 1, 14.5% grade 2, one patient (1.4%) experienced grade 3, and no higher events occurred. No case of ICANS or other clinically significant neurologic AEs were observed. The most common (≥20% all grades) treatment related adverse events (TRAEs) included CRS (66.7%), neutrophil count decreased (63.8%), lymphocyte count decreased (50.7%), anemia (46.4%), platelet count decreased (46.4%), and hypokalemia (40.6%). No patients required a EX103 dose reduction due to AEs.

Conclusions:

EX103 could induce high response rates in heavily pretreated R/R B-NHL patients, including impressive results for those who failed prior CD19 targeting therapies. It also has a favorable safety profile with low rates of severe CRS and without ICANS.