ALPHA2/ALPHA Trials: Cema-Cel Shows Promising Results in LBCL

Cemacabtagene ansegedleucel (cema-cel) showed promising survival and responses with manageable safety in patients with relapsed or refractory large B-cell lymphoma (LBCL), according to results of the ALPHA2/ALPHA studies published in the Journal of Clinical Oncology.

The phase 1/2 ALPHA2 study evaluated cema-cel after ALLO-647–containing lymphodepletion, and the phase 1 ALPHA study evaluated cema-cel’s predecessor, ALLO-501, after ALLO-647–containing lymphodepletion. The patients were combined in an analysis of efficacy, safety, and pharmacokinetics/pharmacodynamics led by Frederick L. Locke, MD, a medical oncologist and translational researcher at the Moffitt Cancer Center.

“Since the FDA approval of the first autologous CAR [chimeric antigen receptor] T-cell therapy for large B-cell lymphoma in 2017, there has been major interest in developing allogeneic CAR T-cell therapy approaches to address the many limitations of autologous CAR T products including the expensive and time-consuming process required to generate a CAR T product for each patient, the frequent generation of a poor-quality CAR T-cell product due to dysfunctional T cells in the starting material harvested from the patient, and the limited access to these therapies,” Sattva Neelapu, MD, senior author of the study and a professor in the Department of Lymphoma/Myeloma at the MD Anderson Cancer Center, told Blood Cancers Today.

Eighty-seven patients (median age, 66 years) were included in the analysis. Eligible patients had relapsed or refractory LBCL after 2 or more lines of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and at least 1 measurable lesion per the revised International Working Group Response Criteria for Malignant Lymphoma.

Patients received lymphodepletion conditioning for 3 days with fludarabine (30 mg/m² per day), cyclophosphamide (300 or 500 mg/m² per day), and varying doses of ALLO-647. Patients in the single-dose cohort received a single dose of cema-cel/ALLO-501 (120 × 10⁶ CAR+ cells), but patients in consolidation cohorts who achieved a complete response (CR), partial response (PR), or stable disease at day 28 were eligible for an additional dose.

Efficacy and Safety

At a median follow-up of 10.1 months, the overall response rate (ORR) was 58% and the CR rate was 42%. Among those who received the selected phase 2 regimen (90 mg of ALLO-647 plus a single dose of cema-cel), 67% had disease response and 58% achieved a CR.

The ORR was higher in those with baseline tumor burden of less than 1,000 mm² sum of the products of longest diameters (SPD; 100% vs 50%), baseline lactate dehydrogenase (LDH) lower than the upper limit of normal (ULN) (91% vs 41%), and double- or triple-hit LBCL compared with those without (75% vs 52%). The CR rate was also higher in those with baseline tumor burden of less than 1,000 mm² SPD (100% vs 31%; P=0.0033) and LDH lower than ULN (82% vs 23%; P=0.0023).

The median progression-free survival was longer in patients who achieved a CR compared with that of the overall population (24.0 months vs 3.9 months, respectively). The median overall survival (OS) was 14.4 months for the overall population and not reached among those who achieved a CR. For those who received the selected phase 2 regimen, the median duration of response was 23.1 months, and the median OS was not reached.

The most common grade 3 or higher treatment-emergent adverse events were neutropenia (82%), anemia (46%), and thrombocytopenia (42%). Cytokine release syndrome occurred in 24% of patients, and events were grade 2 or lower. No cases of immune effector cell–associated neurotoxicity syndrome, dose-limiting toxicities, or graft-vs-host disease were reported.

“In this study, we show for the first time that allogeneic off-the-shelf CD19-targeting CAR T-cell therapy is feasible and can induce durable responses in patients with large B-cell lymphoma with a manageable safety profile. Importantly, these benefits were observed with a single infusion of allogeneic CAR T cells similar to autologous CAR T-cell strategies,” Dr. Neelapu told Blood Cancers Today.

ALPHA3 Trial

The ongoing ALPHA3 clinical trial is evaluating cema-cel in patients with newly diagnosed LBCL in the first-line setting.

“What sets this trial apart is its potential to predict and prevent disease relapse through minimal residual disease (MRD) detection,” Dr. Locke told Blood Cancers Today. “If a patient tests MRD positive, they have the opportunity to be treated with a single dose of cema-cel, potentially consolidating their response and offering a chance to be cured. This innovative approach could be a game changer for how we treat the disease, as 1 in 3 patients are expected to relapse after standard first-line treatment.”

Reference

Locke FL, Munoz JL, Tees MT, et al. Allogeneic CAR T cell products cemacabtagene ansegedleucel/ALLO-501 in relapsed/refractory large B-cell lymphoma: phase 1 experience from the ALPHA2/ALPHA clinical studies. J Clin Oncol. Published online February 13, 2025. doi:10.1200/JCO-24-01933