Cema-Cel Induces CRs and Has Manageable Safety Profile in CD19 CAR T-Cell Therapy–Naive R/R LBCL

Treatment with the next-generation allogeneic CAR T-cell product cemacabtagene ansegedleucel (cema-cel; formerly ALLO-501/A) had a manageable safety profile and generated responses comparable with those seen with approved autologous CD19-directed CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL) without prior exposure to CD19-directed CAR T-cell therapy.1,2

Findings from a joint analysis of the phase 1 ALPHA (NCT03939026) and phase 2 ALPHA2 (NCT04416984) studies published in the Journal of Clinical Oncologyshowed that among 33 evaluable patients, the overall response rate (ORR) was 58% (95% CI, 39.2%-74.5%), and the complete response (CR) rate was 42% (95% CI, 25.5%-60.8%).1Furthermore, the median duration of response (DOR) was 11.1 months (95% CI, 3.1-not reached [NR]) for all patients; for patients who achieved a CR, the median DOR was 23.1 months. Most CRs were durable. The median progression-free survival was 3.9 months (95% CI, 1.9-6.1) for all patients and 24.0 months (95% CI, 4.5-not evaluable [NE]) among complete responders. The median overall survival (OS) was 14.4 months (95% CI, 7.0-NR) in all patients and NE (95% CI, 22.2 months-NE) for complete responders.

All treatment regimens studied demonstrated clinical benefit.2However, 67% (95% CI, 34.9%-90.1%) of patients receiving the selected phase 2 regimen (n = 12) experienced a response.1 CRs were achieved in 58% (95% CI, 27.7%-84.8%) of these patients, the median DOR was 23.1 months (95% CI, 1.0-NR), and the median overall survival (OS) was NR (95% CI, 4.6 months-NR). The recommended phase 2 regimen consisted of fludarabine/cyclophosphamide lymphodepletion with 90 mg of the anti–CD52 antibody ALLO-647 followed by a single dose of at least 120 × 106 CAR-positive cells.

“Publication of the phase 1 ALPHA/ALPHA2 trials in relapsed/refractory LBCL marks a landmark moment for the field. These findings represent the most robust allogeneic CAR [T-cell therapy] experience yet presented and show, for the first time, that an ‘off-the-shelf’ CAR T can induce durable CRs in a large fraction of patients with heavily pretreated LBCL,” Frederick L. Locke, MD, lead study investigator and chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center and Research Institute, stated in a news release.2 “These peer-reviewed results highlight how cema-cel development is on the cutting edge of lymphoma care, particularly with the [phase 2] ALPHA3 trial [NCT06500273] targeting only those patients who are minimal residual disease [MRD] positive at the end of first-line treatment. If successful, ALPHA3 and cema-cel could transform the treatment paradigm for newly diagnosed patients.”

Notably, in June 2022, the FDA granted regenerative medicine advanced therapy designation to cema-cel for relapsed/refractory LBCL.

Overview of ALPHA and ALPHA2

The ALPHA and ALPHA2 studies were single-arm, multicenter, open-label, phase 1/2 trials evaluating cema-cel in patients with relapsed/refractory non-Hodgkin lymphoma (NHL). Due to product similarities, data from both studies were combined in 1 analysis. As of the September 26, 2024, data cutoff, 87 heavily pretreated patients with relapsed/refractory NHL were treated on these trials between May 2019 and September 2022.1

The current analysis focused on 33 patients naive to CD19-directed CAR T-cell therapy with a diagnosis of relapsed/refractory LBCL per 2017 World Health Organization criteria, following 2 or more prior lines of chemotherapy, including an anti-CD20 monoclonal antibody and an anthracycline.1 Other eligibility criteria included 1 or more measurable lesions per the revised International Working Group Response Criteria for Malignant Lymphoma; an ECOG performance status of 0 or 1; adequate organ function; and no previous exposure to CD19-directed CAR T-cell therapy or another engineered adoptive cellular therapy. Notably, human leukocyte antigen (HLA) haplotype was not an eligibility criterion, and no attempt was made to match patients to a specific product lot based on HLA compatibility.

Upon enrollment, patients underwent a 3-day lymphodepletion regimen of 30 mg/m² of fludarabine daily, 300 mg/m² or 500 mg/m² of daily cyclophosphamide, and cumulative doses of ALLO-647 at 39 mg (n = 5), 60 mg (n = 16; including patients who received consolidation [n = 8]), and 90 mg (n = 12). Bridging therapy was not permitted. Patients in the single-dose cohorts received a single infusion of cema-cel/ALLO-501 at a dose of 120 × 10⁶ CAR-positive cells on day 0. Patients in consolidation cohorts who achieved a CR, partial response, or stable disease at the day 28 assessment were eligible for a second infusion of cema-cel on day 30, following a 30-mg dose of ALLO-647 lymphodepletion on day 29.

The primary end points of ALPHA/ALPHA2 were to determine the maximum tolerated dose and the recommended phase 2 dose of cema-cel and ALLO-647. Secondary end points included safety, pharmacokinetics/pharmacodynamics, and investigator-assessed ORR with cema-cel.

The median age among these patients was 66 years (range, 31-76), and the median number of prior regimens was 3 (range, 2-8). The median follow-up time from patient end of study date or the data cutoff date was 10.1 months (range, 0.4-62.7), and the minimum potential follow-up time was 24 months. The median time from enrollment to initiation of study treatment for this patient population was 2 days. Study investigators noted that, in comparison, wait times for autologous CAR T-cell products often exceed 1 month despite improvements in manufacturing and supply chains.

Additional Efficacy and Safety Data

ORRs were higher in patients with a baseline tumor burden of less than 1000 mm2 sum of the products of longest diameters (SPD) vs greater than 1000 mm2 SPD (100% vs 50%); those displaying baseline lactate dehydrogenase (LDH) levels lower than the upper limit of normal (ULN) vs greater than ULN (91% vs 41%); and those with vs without double-/triple-hit disease (75% vs 52%). CR rates were also increased for patients with lower baseline tumor burden vs higher burden (100% vs 31%, P = .0033) and baseline LDH levels lower than vs at least as high as the ULN (82% vs 23%, P = .0023).

The most common reasons for study discontinuation were death (48%) and consent withdrawal (12%).

Cema-cel was associated with a manageable safety profile, with no dose-limiting toxicities, graft-vs-host disease, or immune effector cell–associated neurotoxicity syndrome. Cytokine release syndrome occurred in 24% of patients, but no grade 3 or higher cases were reported.2

The most common any-grade treatment-emergent adverse effects (TEAEs) included neutropenia (85%), anemia (67%), thrombocytopenia (58%), infusion-related reactions (IRRs; 58%), fatigue (52%), pyrexia (49%), nausea (39%), lymphopenia (36%), hypotension (36%), peripheral edema (33%), decreased white blood cell (WBC) count (30%), cytomegalovirus (CMV) reactivation (30%), decreased appetite (30%), chills (30%), and hypoxia (27%).

Grade 3 or higher TEAEs occurred in 94% of patients, with neutropenia (82%), anemia (46%), thrombocytopenia (42%), lymphopenia (33%), and decreased WBC count (30%) being the most common.1 

Grade 3 or higher IRRs were reported in 9% of patients; all were deemed related to ALLO-647. Any-grade infections occurred in 58% of patients, with 15% of patients experiencing grade 3 or higher infections. Opportunistic infections were uncommon, with isolated cases of fungal and BK virus infections.

The proportion of patients with ongoing grade 3 or higher cytopenias decreased from 30% at day 28 to 18% at day 56. The median times to recovery of grade 3 or higher absolute neutrophil count and absolute lymphocyte count were 7 days (n = 30) and 17.5 days (n = 22), respectively. B-cell recovery was observed starting at 4 months post-treatment in responders, and T-cell counts returned to baseline between 6 and 9 months after infusion. Hypogammaglobulinemia was reported in 15% of patients, with 1 patient requiring intravenous immunoglobulin.

Serious TEAEs occurred in 42% of patients, with IRRs to ALLO-647 (6%), pyrexia (6%), bacteremia (6%), CMV reactivation (6%), pneumonia (6%), and COVID-19 (6%) being the most common. Two patients (6%) with progressive disease died due to TEAEs (respiratory failure and torsade de pointes, n = 1 each); neither death was considered related to cema-cel or ALLO-647.

Together, these findings support the ongoing ALPHA3 trial, which is evaluating cema-cel as consolidation therapy for patients with LBCL who achieve remission following first-line treatment but remain MRD positive. Initiated in June 2024, ALPHA3 is the first trial to investigate CAR T-cell therapy as part of a first-line consolidation strategy for LBCL, Allogene stated in their news release.2

“With multiple patients in ongoing CRs beyond 4 years, the lingering question of whether an allogeneic CAR T could deliver durable responses has now been answered,” Zachary Roberts, MD, PhD, executive vice president of Research and Development and chief medical officer of Allogene, concluded. “Furthermore, these results provide potent evidence supporting the use of CAR T in patients with low disease burden and the unique opportunity for the ALPHA3 trial to achieve something novel in this disease—predict and intervene before relapse. Opportunities to redefine the standard of care in oncology are rare, but if successful, ALPHA3 has the potential to achieve precisely that.”

References

1. 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
2. Allogene Therapeutics announces publication of durable response data from phase 1 ALPHA/ALPHA2 trials of the allogeneic CAR T cemacabtagene ansegedleucel/ALLO-501 in relapsed/refractory large B-cell lymphoma in the Journal of Clinical Oncology. News Release. Allogene. February 14, 2025. Accessed March 4, 2025. https://www.biospace.com/press-releases/allogene-therapeutics-announces-publication-of-durable-response-data-from-phase-1-alpha-alpha2-trials-of-the-allogeneic-car-t-cemacabtagene-ansegedleucel-allo-501-in-relapsed-refractory-large-b-cell-lymphoma-in-the-journal-of-clinical-oncology