FDA has granted RMAT and fast track designations to cema-cel as a frontline consolidation in large B-cell lymphoma.
The FDA has granted regenerative medicine advanced therapy (RMAT) and fast track designations to off-the-shelf, anti-CD19 chimeric antigen receptor (CAR) T-cell therapy cemacabtagene ansegedleucel (cema-cel) for the treatment of adult patients with large B-cell lymphoma (LBCL) who have a complete response (CR) or partial response (PR) and minimal residual disease (MRD) positivity.1
The RMAT designation was granted following a review of an interim futility analysis from the pivotal phase 2 ALPHA3 trial (NCT06500273), which is evaluating cema-cel as first-line consolidation therapy in patients with high-risk LBCL.
At the protocol-defined data cutoff, evaluable patients in the cema-cel arm (n = 12) achieved an MRD-negativity rate of 58.3% compared with 16.7% in the observation arm (n = 12), resulting in a 41.6% absolute difference in MRD negativity rates between each arm. Moreover, plasma circulating tumor DNA decreased by a median of 97.7% from baseline in the cema-cel arm vs a median increase of 26.6% in the observation arm.
“The FDA’s decision to grant both RMAT and fast track designations provides additional validation for the strategy we defined with the ALPHA3 trial and strengthens our ability to work closely with the agency on an efficient path to advance cema-cel as a first-line consolidation therapy for LBCL,” Zachary Roberts, MD, PhD, president and chief executive officer of Allogene Therapeutics, said in a news release.
The randomized, open-label study enrolled patients who were at least 18 years old, completed first-line chemoimmunotherapy, and achieved a CR or PR.2 Patients also needed to have MRD positivity, an ECOG performance status of 1 or less, and adequate hematological, renal, hepatic, pulmonary, and cardiac function.
If patients had LBCL with central nervous system involvement, received prior anti-CD19 treatments, autoimmune disease, or history of other primary malignancies or bone marrow disorders within 3 years prior, they were not enrolled.
Patients were randomly assigned to receive of cema-cel following fludarabine and cyclophosphamide lymphodepletion, or standard-of-care observation. The interim futility analysis supporting the designation was conducted on the 24th randomly assigned patient completing MRD assessment at day 45.1 MRD status is also assessed at month 3 and every 3 months during the first year of follow-up for the remainder of the study.3
The primary end point of the trial was event-free survival, alongside progression-free survival and overall survival as key secondary end points.
Baseline characteristics revealed that 33% of patients in the cema-cel arm had bone marrow involvement compared with 25% in the observation arm. All patients in the cema-cel arm had stage III to IV disease vs 83% in the observation arm. International Prognostic Index (IPI) scores in the cema-cel arm broke down as 0 to 1 (0%), 2 to 3 (58.3%), and 4 to 5 (41.7%). Rates of IPI scores in the observational arm were 33.3%, 41.7%, 16.7%, and 8.3% for scores of 0 to 1, 2 to 3, 4 to 5, and unknown, respectively.
Cema-cel was well tolerated, with cases of no serious treatment-related adverse effects (TRAEs), cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, graft-vs-host disease, or high-grade infections were reported.1 Additionally, no patients were hospitalized due to any TRAEs.
Notably, any-grade infections occurred in 16.7% of patients in both arms, and half of patients experienced any-grade neurologic AEs in the cema-cel arm vs 8.3% in the observation arm.
“There is a shared goal across the treatment community to reach patients earlier in their disease course and reduce the barriers that limit access to CAR T-cell therapy. The interim ALPHA3 findings, which showed rapid and substantial MRD reduction, with most patients treated in the outpatient setting, support cema-cel’s potential as an off-the-shelf therapy that can be delivered at scale in community settings where approximately 80% of first-line patients receive their care,” Roberts emphasized.
