Poseida Therapeutics’ Allogeneic CAR-T P-BCMA-ALLO1 Demonstrates 91% ORR in Enhanced Lymphodepletion Arm of R/R MM Study
The ORR in the enhanced lymphodepletion arm was 100% in patients who had not previously received an antiBCMA therapy.
Poseida Therapeutics’ P-BCMA-ALLO1, an allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, has generated positive data, including a 91% overall response rate (ORR) in an enhanced lymphodepletion arm, in interim data from a phase 1/1b clinical trial (NCT04960579) in relapsed/refractory (r/r) multiple myeloma (MM).1
Among 72 patients in total who were treated across 4 study arms, which were based on different dose level and lymphodepletion regimen combinations, an ORR of 54% was recorded as of the September 6, 2024 data cutoff. Poseida noted that complete responses (CRs) or stringent CRs (sCRs) were seen in 11% of patients and very good partial responses or better were seen in 33% of patients.
The study arms include arm A (cyclophosphamide 500 mg/m2/day), arm B (cyclophosphamide 1,000 mg/m2/day), arm C (cyclophosphamide 750 mg/m2/day), and arm S (cyclophosphamide 300 mg/m2/day). For the 2 arms that had at least 6 months of follow-up (arms A and B), the median duration of response was 232 days. Poseida pointed out that none of the patients treated in the trial necessitated antimyeloma bridging therapy and that the median time for enrollment to initiation of treatment was 1 day.
Arm C, which was determined to be the optimized lymphodepletion arm via assessment of cellular kinetics, safety, and efficacy, treated 23 patients in total with each patient receiving approximately 2x106 cells/kg of P-BCMA-ALLO1 following a lymphodepletion regimen that comprised cyclophosphamide 750 mg/m2/day and fludarabine 30 mg/m2/day. The ORR in arm C was 91%, 100% in patients who had not previously received an antiBCMA therapy, 86% in patients who had previously received antiBCMA CAR-T or T-cell engager therapy, and 86% in patients who had previously received antiBCMA therapy and/or talquetamab. Furthermore, the CR rate in arm C was 22%, including sCRs. Very good partial responses or better were reported in 48% of patients.
In terms of safety for arm C, 39% of patients experienced grade 1 to 2 cytokine release syndrome (CRS) and 13% of patients experienced grade 1 to 2 immune effector cell neurotoxicity syndrome (ICANS). There were no dose-limiting toxicities, no grade 3 or higher CRS, and no grade 3 or higher ICANS. Grade 1-2 infections occurred in 30% of patients and grade 3 infections occurred in 17% of patients. Poseida noted that in the “vast majority of cases” cytopenia recovery was rapid. There were no instances of graft versus host disease, hemophagocytic lymphohistiocytosis, Parkinsonism, or cranial neuropathies. The company stated that the safety findings in arm C were consistent with those of the study’s other arms.
"The compelling and differentiated results from the optimized lymphodepletion arms of the ongoing phase 1 trial of P-BCMA-ALLO1 showed deep responses and a high response rate in patients with heavily pre-treated relapsed or refractory multiple myeloma, regardless of prior exposure to B-cell maturation antigen (BCMA)-targeting therapy,” study investigator Bhagirathbhai R. Dholaria, MD, an associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center, said in a statement.1 “The high ORR of 91% is remarkable because most study participants in my center had rapidly proliferative refractory disease, in contrast with those treated in the pivotal clinical trials of FDA-approved autologous CAR-T therapies. Such patients treated in the current trial of P-BCMA ALLO1 would not have qualified for standard of care autologous CAR-T therapy. All patients in the phase 1 trial have been treated quickly once enrolled, with no waiting for manufacturing, with no need for apheresis or bridging therapy, demonstrating key advantages of allogeneic CAR-T cell therapy.”
It was noted that 48% of the patients in arm C were 65 years of age or older and that the median number of prior lines of antimyeloma therapy was 6. Furthemore, 62% of the patients had previously been treated with antiBCMA therapy, 29% of patients had unsuccessful treatment with both a prior antiBCMA CAR-T and a bispecific T-cell engager, and 29% of patients had unsuccessful treatment with both a prior antiBCMA therapy and talquetamab. High-risk disease, assessed via cytogenetics, was seen in 62% of the patients at baseline, with 38% of patients having extramedullary disease.
Less than a month ago, P-BCMA-ALLO1 was granted regenerative medicine advanced therapy (RMAT) designation from the FDA for the treatment of adults with multiple myeloma (MM) whose disease is relapsed/refractory (r/r) following at least 3 previous lines of treatment that included a proteasome inhibitor, an immunomodulatory agent, and an antiCD38 antibody.2 P-BCMA-ALLO1 is comprised of T-cells, rich in stem cell memory T-cells (TSCM), that are genetically modified to target B-cell maturation antigen (BCMA) with a VH-based binder. The subject of a strategic collaboration agreement between Poseida and Roche that was established in 2022, the CAR-T product has previously received orphan drug designation from the FDA for MM.2,3
"Today, far too many patients are unable to benefit from autologous CAR-T therapy due to its limited supply, lengthy timelines, complex logistics, and cost," Kristin Yarema, PhD, the president and chief executive officer of Poseida Therapeutics, said in a December 2023 statement regarding an earlier data update from the trial.4 "We have long believed that readily produced, off-the-shelf allogeneic, TSCM-rich CAR-T products have the potential to offer a compelling efficacy and safety profile while also supporting patient access. TSCM-rich CAR-T products can be difficult to produce with older virus-based technology, but we are able to create a portfolio of such products using Poseida's unique, nonviral set of technologies. We see these early P-BCMA-ALLO1 results in MM, in which all enrolled patients received CAR-T therapy and most patients receiving adequate lymphodepletion achieved a sCR or very good partial response, as validating our vision and eagerly await additional data yet to come from this study. This is also the first known publicly presented data set that provides clear clinical evidence supporting the hypothesis that TSCM cells are the ideal cell type for allogeneic CAR-T, extending our previous findings with autologous TSCM cells to the allogeneic setting.”
