Phase Ⅱ Study of Fully Human BCMA-Targeting CAR-T Cells (Zevorcabtagene Autoleucel) in Patients with Relapsed/Refractory Multiple Myeloma

Background: Zevorcabtagene autoleucel (Zevor-cel, CT053), a fully human autologous anti- B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell, is under investigation in patients (pts) with relapsed/refractory multiple myeloma (RRMM) of an ongoing phase 1/2 study, LUMMICAR STUDY1 (NCT03975907) in China. Results from the phase 1 LUMMICAR STUDY1 indicated that Zevor-cel is well tolerated with encouraging efficacy of an overall response rate (ORR) of 100% and very good partial response or better (≥VGPR) rate of 92.9% in 14 pts evaluated by investigators. Here we report for the first time the safety and efficacy data from the phase 2 pivotal study of LUMMICAR STUDY1.

Methods: All patients had received ≥3 prior lines of therapies, including at least an immunomodulatory drug and a proteasome inhibitor regardless exposure to an anti-CD38 antibody. All subjects were relapse or refractory to the last line of therapy. After lymphodepletion (fludarabine at 25mg/m² and cyclophosphamide at 300 mg/ m² daily for 3 consecutive days), patients received a recommended phase 2 dose (RP2D) of 1.5 ×10⁸ Zevor-cel （permit 1.8×10⁸ Zevor-cel when body weight over 80 kilogram). Disease response was evaluated by independent review committee (IRC) per the IMWG 2016 criteria. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). Minimal residual disease (MRD) was tested by next-generation flow cytometry on bone marrow aspirates by the EuroFlow assay at a minimum sensitivity of 10^-5. CAR copies in the patient peripheral blood were monitored by quantitative real-time polymerase chain reaction (qPCR).

Results: Between December 1^st, 2020, and March 2^nd, 2022, 102 eligible patients received Zevor-cel . Among them, the median age was 59.5 years (38 to 75) and the median prior lines of therapy were 4 (3 to 15). 24 (23.5%) patients ever received auto-ASCT, 91 (89.2%) patients were double refractory, and 23 (22.5%) patients were triple refractory. 39 (38.2%) patients had stage III disease at screening according to International Staging System, 7 (6.9%) patients had extramedullary disease (EMD), and 46 (45.1%) patients had high-risk cytogenetic abnormality, defined as del(17p), t(4;14), t(14;16), or t(14;20).

At the time of data cutoff (March 30, 2022), 102 patients had at least 1 month safety data and 83 patients had at least 3 months efficacy follow-up. Of the 83 patients, with a median follow-up of 227 (11,437) days, the overall response (partial response [PR] or better) rate per IRC was 92.8% (95%CI, 84.9-97.3), complete response/ stringent complete response (CR/sCR) rate was 42.2% (95%CI, 31.4-53.5), and the rate of very good partial response (VGPR) and above was 81.9% (95%CI, 72.0-89.5). The median progression-free survival (PFS) was not reached, and the 6-month PFS rate was 90.2% (95%CI, 80.4-95.2). The median duration of objective response (DoR) was not reached, and the probabilities of the responders remaining in response at 6 months were 92.2% (95% CI,80.1-97.1). MRD status was assessed in patients achieving VGPR and better. MRD negative (<10⁻⁵ nucleated cells) was confirmed in 95.2% CR/sCR patients and in 88.3% VGPR and better patients respectively.

CRS was reported in 92 patients (90.2%), including 7 (6.9%) who had events of grade 3/4, and all grade 3 or 4 CRS were fully recovered. ICANS developed in 2 (2%) patients and both were of grade 1, no neurotoxic effects of grade 3 or higher occurred. Frequently reported treatment related adverse events including hypogammaglobulinemia (23.5%) and pneumonia (24.5%) were manageable and reversible. Four deaths occurred in the study and none due to treatment related adverse events.

The CAR copies were detected at serial points after infusion. The median time of Zevor-cel CAR copies reaching peak was 14 days (3-22 days) and the median time of persistence was 77 days (3-283 days), with detectable CAR copies in 44% (20/45) patients at 6 months after infusion.

Conclusions: These preliminary data demonstrate that targeting BCMA with Zevor-cel results in deep and durable responses in patients with r/r MM.

A well-tolerated safety profile similar to other BCMA targeting cell therapy was established.

Yuan:CARsgen Therapeutics Corp: Current Employment. Zhao:CARsgen Therapeutics Corp: Current Employment. Xiao:CARsgen Therapeutics Corp: Current Employment. Wang:CARsgen Therapeutics Corp: Current Employment. Wang:CARsgen Therapeutics Corp: Current Employment, Current equity holder in publicly-traded company. LI:CARsgen Therapeutics Corp: Current Employment, Current equity holder in publicly-traded company.