Relmacabtagene autoleucel (relma-cel) CD19 CAR-T therapy for adults with heavily pretreated relapsed/refractory large B-cell lymphoma in China

Abstract

Background: Despite numerous chimeric antigen receptor T-cell (CAR-T) trials conducted in China, no CAR-T has been registered in the country. Furthermore, China law and regulations restrict the export of patient material for CAR-T manufacture abroad. Relma-cel (JWCAR029), an anti-CD19 product produced with a commercial-ready process in China, was evaluated in the first prospective, single-arm, multicenter, pivotal study of CAR-T therapy conducted under Chinese IND to support an NMPA-accepted BLA submission in relapsed/refractory (r/r) LBCL (NCT04089215).

Methods: Patients were randomized to receive either 100 × 10⁶ (low dose, n = 27) or 150 × 10⁶ (high dose, n = 32) CAR+ T-cells as a single infusion following lymphodepleting chemotherapy (fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² daily × 3), and then, monitored for efficacy and safety outcomes and pharmacokinetics. The primary endpoint was ORR at 3 months, as assessed by the investigators. Secondary endpoints included DOR, PFS, OS, and adverse event frequency/severity and cell expansion kinetics.

Results: As of the data cutoff on 17 June 2020, 68 patients were enrolled, and 59 were treated. Among the 58 efficacy-evaluable patients, the primary endpoint of 3 month ORR was 60.3% (95% CI, 46.6-73.0), excluding the null hypothesis rate of 20%. Any grade and severe grade CRS occurred in 47.5% and 5.1%, respectively, and any grade and severe grade neurotoxicity events occurred in 20.3% and 5.1%.

Conclusions: Relma-cel met the primary endpoint analysis and demonstrated a high rate of durable responses and low rate of CAR-T-associated toxicities in patients with r/r LBCL in a multicenter trial supporting regulatory submission in China.

Keywords: CAR-T; CD19; LBCL; Relma-cel; cellular kinetics.

FIGURE 1

The study schema for RELIANCE Trial demonstrates the sequential phases for enrolled patients including screening phase, pretreatment phase, and treatment and study follow‐up phase. D, day; M, month; Y, year.

FIGURE 2

Patients screening, enrollment and treatment. Ninety patients were screened, 68 apheresed, and 59 treated. Among the six patients who were not received relma‐cel, one died before infusion, five withdraw. *One patient, excluded from efficacy analysis set, received relma‐cel infusion that did not meet potency threshold criterion, but achieved CR by D29 that continued for more than 1 year.

FIGURE 3

Efficacy assessed by investigators. A, BOR evaluation among the 58 patients who received relma‐cel infusion, an anti‐CD19 chimeric antigen receptor T‐cell therapy (ORR defined as CR plus PR). B, Forest plot showing the result of ORRs. CI=confidence interval. C, Kaplan–Meier curve of DOR among 44 patients, PFS and OS in the 58 patients. DOR, Time from the date of first documented disease response (CR or PR) to the date of first documented PD or death due to LBCL. PFS, Time from the date of relma‐cel infusion to the date of PD or death from 58 patients. OS, time from the date of relma‐cel infusion to the date of death. D, The change of tumor volume from the baseline according to SPD in 55 evaluable cases. The other four cases were excluded because they had clinical disease progression prior to the 1 month restaging assessments. The vertical axis indicates best percent changes from the baseline after relma‐cel infusion for 6 month. Patients are indicated on the horizontal axis. Negative values in the vertical axis indicate tumor volume decrease from the baseline. NA, Not Available.

FIGURE 4

Cell Kinetic. A, CAR‐T expansion and persistence in peripheral blood were assessed via qPCR and flow cytometry on days 1, 2, 3, 4, 8, 11, 15, 22, and 29, monthly up to 3 months, every 3 months up to 1 year, then, every 6 months up to 2 years post infusion. The mean values were presented in the plots. B, The analysis of cellular kinetics exposure parameters (Cmax, AUC_1‐29) for tocilizumab or steroid use. (N1: the number of subjects within the specific subgroup; n: the number of response subjects within the specific subgroup). C, The comparison of peak cytokines (IFN‐γ and TNF‐α) in patients with different therapeutic outcomes (OR/non‐OR and CR/non‐CR). D, The mean of absolute counts of CD3+CAR+, CD3+CD4+CAR+, and CD3+CD8+CAR+ over time from PB in total patients. IFN‐γ, Interferon gamma; TNF‐α, tumor necrosis factor alpha.

FIGURE 5

Analysis of serum biomarkers (CAR‐T expansion and Cytokines) associated with CRS/NT classified as none, grade 1–2 and grade ≥3 (**p < 0.01, ***p < 0.001). A, The comparison of AUC_1‐29 and CRS/NT. B, The comparison of Cmax and CRS/NT. C, comparison of peak measured serum IL‐6 levels and CRS/NT. CRS, cytokine release syndrome; NT, neurotoxicity, IL‐6, Interleukin‐6. p‐values were calculated by means of the Wilcoxon rank‐sum test.