Preliminary efficacy and safety of Relmacabtagene autoleucel (Carteyva) in adults with relapsed/refractory follicular lymphoma in China: A phase I/II clinical trial

Follicular lymphoma (FL) is an indolent B cell lymphoproliferative disorder and the second most common type of non-Hodgkin lymphoma. The recent development of chimeric antigen receptor (CAR)-T cell therapy has provided a novel and effective treatment strategy for patients with relapsed/refractory (r/r) FL.1, 2 Relmacabtagene autoleucel (relma-cel, also known as Carteyva and JWCAR029) is a second-generation CD19-targeted CAR-T cell with a 4-1BB co-stimulatory domain that was developed in China. A single-arm, multicenter study in China reported that relma-cel achieved a 3-month ORR of 60.3% in patients with r/r diffuse large B-cell lymphoma (LBCL),3 and relma-cel is approved by the National Medical Products Administration (NMPA) for the treatment of r/r LBCL. However, the efficacy, safety and optimal dose of relma-cel in patients with r/r FL has yet to be determined. This study analyzed the r/r FL cohort in dose expansion and subjects in dose escalation administrated with either 100 × 106 or 150 × 106 CAR-T cells of the RELIANCE trial (NCT04089215), which enrolled patients with LBCL or FL at 6 tertiary hospitals in China. The inclusion criteria of r/r FL cohort were as follows: (1) age ≥ 18 years-old; (2) grade 1, 2 or 3a FL confirmed histologically within 6 months; (3) treated with anthracyclines and rituximab (or other CD20-targeted therapies); (4) primary r/r disease within 24 months after at least two lines of therapy or autologous hematopoietic stem cell transplantation; and (5) Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0–1. Full details of the inclusion and exclusion criteria are provided in Supplementary Methods. All subjects underwent leukapheresis for relma-cel preparation (Figure S1A). Bridging therapy including low-dose chemotherapy or targeted therapy was allowed after leukapheresis, and should be completed 7 days before lymphodepletion chemotherapy. The 3-day lymphodepletion chemotherapy regimen (fludarabine 25 mg/m2/day plus cyclophosphamide 250 mg/m2/day) was completed 2–7 days before relma-cel infusion. Patients received relma-cel at a fixed dose of either 100 × 106 CAR-T cells or 150 × 106 CAR-T cells. Dose adjustments were not generally permitted, and any investigator-agreed adjustment was documented. The primary endpoint of the study was complete response rate (CRR) at 3 months assessed by investigator. Other endpoints are presented in the Supplementary Methods. Based on the primary endpoint and under the null hypothesis assumption of 3-month CRR ≤35% for standard therapy in this setting and an alternative hypothesis assumption of 70% 3-month CRR, with the sample size of 26 patients, this study has 94% power and one-sided α of 0.025. Statistical methods are provided in the Supplementary Methods. Among 30 patients with r/r FL screened for enrollment, 24 patients were treated with relma-cel and included in this study. An additional 4 patients were included from the phase I study. Thus, the final analysis included a total of 28 patients with r/r FL (Figure S1B), among which 9 (32.1%) received bridging therapies. No patient had complete response (CR) following bridging therapy before lymphodepleting chemotherapy. Sixteen patients received 100 × 106 CAR-T cells, and 12 patients received 150 × 106 CAR-T cells. The median time from leukapheresis to relma-cel infusion was 34 (range: 24–79) days. One patient treated with relma-cel was diagnosed as a second malignancy (gastric adenocarcinoma). The patient was excluded from the efficacy analysis (n = 27), but included in the safety analysis (n = 28). The median age of the 28 patients was 54 (range: 36–71) years. The baseline characteristics were presented in Table S1. The data cutoff date was December 17, 2021. Among 27 patients in the efficacy analysis, the investigator-assessed 3-month CRR was 85.2% (95% confidence interval [CI]: 66.3%–95.8%) (Figure 1A). The independent review committee (IRC)-assessed 3-month CRR was 81.5% (95% CI: 61.9%–93.7%) and the investigator-assessed 3-month overall response rate (ORR) was 100.0% (95% CI: 87.2%–100.0%) in the entire cohort (Table S2). The investigator-assessed 1-, 6-month and best CRR was 66.7% (95% CI: 46.0%–83.5%), 77.8% (95% CI: 57.7%–91.4%) and 92.9% (95% CI: 76.5%–99.1%), respectively for all patients in the efficacy analysis (Table S2). The time to response was 0.89 (range: 0.76–0.95) month. Among 25 patients with complete response as best response, the time to CR was 0.95 (range: 0.76–12.02) month. The 3-month ORR was 100% in all subgroups and the 3-month CRR was above 60.0% in all subgroups (Figure 1B). With a median follow-up time of 11.7 (range: 5.4–24.7) months, the median duration of response and median progression-free survival were not reached in the overall population or in either of the two dose groups (Figure 1C). No patients died during follow-up. The incidence of treatment-emergent adverse events (TEAEs) was 96.4% in all 28 patients, 93.8% in the 100 × 106 dose group and 100.0% in the 150 × 106 dose group (Table S3). The most common TEAEs were leukopenia (78.6%). The incidence of grade ≥3 TEAEs was 64.3% in the entire cohort. The most common grade ≥3 TEAEs were neutropenia (39.3%). The incidence of relma-cel-related TEAEs was 92.9% in all patients. No patient died due to adverse events. The overall incidence of cytokine release syndrome (CRS) was 42.9% and no patients had CRS of grade ≥ 3. CRS requiring tocilizumab occurred in 17.9% of patients. The median time to CRS occurrence after infusion and the median duration of CRS were 7 (range: 5–9) days and 5 (2–7) days in all patients, respectively. The incidence of neurologic toxicity (NT) was 17.9% in the entire cohort. NT of grade ≥ 3 occurred in one patient administered 100 × 106 CAR-T cells and required treatment with steroids. The median time to the occurrence of NT after infusion and the median duration of NT was 9 (range: 4–9) days and 7 (2–25) days in all 28 patients, respectively. Fifteen patients (53.6%) experienced cytopenia lasting more than 1 month (Table S4). Relma-cel was detectable in vivo between days 4 and 15 after infusion, and the peak concentration occurred between days 7 and 23 after infusion. The average concentration-time curve (Figure S2) and plots of the absolute numbers of CD3+, CD3+CD4+ and CD3+CD8+ CAR-T cells (Figure S3) suggested that the peak levels were broadly similar between dose groups. Sixteen patients (57.19%) reached the lower limit of quantification (BLQ) at days 22–90, whereas 12 patients did not exhibit a decrease to the BLQ level within 90 days. The pharmacokinetics parameters are shown in Table S5. The maximal plasma concentration (Cmax) was 23.44 (range: 0.59–117.31) cells/μl. The time to maximal plasma concentration (Tmax) was 14.5 (range: 7–23) days. The area under the concentration-time curve for days 1–29 (AUC1–29) was 242.2 (range: 5.7–1058.6) × 103 day×copies/μg overall. Subgroup analyses showed that there were no significant differences in Cmax, Tmax, AUC1–29, or AUC1–90 between subgroups based on age or sex (Table S6). The group of patients who experienced CRS had a numerically higher Cmax (non-significant) and significantly higher AUC1–29 (p = 0.020) and AUC1–90 (p = 0.009). The levels of ferritin, C-reactive protein (CRP), interleukin (IL)-6, IL-8, and interferon-gamma (IFN-γ) increased after relma-cel infusion (Figure S4). Notably, patients with grade 1/2 CRS, or grade 1–2 NT exhibited larger increases in the levels of ferritin, CRP, IL-6, IL-8, and IFN-γ than patients without CRS or NT. Furthermore, grade 3 NT was associated with particularly large increases in ferritin, CRP, IL-6, IL-8 and IFN-γ (Table S7). Similarly, the results of the ZUMA-5 trial demonstrated the CRR and ORR of axi-cel in grade 1-3a r/r FL patients were 79% and 94%.1 Meanwhile, the phase 2 ELARA trial recently reported that tisagenlecleucel achieved a CRR of 69.1% and an ORR of 86.2% in patients with grade 1-3a r/r FL.2 The findings of this study, along with the ELARA and ZUMA-5 trial, illustrated the potential benefits of CD19 CAR-T therapy in patients with r/r FL patients. The incidences and types of AEs in this study were comparable with those reported in several previous studies of CAR-T cell therapy,1, 2, 4-6 and no new safety concerns were identified. The incidence of CRS was 42.9% in this study, which was comparable to 42%–48.5%,2, 6 or lower than previously described values of 50%–92%.1, 4, 5 Similarly, the incidence of NT (17.9%) and grade ≥3 NT (3.6%) in this study was lower than previously reported of 30%–67% and 0%–32%, with a similar median time of NT onset.1, 2, 4-6 The results of this phase II trial indicate that fixed doses of relma-cel (100 × 106 cells or 150 × 106 cells) demonstrated promising short-term efficacy and had a favorable safety profile in adults with r/r FL in China. These findings suggest that a fixed dose of relma-cel is a feasible alternative to dosing according to body weight in adult patients with r/r FL. Further studies of CD19 CAR-T cell immunotherapy for patients with r/r FL are warranted to optimize the treatment regimen. Jun Zhu: Project administration, patient enrollment, data acquisition, and article review. Zhitao Ying: Patient enrollment, data acquisition, patient evaluation, and article preparation. Yuqin Song: Data acquisition, statistical analysis, blood sample collection, and patient evaluation. Dehui Zou, Haiyan Yang, Jianqiu Wu, Ye Guo, Wenyu Li, Hui Liu: Patient enrollment and data acquisition. Chris Wang, Laura Ma, Su Yang, Zisong Zhou, and Yun Qin: Project administration and supervision. We thank the participants of this trial and the investigating team at each participating site. The study was sponsored by JW Therapeutics (Shanghai) Co. Ltd. They had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript. Chris Wang, Laura Ma, Su Yang, Zisong Zhou and Yun Qin are employed by JW Therapeutics (Shanghai) Co., Ltd. The other authors declare that they have no competing interests. All data generated or analyzed during this study are included in this published article and its supplementary information files. This study was approved by the Ethics committee of Peking University Cancer Hospital & Institute (Approval No. 2018YW86-ZY04), This study was conducted in conformance with the Good Clinic Practice and adhered to the Declaration of Helsinki. All participants provided written informed consent. The trial was registered with ClinicalTrials.gov (NCT04089215). All data generated or analyzed during this study are included in this published article and its supplementary information files. Appendix S1 Supporting information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.