Updated Phase 1 Results of a First-in-Human Open-Label Study of Lcar-B38M, a Structurally Differentiated Chimeric Antigen Receptor T (CAR-T) Cell Therapy Targeting B-Cell Maturation Antigen (Bcma)
Authors: Chen Lijuan , Xu Jie , Fu Weijun , Jin Shiwei , Yang Shuangshuang , Yan Sun , Wu Wen , Liu Yuanfang , Zhang Wu , Weng Xiangqin , Wang Yan , WANG Jin , Ding Xiaoyi , Li Biao , Zhu Jiang , Chen Zhu , Fan Frank Xiao-Hu , Li Jianyong , Hou Jian , Chen Sai-Juan , Mi Jian-Qing 
Published: November 2019

Background:
LCAR-B38M is a structurally differentiated CAR-T cell therapy containing 2 BCMA-targeting single-domain antibodies designed to confer avidity. LEGEND-2 (NCT03090659) is an exploratory study using LCAR-B38M CAR-T cells for the treatment of patients (pts) with relapsed or refractory (R/R) multiple myeloma (MM). Key eligibility criteria included R/R MM ³3 prior lines of therapy. Earlier results from LEGEND-2 showed encouraging overall efficacy and manageable safety (N=74). Here, we present updated results of LCAR-B38M in 17 R/R MM pts published in PNAS (Xu J et al. Proc Natl Acad Sci USA. 2019;116:9543-9551), with a median follow-up of 22 months, from 3 sites: Jiangsu Provincial People's Hospital, Nanjing (JS); Ruijin Hospital, Shanghai (RJ); and Changzheng Hospital, Shanghai (CZ).
Methods:
Different sites adopted different lymphodepletion and dosing regimens. Eight pts (age, 18-75 years) with R/R MM received a lymphodepletion regimen of cyclophosphamide (Cy) 250 mg/m2 + fludarabine (Flu) 25 mg/m2, intravenously daily for 3 days (RJ and CZ), while 9 pts received Cy 300 mg/m2 intravenously daily for 3 days (JS). CAR-T cells were administered via 3 infusions (day 0, 3, and 6; n=8, RJ and CZ) or 1 infusion (day 0; n=9, JS) 5 days after lymphodepletion. Response was assessed per the International Myeloma Working Group criteria, adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03, and cytokine release syndrome was graded using CARTOX criteria (Neelapu SS et al. Nat Rev Clin Oncol. 2018;15:47-62).
Results:
Overall, 17 pts were enrolled. The mean dose was 0.7x106 (range, 0.2-1.5x106) CAR+ T cells/kg.
The most common adverse events observed were cytokine release syndrome (100%; grade 1/2 [n=10]; grade 3 [n=6]; grade 5 [n=1]); cytopenia (82%; grade 1/2 [n=4]; grade 3 [n=5]; grade 4 [n=5]); and liver toxicity: 100%; elevated alanine aminotransferase (41%; grade 1/2 [n=7]; grade ≥3 [n=0]), elevated aspartate aminotransferase (94%, grade 1/2 [n=11]; grade 3 [n=5]), and elevated bilirubin (6%, grade 3 [n=1]). Tumor lysis syndrome was reported in 3 pts (18%) and no neurotoxicity was reported.
The overall best response rate (partial response or better) was 88% (95% confidence interval [CI], 64-99). Complete response (CR) was achieved by 14 pts (82%; 62-99), and very good partial response by 1 pt (6%; 6-18). All of the 14 pts with CR were minimal residual disease negative (MRD-neg, by 8-color flow cytometry). The median time to first response was 1.0 months.
At the July 20, 2019 data cutoff (median follow-up, 22 months [95% confidence interval, 16-23]), 6 (38%) pts remain progression-free. The median progression-free survival (PFS) for all-treated pts was 12 months (12-NE); median PFS for MRD-neg pts with CR was 18 months (13-NE). The median overall survival has not yet been reached (NE [12-NE]). At 18 months, 65% (39-90) of all-treated pts and 79% (54-99) of MRD-neg pts with CR were still living.
In a post-hoc analysis, PFS was longer in pts at the RJ and CZ sites than in those at the JS site. Relapse occurred in 8/9 pts at the JS site, while relapse or progressive disease occurred in 2/7 evaluable pts at the RJ and CZ sites. In addition, 5/7 (71%) RJ/CZ pts remained stable in sCR (median follow-up, 745 days). Key differences between these sites included lymphodepletion regimens and the number of CAR-T infusions.
Conclusions:
LCAR-B38M has a safety profile consistent with other BCMA-targeted CAR-T cell therapy. This exploratory study has provided key evidence that LCAR-B38M may be a highly effective therapy for pts with R/R MM. It demonstrated deep and durable responses, particularly following Cy/Flu lymphodepletion. Although the sample size is too small to draw firm conclusions and multiple other factors may contribute, these outcomes suggest that different lymphodepletion regimens may contribute to differences in long-term efficacy.
The study is ongoing for long-term safety and follow-up. A phase 1b/2 clinical study is ongoing in the United States (CARTITUDE-1, NCT03548207, JNJ-4528), and a phase 2 confirmatory study is ongoing in China (CARTIFAN-1, NCT03758417, LCAR-B38M). Pts in both of these studies will undergo Cy/Flu lymphodepletion and 1 single infusion of drug product.

Disclosures
Xu: National Natural Science Foundation of China: Other: Grants; Shanghai Rising-Star Program: Other: Grants; Shanghai Excellent Youth Medical Talents Training Program: Other: Grants.