ASH 2018：LCAR-B38M update
955 Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a Chimeric Antigen Receptor T Cell Therapy Directed Against B-Cell Maturation Antigen, in Patients with Relapsed/Refractory Multiple Myeloma
反正是在西安的数据，也不是严格的clinical trial，看看无妨，不下结论，也拒绝直接横向比较。
LCAR-B38M是一个双特异性的CAR-T，scFv识别并结合BCMA上的两个表位，相比其他靶向BCMA的CAR有着更高的结合能力。17年ASCO上就报道过早期的令人鼓舞的研究结果，现在更新下安全性和疗效。
LCAR-B38M is a bispecific chimeric antigen receptor T cell (CAR T) therapy directed against B-cell maturation antigen (BCMA). The bi-epitope BCMA binding moieties confer high avidity binding and distinguish LCAR-B38M from other BCMA CAR constructs. Preliminary results of LCAR-B38M in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM) showed encouraging efficacy and manageable safety (Fan et al. JCO 2017;35:18_suppl LBA3001). Here we present updated safety and efficacy results of the trial.
正文
LEGEND-2 (NCT03090659)是一项正在进行中的单臂开放多中心1期研究评估LCAR-B38M治疗18-80岁的复发或难治多发性骨髓瘤患者中的研究。环磷酰胺300mg/m^2在day-5、-3和-2分三次清除淋巴细胞，清除5天后分三次输注LCAR-B38M CAR T 细胞 (median CAR+ cell dose = 0.5x10^6 cells/kg, [range, 0.07–2x106]) ，分别总剂量的20%、30%和50%。主要终点评估安全性，次要终点评估骨髓瘤的应答。这次的分析结果来自单个中心，也就是西交大二附院。
LEGEND-2 (NCT03090659) is an ongoing phase 1, single-arm, open-label multicenter study evaluating LCAR-B38M in pts (18–80 years) with R/R MM. Lymphodepletion was performed using 3 doses of cyclophosphamide 300 mg/m2 on days -5, -4, and -3. Five days after lymphodepletion, LCAR-B38M CAR T cells (median CAR+ cell dose = 0.5x106 cells/kg, [range, 0.07–2x106]) were given in 3 infusions (20, 30, and 50% of total dose). The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the anti-myeloma response of the treatment. Adverse events (AEs) were graded using the Common Terminology Criteria for AE, v.4.03, and cytokine release syndrome (CRS) was assessed according to Lee et al. (Blood 2014;124:188-95). Response was evaluated using International Myeloma Working Group criteria. This analysis presents data from a single institution.
截止18年6月25日57名患者输注了LCAR-B38M CAR T 细胞，中位年龄54，先前接受治疗的中位次数是3（这个少于国外同类，大家懂的，ASCT不普及外加之前至少临床开展的时候很多人用不起来那度胺和硼替佐米等进口药），74%患者处在Durie-Salmon分期的第3阶段。中位随访间隔12个月。
As of June 25, 2018, 57 pts have been infused with LCAR-B38M CAR T cells. The median age was 54 years (range, 27–72), median number of prior therapies was 3 (range, 1–9), and 74% of pts had stage III disease by Durie-Salmon staging. The median duration of follow-up for all pts was 12 months (range, 0.7–25).
所有患者都报道有，最常见的：发热 (91%), CRS (90%), 血小板减少(49%), 和白细胞减少（47%)。65%患者中报道发生≥3 级AEs，最常见：白细胞减少 (30%), 血小板减少 (23%)和AST升高 (21%)。
CRS 通常为1级(47%) 和2级（35%); 只有4pts (7%) 发生3级。肝功能异常是发生CRS的患者中最常见的器官损伤。中位CRS发生时间是9 d (range，1–19)。仅1例CRS没有恢复，中位持续也是9 d(range, 3–57)。
图1A表明，剂量和CRS的发生没有明确的相关，高剂量可能会有些许影响，但是3级CRS组的样本太小 (n=4）。另外在1例1级失语、躁动及癫痫样患者身上发现神经毒性
图1B显示：ORR 88% (95% CI，76-95），其中42名患者CR（74%; 95% CI, 60–85), 2名患者VGPR（4%; 95% CI, 0.4–12), 6 名患者PR（11%; 95% CI, 4–22）。
在42名获得CR的患者中有39名MRD阴性！
至初次缓解时间中位值1 mo（range, 0.4–4)。图1C表明：剂量和缓解也不明确相关。另外BCMA的表达也与缓解无关。
AEs were reported by all pts; most common were pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts; most common were leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%).
CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 cases. Liver function abnormalities were the most common signs of end organ injury among pts with CRS. The median time to onset of CRS was 9 days (range, 1–19). All but 1 CRS events resolved, with a median duration of 9 days (range, 3–57). No clear relationship was demonstrated between dose and CRS; there may be some effect at higher doses, but conclusions are limited by the small number of pts in the grade 3 CRS group (n=4; Figure 1A). Neurotoxicity was observed in 1 pt who had grade 1 aphasia, agitation, and seizure-like activity.
The overall response rate (partial response [PR] or better) was 88% (95% confidence interval [CI], 76–95). Complete response (CR) was achieved by 42 pts (74%; 95% CI, 60–85), very good partial response was achieved by 2 pts (4%; 95% CI, 0.4–12), and PR was achieved by 6 pts (11%; 95% CI, 4–22; Figure 1B). Among pts with CR, 39/42 were minimal residual disease (MRD) negative by 8-color flow cytometry. The median time to initial response was 1 month (range, 0.4–4). No clear relationship between LCAR-B38M CAR T cell dose and response was observed (Figure 1C). BCMA expression did not correlate with clinical response.
生存数据方面：
1）中位持续缓解时间/mDoR 16 mo（95% CI, 12–NR），其中获得CR的患者中位持续缓解时间22 mo（95% CI, 14-NR）。至数据截止日，产生PR及更好缓解的患者中有36%（18/50）疾病进展。
2）所有治疗患者的中位无进展生存/mPFS 15 mo (95% CI, 11–NR); 其中获得CR患者的mPFS24 mo (95% CI, 15–NR)。
3）中位总生存/OS尚未达到。17名患者在治疗及随访期间死亡，其中14人因为PD，另外分别1例PD后自杀、1例食管炎和1例肺栓塞外加急性冠脉综合征。
The median duration of response (DOR) was 16 months (95% CI, 12–not reached [NR]). The median DOR for pts who achieved a CR was 22 months (95% CI, 14–NR). At data cutoff, 18 pts (36%) who achieved PR or better progressed. The median progression-free survival (PFS) for all treated pts was 15 months (95% CI, 11–NR); median PFS for pts who achieved CR was 24 months (95% CI, 15–NR). The median overall survival was not reached. Overall, 17 pts died during the study and follow-up period; causes of death were progressive disease (PD; n=14), suicide after PD (n=1), esophagitis (n=1), and pulmonary embolism and acute coronary syndrome (n=1).
大多数患者（n=32）的血样分析中发现LCAR-B38M达到峰值，即≥1x10^4 copies/µg genomic DNA。在4个月的时候有71%患者外周血中检测不到CAR-T细胞。另外有5名患者中CAR-T细胞持久存在超过10个月。
Peak levels of LCAR-B38M (≥1x10^4 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M CAR T cells were not detectable in peripheral blood in 71% of pts at 4 months; 5 pts showed CAR T cell persistence up to 10 months.
提供了双特异的LCAR-B38M CAR T有效治疗复发或难治多发性骨髓瘤的初步证据。
总结一下：安全可控，缓解深度、持久，目前在米国正开展1/2期研究，登记号NCT03548207，对于这个临床，我还是很期待关注的。
This ongoing first-in-human study has provided initial proof-of-concept that bispecific LCAR‑B38M CAR T cells may be a highly effective therapy for R/R MM. LCAR-B38M CAR T cell therapy displayed a manageable safety profile consistent with its known mechanism of action and demonstrated deep and durable responses in pts with R/R MM. A phase 1/2 study of LCAR-B38M in R/R MM has been initiated in the US (NCT03548207).