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 Wan-Hong Zhao , 1 Jie Liu, 1 Bai-Yan Wang, 1 Yin-Xia Chen, 1 Xing-Mei Cao, 1 Yun Yang, 1 Yi-Lin Zhang, 1 Fang-Xia Wang, 1 Peng-Yu Zhang, 1 Bo Lei, 1 Liu-Fang Gu, 1 Jian-Li Wang, 1 Nan Yang, 1 Ru Zhang, 1 Hui Zhang, 1 Ying Shen, 1 Ju Bai, 1 Yan Xu, 1 Xu-Geng Wang, 1 Rui-Li Zhang, 1 Li-Li Wei, 1 Zong-Fang Li, 2 Zhen-Zhen Li, 2 Yan Geng, 3 Qian He, 3 Qiu-Chuan Zhuang, 4 Xiao-Hu Fan, 4 Ai-Li He, 1,2 Wang-Gang Zhang 1 1 Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ShaanXi, China; 2 National- Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, ShaanXi, China; 3 Department of Clinical Laboratory, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, ShaanXi, China; 4 Nanjing Legend Biotech Inc., Nanjing, Jiangsu, China
LEGEND-2 Study LCAR-B38M is a chimeric antigen receptor (CAR) T cell Binding domains therapy with 2 BCMA targeting domains o Confers high avidity binding and distinguishes LCAR-B38M from other BCMA-targeted CAR T cell therapies LEGEND-2 (N=74): Phase 1 investigator-initiated study in V H R/R multiple myeloma (MM) conducted at 4 sites in China V H V H V L o Variable preconditioning regimens (Cy-Flu vs. Cy) o Variable CAR T infusion methods (split vs. single infusion) LEGEND-2 results previously presented o First 35/57 patients at the Xi’an site at ASCO and EHA 2017 o First 11/17 patients at the 3 other sites at ASH 2017 57 patient experience at Xi’an site as of 25 June 2018 are presented here, with a 12-month (0.7–25.1) follow-up Typical CAR LCAR-B38M CAR BCMA=B-cell maturation antigen; Cy=cyclophosphamide; Flu=fludarabine; 2 R/R=relapsed/refractory; V H =variable heavy chain; V L =variable light chain 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
LEGEND-2 Study Design Key Inclusion Criteria Key Objectives Primary: Safety of LCAR-B38M CAR T cells Active MM defined by IMWG criteria Secondary: Antimyeloma activity based Relapsed on prior regimens on IMWG response criteria 0.07–2.1x10 6 Cyclophosphamide Screening & CAR+ T cells/kg 300 mg/m 2 Enrollment Median dose: 0.5x10 6 cells/kg First Efficacy Assessment Leukapheresis 20% 30% 50% Day -5 to -3 Day 30 3 IMWG=International Myeloma Working Group 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Demographics and Disease Characteristics Total (N=57) Total (N=57) Median age, (range) 54 (27–72) Median prior lines of therapy, n (range) 3 (1–9) Male, n (%) 34 (60) Prior auto-SCT, n (%) 10 (18) ECOG PS, n (%) Prior PI, n (%) 39 (68) 0 21 (37) Bortezomib 39 (68) 1 27 (47) Carfilzomib 1 (2) 2 9 (16) Prior IMiD, n (%) 49 (86) Durie-Salmon stage III, n (%) 42 (74) Thalidomide 39 (68) ISS stage III, n (%) 21 (37) Lenalidomide 25 (44) Median time from initial Pomalidomide 2 (4) 4 (1–9) diagnosis, years (range) Prior PI + IMiD, n (%) 34 (60) auto-SCT=autologous-stem cell transplantation; ECOG PS=Eastern Cooperative Oncology Group performance 4 status; IMiD=immunomodulatory drug; ISS=International Staging System; PI=proteasome inhibitor 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Adverse Events AEs (≥20% in All Patients) Grade 1 Grade 2 Grade 3 Grade 4 Total (N=57) Pyrexia 14 (25) 27 (47) 10 (18) 1 (2) 52 (91) Cytokine release syndrome 27 (47) 20 (35) 4 (7) 0 51 (90) Thrombocytopenia 8 (14) 7 (12) 3 (5) 10 (18) 28 (49) Leukopenia 3 (5) 7 (12) 15 (26) 2 (4) 27 (47) Increased AST 7 (12) 3 (5) 12 (21) 0 22 (39) Anemia 2 (4) 5 (9) 9 (16) 1 (2) 17 (30) Hypotension 7 (12) 2 (4) 3 (5) 0 12 (21) Other AE of interest Neurotoxicity a 1 (2) 0 0 0 1 (2) a Aphasia, seizure-like activity, and agitation reported in one patient dosed at 1x10 6 cells/kg 5 CRS=cytokine release syndrome 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955. AST = aspartate aminotransferase
Cytokine Release Syndrome Cytokine Release Syndrome Grade 3 End Organ Abnormalities Total (n=51) in Patients with CRS, n (%) [VALUE] (47%) AST high 15 (29) [VALUE] (35%) aPTT prolonged a 3 (7) Hypotension 3 (6) [VALUE] Creatinine high 2 (4) (7%) ALT high 1 (2) a Only 46 patients had laboratory results available Grade 1 Grade 2 Grade 3 No grade 4 CRS One patient died of PE/ACS before resolution of grade 2 CRS Median time to onset of CRS = 9 days (range, 1–19) Median duration of CRS = 9 days (range, 3–57) Tocilizumab (46%), oxygen (35%), vasopressor (11%), and intubation (1 patient) to treat CRS 6 aPTT=activated partial thromboplastin time; PE/ACS=pulmonary embolism/acute coronary syndrome 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Efficacy Best Overall Response (N=57) Best Overall Response by Dose [VALUE] (74%) N=57 n=25 n=32 100% 90% 80% ORR = 88% NE 70% PD 39 (68%) 39 (68%) 60% MRD-neg a SD MRD-neg 50% PR 40% VGPR 30% [VALUE] (11%) [VALUE] (7%) CR [VALUE] (4%) [VALUE] (2%) [VALUE] (4%) 20% 10% CR VGPR PR SD PD NE 0% 1 2 3 All <0.5x10 6 ≥0.5x10 6 mDOR = 16 mo (95% CI, 12–NR) Doses cells/kg cells/kg mDOR for MRD-neg CR = 22 mo (95% CI, 14–NR) Median time to initial response = 1 mo (0.4–3.6) BCMA <40% (n=26/53) b = 92% ORR BCMA ≥40% (n=27/53) b = 82% ORR a 8-color flow cytometry with cell count up to 500,000 cells; b BCMA expression data available for 53 patients CR=complete response; mDOR=median duration of response; MRD-neg=minimal residual disease-negative; NE=not evaluable; ORR=overall response rate; PD=progressive disease; 7 PR=partial response; SD=stable disease; VGPR=very good partial response 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Progression-Free Survival 100 Patients Achieving MRD-neg CR a Progression-Free Survival (%) mPFS: 24 mo 80 (95% CI, 15–NR) 12-mo PFS: 87% 60 40 All Patients Patients Not Achieving mPFS: 15 mo MRD-neg CR 20 (95% CI, 11–NR) mPFS: 6 mo 12-mo PFS: 61% (95% CI, 3–8) 12-mo PFS: 6% 0 Months 0 3 6 9 12 15 18 21 24 27 Patients at risk: All Patients 57 53 48 37 21 11 7 4 1 0 Patients Achieving MRD-neg CR 39 39 38 33 20 10 7 4 1 0 Patients Not Achieving MRD-neg CR 18 14 10 4 1 1 0 0 0 0 a 30/39 patients still in remission 8 mPFS=median progression-free survival 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Overall Survival 100 Patients Achieving MRD-neg CR mOS: not reached 12-mo survival: 94% 80 Overall Survival (%) 60 Patients Not Achieving All Patients MRD-neg CR mOS: not reached 40 mOS: 8 mo (95% CI, 4–14) 12-mo survival: 75% 12-mo survival: 29% 20 0 27 Months 0 3 6 9 12 15 18 21 24 Patients at risk: All Patients: 57 55 51 40 25 15 9 5 3 0 Patients Achieving MRD-neg CR: 39 39 39 34 21 13 9 5 3 0 Patients Not Achieving MRD-neg CR: 18 16 12 6 4 2 0 0 0 0 9 OS=overall survival 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Deaths Deaths n=17 Day of Death (Study Day) Progressive disease (PD) 14 Median: Day 261 (99–484) Suicide after PD a 1 Day 127 Pulmonary embolism/ 1 Day 22 Acute coronary syndrome a Esophagitis a 1 Day 524 a Unrelated to study treatment Suicide: The patient had rapid progression of extramedullary disease which invaded the vertebrae, resulting in paralysis; the patient subsequently died due to suicide on day 127 PE/ACS: The patient experienced grade 2 CRS, which was resolving. The patient developed sudden, severe dyspnea and died 2 hours later; cause of death was potential PE and ACS Esophagitis: The patient developed progressive difficulty in swallowing, leading to subsequent cachexia; no neoplasm was confirmed. The patient died on day 524; cause of death was esophagitis 10 PE/ACS=pulmonary embolism/acute coronary syndrome 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Conclusions LCAR-B38M displayed a safety profile consistent with BCMA-targeted CAR T cell therapy o CRS mostly grade 1–2; median onset of CRS = 9 days o One grade 1 neurotoxicity Durable MRD-neg CRs were observed in most patients o ORR: 88%; 68% of patients achieved MRD-neg CR o mPFS: 15 mo; 24 mo for patients achieving MRD-neg CR o 12-mo OS: 75%; 94% for patients achieving MRD-neg CR o Patients who did not achieve MRD-neg CR had poor outcome: mPFS of 6 mo, mOS of 8 mo, 12-mo OS 29% Response was achieved with low CAR+ T cell doses (median dose = 0.5x10 6 cells/kg) BCMA expression did not correlate with clinical response A phase 1b/2 study with JNJ-68284528 is ongoing in the US (NCT03548207) and a phase 2 study will be initiated in China (CTR20181007) in 2019 11 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
Acknowledgments We thank the patients who participated in the study and their families We also thank the physicians and nurses who cared for patients and supported this clinical trial 12 60 th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.
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