Updated Analysis of a Phase 1, Open-Label Study of LCAR-B38M, a - - PowerPoint PPT Presentation

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 Zhang1

1Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, ShaanXi, China; 2National-

Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, ShaanXi, China; 3Department of Clinical Laboratory, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi'an, ShaanXi, China; 4Nanjing Legend Biotech Inc., Nanjing, Jiangsu, China

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

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LEGEND-2 Study

VH VL

Typical CAR LCAR-B38M CAR

VH VH

Binding domains

 LCAR-B38M is a chimeric antigen receptor (CAR) T cell therapy with 2 BCMA targeting domains

• Confers high avidity binding and distinguishes LCAR-B38M from
• ther BCMA-targeted CAR T cell therapies

 LEGEND-2 (N=74): Phase 1 investigator-initiated study in R/R multiple myeloma (MM) conducted at 4 sites in China

• Variable preconditioning regimens (Cy-Flu vs. Cy)
• Variable CAR T infusion methods (split vs. single infusion)

 LEGEND-2 results previously presented

• First 35/57 patients at the Xi’an site at ASCO and EHA 2017
• 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

BCMA=B-cell maturation antigen; Cy=cyclophosphamide; Flu=fludarabine; R/R=relapsed/refractory; VH=variable heavy chain; VL=variable light chain

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

Key Inclusion Criteria  Active MM defined by IMWG criteria  Relapsed on prior regimens

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LEGEND-2 Study Design

Screening & Enrollment Leukapheresis Cyclophosphamide 300 mg/m2 0.07–2.1x106 CAR+ T cells/kg Median dose: 0.5x106 cells/kg First Efficacy Assessment Day -5 to -3 Day 30

20% 30% 50%

Key Objectives  Primary: Safety of LCAR-B38M CAR T cells  Secondary: Antimyeloma activity based

• n IMWG response criteria

IMWG=International Myeloma Working Group

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

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Demographics and Disease Characteristics

Total (N=57) Median age, (range) 54 (27–72) Male, n (%) 34 (60) ECOG PS, n (%) 21 (37) 1 27 (47) 2 9 (16) Durie-Salmon stage III, n (%) 42 (74) ISS stage III, n (%) 21 (37) Median time from initial diagnosis, years (range) 4 (1–9) Total (N=57) Median prior lines of therapy, n (range) 3 (1–9) Prior auto-SCT, n (%) 10 (18) Prior PI, n (%) 39 (68) Bortezomib 39 (68) Carfilzomib 1 (2) Prior IMiD, n (%) 49 (86) Thalidomide 39 (68) Lenalidomide 25 (44) Pomalidomide 2 (4) Prior PI + IMiD, n (%) 34 (60)

auto-SCT=autologous-stem cell transplantation; ECOG PS=Eastern Cooperative Oncology Group performance status; IMiD=immunomodulatory drug; ISS=International Staging System; PI=proteasome inhibitor

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

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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) 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) 22 (39) Anemia 2 (4) 5 (9) 9 (16) 1 (2) 17 (30) Hypotension 7 (12) 2 (4) 3 (5) 12 (21) Other AE of interest Neurotoxicitya 1 (2) 1 (2)

aAphasia, seizure-like activity, and agitation reported in one patient dosed at 1x106 cells/kg

AST = aspartate aminotransferase

CRS=cytokine release syndrome

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

 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

Cytokine Release Syndrome

Grade 3 End Organ Abnormalities in Patients with CRS, n (%) Total (n=51) AST high 15 (29) aPTT prolongeda 3 (7) Hypotension 3 (6) Creatinine high 2 (4) ALT high 1 (2)

aOnly 46 patients had laboratory results available

[VALUE] (47%) [VALUE] (35%) [VALUE] (7%)

Grade 1 Grade 2 Grade 3

Cytokine Release Syndrome

aPTT=activated partial thromboplastin time; PE/ACS=pulmonary embolism/acute coronary syndrome

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

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Efficacy

Best Overall Response by Dose

 mDOR = 16 mo (95% CI, 12–NR)  mDOR for MRD-neg CR = 22 mo (95% CI, 14–NR)  Median time to initial response = 1 mo (0.4–3.6)

Best Overall Response (N=57)

39 (68%) MRD-neg

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

1 2 3

NE PD SD PR VGPR CR

N=57 n=25 n=32 All Doses <0.5x106 cells/kg ≥0.5x106 cells/kg

ORR = 88%

[VALUE] (74%) [VALUE] (4%) [VALUE] (11%) [VALUE] (7%) [VALUE] (2%) [VALUE] (4%)

CR VGPR PR SD PD NE

39 (68%) MRD-nega CR=complete response; mDOR=median duration of response; MRD-neg=minimal residual disease-negative; NE=not evaluable; ORR=overall response rate; PD=progressive disease; PR=partial response; SD=stable disease; VGPR=very good partial response

BCMA <40% (n=26/53)b = 92% ORR BCMA ≥40% (n=27/53)b = 82% ORR

a8-color flow cytometry with cell count up to 500,000 cells; bBCMA expression data available for 53 patients

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

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Progression-Free Survival

3 6 9 12 15 18 21 24 27

Patients at risk: 57 53 48 37 21 11 7 4 All Patients 1

Progression-Free Survival (%) Months

mPFS=median progression-free survival

100 80 60 40 20 39 39 38 33 20 10 7 4 Patients Achieving MRD-neg CR 1 18 14 10 4 1 1 Patients Not Achieving MRD-neg CR Patients Achieving MRD-neg CRa mPFS: 24 mo (95% CI, 15–NR) 12-mo PFS: 87% Patients Not Achieving MRD-neg CR mPFS: 6 mo (95% CI, 3–8) 12-mo PFS: 6%

a30/39 patients still in remission

All Patients mPFS: 15 mo (95% CI, 11–NR) 12-mo PFS: 61%

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

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Overall Survival

OS=overall survival

All Patients: 57 55 51 40 25 15 9 5 3 100 80 60 40 20 3 6 9 12 15 18 21 24 27 Months

Overall Survival (%)

All Patients mOS: not reached 12-mo survival: 75% Patients at risk: Patients Achieving MRD-neg CR mOS: not reached 12-mo survival: 94% Patients Not Achieving MRD-neg CR mOS: 8 mo (95% CI, 4–14) 12-mo survival: 29% Patients Achieving MRD-neg CR: 39 39 39 34 21 13 9 5 3 Patients Not Achieving MRD-neg CR: 18 16 12 6 4 2

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

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Deaths

Deaths n=17 Day of Death (Study Day) Progressive disease (PD) 14 Median: Day 261 (99–484) Suicide after PDa 1 Day 127 Pulmonary embolism/ Acute coronary syndromea 1 Day 22 Esophagitisa 1 Day 524

aUnrelated to study treatment

PE/ACS=pulmonary embolism/acute coronary syndrome

 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

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

 LCAR-B38M displayed a safety profile consistent with BCMA-targeted CAR T cell therapy

• CRS mostly grade 1–2; median onset of CRS = 9 days
• One grade 1 neurotoxicity

 Durable MRD-neg CRs were observed in most patients

• ORR: 88%; 68% of patients achieved MRD-neg CR
• mPFS: 15 mo; 24 mo for patients achieving MRD-neg CR
• 12-mo OS: 75%; 94% for patients achieving MRD-neg CR
• 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 = 0.5x106 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

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Conclusions

60th ASH Annual Meeting 2018, Zhao W-H, et al. Abstract #955.

 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

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Acknowledgments