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579 Long-Term Follow-up of a Phase 1, 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), in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Novelty in CAR T in Relapsed/Refractory Multiple Myeloma
Hematology Disease Topics & Pathways:
multiple myeloma, Biological, Adult, Diseases, Therapies, CAR-Ts, Study Population, Plasma Cell Disorders, Lymphoid Malignancies
Monday, December 9, 2019: 7:30 AM
Hall D, Level 2 (Orange County Convention Center)

Bai-Yan Wang, MD, PhD1*, Wan-Hong Zhao, MD, PhD1*, Jie Liu, MD1*, Yin-Xia Chen, MD1*, Xing-Mei Cao, MD1*, Yun Yang, MD1*, Yi-Lin Zhang, MD1*, Fang-Xia Wang, MD, PhD1*, Peng-Yu Zhang, MD, PhD1*, Bo Lei, MD1*, Liu-Fang Gu, MD, PhD1*, Jian-Li Wang, MD, PhD1*, Jia-Jia Zhang, MD1*, Ru Zhang, MD1*, Hui Zhang, MD1*, Ying Shen, MD1*, Ju Bai, PhD1*, Yan Xu, MD1*, Xu-Geng Wang, MD, PhD1*, Rui-Li Zhang, MD1*, Li-Li Wei, MD1*, Zong-Fang Li, MD, PhD2*, Gai-Xia He, PhD2*, Yan Geng, MD, PhD3*, Qian He, MD, PhD3*, Qiu-Chuan Zhuang, Msc4*, Frank Xiao-Hu Fan, MD, PhD4*, Wang-Gang Zhang, MD, PhD1* and Ai-Li He, MD, PhD5*

1Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
2National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
3Department of Clinical Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
4Nanjing Legend Biotech, Nanjing, China
5Department of Hematology and National-Local Joint Engineering Research Center of Biodiagnostics & Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China

Background:

In RRMM, the median overall survival (OS) of pts with RRMM who progressed after exposure to ≥3 prior therapies is ~13 mo, indicating a high unmet need. LCAR-B38M is a structurally differentiated CAR-T cell therapy containing a 4-1BB co-stimulatory domain and 2 BCMA-targeting single-domain antibodies designed to confer avidity. Earlier results from LEGEND-2 (NCT03090659), a first-in-human phase 1 study using LCAR-B38M CAR-T cells in 74 pts with RRMM conducted in 4 hospitals in China (Jiangsu Provincial People's Hospital; Ruijin Hospital; Changzheng Hospital; and the Second Affiliated Hospital of Xi’an Jiaotong University), showed encouraging efficacy and manageable safety. Key eligibility criteria included RRMM with ≥3 prior lines of therapy. Here, we present long-term follow-up data on safety and efficacy from the Xi’an site.

Methods:

In the Xi’an site-specific protocol (n=57), lymphodepletion was performed using cyclophosphamide (Cy; 300 mg/m2) alone for 3 days. LCAR-B38M (median CAR+ T cells, 0.5×106 cells/kg; range, 0.07–2.1 × 106) was infused in 3 split infusions. The primary objective was to evaluate the safety of LCAR-B38M; the secondary objective was to evaluate anti-myeloma response of treatment. Adverse events (AEs) were graded using the NCI-CTCAE v4.03, cytokine release syndrome (CRS) was assessed per Lee et al. 2014, and response was evaluated using IMWG criteria.

Results:

As of the 12/31/18 cutoff date (median follow-up, 19 mo; 95% confidence interval [CI], 17–22), enrollment at Xi’an is complete, and 57 pts have been infused with LCAR-B38M.

AEs were reported by all pts: pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts: leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 events; no grade 4/5 CRS was observed. Neurotoxicity was observed in 1 pt (grade 1 aphasia, agitation, seizure-like activity). The median time to onset of CRS was 9 days (range, 1–19) with a median duration of 9 days (range, 3–57); all but 1 CRS events resolved.

Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M was not detectable in peripheral blood in 71% of pts at 4 mo; 5 pts showed CAR-T cell persistence for up to 10 months.

The overall response rate (partial response [PR] or better) was 88% (95% CI, 76–95), complete response (CR) was achieved by 42 pts (74%; 60–85), very good partial response (VGPR) by 2 pts (4%; 0.4–12), and PR by 6 pts (11%; 4–22). Of pts with CR, 39/42 were minimal residual disease negative (MRD-neg, 8-color flow cytometry). The median time to first response was 1.2 mo. There was no relationship between best response and baseline BCMA expression level or weight-adjusted CAR+ cells infused (Fig 1a,b).

At cutoff, the median follow-up was 19 mo [17–22]. Median OS has not yet been reached. The OS rate at 18 mo was 68% (54─79) with a median duration of response (mDOR) of 22 mo (13–29). Of MRD-neg pts with CR, 91% (75–97) are still alive at data cut, with a 27 mo (16–NE) mDOR.

Overall, 26 (46%) of 57 all-treated pts and 25 (64%) of 39 MRD-neg pts with CR remain progression-free. The median progression-free survival (PFS) for all-treated pts was 20 mo (10–28); median PFS for MRD-neg pts with CR was 28 mo (20–31). At 18 months, the PFS rate was 50% (36–63) for all pts and 71% (52–84) for MRD-neg pts with CR. Factors contributing to long-term response are shown in Fig 1c,d.

Seventeen pts died during the study and the follow-up period: progressive disease (PD; n=11), disease relapse, PD + lung infection, suicide after PD, esophageal carcinoma, infection, and pulmonary embolism and acute coronary syndrome (n=1 each). Of these, 4 did not achieve PR or better; 1 was not evaluable.

Conclusions:

This study provides evidence that LCAR‑B38M is a highly effective therapy for RRMM, regardless of baseline BCMA expression. LCAR-B38M displayed a manageable safety profile consistent with its known mechanism of action and, with a median follow-up of 19 months, demonstrated deep and durable responses in pts with RRMM. A phase 1b/2 clinical study is ongoing in the United States (CARTITUDE-1, NCT03548207, JNJ-68284528), and a phase 2 confirmatory study has initiated in China (CARTIFAN-1, NCT03758417).

Disclosures: Zhuang: Nanjing Legend Biotech: Employment. Fan: Legend Biotech: Employment, Equity Ownership.

*signifies non-member of ASH