Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study,The Lancet

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Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study
The Lancet ( IF 98.4 ) Pub Date : 2021-06-24 , DOI: 10.1016/s0140-6736(21)00933-8
Jesus G Berdeja ₁ , Deepu Madduri ₂ , Saad Z Usmani ₃ , Andrzej Jakubowiak ₄ , Mounzer Agha ₅ , Adam D Cohen ₆ , A Keith Stewart ₇ , Parameswaran Hari ₈ , Myo Htut ₉ , Alexander Lesokhin ₁₀ , Abhinav Deol ₁₁ , Nikhil C Munshi ₁₂ , Elizabeth O'Donnell ₁₃ , David Avigan ₁₄ , Indrajeet Singh ₁₅ , Enrique Zudaire ₁₅ , Tzu-Min Yeh ₁₆ , Alicia J Allred ₁₅ , Yunsi Olyslager ₁₇ , Arnob Banerjee ₁₅ , Carolyn C Jackson ₁₆ , Jenna D Goldberg ₁₆ , Jordan M Schecter ₁₆ , William Deraedt ₁₇ , Sen Hong Zhuang ₁₆ , Jeffrey Infante ₁₆ , Dong Geng ₁₈ , Xiaoling Wu ₁₈ , Marlene J Carrasco-Alfonso ₁₈ , Muhammad Akram ₁₈ , Farah Hossain ₁₈ , Syed Rizvi ₁₈ , Frank Fan ₁₉ , Yi Lin ₂₀ , Thomas Martin ₂₁ , Sundar Jagannath ₂

Affiliation

Sarah Cannon Research Institute, Nashville, TN, USA.
Mount Sinai Medical Center, New York, NY, USA.
Levine Cancer Institute-Atrium Health, Charlotte, NC, USA.
University of Chicago Medical Center, Chicago, IL, USA.
UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
University Health Network and the Princess Margaret Cancer Centre, Toronto, ON, Canada.
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Janssen Research and Development, Spring House, PA, USA.
Janssen Research and Development, Raritan, NJ, USA.
Janssen Research and Development, Beerse, Belgium.
Legend Biotech USA, Piscataway, NJ, USA.
Nanjing Legend Biotechnology, Nanjing, China.
Mayo Clinic, Rochester, MN, USA.
University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Background

CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.

Methods

This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10⁶ CAR-positive viable T cells per kg) was administered 5–7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.

Findings

Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10⁶ CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6–15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2–99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9–1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9–not estimable), neither was progression-free survival (16·8–not estimable). The 12-month progression-free rate was 77% (95% CI 66·0–84·3) and overall survival rate was 89% (80·2–93·5). Haematological adverse events were common; grade 3–4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5–8) and median duration of 4·0 days (IQR 3–6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.

Interpretation

A single cilta-cel infusion at the target dose of 0·75 × 10⁶ CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions.

Funding

Janssen Research & Development and Legend Biotech.

中文翻译：

Ciltacabtagene autoleucel，一种针对复发或难治性多发性骨髓瘤 (CARTITUDE-1) 患者的 B 细胞成熟抗原导向嵌合抗原受体 T 细胞疗法：一项 1b/2 期开放标签研究

背景

CARTITUDE-1 旨在评估 ciltacabtagene autoleucel (cilta-cel)，一种具有两种 B 细胞成熟抗原靶向单域抗体的嵌合抗原受体 T 细胞疗法，在复发或难治性多发性骨髓瘤患者中的安全性和临床活性预后不良。

方法

这项在美国 16 个中心进行的单臂、开放标签、1b/2 期研究招募了年龄在 18 岁或以上、诊断为多发性骨髓瘤且东部肿瘤协作组体能状态评分为 0 或 1 分的患者，他们接受了3 种或更多以前的治疗线或对蛋白酶体抑制剂和免疫调节药物具有双重耐药性，并且已接受蛋白酶体抑制剂、免疫调节药物和抗 CD38 抗体。单次 cilta-cel 输注（目标剂量 0·75 × 10 ⁶CAR 阳性活 T 细胞/kg）在淋巴去除开始后 5-7 天给药。主要终点是安全性和推荐的 2 期剂量（1b 期）的确认，以及所有接受治疗的患者的总体反应率（2 期）。关键的次要终点是反应持续时间和无进展生存期。该试验已在 ClinicalTrials.gov 注册，NCT03548207。

发现

2018 年 7 月 16 日至 2019 年 10 月 7 日期间，共招募了 113 名患者。97 名患者（1b 期 29 名，2 期 68 名）接受了 cilta-cel 输注，推荐的 2 期剂量为 0·75 × 10 ⁶每公斤 CAR 阳性活 T 细胞。截至 2020 年 9 月 1 日的临床截止日期，中位随访时间为 12·4 个月（IQR 10·6–15·2）。97 名之前接受过中位数为 6 次治疗的患者接受了 cilta-cel。总体反应率为 97%（95% CI 91·2–99·4；97 名患者中的 94 名）；65 (67%) 达到了严格的完全反应；首次反应时间为 1 个月（IQR 0·9–1·0）。随着时间的推移，反应越来越深。未达到中位缓解持续时间（95% CI 15·9——不可估计），无进展生存期也未达到（16·8——不可估计）。12 个月无进展率为 77%（95% CI 66·0–84·3），总生存率为 89%（80·2-93·5）。血液学不良事件很常见；3-4 级血液学不良事件是中性粒细胞减少（97 名患者中的 92 [95%]）、贫血（66 [68%]）、白细胞减少（59 [61%]）、血小板减少（58 [60%]）、和淋巴细胞减少症（48 [50%]）。97 名患者中有 92 名（95%）（4% 为 3 或 4 级）发生细胞因子释放综合征；发病时间中位数为 7·0 天（IQR 5-8），持续时间中位数为 4·0 天（IQR 3-6）。除了 5 级细胞因子释放综合征和噬血细胞淋巴组织细胞增生症外，所有细胞因子释放综合征均得到解决。20 名（21%）患者（9% 为 3 或 4 级）发生了 CAR T 细胞神经毒性。研究中有 14 人死亡；6 个是由于治疗相关的不良事件，5 个是由于疾病进展，3 个是由于与治疗无关的不良事件。除了 5 级细胞因子释放综合征和噬血细胞淋巴组织细胞增生症外，所有细胞因子释放综合征均得到解决。20 名（21%）患者（9% 为 3 或 4 级）发生了 CAR T 细胞神经毒性。研究中有 14 人死亡；6 个是由于治疗相关的不良事件，5 个是由于疾病进展，3 个是由于与治疗无关的不良事件。除了 5 级细胞因子释放综合征和噬血细胞淋巴组织细胞增生症外，所有细胞因子释放综合征均得到解决。20 名（21%）患者（9% 为 3 或 4 级）发生了 CAR T 细胞神经毒性。研究中有 14 人死亡；6 个是由于治疗相关的不良事件，5 个是由于疾病进展，3 个是由于与治疗无关的不良事件。