Jesus G Berdeja1, Deepu Madduri2, Saad Z Usmani3, Andrzej Jakubowiak4, Mounzer Agha5, Adam D Cohen6, A Keith Stewart7, Parameswaran Hari8, Myo Htut9, Alexander Lesokhin10, Abhinav Deol11, Nikhil C Munshi12, Elizabeth O'Donnell13, David Avigan14, Indrajeet Singh15, Enrique Zudaire15, Tzu-Min Yeh16, Alicia J Allred15, Yunsi Olyslager17, Arnob Banerjee15, Carolyn C Jackson16, Jenna D Goldberg16, Jordan M Schecter16, William Deraedt17, Sen Hong Zhuang16, Jeffrey Infante16, Dong Geng18, Xiaoling Wu18, Marlene J Carrasco-Alfonso18, Muhammad Akram18, Farah Hossain18, Syed Rizvi18, Frank Fan19, Yi Lin20, Thomas Martin21, Sundar Jagannath22. 1. Sarah Cannon Research Institute, Nashville, TN, USA. 2. Mount Sinai Medical Center, New York, NY, USA. 3. Levine Cancer Institute-Atrium Health, Charlotte, NC, USA. 4. University of Chicago Medical Center, Chicago, IL, USA. 5. UPMC Hillman Cancer Center, Pittsburgh, PA, USA. 6. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. 7. University Health Network and the Princess Margaret Cancer Centre, Toronto, ON, Canada. 8. Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA. 9. City of Hope Comprehensive Cancer Center, Duarte, CA, USA. 10. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 11. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA. 12. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. 13. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. 14. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. 15. Janssen Research and Development, Spring House, PA, USA. 16. Janssen Research and Development, Raritan, NJ, USA. 17. Janssen Research and Development, Beerse, Belgium. 18. Legend Biotech USA, Piscataway, NJ, USA. 19. Nanjing Legend Biotechnology, Nanjing, China. 20. Mayo Clinic, Rochester, MN, USA. 21. University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. 22. Mount Sinai Medical Center, New York, NY, USA. Electronic address: sundar.jagannath@mountsinai.org.
Abstract
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.
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.
Authors: Shwetha H Manjunath; Adam D Cohen; Simon F Lacey; Megan M Davis; Alfred L Garfall; J Joseph Melenhorst; Russell Maxwell; W Tristram Arscott; Amit Maity; Joshua A Jones; John P Plastaras; Edward A Stadtmauer; Bruce L Levine; Carl H June; Michael C Milone; Ima Paydar Journal: Clin Cancer Res Date: 2021-09-15 Impact factor: 13.801