065: Clinical Pharmacological Characterization of Cilta-cel, a CAR-T Therapy Directed Against BCMA in Adult Patients With Multiple Myeloma in a Multicohort CARTITUDE-2 Study

Statement of Purpose, Innovation or Hypothesis: Ciltacabtagene autoleucel (cilta-cel) is an autologous chimeric antigen receptor T cell (CAR-T) therapy that targets B cell maturation antigen (BCMA) expressed on the surface of mature B lymphocytes and malignant plasma cells. Cilta-cel was approved based on results of Phase 1b/2 CARTITUDE-1 study (NCT03548207), which demonstrated that cilta-cel yielded deep and durable responses in heavily pre-treated patients with relapsed and refractory (RR) multiple myeloma (MM). CARTITUDE-2 (NCT04133636) is a phase 2, multicohort, open-label study evaluating safety and efficacy of cilta-cel in various MM patient populations. Cohort A patients had received 1 to 3 prior lines of therapy, Cohort B patients received one line of prior therapy including a PI and an IMiD and had disease progression ≤12 months after ASCT, and Cohort C patients were previously treated with a PI, an IMiD, an anti-CD38 monoclonal antibody and BCMA-directed therapy. Cellular kinetics, pharmacodynamics, and immunogenicity results of cilta-cel are presented for Cohorts A initial group [A(i)], B and C to improve our understanding of cilta-cel in vivo expansion and its relationships with clinical factors in various MM populations.

Description of Methods & Materials: Cellular kinetics was assessed using CAR transgene copy level and CAR+CD3+ cell level in blood after a single infusion of 0.75 (range: 0.5-1.0) x 10⁶ CAR-positive viable T cells/kg. PK parameters were estimated by NCA using Phoenix WinNonlin (version 8.0). Pharmacodynamics: soluble BCMA (sBCMA) level in serum was assessed using a ligand binding assay. Anti-drug antibodies (ADA) were evaluated for antibodies binding to cilta-cel and the titer to confirm treatment-emergent ADA positive samples.

Data & Results: Cellular Kinetics: Cilta-cel PK measurements using transgene and cellular levels were concordant. Similar cellular kinetic profiles were exhibited across the 3 cohorts with an initial expansion phase followed by a rapid then a slower decline over months. High interindividual variability was observed. Although higher mean C_max was observed in Cohort A(i) and Cohort B, and lower Cmax in Cohort C, the AUC0-28d was comparable across cohorts. The median t_max ranged 11 days to 15 days, and median t_bql (time to reach BQL level) were comparable ranging from 125 days to 157 days among Cohorts A(i), B, and C. There was no clear dose-exposure relationship observed across 3 cohorts. Pharmacodynamics: Following a single cilta‑cel infusion, expansion and persistence of CAR-positive T cells coincided with decreases of sBCMA levels. Mean sBCMA levels reached nadir (i.e. LLOQ value < 0.25000 µg/L) at Day 56 for Cohort A(i) and at Day 100 for Cohorts B and C. Thereafter, sBCMA levels showed gradual increase in some patients; however, the reversed sBCMA levels in most patients were substantially lower than baseline sBCMA. Immunogenicity: The overall incidence of treatment emergent ADA to cilta-cel was 25.0% for Cohorts A(i) and C, 42% for Cohort B, with median onset time ranging from 57 to 186 days across 3 cohorts. Cellular kinetics was similar between ADA positive and ADA negative patients across cohorts, suggesting no apparent impact of ADA on cilta-cel cellular kinetics.

Interpretation, Conclusion or Significance:

Disclosures: Jianmei Wu, Shih-Yu Chang, Yupeng Ren, Helen Varsos, Yogesh Jethava, Qingxuan Song, Christina Corsale, Nikoletta Lendvai, and Indrajeet Singh are currently employed by Janssen R&D. Muhammad Akram and Tairan Yang are currently employed by Legend Biotech.

Citations/References: Clinical Protocol, A Phase 2, Multicohort Open-Label Study of JNJ-68284528, a Chimeric Antigen Receptor T cell (CAR-T) Therapy Directed Against BCMA in Subjects with Multiple Myeloma. Dated Oct. 23, 2023. >2023 ACCP: Pharmacokinetics, Pharmacodynamics, and Exposure- Response for Neurotoxicity Adverse Events in a Phase Ib/II CARTITUDE-1 Open-Label Study. Shih-Yu Chang¹, Jianmei Wu¹, Yupeng Ren¹, Dong Geng², Tairan Yang², Deepu Madduri¹, Carolyn Jackson¹, Jordan Schecter¹, and Xuewen Ma¹

Additional Information/Authors: Nikoletta Lendvai, nlendvai@its.jnj.com, Global Clinical Leader, Janssen Research & Development LLC, Spring House, PA, United States